terça-feira, outubro 18, 2005

Bird Flu

What is a pandemic?
The word "pandemic" is used to describe a disease that is epidemic on a worldwide scale over a similar time span. While we are used to experiencing epidemics of influenza in most winters, these would not be described as pandemics because they are not consistently present in all countries at the same time.
The other criterion for defining a pandemic is concerned with the causative virus. A pandemic occurs when a completely new virus emerges. Influenza viruses are changing continuously so the term "completely new" implies a more radical change.
The influenza virus belongs to a class of orthomyxoviruses. Genetic material is contained in the virus nucleus and includes eight RNA segments.
The lipid membrane, which forms the outer lining of the virus cell, has three embedded proteins:
• Haemagglutinin
• Neuraminidase
• Membrane channel protein.
Altogether there are 15 variants of haemagglutinin and nine variants of neuraminidase: these are used to define the virus subtype. Not all these variants offer the virus the potential to infect humans. The influenza virus can infect many animal species, but the number of haemagglutinin and neuraminidase variants that typically infect one species is limited.
In human infections the common influenza viruses belong to:
• Haemagglutinin subtypes 1, 2, and 3
• Neuraminidase subtypes 1 and 2.
Antigenic drift
Viruses with these combinations of surface proteins readily transmit from one person to another, mostly by airborne spread. Small changes in the surface proteins of the virus, particularly the haemagglutinin, take place continuously and this process is known as "antigenic drift." As a result of these changes, the protection given by influenza vaccination in one winter does not carry over into the next. Even if a subtype of influenza virus (for example type H3N2) is epidemic in successive winters, the change that will have occurred by the second winter is such that there will be imperfect immunity, which explains the need for repeated annual vaccination.
Antigenic shift
A different type of change involving the virus nucleus occurs less frequently and this is known as "antigenic shift." This may occur as a result of simultaneous infection with different strains of virus, which presents an opportunity for "interbreeding of viruses" and genetic reassortment among the eight RNA segments of the virus nucleus.
Simultaneous infections can take place in different species and may occur even if infection is at a subclinical level. Pigs, in particular, can become infected with human and avian viruses. Humans infected with avian viruses could also become infected with one of the more typical human strains, presenting an opportunity for genetic reassortment.
The pathogenicity of a novel virus arising from reassortment is unpredictable. But direct transmission from person to person is a requirement for a pandemic to occur.
Not all influenza viruses have the same transmission properties. The virus causing avian influenza in poultry spreads by faeco-oral transmission. It is widely believed that humans contracting this condition have acquired it as a result of contact with infected poultry, either by airborne spread from infected birds or their faeces or by contamination during food preparation. Anxieties surrounding the H5N1 avian influenza virus arise because it has infected and caused serious illness in humans; because a further small antigenic shift might result in a virus with a capacity to spread between humans; and because of increased opportunities for genetic reassortment.
Learning point
The Department of Health recommends annual influenza vaccination for people older than six months with:
• Chronic respiratory disease (this includes people with asthma who need repeated use of inhaled or systemic steroids, or with previous exacerbations that resulted in hospital admission. It also includes children who have been admitted to hospital for lower respiratory tract disease)
• Chronic heart disease
• Chronic renal failure
• Diabetes mellitus receiving treatment
• Chronic liver disease
• Immunosu
• imppression due to disease or treatment (including people with splenic dysfunction).
The department also recommends vaccination for:
• People older than 65
• People who live in care homes
• Healthcare workers with direct patient contact.
The overall national target is that 70% of people aged 65 and older should receive the vaccine.

Why do we fear a pandemic?
By definition, a novel virus means that people will have no immunity to it.
Not all pathogenic viruses necessarily cause serious illness. In 1977 the H1N1 virus met the definition of a pandemic virus, but illness in humans associated with infection from this virus was not serious.
In contrast, the pandemic in 1918-20 (almost certainly caused by an H1N1 virus) caused a much more serious illness. This pandemic caused more deaths worldwide than did the first world war.
Excess influenza related mortality in recent years has largely been in the elderly population, especially those with underlying cardiorespiratory disease.1 During pandemics, however, excess mortality is also evident in much younger people. In the pandemic of 1918-20 the highest mortality was reported in people of middle age. It has been suggested that elderly people might have been spared because of residual immunity from a similar but less virulent virus circulating in the early 1880s.
Starr described the mortality of influenza exceeding 25% per night among patients admitted to hospital at the peak of the epidemic.2 The time between illness onset and death was often short and the mortuary capacity was totally inadequate.
The clinical features of 1918 influenza were particularly dramatic. The usual features associated with influenza were present, but they were more severe; pulmonary oedema and epistaxis occurred frequently. In people who were severely affected, the face was discoloured from a combination of haemorrhagic spots and cyanosis: this was known as heliotropic cyanosis. Sera from people living through the pandemic period contained influenza A (H1) virus similar to a virus causing swine influenza.3
After a relatively mild pandemic in 1946, the World Health Organization (WHO) set up a worldwide network of laboratories to monitor influenza. The surveillance activity identified a new influenza virus subtype (H2N2), which gave forewarning of the pandemic in 1957-8. It was first seen in China in February 1957: two months later pandemic conditions were seen throughout the Far East, India, and Australia, and shortly afterwards in North America. It reached Africa, Europe, and South America before the end of the year.
This pandemic caused considerable morbidity in Europe in late summer, contrasting with the more usual appearance of influenza in winter. It was estimated to have caused infection in 40-50% of people (although not all of these experienced clinical illness).
In a study of 66 GPs in England working during the influenza epidemic of 1957-8, 19 reported clinical illness but not all were sufficiently ill to stay off work. A further 22 provided blood specimens that were investigated serologically for antibodies: five of them had positive antibodies but no clinical illness.
All influenza epidemics cause infection in many more people than those who are recognised as ill. This is one of the reasons that influenza cannot be excluded as the cause of a respiratory infection simply because the symptoms are mild. However, influenza probably causes people to have a more serious illness than do most other respiratory viruses. Even in a usual winter epidemic period, increased morbidity can overstretch the capacity of health services, as was seen in the UK during the winter of 2000.
Although influenza is associated primarily with spread via respiratory airborne droplets, we should not assume that a pandemic virus will be transmitted exclusively in this way.
Learning point
The time from exposure to the influenza virus and the onset of symptoms is usually two days, but it can vary from one to five days.
Symptoms vary with age but typically include:
• Dry cough
• Muscle pains
• Sore throat
• Raised temperature (not always present in elderly people)
• Headache
• Feeling weak and tired.
Symptoms typically last about five to seven days.
Complications include:
• Otitis media
• Primary influenza pneumonia
• Secondary bacterial bronchitis and pneumonia
• Encephalitis (rare)
• Worsening or destabilisation of pre-existing diseases, such as cardiac failure and diabetes.
People typically acquire influenza by inhaling the virus or by being in direct contact with the respiratory tract secretions of people who are infected. The potential to infect others lasts as long as viruses are being shed from the respiratory tract. Healthy adults shed viruses from about one day before the onset of symptoms until about five days thereafter. Children shed virus for about two days longer, and people who are immunocompromised shed virus for longer still.

Influenza pandemics: bird flu
Planning for a pandemic

It is not possible to halt the mutation of the influenza virus, but it is possible that we can slow down the onset of a pandemic. We need to direct our efforts towards minimising the effect of a pandemic.
International collaboration
International efforts have been made to produce plans for a possible pandemic. Different agencies have slightly different slants to their activities. For example, governments are concerned with the intricacies of emergency legislation, health ministries with the optimal allocation of resources, and public health departments with the best use of medical evidence to contain the illness.
All plans have much in common and they all have an element of international collaboration by WHO. They are organised into:
• Two inter-epidemic preparatory phases
• Three pandemic alert phases
• The pandemic period phase.
We are currently in the international preparatory phase 3, which is the first level of pandemic alert; "human infection with a new subtype, but no human-to-human spread, or at most instances of spread to a close contact."
Worldwide surveillance of influenza viruses (in humans and animals) at least gives us an opportunity to recognise new strains early. When there is high risk of a pandemic strain emerging (for example with the recent H5 viruses) we can develop vaccines that might offer at least some protection should a transmissible strain appear.
Slowing spread
Most Western countries have national plans to manage a pandemic. Part of that planning concerns measures appropriate to retarding transmission so there will be more time to prepare a vaccine and to spread the pressures created by the pandemic. For example, limiting travel from the country in which a pandemic virus is identified and screening air travellers for febrile illness may reduce the potential for spread.
Organising health services
There are finite limits to the availability of health services, including nurses and doctors, hospital beds, mortuary facilities, vaccines, and antiviral drugs. Organisations need to make decisions about how to best use these; arrangements for decision making have now been determined in many countries.
The implementation of policy will involve a coordinated effort with surveillance agencies, primary care trusts (PCTs), hospital authorities, and medical and nursing professional organisations each playing a part. In the UK each PCT will need to appoint an influenza planning coordinator. Effective communication between these organisations and with individual healthcare workers within them will be paramount.
Although health administration in the UK has been devolved to the separate countries, there is close collaboration between them on policy in relation to the pandemic threat.
Stockpiling drugs and vaccines
Several countries (including the UK) have arranged to stockpile antiviral drugs. Nonetheless, it will take time to accumulate these stockpiles. It would be desirable to stockpile vaccines also, but until the virus has "shown itself" it is not possible to develop a pandemic specific virus vaccine. Research is underway to investigate possible problems or difficulties associated with the manufacture of a pandemic vaccine.
The Department of Health has recently made arrangements to obtain some limited supplies of an H5N1 vaccine based on the avian virus that has caused avian flu in humans infected from poultry in south-east Asia.
Determining risk
Issues such as prioritising people according to risk, or perhaps according to occupational groups, cannot easily be determined in advance. If a pandemic emerges when we have only limited supplies of a vaccine, we will need a rational basis for prioritising vaccinations. We might need to change our current vaccination programme, which is directed towards elderly people and people with chronic illness, in favour of vaccinating healthcare workers or others shown to be at greater risk of serious illness.
Emergency legislation
Decisions made by governments will need to be put into effect using emergency legislation. They will be advised by medical experts assembled on special committees. Planning strategy is tiered in phases depending on the proximity of a pandemic virus: evidence of human to human transmission is particularly important when phasing the plan.
Learning point
You advise a 70 year old man to have the influenza vaccine. But he says he had it last year and still got "flu." What should you say to him?
He may not have had influenza. There are many respiratory pathogens circulating each winter, and influenza vaccination won't prevent infections with other respiratory viruses. Such viruses can cause an influenza-like illness. But the illness isn't usually as severe as influenza, and it isn't life threatening. So you should urge him to continue getting the influenza vaccine.

Influenza pandemics: bird flu
What should GPs be doing about the pandemic threat?
It is important that you take this threat seriously. The time has come for practices to meet together (medical and non-medical staff) to consider the implications to the running of their practices. You should first read the UK Health Departments' influenza pandemic contingency plan published by the Department of Health (see Further Reading) or, in the case of non-UK nationals, by your own health ministry.
If a pandemic does occur, general practice is likely to carry the major burden of disease management in the community and it is unrealistic to think that it will be contained in routine office hours. We have experienced pandemics in our lifetime and it undoubtedly pressurised the system, but the country has never come to a halt.
Advising patients
Doctors and their staff will be responsible for providing accurate information to a fearful and anxious population. This will involve minimising rather than inflaming the hype that is likely to occur.
A pandemic is likely to cause illness in several members of a household. You can use your experience of the first person to become ill to brief the entire family on management and alert them to risk symptoms. However, the advice you give to the 30 year old man consulting you today might not be appropriate for his three month old son, who may be the next family member to become ill.
Targeting patients
GPs will be required to implement policies determined by the Department of Health. You will need to consider how best you can contact target groups for vaccination, if a vaccine becomes available.
You will need to consider whether you have registration procedures that reliably identify patients in the likely risk categories. Have you generated lists of such patients and were they reliable and comprehensive? Practices will also deal with aggrieved people who do not accept their exclusion from a priority group.
Coping with demand
You should now be thinking about how best to cope with a large increase in demand, especially for home and out of hours visits. Can you learn from your experience of telephone consultations and think of ways you can use these to best effect? You may be working with a depleted staff. Can you simulate the situation and test your capacity to deal with such a contingency?
Influenza infection is associated with high fever, and febrile convulsions are likely to lead to fears about meningitis. Influenza spreads rapidly and it will therefore be preferable to keep those affected out of hospital, but can we do this safely?
In recent years medical care has increasingly used triage methods, which have usually involved nurses. The art of triage is not learnt overnight. Do you need to train certain staff so they can select who needs to consult a doctor? During a severe pandemic your nurses will be engaged in disease management and may have limited time for triage.
Continuing routine care
To restrict spread of infection, schools and places of congregation may be closed. Health centres may become places where people are likely to catch influenza. How will you care for people with chronic disease who will still need their routine medication? And what about people needing to consult for other conditions, such as urinary disorders, psychiatric emergencies, and the unexplained pains of everyday medical practice? How many of these could you manage by telephone?
There are no universal solutions to all the questions posed here, but the time is ripe for us to consider them in formal practice meetings. These should be minuted so that you can prepare a document outlining contingency plans for your practice.

Influenza pandemics: bird flu
Avian influenza
Influenza viruses can affect many species including horses, whales, seals, pigs, and birds (particularly ducks and wildfowl). The virus now commonly referred to as "avian flu," because of the extensive outbreaks in poultry in China and south-east Asia, is categorised H5N1, although some other viruses also cause influenza epidemics in birds. All haemagglutinin and neuraminidase subtypes circulate in aquatic birds.5
Some influenza epidemics in birds have been the cause of considerable mortality. In 1983, an epidemic in poultry of an H5N2 virus infection was reported in the US with a mortality rate approaching 90%. This epidemic was associated with 13 million poultry deaths either as a result of infection or because of the poultry cull instituted to control it.
Avian flu in humans
Human infection with an avian H5N1 virus was first described in Hong Kong in 1997: 18 patients were affected, six of whom died. Close links with domestic birds were a common feature and there was no good evidence of spread between people. Episodes caused by various avian viruses (including H5 and H7 strains) have continued to appear. These occurred mainly in clusters, although not solely in south-east Asia: an H7N7 infection has been described in Dutch poultry workers, which caused the death of a veterinary surgeon.
So far, episodes have occurred among patients or in communities with close links with poultry; none has occurred where human to human transmission was implicated beyond doubt. Where human infection has occurred, the symptoms were not solely respiratory.6
Limiting incidence
To limit the occurrence of avian flu there have been large culls of poultry, particularly in markets in Hong Kong. Culling animals possibly infected with H5 influenza virus is one of the measures needed to minimise the risk of novel viruses with pandemic potential. This action will, of course, not stop the spread of influenza, but it might limit opportunities for H5 viruses to infect other animals (for example pigs) thereby increasing the possibility of genetic reassortment.
Another strain of H5 virus subtype that we are concerned about has caused infection in humans in Vietnam, Cambodia, and Thailand. Between December 2003 and June 2005, 108 episodes have been reported and 54 patients have died. Surveillance programmes are in place to investigate patients with influenza-like illnesses, especially in south-east Asia.
Intensive investigation of the circumstances in which human infection has occurred, particularly for evidence of human to human transmission, is now routine.
Learning point
A 69 year old woman comes to see you in December. She forgot to have the influenza vaccine and now there is an outbreak of influenza. What should you advise her?
She can still have the vaccine if it is still available. But antibody levels take 7-13 days to rise after vaccination. If she has been exposed to the influenza virus and the exposure has been in the past 48 hours, you could give her oseltamivir to prevent her getting influenza.
If influenza A or influenza B is circulating in the community, you should consider oseltamivir for the post-exposure prophylaxis of influenza in people who:
• Have been exposed (same household) to someone with an influenza-like illness in the past 48 hours and
• Are in the influenza targeted population and at risk of complications of influenza and
• Are not adequately protected by vaccination.
You should consider people not to be adequately protected by vaccination if:
• They haven't received the vaccine
• The vaccine has yet to take effect
• The vaccine and the circulating strain of influenza are not well matched.

Influenza pandemics: bird flu
Severe acute respiratory syndrome
SARS was first recognised as a clinical entity in 2003, but it probably originated in China in November 2002. A 32 year old doctor was one of the earliest affected patients, and as a result of his travel to neighbouring countries and contact with healthcare workers and international travellers, the illness spread to other countries.7
He presented with severe symptoms of an influenza-like illness with erythema on his trunk, and he rapidly developed radiological signs of bronchopneumonia. Initial tests failed to clarify the virus responsible and people became anxious that it might prove to be a new and potentially pandemic viral strain.
After some days the culprit organism was found to be a new coronavirus variant (which was given the name SARS-CoV). After the initial episode, there were several clusters, mainly in the Far East although some also in Canada.
Coronavirus infection
Infection with coronavirus is common and previously has largely been associated with the common cold rather than more serious respiratory infections. The coronavirus variant causing SARS spread from person to person probably more by contact than by aerosol transmission. It proved a particular problem for the medical and nursing staff involved in the treatment of the early patients in Hong Kong. A prominent infectious disease specialist (Carlo Urbani) called in to investigate the cause of the illness was one of its early victims.
The illness caused severe respiratory symptoms in people of all ages. By July 2003 some 8096 patients had been reported to WHO, of whom 774 (9.6%) died (see http://www.who.int/csr/disease/avian_influenza for more information). In July 2003 WHO issued a statement to the effect that the global outbreak of SARS had been contained, but it stressed the need for continuing medical vigilance.
There have been isolated episodes reported subsequently but these have occurred among virology laboratory workers, which highlights the need for high security laboratory facilities when dealing with new and unfamiliar viruses.
Managing SARS
The main strategy for managing SARS involves isolation. In Canada, a strict policy of isolating infected people was critical for achieving control of the outbreak. Isolation is a practical policy when episodes are few and occur in clusters. Isolation is not practical for containing a condition such as influenza, although closing places where people congregate might curtail the spread.
SARS did not spread elsewhere, but its appearance in Canada provided a blunt reminder of the potential for rapid transmission across the world of any respiratory virus.

Commercial and ethical issues exposed by the pandemic threat
In the commercial world there is generally an equilibration between the supply and demand sides of manufacture. Products are developed and sold according to their usefulness and price, as judged by the consumer.
The pharmaceutical industry operates within this framework. New vaccines and drugs are developed according to likely sales and the potential for profit. Manufacturing protocols are observed; products are tested, licensed, and marketed; and manufacturing capacity is adapted to the market potential. There are successes and failures in all manufacturers' programmes. But the threat of a pandemic brings a new perspective to these familiar commercial principles.
Vaccine production
An appropriate vaccine cannot be developed before we have a virus that can be replicated in sufficient quantities to manufacture the vaccine. Experimental work with potentially serious pathogens is conducted only in laboratory conditions of high security and the availability of such conditions is limited. Although there may be some benefit in developing a vaccine against an H5 virus, the chances of a good match with a truly pandemic strain may be low and certainly not such that it might tempt a manufacturer to incur the costs of preparing a vaccine on a significant scale (which would require using the facilities normally used to produce routine influenza vaccines).
Even if there were considerable assurance about the protective value against all H5 viruses, the commercial risk would be considerable: an H5 virus may never cause a pandemic and there may never be a market for it. Developing a suitable vaccine, manufacturing and testing it, and, finally, licensing it is unlikely to take less than 12 months. Normally, a new vaccine is subjected to detailed clinical trials before licensing. This step may not be possible in a pandemic situation.
Vaccines are largely developed using fertilised hens' eggs, but we don't have several million fertilised eggs immediately available for producing supplies for a pandemic. Long term planning is needed to secure such supplies.
Alternative manufacturing processes have been developed in which the virus is grown on continuous cell lines, for example the Madin Darby canine kidney. However, we cannot assume that a new pandemic virus, perhaps of avian origin, would necessarily grow easily on such a cell line. Nor can we assume that a vaccine generated from this manufacturing process would have good antigenic properties. Experience of vaccines developed using these methods is much more limited than that associated with egg manufacture.
In recent years, several influenza vaccines have been prepared using vaccine adjuvants. They have the advantage of allowing smaller doses to be used: this may be important if supplies are limited.
Antiviral drugs
Antiviral drugs against influenza have scarcely been used in Europe and the manufacturing capacity has accordingly been matched to current rather than exceptional use. Manufacturers cannot accommodate a surge in demand without sufficient notice. If these drugs are to be made available to manage a pandemic, they will have to be manufactured (and sold) well in advance.
For these reasons, many European governments (including the UK) have placed orders so they can stockpile these drugs. They will buy the stockpiles regardless of whether there is ever a pandemic in which the drugs will be used. The drugs may well be used in situations in which the medical profession have limited knowledge of optimum use (as opposed to use in the conditions of a clinical trial). Furthermore, we cannot be sure how useful they would be to treat a completely new virus, or how significant the risks from resistant strains would be.
Neuraminidase inhibitor antiviral drugs are licensed for prophylaxis in high risk groups (as recommended by the National Institute for Health and Clinical Excellence). However, prescribing them for prophylaxis in a pandemic situation might be an extravagant use of limited resources. This could be justified only if there were good grounds to think a vaccine was imminent. It might be preferable to institute early treatment rather than offer prophylaxis, because the stimulus of infection will prompt an antibody response.
Supply shortages
Vaccines and drugs will be manufactured at selected plants. In the event of a serious pandemic, countries may suspend routine trading practices. There will be a great temptation to suspend the export of drugs in short supply and, in some countries there may be no local manufacturer and no drugs or vaccines available. There is clearly an ethical dilemma between the competing interests of countries with manufacturing capacity and those without. There is also an ethical dilemma with respect to people in countries with inadequate resources to meet the cost of these drugs.
There will be limited availability of antiviral drugs and there will be a need to prioritise people in risk groups, which may differ from those conventionally associated with the routine annual vaccination programme. Healthcare workers and people operating essential services might be the most important groups to protect.
The media coverage during the 1918 pandemic, the recent incidence of SARS, the emergence of avian flu, and the coverage of the pressures imposed by influenza over the millennium period all demonstrate the reaction of the public to health risks: many people will not accept the principles of prioritisation and rationing.
It is usual to license new drugs or vaccines for age groups in which they have been tested. In a pandemic situation there will be limited opportunity to test a new vaccine, and certainly not in the people who may be at most risk (for example, young children). This poses a dilemma when determining appropriate use of vaccines and antiviral drugs.
Side effects
There is also the question of liability for unrecognised side effects. A pharmaceutical manufacturer is not likely to release a product for use in untested situations because of the fear of litigation, unless the liability is underwritten by governments.
The dilemmas posed by the threat of an influenza pandemic will not be resolved until an emergency situation arises and there is time to reflect on all these issues.
Learning point
A 76 year old woman says she had the influenza vaccine two years ago and it gave her "flu." She says she never wants to have it again. What should you advise her?
Influenza vaccine can't cause influenza because it is an inactivated vaccine. The symptoms of influenza come from the destruction caused by a replicating virus. Inactivated vaccines contain no living influenza virus and therefore there is no possibility of virus replication.
It's likely that this woman had some other respiratory virus. But it's possible that she could have been exposed to influenza just after vaccination, at a time when she had not yet mounted an immune response. The delay between vaccination and effective protection is about two weeks. The best time to be vaccinated is therefore at the beginning of the influenza season.

Learning point
A 66 year old man with a history of stroke has read about the influenza vaccine. He read that the vaccine can cause strange neurological illnesses. What should you say to him?
Influenza vaccination does not cause strokes, so you can reassure him on that count. He may have read about Guillain-Barre syndrome. But this is exceedingly rare. It occurs at a rate of about one additional case per million people vaccinated.
A history of Guillain-Barre syndrome is a contraindication for vaccination. So is a known hypersensitivity to eggs and being aged less than 3 months. Pregnancy is not an absolute contraindication for vaccination.

Influenza pandemics: bird flu
a. Avian flu H5N1 is now a pandemic influenza virus
To date there has been no instance in which avian flu has spread from human to human. Avian flu H5N1 has not yet caused a pandemic (hopefully it never will). Nor has the most recent strain spread throughout the whole of south-east Asia. Humans can and have been infected by avian flu viruses.
b. Humans cannot be infected by avian influenza viruses
To date there has been no instance in which avian flu has spread from human to human. Avian flu H5N1 has not yet caused a pandemic (hopefully it never will). Nor has the most recent strain spread throughout the whole of south-east Asia. Humans can and have been infected by avian flu viruses.
c. Avian flu does not spread between humans
To date there has been no instance in which avian flu has spread from human to human. Avian flu H5N1 has not yet caused a pandemic (hopefully it never will). Nor has the most recent strain spread throughout the whole of south-east Asia. Humans can and have been infected by avian flu viruses.
d. Avian flu has spread throughout the whole of south-east Asia
To date there has been no instance in which avian flu has spread from human to human. Avian flu H5N1 has not yet caused a pandemic (hopefully it never will). Nor has the most recent strain spread throughout the whole of south-east Asia. Humans can and have been infected by avian flu viruses.