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What is special about the current outbreaks in
poultry?
The current outbreaks of highly pathogenic avian influenza, which
began in South-East Asia in mid-2003, are the largest and most severe
on record. Never before in the history of this disease have so many
countries been simultaneously affected, resulting in the loss of
so many birds. The causative agent, the H5N1 virus, has proved to
be especially tenacious. Despite the death or destruction of an
estimated 150 million birds, the virus is now considered endemic
in many parts of Indonesia and Viet Nam and in some parts of Cambodia,
China, Thailand, and possibly also the Lao People’s Democratic Republic.
Control of the disease in poultry is expected to take several years.
The H5N1 virus is also of particular concern for human health, as
explained below.
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Which countries have been affected by outbreaks
in poultry?
From mid-December 2003 through early February 2004, poultry outbreaks
caused by the H5N1 virus were reported in eight Asian nations (listed
in order of reporting): the Republic of Korea, Viet Nam, Japan,
Thailand, Cambodia, Lao People’s Democratic Republic, Indonesia,
and China. Most of these countries had never before experienced
an outbreak of highly pathogenic avian influenza in their histories.
In early August 2004, Malaysia reported its first outbreak of H5N1
in poultry, becoming the ninth Asian nation affected. Russia reported
its first H5N1 outbreak in poultry in late July 2005, followed by
reports of disease in adjacent parts of Kazakhstan in early August.
Deaths of wild birds from highly pathogenic H5N1 were reported in
both countries. Almost simultaneously, Mongolia reported the detection
of H5N1 in dead migratory birds. In October 2005, H5N1 was confirmed
in poultry in Turkey and Romania. Outbreaks in wild and domestic
birds are under investigation elsewhere. Japan, the Republic of
Korea, and Malaysia have announced control of their poultry outbreaks
and are now considered free of the disease.In the other affected
areas, outbreaks are continuing with varying degrees of severity.
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What are the implications for human health?
The widespread persistence of H5N1 in poultry populations poses
two main risks for human health. The first is the risk of direct
infection when the virus passes from poultry to humans, resulting
in very severe disease. Of the few avian influenza viruses that
have crossed the species barrier to infect humans, H5N1 has caused
the largest number of cases of severe disease and death in humans.
Unlike normal seasonal influenza, where infection causes only mild
respiratory symptoms in most people, the disease caused by H5N1
follows an unusually aggressive clinical course, with rapid deterioration
and high fatality. Primary viral pneumonia and multi-organ failure
are common. In the present outbreak, more than half of those infected
with the virus have died. Most cases have occurred in previously
healthy children and young adults. A second risk, of even greater
concern, is that the virus – if given enough opportunities – will
change into a form that is highly infectious for humans and spreads
easily from person to person. Such a change could mark the start
of a global outbreak (a pandemic).
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Where have human cases occurred?
In the current outbreak, laboratory-confirmed human cases have been
reported in four countries: Cambodia, Indonesia, Thailand, and Viet
Nam. Hong Kong has experienced two outbreaks in the past. In 1997,
in the first recorded instance of human infection with H5N1, the
virus infected 18 people and killed 6 of them. In early 2003, the
virus caused two infections, with one death, in a Hong Kong family
with a recent travel history to southern China.
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How do people become infected?
Direct contact with infected poultry, or surfaces and objects contaminated
by their faeces, is presently considered the main route of human
infection. To date, most human cases have occurred in rural or periurban
areas where many households keep small poultry flocks, which often
roam freely, sometimes entering homes or sharing outdoor areas where
children play. As infected birds shed large quantities of virus
in their faeces, opportunities for exposure to infected droppings
or to environments contaminated by the virus are abundant under
such conditions. Moreover, because many households in Asia depend
on poultry for income and food, many families sell or slaughter
and consume birds when signs of illness appear in a flock, and this
practice has proved difficult to change. Exposure is considered
most likely during slaughter, defeathering, butchering, and preparation
of poultry for cooking.
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Is it safe to eat poultry and poultry products?
Yes, though certain precautions should be followed in countries
currently experiencing outbreaks. In areas free of the disease,
poultry and poultry products can be prepared and consumed as usual
(following good hygienic practices and proper cooking), with no
fear of acquiring infection with the H5N1 virus. In areas experiencing
outbreaks, poultry and poultry products can also be safely consumed
provided these items are properly cooked and properly handled during
food preparation. The H5N1 virus is sensitive to heat. Normal temperatures
used for cooking (70oC in all parts of the food) will kill the virus.
Consumers need to be sure that all parts of the poultry are fully
cooked (no “pink” parts) and that eggs, too, are properly cooked
(no “runny” yolks). Consumers should also be aware of the risk of
cross-contamination. Juices from raw poultry and poultry products
should never be allowed, during food preparation, to touch or mix
with items eaten raw. When handling raw poultry or raw poultry products,
persons involved in food preparation should wash their hands thoroughly
and clean and disinfect surfaces in contact with the poultry products
Soap and hot water are sufficient for this purpose. In areas experiencing
outbreaks in poultry, raw eggs should not be used in foods that
will not be further heat-treated as, for example by cooking or baking.
Avian influenza is not transmitted through cooked food. To date,
no evidence indicates that anyone has become infected following
the consumption of properly cooked poultry or poultry products,
even when these foods were contaminated with the H5N1 virus.
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Does the virus spread easily from birds to
humans?
No. Though more than 100 human cases have occurred in the current
outbreak, this is a small number compared with the huge number of
birds affected and the numerous associated opportunities for human
exposure, especially in areas where backyard flocks are common.
It is not presently understood why some people, and not others,
become infected following similar exposures.
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What about the pandemic risk?
A pandemic can start when three conditions have been met: a new
influenza virus subtype emerges; it infects humans, causing serious
illness; and it spreads easily and sustainably among humans. The
H5N1 virus amply meets the first two conditions: it is a new virus
for humans (H5N1 viruses have never circulated widely among people),
and it has infected more than 100 humans, killing over half of them.
No one will have immunity should an H5N1-like pandemic virus emerge.
All prerequisites for the start of a pandemic have therefore been
met save one: the establishment of efficient and sustained human-to-human
transmission of the virus. The risk that the H5N1 virus will acquire
this ability will persist as long as opportunities for human infections
occur. These opportunities, in turn, will persist as long as the
virus continues to circulate in birds, and this situation could
endure for some years to come.
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What changes are needed for H5N1 to become
a pandemic virus?
The virus can improve its transmissibility among humans via
two principal mechanisms. The first is a “reassortment” event, in
which genetic material is exchanged between human and avian viruses
during co-infection of a human or pig. Reassortment could result
in a fully transmissible pandemic virus, announced by a sudden surge
of cases with explosive spread. The second mechanism is a more gradual
process of adaptive mutation, whereby the capability of the virus
to bind to human cells increases during subsequent infections of
humans. Adaptive mutation, expressed initially as small clusters
of human cases with some evidence of human-to-human transmission,
would probably give the world some time to take defensive action.
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What is the significance of limited human-to-human
transmission?
Though rare, instances of limited human-to-human transmission of
H5N1 and other avian influenza viruses have occurred in association
with outbreaks in poultry and should not be a cause for alarm. In
no instance has the virus spread beyond a first generation of close
contacts or caused illness in the general community. Data from these
incidents suggest that transmission requires very close contact
with an ill person. Such incidents must be thoroughly investigated
but – provided the investigation indicates that transmission from
person to person is very limited – such incidents will not change
the WHO overall assessment of the pandemic risk. There have been
a number of instances of avian influenza infection occurring among
close family members. It is often impossible to determine if human-to-human
transmission has occurred since the family members are exposed to
the same animal and environmental sources as well as to one another.
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How serious is the current pandemic risk?
The risk of pandemic influenza is serious. With the H5N1 virus now
firmly entrenched in large parts of Asia, the risk that more human
cases will occur will persist. Each additional human case gives
the virus an opportunity to improve its transmissibility in humans,
and thus develop into a pandemic strain. The recent spread of the
virus to poultry and wild birds in new areas further broadens opportunities
for human cases to occur. While neither the timing nor the severity
of the next pandemic can be predicted, the probability that a pandemic
will occur has increased.
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Are there any other causes for concern?
Yes. Several.
• Domestic ducks can now excrete large quantities of highly pathogenic
virus without showing signs of illness, and are now acting as
a “silent” reservoir of the virus, perpetuating transmission to
other birds. This adds yet another layer of complexity to control
efforts and removes the warning signal for humans to avoid risky
behaviours.
• When compared with H5N1 viruses from 1997 and early 2004, H5N1
viruses now circulating are more lethal to experimentally infected
mice and to ferrets (a mammalian model) and survive longer in
the environment.
• H5N1 appears to have expanded its host range, infecting and
killing mammalian species previously considered resistant to infection
with avian influenza viruses.
• The behaviour of the virus in its natural reservoir, wild waterfowl,
may be changing. The spring 2005 die-off of upwards of 6,000 migratory
birds at a nature reserve in central China, caused by highly pathogenic
H5N1, was highly unusual and probably unprecedented. In the past,
only two large die-offs in migratory birds, caused by highly pathogenic
viruses, are known to have occurred: in South Africa in 1961 (H5N3)
and in Hong Kong in the winter of 2002–2003 (H5N1).
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Why are pandemics such dreaded events?
Influenza pandemics are remarkable events that can rapidly infect
virtually all countries. Once international spread begins, pandemics
are considered unstoppable, caused as they are by a virus that spreads
very rapidly by coughing or sneezing. The fact that infected people
can shed virus before symptoms appear adds to the risk of international
spread via asymptomatic air travellers. The severity of disease
and the number of deaths caused by a pandemic virus vary greatly,
and cannot be known prior to the emergence of the virus. During
past pandemics, attack rates reached 25-35% of the total population.
Under the best circumstances, assuming that the new virus causes
mild disease, the world could still experience an estimated 2 million
to 7.4 million deaths (projected from data obtained during the 1957
pandemic). Projections for a more virulent virus are much higher.
The 1918 pandemic, which was exceptional, killed at least 40 million
people. In the USA, the mortality rate during that pandemic was
around 2.5%. Pandemics can cause large surges in the numbers of
people requiring or seeking medical or hospital treatment, temporarily
overwhelming health services. High rates of worker absenteeism can
also interrupt other essential services, such as law enforcement,
transportation, and communications. Because populations will be
fully susceptible to an H5N1-like virus, rates of illness could
peak fairly rapidly within a given community. This means that local
social and economic disruptions may be temporary. They may, however,
be amplified in today’s closely interrelated and interdependent
systems of trade and commerce. Based on past experience, a second
wave of global spread should be anticipated within a year. As all
countries are likely to experience emergency conditions during a
pandemic, opportunities for inter-country assistance, as seen during
natural disasters or localized disease outbreaks, may be curtailed
once international spread has begun and governments focus on protecting
domestic populations.
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What are the most important warning
signals that a pandemic is about to start?
The most important warning signal comes when clusters of patients
with clinical symptoms of influenza, closely related in time and
place, are detected, as this suggests human-to-human transmission
is taking place. For similar reasons, the detection of cases in
health workers caring for H5N1 patients would suggest human-to-human
transmission. Detection of such events should be followed by immediate
field investigation of every possible case to confirm the diagnosis,
identify the source, and determine whether human-to-human transmission
is occurring. Studies of viruses, conducted by specialized WHO reference
laboratories, can corroborate field investigations by spotting genetic
and other changes in the virus indicative of an improved ability
to infect humans. This is why WHO repeatedly asks affected countries
to share viruses with the international research community.
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What is the status of vaccine development
and production?
Vaccines effective against a pandemic virus are not yet available.
Vaccines are produced each year for seasonal influenza but will
not protect against pandemic influenza. Although a vaccine against
the H5N1 virus is under development in several countries, no vaccine
is ready for commercial production and no vaccines are expected
to be widely available until several months after the start of a
pandemic. Some clinical trials are now under way to test whether
experimental vaccines will be fully protective and to determine
whether different formulations can economize on the amount of antigen
required, thus boosting production capacity. Because the vaccine
needs to closely match the pandemic virus, large-scale commercial
production will not start until the new virus has emerged and a
pandemic has been declared. Current global production capacity falls
far short of the demand expected during a pandemic.
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What drugs are available for treatment?
Two drugs (in the neuraminidase inhibitors class), oseltamivir (commercially
known as Tamiflu) and zanamivir (commercially known as Relenza)
can reduce the severity and duration of illness caused by seasonal
influenza. The efficacy of the neuraminidase inhibitors depends,
among others, on their early administration ( within 48 hours after
symptom onset). For cases of human infection with H5N1, the drugs
may improve prospects of survival, if administered early, but clinical
data are limited. The H5N1 virus is expected to be susceptible to
the neuraminidase inhibitors. Antiviral resistance to neuraminidase
inhibitors has been clinically negligible so far but is likely to
be detected during widespread use during a pandemic. An older class
of antiviral drugs, the M2 inhibitors amantadine and rimantadine,
could potentially be used against pandemic influenza, but resistance
to these drugs can develop rapidly and this could significantly
limit their effectiveness against pandemic influenza. Some currently
circulating H5N1 strains are fully resistant to these the M2 inhibitors.
However, should a new virus emerge through reassortment, the M2
inhibitors might be effective. For the neuraminidase inhibitors,
the main constraints – which are substantial – involve limited production
capacity and a price that is prohibitively high for many countries.
At present manufacturing capacity, which has recently quadrupled,
it will take a decade to produce enough oseltamivir to treat 20%
of the world’s population. The manufacturing process for oseltamivir
is complex and time-consuming, and is not easily transferred to
other facilities. So far, most fatal pneumonia seen in cases of
H5N1 infection has resulted from the effects of the virus, and cannot
be treated with antibiotics. Nonetheless, since influenza is often
complicated by secondary bacterial infection of the lungs, antibiotics
could be life-saving in the case of late-onset pneumonia. WHO regards
it as prudent for countries to ensure adequate supplies of antibiotics
in advance.
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Can a pandemic be prevented?
No one knows with certainty. The best way to prevent a pandemic
would be to eliminate the virus from birds, but it has become increasingly
doubtful if this can be achieved within the near future. Following
a donation by industry, WHO will have a stockpile of antiviral medications,
sufficient for 3 million treatment courses, by early 2006. Recent
studies, based on mathematical modelling, suggest that these drugs
could be used prophylactically near the start of a pandemic to reduce
the risk that a fully transmissible virus will emerge or at least
to delay its international spread, thus gaining time to augment
vaccine supplies. The success of this strategy, which has never
been tested, depends on several assumptions about the early behaviour
of a pandemic virus, which cannot be known in advance. Success also
depends on excellent surveillance and logistics capacity in the
initially affected areas, combined with an ability to enforce movement
restrictions in and out of the affected area. To increase the likelihood
that early intervention using the WHO rapid-intervention stockpile
of antiviral drugs will be successful, surveillance in affected
countries needs to improve, particularly concerning the capacity
to detect clusters of cases closely related in time and place.
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What strategic actions are recommended
by WHO?
In August 2005, WHO sent all countries a document outlining recommended
strategic actions for responding to the avian influenza pandemic
threat. Recommended actions aim to strengthen national preparedness,
reduce opportunities for a pandemic virus to emerge, improve the
early warning system, delay initial international spread, and accelerate
vaccine development.
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Is the world adequately prepared?
No. Despite an advance warning that has lasted almost two years,
the world is ill-prepared to defend itself during a pandemic. WHO
has urged all countries to develop preparedness plans, but only
around 40 have done so. WHO has further urged countries with adequate
resources to stockpile antiviral drugs nationally for use at the
start of a pandemic. Around 30 countries are purchasing large quantities
of these drugs, but the manufacturer has no capacity to fill these
orders immediately. On present trends, most developing countries
will have no access to vaccines and antiviral drugs throughout the
duration of a pandemic.
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1 Influenza viruses are grouped into three
types, designated A, B, and C. Influenza A and B viruses are of
concern for human health. Only influenza A viruses can cause pandemics.
2 The H subtypes are epidemiologically most important, as they
govern the ability of the virus to bind to and enter cells, where
multiplication of the virus then occurs. The N subtypes govern
the release of newly formed virus from the cells
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