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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”

 

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Bird flu – the pandemic clock is ticking

http://www.science.org.au/nova/090/090print.htm


Diseases caused by viruses from animals are an ongoing threat to people's health. With the number of deaths in Asia from bird flu rising, scientists say it is only a matter of time before the next flu pandemic strikes.

Key text

Emerging and re-emerging diseases

Every year for the past thirty years a new infectious agent, or an old one thought to be under control, has emerged to cause disease in humans.  Nearly two thirds of infectious diseases in humans come from animals, and they are known as zoonoses or zoonotic infections.  Viruses are particularly good at jumping the species barrier because they are able to infect a wide range of animals, including humans.  Some notable examples of viruses that cause zoonoses include rabies, Ebola, Marburg, Lassa, hanta, morbilli and influenza.

So why do known viral diseases continue to cause problems?  The answer is that whenever there is a change in the environment or the virus, a new opportunity is created to cause disease in humans.  The trigger could be localised increases in human population, removal of forests, climate change, humans settling in new geographic areas or humans encountering exotic animals and the viruses they carry.

Viruses that cause colds and flu

The influenza virus is an example of a zoonotic infection that re-emerges year after year. In humans, 'the flu' is caused by either influenza A or B viruses.  Influenza B viruses infect only humans and although they can cause flu epidemics, do not cause pandemics (world-wide epidemics).  Influenza A viruses can infect birds – including chickens, ducks and wild birds – and mammals, including humans, pigs, cats, horses and whales to name a few. ‘Avian flu’ or ‘bird flu’ is caused by avian influenza A viruses that can also infect humans.

We tend to think of colds and flu as the same thing – an infection that makes you suffer from a running nose, sore throat, fever, aches and pains. Although the symptoms are similar, a head cold and the flu are caused by different viruses.  About half of all cases of the common cold are caused by Rhinovirus, the rest being caused by Coronavirus or Respiratory Syncytial Virus (RSV). 

For most of us, the flu causes irritating symptoms for about a week.  But it can be a very dangerous disease.  World wide, the flu infects between 3 and 5 million people every year, causing 300,000 to 500,000 deaths. In Australia, up to 3500 cases of the flu are confirmed every year, mostly in the very young, the old, or people with underlying medical conditions. 

Why can you get the flu more than once?

The influenza virus infects cells of the nose, throat and bronchi of the upper respiratory tract. Once inside a cell, the virus takes control of the function of the cell to make more copies of itself.  Eventually, the cell loaded with virus particles dies and the virus is released to spread to other cells.

During an infection, the immune system only ‘sees’ the outside surface of the virus particle.  If the immune system doesn’t recognise the virus from previous infections, the virus multiplies and spreads to other cells, and you get another dose of the flu.  The reason the immune system doesn’t recognise the virus is because its outer surface is constantly changing in subtle ways. New flu types come along every year as minor variants of existing viruses.  A slightly different vaccine is made each year to try to keep up with the changing virus.  This is why doctors recommend that particular groups of people in the population are vaccinated each year for the flu. 

The H5N1 bird flu story – so far

Occasionally, a radically different virus emerges which has the potential to cause a pandemic (Past flu pandemics). 

Past flu pandemics

There were three influenza pandemics in the 20th century, the most deadly being the Spanish flu of 1918-19, which occurred immediately after World War I.  At the time, it was not known what caused the flu.  We now know that the Spanish flu was caused by a H1N1 type Influenza A virus, which killed between 20 and 50 million people world wide.

Human influenza viruses are normally types H1, 2 or 3 and N1 or 2.  The Asian flu of 1957-58 was caused by a H2N2 virus and the 1968-69 Hong Kong flu was caused by a H3N2 type influenza virus.  Both were created by the genetic rearrangement of human flu virus and avian flu virus. In the past, pandemics have occurred every 30 years or so.  The last pandemic was in 1968, so scientists predict that another pandemic could occur any time soon, if given the right conditions. There is the added concern that the worlds' ageing population and others with a poor immune system are especially vulnerable to the flu.

The 1918-19 flu pandemic in Australia

The following article from A History of the Pharmacy Board of New South Wales by Dr Gregory Haines, published by the Pharmacy Board of New South Wales and the Australian Pharmaceutical Publishing Company (1997), is reproduced with the kind permission of Dr Haines and the Pharmacy Board of New South Wales.  

Before the emergency of the Great War had passed, a new crisis which would fully engage pharmacists had already begun to show itself. The winter of 1918 saw a sudden increase in the incidence of influenza in New South Wales. This was the prelude to the 1919 influenza pandemic which was to claim 6387 lives in the state. The death rate was about to frighten and generate enormous alarm: for each 100,000 people in the population, 319 were going to die.

Just over half of all Australian deaths due to the 1919 influenza pandemic were recorded in New South Wales. The state government took initial steps in 1918 to try to prevent the spread of the anticipated outbreak of the disease. Health authorities had been aware of the influenza outbreaks in Europe and Britain from July 1918. At that stage, what became known as Spanish Influenza was not exhibiting unusual virulence, though its spread was anticipated.

The government made the wearing of masks compulsory in shops, hotels, churches, theatres and on public transport in the populous parts of the state. Those who had become infected were to be isolated and quarantine rules were tightened. Price control on treatments for influenza was enforced and one Sydney pharmacist was severely fined in October 1918 when he was found to have overcharged. In December 1918, representatives of the Pharmaceutical Society and the medical association met and formulated a stock mixture and a solid inhalation for use should the disease spread into Sydney from North Head Quarantine Station.

Early in 1919 the government strengthened its public health measures. It insisted on the use of masks. Libraries, reading rooms, theatres, music halls, auction rooms and billiard rooms and indoor or outdoor church services within the County of Cumberland were prohibited. Space regulations limited the number of people able to gather in shops, hotels, tea rooms and restaurants. Shops were forbidden to hold crowd-attracting bargain or clearance sales. Travel on long-distance trains was restricted and quarantine regulations were further tightened. Troops returning from the war were quarantined at North Head and the Sydney Cricket Ground.

The epidemic peaked in the winter of 1919 and abated by the February of the following year. While it lasted, the influenza pandemic increased work and risk for those engaged in pharmacy. It also prevented or limited the activities of pharmacy organisations, either by preventing their meetings or by robbing erstwhile participants of energy. The Australasian Pharmaceutical Conference, which had not met since 1913, thanks to the war, did not gather until 1921, due to the pandemic.

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In December 2003, an outbreak of bird flu known as H5N1 occurred in poultry in eight Asian countries at the same time.  Like other influenza A viruses, H5N1 is able to infect humans that have close contact with infected birds or water. The disease in humans is particularly virulent, causing death in about half of the adults and children who show symptoms of the flu, although the number is decreasing with time. 

Some of the symptoms caused by H5N1 bird flu are unlike those of other types of flu.  Notably, a sore throat, a runny nose and other symptoms we usually associate with the flu are not always seen.  Indeed, some children in Vietnam who were thought to have died from encephalitis (brain inflammation) probably died from H5N1 bird flu.  A growing number of people are infected by the virus but show no signs of illness, becoming instead carriers of the disease. The variety of symptoms – including the unusual or none at all – means that cases of bird flu could go unnoticed for some time, giving the virus a chance to spread.

Why is H5N1 bird flu such a concern?

Three conditions need to be met for a pandemic to occur.  Firstly, we need the presence of a new virus to which the population has little or no immunity.  The second condition is that the virus has the ability to infect humans and to be passed on to other humans.  And the third condition is that there is no effective vaccine to prevent the spread of the disease in humans.  If all of these conditions are met by a flu virus, or any other type of virus, conditions are perfect for a pandemic to occur. Authorities are worried about H5N1 because it has many of the characteristics of a virus that can cause a pandemic. 

Most cases of bird flu are caused by people being infected by birds or water contaminated with the H5N1 virus.  Authorities have reported a number of cases where infection is likely to have occurred due to close contact between family members with the flu. So far, H5N1 has not shown signs of being very easily transferred from one person to the next via casual contact. However, a more infectious virus may be created if a person with the flu also catches bird flu H5N1.  The different strains may recombine to create a more infectious virus. The concern is that you might get a virus like H5N1, that is already lethal, becoming extremely contagious, which would make it easier for it to spread from person to person.

Fighting the flu

Because H5N1 is so widespread, a global reporting system is required to limit the spread of outbreaks of the flu in humans (Controlling an outbreak).

Controlling an outbreak

Once a virus with the ability to cause a pandemic exists, then control of an outbreak of the virus becomes very important in preventing its spread.  This is true not only of the flu, but of any virus that can cause a zoonotic infection.

Surveillance, development of vaccines, preparedness for an outbreak and planning for a pandemic are all important means of controlling an outbreak.  The behaviour of H5N1 virus is being monitored by researchers from the World Health Organization (WHO) and the United States Centers for Disease Control, looking for early signs that it has changed or altered its ability to infect people, particularly from other people.

Limiting the number of infected animals that are the source of disease in people is important in controlling outbreaks of the flu in people.  For this reason, authorities in Asian countries have culled millions of infected poultry. A number of Asian countries also vaccinate poultry against bird flu. Some scientists are concerned that widespread vaccination will allow the virus to remain in the bird population without causing disease and would put further pressure on the virus to change. 

However, it is not feasible to vaccinate all poultry in Southeast Asia. In Vietnam for example, 90 per cent of chickens are from ’backyard farmers’ who live in close proximity to the animals.  Some countries are simply too poor to vaccinate their poultry.  Such countries are relying on public awareness campaigns to prevent the spread of H5N1 from animals to people.  People are being urged to modify traditional practices so that chickens, ducks and pigs are separated on farms and in market places. 

On a broader scale, countries can prevent the export and import of infected animals, products or people.  Australia does not import products from countries known to have H5N1, but airline passengers need to be checked by quarantine inspectors for bird products in their luggage. Medical professionals need to be alert to the disease in patients and poultry farmers need to recognise signs of the disease in birds.

 

  In 1999, WHO published a world preparedness plan, which includes a network of 112 influenza centres, constantly monitoring reported cases of the flu to determine likely sources of infection and to contain potentially pandemic strains.  Australia has the ‘Australian Action Plan for Pandemic Influenza’ and ‘Ausvetplan’ in place to respond to a potential flu pandemic reaching Australia.

There are two approaches to fighting the flu in humans. They are prevention of infection by vaccination (Vaccines for pandemics)

Vaccines for pandemics

Vaccination against the flu is, in theory, the best way to prevent a flu pandemic. Usually, vaccines are about 70 per cent effective in preventing the flu. However, there are problems associated with widespread vaccination. Knowing which vaccine to stockpile before the outbreak of a pandemic is a major problem, because you don't know which virus will cause the pandemic. It takes months to make enough vaccine for all potential victims, and flu vaccines only last about 12 months in storage. Every year, companies that make the annual flu vaccine have to throw away expired or unused vaccine, so there is little incentive for them to stockpile. Who pays for the stockpiled vaccine if it isn't used?

There are also some technical problems with making a H5N1 vaccine. H5N1 kills chickens, so the usual way of making a vaccine that relies on chicken eggs doesn't work very well. An alternative genetically engineered virus may need to be used to produce enough vaccine in a short period of time.

When vaccinating, it is usual to have at least two shots, one to prime the immune system and the other to boost immunity. Because of the limited availability of a vaccine, the number of shots might have to be limited to one per person. Even with only one shot, the immune system will respond better to the virus or to another vaccine specifically targeted to the strain causing the pandemic. Adults have some resistance to H1 and H3 type viruses from previous cases of the flu , but have no previous exposure to a H5 virus. Trials to test the effectiveness of a vaccine take some months to complete and assume that the vaccine is effective.

In Australia, with a limited supply of vaccine, not everyone can be vaccinated. If the priority is to minimise the number of deaths, then the aged should receive it. But if you want to keep society running, then priority goes to health care workers and other essential personnel. If the priority is to keep economic losses to a mimimum, then children and working adults should get the vaccine.

The people at greatest risk of infection directly from animals live in Southeast Asia. But individuals and governments are too poor to pay for widespread vaccination in these countries. Decisions need to be made at a global and a local level for effective pandemic control.

 

and antiviral medications.  People in direct risk of infection from animals include workers in the poultry industry and farmers and their families in Asian countries.  Medical professionals or family members nursing infected people are also potentially at risk.

Flu vaccines are not normally stockpiled because, until a pandemic starts, you don’t know exactly which one to make.  But for H5N1, the WHO is recommending that vaccines that are an imperfect match of flu be made because it is seen to be a serious threat.  An imperfect vaccine could give some protection, so although you might fall ill, you are unlikely to die from the infection.

Antiviral drugs could be used in the early stages of a pandemic, until vaccines are available.  While H5N1 is resistant to the antivirals called amantadine and rimantidine, it is sensitive to neuraminidase inhibitors such as Relenza and Tamiflu (Antivirals bring hope). 

Antivirals bring hope

The influenza virus has found an ideal strategy – one that makes it difficult for the body's immune system to deal with. The surface of the virus is constantly changing, making it difficult for the immune system to 'recognise' the virus and fight off the infection. But the flu virus does have a 'weak spot'. The enzyme neuraminidase is needed for the virus to get to the site of infection and to release new viruses from infected cells. Both of these activities are associated with a pocket-shaped structure on neuraminidase that does not change shape. A group of Australian researchers thought that if the unchanging pocket was blocked by a dummy molecule, then the virus would be unable to increase in number and spread to other cells. The compound they found is called zanamivir, and is now marketed by the name Relenza. Three researchers – Peter Colman, Graeme Laver and Mark von Itzstein – shared the 1996 Australia Prize for excellence in the field of pharmaceutical design for their work on Relenza.

Based on the Australian research, another compound that worked in a similar way was found by overseas researchers, and that compound is now marketed as Tamiflu.

Relenza is used as a nasal spray, whereas Tamiflu is taken orally as a tablet. They are both very effective at preventing the flu in human volunteers. If taken within 48 hours of the first signs of the flu, they decrease the number of people who get the flu, the severity of the symptoms and the duration of the infection. Importantly, they also work against H5N1 viruses in laboratory tests.

Although vaccination is the preferred option to prevent the flu, Tamiflu and Relenza also have the ability ability to prevent the flu when taken as a prophylactic, before exposure to the virus. The combination of vaccination and prevention with Tamiflu or Relenza can also be used.

One question still remains. Will pressure on the virus, arising from widespread use of Relenza or Tamiflu select virus resistant to the drugs? Work to date indicates that the virus is having a difficult time changing the pocket structure and still being able to multiply in cells. But that may be a matter of time and opportunity. New forms of drugs similar to Relenza and Tamiflu are being made and tested, to add to the number of drugs available to prevent and treat the flu.

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 Tests for the effectiveness of antiviral drugs show that they need to be taken in the early stages of infection and they tend to decrease the severity and duration of the infection. 

Most health officials believe that a pandemic is due to occur some time soon, and that it is a case of when, not if.  In which case, it would be wise to be ready for it.

Related Nova topic:

Immunisation – protecting our children from disease

Glossary

antibiotic. A substance produced by bacteria or fungi that destroys or prevents the growth of other bacteria and fungi.

antibody. A protein produced by the body’s immune system in response to a foreign substance (antigen). An antibody reacts specifically with the antigen that induced its formation and inactivates the antigen. Our bodies fight off an infection by producing antibodies.

antigen. Any foreign substance, usually a protein, that stimulates the body's immune system to produce antibodies. (The name antigen reflects its role in stimulating an immune response – antibody generating.)

antivirals. Drugs that are used to prevent or cure a disease caused by a virus, by interfering with the ability of the virus to multiply in number or spread from cell to cell.

carrier. Is a person who is infected with an agent that causes a disease who shows no sign of illness. Asymptomatic carriers shed the causative agent, such as a virus or bacteria, and so can pass the disease on to others. The most famous asymptomatic carrier was Mary Mallon, or Typhoid Mary.

contagious. A contagious disease is easily spread from one person to another by contact with the infectious agent that causes the disease. The agent may be in droplets of aerosols made by coughing or sneezing, contaminated food utensils, water or food.

cytokine. A hormone-like molecule, produced by one cell, that has an effect on another cell. Some types of cytokines are normally produced in low concentration by the immune system as part of the body’s defence mechanism. Some cytokines are toxic at high concentrations and cause disease symptoms such as fever.

enzyme. A protein that acts as a catalyst. Every chemical reaction in living organisms is facilitated by an enzyme.

epidemiology. The study of diseases or conditions in human populations and the factors that influence their incidence and prevalence.

gene. The basic unit of inheritance. A gene is a segment of DNA that specifies the structure of a protein or an RNA molecule.

genetic mutation. A change in the genetic material (DNA, or RNA in the case of some viruses) resulting in new or rearranged hereditary determinants. Mutations are rare, random events in which the base sequence of the nucleic acid molecule is changed. The frequency of mutations may be increased by chemicals or radiation.

haemagglutinin. A protein which forms a rod-shaped spike on the surface of influenza virus. The name haemagglutinin is given because the spikes are capable of adhering to red blood cells, causing them to be agglutinated (clumped).

host. An organism on or in which a parasite lives.

immune system. The cells, tissues and organs that assist the body to resist infection and disease by producing anitbodies and/or altered cells that inhibit the multiplication of the infectious agent.

neuraminidase. An enzyme which forms a mushroom-shaped projection on the surface of an influenza virus particle. The enzyme assists in the release of newly-formed virus particles from the surface of an infected cell.

nucleic acid. A large molecule made up of a sequence of phosphorylated nitrogen-containing bases. DNA and RNA are both nucleic acids.

pandemic. The worldwide outbreak of a disease.

prophylactic. A medical procedure or practice that prevents or protects against a disease or condition (eg, vaccines, antibiotics, drugs).

protein. A large molecule composed of a linear sequence of amino acids. This linear sequence is a protein's primary structure. Short sequences within the protein molecule can interact to form regular folds (eg, alpha helix and beta pleated sheet) called the secondary structure. Further folding from interaction between sites in the secondary structure forms the tertiary structure of the protein.

Proteins are essential to the structure and function of cells. They account for more than 50 per cent of the dry weight of most cells, and are involved in most cell processes. Examples of proteins include enzymes, collagen in tendons and ligaments and some hormones. For more information see Protein structure and diversity (Molecular Biology Notebook, Rothamsted Research, UK).

public health. The aspect of medical activity directed towards improving the health of the whole community.

species. Living things of the same kind that are potentially capable of breeding and producing fertile offspring. Theoretically, plants or animals of different species cannot interbreed. However, occasionally this does not hold true.

vaccine. A preparation consisting of antigens of a disease-causing organism which, when introduced into the body, stimulates the production of specific antibodies or altered cells. This produces an immunity to the disease-causing organism. The antigen in the preparation can be whole disease-causing organisms (killed or weakened) or parts of these organisms.

virulent. Highly lethal; causing severe illness or death.

virus. A submicroscopic infectious agent consisting of a nucleic acid (DNA or RNA) molecule surrounded by a protein coat. Viruses cannot replicate outside a living cell. More information can be found at How viruses work (How Stuff Works, USA).

zoonoses. Diseases that are transferable to humans from animals.