Epidemiology and
Transmission:

Clinical Findings and
Lesions:

Low Pathogenicity AI Viruses:

High Pathogenicity AI Viruses:

Even in the absence of secondary pathogens, HP viruses cause severe, systemic disease with high mortality in chickens, turkeys, and other gallinaceous birds. In peracute cases, clinical signs or gross lesions may be lacking before death. However, in acute cases, lesions may include cyanosis and edema of the head, comb, and wattle; edema and discoloration of the shanks and feet due to subcutaneous ecchymotic hemorrhages; petechial hemorrhages on visceral organs and in muscles; and blood-tinged oral and nasal discharges. In severely affectedbirds, greenish diarrhea is common. Birds that survive the fulminating infection may develop CNS involvement evident as torticollis, opisthotonos, or incoordination. The location and severity of microscopic lesions are highly variable and may consist of edema, hemorrhage, and necrosis in parenchymal cells of multiple visceral organs, skin, and CNS. Avian influenza, hemorrhagic skin, chicken Avian influenza, hemorrhagic skin, chicken

Avian influenza is an infectious disease of birds caused by
type A strains of the influenza virus. The disease occurs worldwide. While all
birds are thought to be susceptible to infection with avian influenza viruses,
many wild bird species carry these viruses with no apparent signs of harm.

Other bird species, including domestic poultry, develop
disease when infected with avian influenza viruses. In poultry, the viruses
cause two distinctly different forms of disease – one common and mild, the
other rare and highly lethal. In the mild form, signs of illness may be
expressed only as ruffled feathers, reduced egg production, or mild effects on
the respiratory system. Outbreaks can be so mild they escape detection unless
regular testing for viruses is in place.

In contrast, the second and far less common highly
pathogenic form is difficult to miss. First identified in Italy in 1878, highly
pathogenic avian influenza is characterized by sudden onset of severe disease,
rapid contagion, and a mortality rate that can approach 100% within 48 hours.
In this form of the disease, the virus not only affects the respiratory tract,
as in the mild form, but also invades multiple organs and tissues. The
resulting massive internal haemorrhaging has earned it the lay name of “chicken
Ebola”.

All 16 HA (haemagluttinin) and 9 NA (neuraminidase)
subtypes of influenza viruses are known to infect wild waterfowl, thus
providing an extensive reservoir of influenza viruses perpetually circulating
in bird populations. In wild birds, routine testing will nearly always find
some influenza viruses. The vast majority of these viruses cause no harm.

To date, all outbreaks of the highly pathogenic form of
avian influenza have been caused by viruses of the H5 and H7 subtypes. Highly
pathogenic viruses possess a tell-tale genetic “trade mark” or signature – a
distinctive set of basic amino acids in the cleavage site of the HA – that
distinguishes them from all other avian influenza viruses and is associated
with their exceptional virulence.

Not all virus strains of the H5 and H7 subtypes are highly
pathogenic, but most are thought to have the potential to become so. Recent
research has shown that H5 and H7 viruses of low pathogenicity can, after
circulation for sometimes short periods in a poultry population, mutate into
highly pathogenic viruses. Considerable circumstantial evidence has long
suggested that wild waterfowl introduce avian influenza viruses, in their low pathogenic
form, to poultry flocks, but do not carry or directly spread highly pathogenic
viruses. This role may, however, have changed very recently: at least some
species of migratory waterfowl are now thought to be carrying the H5N1 virus in
its highly pathogenic form and introducing it to new geographical areas located
along their flight routes.

Apart from being highly contagious among poultry, avian
influenza viruses are readily transmitted from farm to farm by the movement of
live birds, people (especially when shoes and other clothing are contaminated),
and contaminated vehicles, equipment, feed, and cages. Highly pathogenic
viruses can survive for long periods in the environment, especially when
temperatures are low. For example, the highly pathogenic H5N1 virus can survive
in bird faeces for at least 35 days at low temperature (4oC). At a much higher
temperature (37oC), H5N1 viruses have been shown to survive, in faecal samples,
for six days.

For highly pathogenic disease, the most important control measures
are rapid culling of all infected or exposed birds, proper disposal of
carcasses, the quarantining and rigorous disinfection of farms, and the
implementation of strict sanitary, or “biosecurity”, measures. Restrictions on
the movement of live poultry, both within and between countries, are another
important control measure. The logistics of recommended control measures are
most straightforward when applied to large commercial farms, where birds are
housed indoors, usually under strictly controlled sanitary conditions, in large
numbers. Control is far more difficult under poultry production systems in
which most birds are raised in small backyard flocks scattered throughout rural
or periurban areas.

When culling – the first line of defence for containing
outbreaks – fails or proves impracticable, vaccination of poultry in a
high-risk area can be used as a supplementary emergency measure, provided
quality-assured vaccines are used and recommendations from the World Organisation for Animal
Health (OIE) are strictly followed. The use of poor quality vaccines
or vaccines that poorly match the circulating virus strain may accelerate
mutation of the virus. Poor quality animal vaccines may also pose a risk for
human health, as they may allow infected birds to shed virus while still
appearing to be disease-free.

Apart from being difficult to control, outbreaks in
backyard flocks are associated with a heightened risk of human exposure and
infection. These birds usually roam freely as they scavenge for food and often
mingle with wild birds or share water sources with them. Such situations create
abundant opportunities for human exposure to the virus, especially when birds
enter households or are brought into households during adverse weather, or when
they share areas where children play or sleep. Poverty exacerbates the problem:
in situations where a prime source of food and income cannot be wasted,
households frequently consume poultry when deaths or signs of illness appear in
flocks. This practice carries a high risk of exposure to the virus during
slaughtering, defeathering, butchering, and preparation of poultry meat for
cooking, but has proved difficult to change. Moreover, as deaths of birds in
backyard flocks are common, especially under adverse weather conditions, owners
may not interpret deaths or signs of illness in a flock as a signal of avian
influenza and a reason to alert the authorities. This tendency may help explain
why outbreaks in some rural areas have smouldered undetected for months. The
frequent absence of compensation to farmers for destroyed birds further works
against the spontaneous reporting of outbreaks and may encourage owners to hide
their birds during culling operations.

During 2005, an additional and significant source of
international spread of the virus in birds became apparent for the first time,
but remains poorly understood. Scientists are increasingly convinced that at
least some migratory waterfowl are now carrying the H5N1 virus in its highly
pathogenic form, sometimes over long distances, and introducing the virus to
poultry flocks in areas that lie along their migratory routes. Should this new
role of migratory birds be scientifically confirmed, it will mark a change in a
long-standing stable relationship between the H5N1 virus and its natural
wild-bird reservoir.

Evidence supporting this altered role began to emerge in
mid-2005 and has since been strengthened. The die-off of more than 6000
migratory birds, infected with the highly pathogenic H5N1 virus, that began at
the Qinghai Lake nature reserve in central China in late April 2005, was highly
unusual and probably unprecedented. Prior to that event, wild bird deaths from
highly pathogenic avian influenza viruses were rare, usually occurring as
isolated cases found within the flight distance of a poultry outbreak.
Scientific studies comparing viruses from different outbreaks in birds have
found that viruses from the most recently affected countries, all of which lie
along migratory routes, are almost identical to viruses recovered from dead
migratory birds at Qinghai Lake. Viruses from Turkey’s first two human cases,
which were fatal, were also virtually identical to viruses from Qinghai Lake.

The outbreaks of highly pathogenic H5N1 avian influenza
that began in south-east Asia in mid-2003 and have now spread to a few parts of
Europe, are the largest and most severe on record. To date, nine Asian countries
have reported outbreaks (listed in order of reporting): the Republic of Korea,
Viet Nam, Japan, Thailand, Cambodia, the Lao People’s Democratic Republic,
Indonesia, China, and Malaysia. Of these, Japan, the Republic of Korea, and
Malaysia have controlled their outbreaks and are now considered free of the
disease. Elsewhere in Asia, the virus has become endemic in several of the
initially affected countries.

In late July 2005, the virus spread geographically beyond
its original focus in Asia to affect poultry and wild birds in the Russian
Federation and adjacent parts of Kazakhstan. Almost simultaneously, Mongolia
reported detection of the highly pathogenic virus in wild birds. In October
2005, the virus was reported in Turkey, Romania, and Croatia. In early December
2005, Ukraine reported its first outbreak in domestic birds. Most of these
newer outbreaks were detected and reported quickly. Further spread of the virus
along the migratory routes of wild waterfowl is, however, anticipated.
Moreover, bird migration is a recurring event. Countries that lie along the
flight pathways of birds migrating from central Asia may face a persistent risk
of introduction or re-introduction of the virus to domestic poultry flocks.

Prior to the present situation, outbreaks of highly
pathogenic avian influenza in poultry were considered rare. Excluding the
current outbreaks caused by the H5N1 virus, only 24 outbreaks of highly
pathogenic avian influenza have been recorded worldwide since 1959. Of these,
14 occurred in the past decade. The majority have shown limited geographical
spread, a few remained confined to a single farm or flock, and only one spread
internationally. All of the larger outbreaks were costly for the agricultural
sector and difficult to control.

Influenza viruses are normally highly species-specific, meaning that viruses
that infect an individual species (humans, certain species of birds, pigs,
horses, and seals) stay “true” to that species, and only rarely spill over to
cause infection in other species. Since 1959, instances of human infection with
an avian influenza virus have been documented on only 10 occasions. Of the
hundreds of strains of avian influenza A viruses, only four are known to have
caused human infections: H5N1, H7N3, H7N7, and H9N2. In general, human
infection with these viruses has resulted in mild symptoms and very little
severe illness, with one notable exception: the highly pathogenic H5N1 virus.

Of all influenza viruses that circulate in birds, the H5N1
virus is of greatest present concern for human health for two main reasons.
First, the H5N1 virus has caused by far the greatest number of human cases of
very severe disease and the greatest number of deaths. It has crossed the species
barrier to infect humans on at least three occasions in recent years: in Hong
Kong in 1997 (18 cases with six deaths), in Hong Kong in 2003 (two cases with
one death) and in the current outbreaks that began in December 2003 and were
first recognized in January 2004.

A second implication for human health, of far greater
concern, is the risk that the H5N1 virus – if given enough opportunities – will
develop the characteristics it needs to start another influenza pandemic. The
virus has met all prerequisites for the start of a pandemic save one: an
ability to spread efficiently and sustainably among humans. While H5N1 is
presently the virus of greatest concern, the possibility that other avian
influenza viruses, known to infect humans, might cause a pandemic cannot be
ruled out.

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,
if detected sufficiently early.

During the first documented outbreak of human infections
with H5N1, which occurred in Hong Kong in 1997, the 18 human cases coincided
with an outbreak of highly pathogenic avian influenza, caused by a virtually
identical virus, in poultry farms and live markets. Extensive studies of the
human cases determined that direct contact with diseased poultry was the source
of infection. Studies carried out in family members and social contacts of
patients, health workers engaged in their care, and poultry cullers found very
limited, if any, evidence of spread of the virus from one person to another.
Human infections ceased following the rapid destruction – within three days –
of Hong Kong’s entire poultry population, estimated at around 1.5 million birds.
Some experts believe that that drastic action may have averted an influenza
pandemic.

All evidence to date indicates that close contact with dead
or sick birds is the principal source of human infection with the H5N1 virus.
Especially risky behaviours identified include the slaughtering, defeathering,
butchering and preparation for consumption of infected birds. In a few cases,
exposure to chicken faeces when children played in an area frequented by
free-ranging poultry is thought to have been the source of infection. Swimming
in water bodies where the carcasses of dead infected birds have been discarded
or which may have been contaminated by faeces from infected ducks or other
birds might be another source of exposure. In some cases, investigations have been
unable to identify a plausible exposure source, suggesting that some as yet
unknown environmental factor, involving contamination with the virus, may be
implicated in a small number of cases. Some explanations that have been put
forward include a possible role of peri-domestic birds, such as pigeons, or the
use of untreated bird faeces as fertilizer. At present, H5N1 avian influenza
remains largely a disease of birds. The species barrier is significant: the
virus does not easily cross from birds to infect humans. Despite the infection
of tens of millions of poultry over large geographical areas since mid-2003,
fewer than 200 human cases have been laboratory confirmed. For unknown reasons,
most cases have occurred in rural and periurban households where small flocks
of poultry are kept. Again for unknown reasons, very few cases have been
detected in presumed high-risk groups, such as commercial poultry workers,
workers at live poultry markets, cullers, veterinarians, and health staff
caring for patients without adequate protective equipment. Also lacking is an
explanation for the puzzling concentration of cases in previously healthy
children and young adults. Research is urgently needed to better define the
exposure circumstances, behaviours, and possible genetic or immunological
factors that might enhance the likelihood of human infection.

Investigations of all the most recently confirmed human cases, in China,
Indonesia, and Turkey, have identified direct contact with infected birds as
the most likely source of exposure. When assessing possible cases, the level of
clinical suspicion should be heightened for persons showing influenza-like
illness, especially with fever and symptoms in the lower respiratory tract, who
have a history of close contact with birds in an area where confirmed outbreaks
of highly pathogenic H5N1 avian influenza are occurring. Exposure to an
environment that may have been contaminated by faeces from infected birds is a
second, though less common, source of human infection. To date, not all human
cases have arisen from exposure to dead or visibly ill domestic birds. Research
published in 2005 has shown that domestic ducks can excrete large quantities of
highly pathogenic virus without showing signs of illness. A history of poultry
consumption in an affected country is not a risk factor, provided the food was
thoroughly cooked and the person was not involved in food preparation. As no
efficient human-to-human transmission of the virus is known to be occurring anywhere,
simply travelling to a country with ongoing outbreaks in poultry or sporadic
human cases does not place a traveller at enhanced risk of infection, provided
the person did not visit live or “wet” poultry markets, farms, or other
environments where exposure to diseased birds may have occurred.

In many patients, the disease caused by the H5N1 virus follows an unusually
aggressive clinical course, with rapid deterioration and high fatality. Like
most emerging disease, H5N1 influenza in humans is poorly understood. Clinical
data from cases in 1997 and the current outbreak are beginning to provide a
picture of the clinical features of disease, but much remains to be learned.
Moreover, the current picture could change given the propensity of this virus
to mutate rapidly and unpredictably.

The incubation period for H5N1 avian influenza may be
longer than that for normal seasonal influenza, which is around two to three
days. Current data for H5N1 infection indicate an incubation period ranging
from two to eight days and possibly as long as 17 days. However, the
possibility of multiple exposure to the virus makes it difficult to define the
incubation period precisely. WHO currently recommends that an incubation period
of seven days be used for field investigations and the monitoring of patient
contacts.

Initial symptoms include a high fever, usually with a
temperature higher than 38oC, and influenza-like symptoms. Diarrhoea, vomiting,
abdominal pain, chest pain, and bleeding from the nose and gums have also been
reported as early symptoms in some patients. Watery diarrhoea without blood
appears to be more common in H5N1 avian influenza than in normal seasonal
influenza. The spectrum of clinical symptoms may, however, be broader, and not
all confirmed patients have presented with respiratory symptoms. In two
patients from southern Viet Nam, the clinical diagnosis was acute encephalitis;
neither patient had respiratory symptoms at presentation. In another case, from
Thailand, the patient presented with fever and diarrhoea, but no respiratory
symptoms. All three patients had a recent history of direct exposure to
infected poultry.

One feature seen in many patients is the development of
manifestations in the lower respiratory tract early in the illness. Many
patients have symptoms in the lower respiratory tract when they first seek
treatment. On present evidence, difficulty in breathing develops around five
days following the first symptoms. Respiratory distress, a hoarse voice, and a
crackling sound when inhaling are commonly seen. Sputum production is variable
and sometimes bloody. Most recently, blood-tinted respiratory secretions have
been observed in Turkey. Almost all patients develop pneumonia. During the Hong
Kong outbreak, all severely ill patients had primary viral pneumonia, which did
not respond to antibiotics. Limited data on patients in the current outbreak
indicate the presence of a primary viral pneumonia in H5N1, usually without
microbiological evidence of bacterial supra-infection at presentation. Turkish
clinicians have also reported pneumonia as a consistent feature in severe
cases; as elsewhere, these patients did not respond to treatment with
antibiotics.

In patients infected with the H5N1 virus, clinical
deterioration is rapid. In Thailand, the time between onset of illness to the
development of acute respiratory distress was around six days, with a range of
four to 13 days. In severe cases in Turkey, clinicians have observed
respiratory failure three to five days after symptom onset. Another common
feature is multiorgan dysfunction. Common laboratory abnormalities, include
leukopenia (mainly lymphopenia), mild-to-moderate thrombocytopenia, elevated
aminotransferases, and with some instances of disseminated intravascular
coagulation.

Limited evidence suggests that some antiviral drugs,
notably oseltamivir (commercially known as Tamiflu), can reduce the duration of
viral replication and improve prospects of survival, provided they are
administered within 48 hours following symptom onset. However, prior to the
outbreak in Turkey, most patients have been detected and treated late in the
course of illness. For this reason, clinical data on the effectiveness of
oseltamivir are limited. Moreover, oseltamivir and other antiviral drugs were
developed for the treatment and prophylaxis of seasonal influenza, which is a
less severe disease associated with less prolonged viral replication.
Recommendations on the optimum dose and duration of treatment for H5N1 avian
influenza, also in children, need to undergo urgent review, and this is being
undertaken by WHO.

In suspected cases, oseltamivir should be prescribed as
soon as possible (ideally, within 48 hours following symptom onset) to maximize
its therapeutic benefits. However, given the significant mortality currently
associated with H5N1 infection and evidence of prolonged viral replication in
this disease, administration of the drug should also be considered in patients
presenting later in the course of illness.

Currently recommended doses of oseltamivir for the
treatment of influenza are contained in the product
information at the manufacturer’s web site. The recommended dose of
oseltamivir for the treatment of influenza, in adults and adolescents 13 years
of age and older, is 150 mg per day, given as 75 mg twice a day for five days.
Oseltamivir is not indicated for the treatment of children younger than one
year of age.

As the duration of viral replication may be prolonged in
cases of H5N1 infection, clinicians should consider increasing the duration of
treatment to seven to ten days in patients who are not showing a clinical
response. In cases of severe infection with the H5N1 virus, clinicians may need
to consider increasing the recommended daily dose or the duration of treatment,
keeping in mind that doses above 300 mg per day are associated with increased
side effects. For all treated patients, consideration should be given to taking
serial clinical samples for later assay to monitor changes in viral load, to
assess drug susceptibility, and to assess drug levels. These samples should be
taken only in the presence of appropriate measures for infection control.

In severely ill H5N1 patients or in H5N1 patients with
severe gastrointestinal symptoms, drug absorption may be impaired. This
possibility should be considered when managing these patients.

Avian influenza: methods
for the disease control

Avian influenza, also known as bird flu, is a
highly contagious viral disease affecting mainly chickens, turkeys, ducks and
other birds.

While avian influenza caused by highly pathogenic
virus strains have sometimes been shown to infect man, this disease should not
be confused with human influenza, a common human disease. However, avian influenza
under certain circumstances could pose a serious threat to humans.

The OIE, through its experts and its world
network of Reference Laboratories and Collaborating Centres remain at the
disposal of all Member Countries requesting assistance in the defintion of
policies on diagnosis, control and eradication of the disease in animals.

The following information is meant to help
Governments and the Veterinary Services of Member Countries which are affected
by or which want to protect the territories from the disease :

Background information

Conclusions
and recommendations: FAO/OIE/WHO Expert Consultation on Avian Influenza,
Rome (Italy) 3-4 February 2004

Message from Dr Bernard Vallat, OIE Director General –
Meeting on Avian Infuenza in Thailand

Letter
addressed to the Honourable Prime Minister of Vietnam

The
use of vaccination as an option for the control of avian influenza (Ilaria
Capua & Stefano Marangon)

Provisional
Report of the Ad hoc Group on Avian Influenza (non official – to be
submitted to OIE International Committee in May 2004)

Safety of International Trade

– Actual
Avian Influenza Chapter (2003)

– Actual Newcastle
Disease Chapter (2003)

– Proposed
Chapter on Avian Influenza (non official – to be submitted to OIE
International Committee in May 2004)

Vaccines and Diagnostic Methods

– Avian
influenza chapter and Sampling
methods

– List
of OIE Reference Laboratories and other experts on avian influenza

Methods of Humane Killing and Carcass
Disposal

– Provisional
Report of the OIE Ad hoc Group on Humane Killing of animals

– Slaughter
of poultry for disease control purposes

– Provisional
Report of the OIE Ad hoc Group on the Slaughter of animals for human
consumption

– Provisional
Report of the OIE Ad hoc Group on Carcass Disposal

– Interim
Guidelines on protection of farmers and slaughterhouses workers (WHO)

Food Safety

– Risks for
consumers

Description of the disease

– Disease card

Guidelines for Control of the Disease

– Conclusions
and recommendations: FAO/OIE/WHO Expert Consultation on Avian Influenza,
Rome (Italy) 3-4 February 2004

– Extract
from IZSV Contingency Manual for Avian Influenza (Avian Influenza, Eds
Edizioni Tecnico Scientifiche, Bologna, Italy, 2000)