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A REPORT ON HOW CAN BIRD FLU BE DETECTED? Bird flu symptoms Although there have been few human cases to determine the exact incubation period of bird flu, it would be expected to be from three to 10 days. The symptoms of bird flu in humans are similar to those of regular influenza and include: • • • • •

Fever Sore throat Cough Headache Aching muscles.

Complications Of Bird flu Bird flu in humans can cause a range of serious and potentially fatal complications, including: • Eye infections • Pneumonia, including viral pneumonia • Acute respiratory distress • Inflammation of the brain and heart. Tell your doctor if you've been to a country where there is bird flu If you have recently returned from a country that had an outbreak of bird flu and you get flu symptoms, see your doctor immediately. When making the appointment, tell the clinic staff about your travel including any visits to markets, farms or anywhere else where birds were present. Influenza viruses can mutate Influenza viruses that infect animal species can mutate and infect humans. The human immune system may have no defences against viruses that previously only infected animals. That's why infection with these viruses can result in more severe disease in people. If the H5N1 bird flu virus were to mix with a human influenza virus, such a 'combined' virus could create a new human influenza virus that could spread rapidly. Health experts are concerned that the current bird flu affecting Asia could become a worldwide pandemic if the virus does mutate. The worst influenza pandemic in modern history was the Spanish flu, which occurred in 1918–19 and killed up to 50 million people. Measures to contain the spread of the current bird flu virus include identifying and culling affected poultry flocks, research into tests and vaccines, and rigorous quarantine practices. Treatment options Several antiviral medications used to treat human influenza are also effective for bird flu. These could be used if a person developed symptoms after possible exposure to bird flu, or to


prevent illness in a person who was in close contact with bird flu. Currently testing for bird flu vaccines is an ongoing process. At the moment, there is no need for people living in USA, or people making short visits to countries with cases of bird flu, to have antiviral medications. Americans living long-term in countries affected by bird flu should consider having a supply of antiviral medications in the home to use on medical advice should the situation change while they are away from the US. The Federal government is stockpiling Relenza and Tamiflu, two drugs that may be used in the treatment of human cases of bird flu. In the case of an outbreak in humans, these drugs would be used to maintain essential services, prevent transmission and provide treatment for people who are already ill. A vaccine against bird flu is in development, but is not currently available. The current influenza vaccines will not protect humans against bird flu. However, people who may be exposed to bird flu should consider being vaccinated against human influenza viruses to reduce the risk of the viruses 'mixing' to form a new flu strain. Advice for travelers Be aware of the risk of bird flu if you are travelling to a country where outbreaks are occurring. Suggestions include: • Avoid contact with wild or domesticated birds such as chickens, ducks and geese. Don't go to farms or market places, since these are the primary carriers of bird flu • Stop young children from putting contaminated objects or their own fingers into their mouths. • Eggshells may be contaminated with bird faeces. Wash eggs thoroughly before breaking and wash your hands thoroughly after handling eggs. • Avoid foods that contain uncooked egg, such as mayonnaise. • Wash hands, chopping boards and utensils thoroughly after handling raw poultry. • Cook poultry at high temperatures. Cooking temperatures of 80°C or higher destroy the bird flu virus in about 60 seconds. Control of avian influenza A(H5N1): public health concerns 10 February 2004 The current outbreaks of highly pathogenic H5N1 avian influenza in poultry in parts of Asia have had immediate and severe consequences for the agricultural sector.1 Human cases, with a high fatality, have been reported in two countries, Viet Nam and Thailand, with very widespread outbreaks in poultry. It can be anticipated that human cases will also be detected in other countries where outbreaks in poultry are rapidly spreading. The number of human cases presently detected is very small compared with the large number of infected birds distributed over a wide geographical area. This suggests that the H5N1 virus strain may not easily infect humans.


To date, no human-to-human transmission is known to have occurred. However, the continuing presence of infection in poultry may also create opportunities for the emergence of a new influenza virus subtype with a capacity to spread easily among humans, thus marking the start of an influenza pandemic. Should this rare event occur (three pandemics occurred during the previous century), it would immediately have serious consequences for human health throughout the world. For this reason, public health concerns about the present H5N1 situation must be given the highest priority when weighing the immediate and measurable economic losses in animals against possible yet unpredictable consequences for humans. Several other diseases in animals can be transmitted to humans. Experience with such diseases, known as “zoonoses”, has shown that strict measures on animal health, imposed by the need to protect human health, helped rebuild consumer confidence.2 Recent experience has also shown that measures for the control of zoonotic diseases, aimed at halting further spread in animals and minimizing economic losses, need to be closely coordinated with measures that minimize the longer-term risks to human health. In the present situation, measures aimed at eliminating the disease in poultry will also reduce the presence of the virus in the environment and thus reduce opportunities for human exposures and infections. These measures must be carried out urgently, giving highest priority to the protection of human health. Previous outbreaks of highly pathogenic avian influenza associated with human infections occurred in areas, such as Hong Kong and the Netherlands, with industrial poultry production and well developed health and agricultural infrastructures. Even so, elimination of infection in poultry was a complex, difficult, and costly undertaking. Both outbreaks were eventually controlled through immediate culling of infected flocks, quarantine and disinfection of farms, strict biosecurity, restrictions on the movement of animals, and compensation for farmers. The present situation is different. Control of outbreaks of highly pathogenic avian influenza is known to be especially difficult in areas where poultry range freely. In several affected countries, up to 80% of the total poultry population is raised in small backyard farms. Most rural families keep a small free-range flock. Given these features of the present situation there is potential that the H5N1 virus could become established in bird populations in this geographical region and possibly spread to other parts of the world. This was one of several conclusions reached during a joint FAO/OIE/WHO technical consultation on the control of avian influenza, held in Rome from 3–4 February. No single blueprint for control in animals, and thus reduction of risks for humans, is available. Over the past four decades, only 18 outbreaks of highly pathogenic avian influenza, most caused by strains other than H5N1, have occurred throughout the world. Existing evidence will not suffice to provide universally applicable recommendations for a rapid and effective response in affected countries. Control measures must be tailored to each country’s unique epidemiological situation and unique capacity, with health and agricultural sectors working hand-in-hand. Agricultural authorities face the immediate challenge of rapidly eliminating the H5N1 reservoir in poultry. Authorities in all affected countries need to work together in a coordinated way


Transparency in reporting of human and animal disease is absolutely essential. Despite the uncertainties, experts fully agree that immediate culling of infected and exposed birds is the first line of defence for both the protection of human health and the reduction of further losses in the agricultural sector. Other measures, such as the vaccination of healthy flocks, may play a supportive role in some cases when undertaken in conjunction with measures for preventing further spread of infection. WHO has repeatedly stressed the need to ensure that culling is carried out in a way that does not fuel more human cases. and that vaccination of poultry should not lead to the dropping of vigilance or compromise other necessary control measures. In responding to the situation, WHO emphasises three strategic goals: to avert an influenza pandemic, to control the present human outbreaks and prevent further spread, and to conduct the research needed for better preparedness and response, including the immediate development of a new vaccine for humans against H5N1. WHO has issued a series of technical guidelines aimed at minimizing the risk of further human cases and facilitating a coordinated international response. 1

Highly pathogenic avian influenza is categorized by OIE as a “list A” disease. List A includes transmissible diseases “which have the potential for very serious and rapid spread, irrespective of national borders, which are of serious socio–economic or public health consequence and which are of major importance in the international trade of animals and animal products.” 2

One example is the spread of bovine spongiform encephalopathy, or “mad cow disease”, in cattle, which led to the emergence of a rare yet invariably fatal new disease in humans. History of Avian Flu The Avian Flu disease has captured considerable international attention over the past year with serious epidemics of this disease affecting Japan, South Korea, and areas of South-east Asia earlier this year. Now considered a pandemic, serious outbreaks of avian influenza had also affected the Netherlands, Belgium, and Germany in 2003. Avian flu had also been reported in Australia, Pakistan, Italy, Chile, and Mexico. The impact of this serious disease has been disruptive to the poultry industries as millions of chickens, geese, and turkeys were slaughtered to prevent further transmission of this highly contagious disease. Besides its devastating effect on domestic poultry, Avian Flu has received unprecedented publicity because of what occurred in Hong Kong in 1997. Before this time, Avian flu was thought to infect birds only, however, a different strain of Avian Flu virus was detected in humans, marking the first time that Avian Flu was transmitted to humans. During this outbreak, 18 people were hospitalized and 6 of them died. To control the outbreak, authorities killed about 1.5 million chickens to remove the source of the virus. Earlier this year in January, a major outbreak of Avian influenza surfaced again in Vietnam’s and Thailand's poultry industry. Within a few short weeks, the disease had spread to ten countries and regions in Asia, including Indonesia, South Korea, Japan and China. Over 50 million chickens, ducks, geese, and turkey were slaughtered in an intensive effort to stop the disease from spreading any further. The outbreak was then contained in March.


Unfortunately, this outbreak took a considerable toll on human lives. There were 34 people infected with the Avian Flu in Vietnam and Thailand, of which 23 of them tragically died. Though scientists determined that the spread of the Avian flu virus from birds to humans are rare occurrences, they were also quick to express grave caution that this problem could become significantly worse if the virus mutated into a more lethal form, or a form that could pass easily from humans to humans. The World Health Organization (WHO) is particularly concerned about the Avian virus' potential to swap genes with a common flu virus, creating a lethal form of the virus that could spread around the globe within months. Avian Flu was first recorded in Italy more than 100 years ago in 1878. As the cause of massive poultry epidemics, this disease was then known as “Fowl Plague”. This disease reared its ugly head in the United States in 1924-25, and then again in 1929. In 1955, it was determined that the virus causing Fowl Plague was one of the influenza viruses. All influenza viruses affecting domestic animals (equine, swine, avian) belong to Type A, and Type A influenza virus is the most common type producing serious epidemics in humans. Types B and C do not affect domestic animals. There are two forms of Influenza A viruses occurring worldwide – (i) highly pathogenic and (ii) mildly pathogenic. The outbreaks in Hong Kong, and those that were found reported recently are caused by the Highly Pathogenic Avian Influenza A virus (HPAI – subtypes H5 and H7). It is a form of this virus that has the ability to be transmitted to humans. Although our understanding of Avian Flu is relatively limited, the recent outbreaks have stimulated research all around the world to further our knowledge of this important disease and virus. History of Avian Influenza Confirmed instances of avian influenza viruses infecting humans since 1997 include : 1997: In Hong Kong, avian influenza A (H5N1) infected both chickens and humans. This was the first time an avian influenza virus had ever been found to transmit directly from birds to humans. During this outbreak, 18 people were hospitalized and 6 of them died. 1999: In Hong Kong, cases of avian influenza A (H9N2) were confirmed in 2 children. Both patients recovered, and no additional cases were confirmed. The evidence suggested that poultry was the source of infection and the main mode of transmission was from bird to human. 2003: Two cases of avian influenza A (H5N1) infection occurred among members of a Hong Kong family that had traveled to China. One person recovered, the other died. How or where these 2 family members were infected was not determined. Another family member died of a respiratory illness in China, but no testing was done. No additional cases were reported. 2003: Avian influenza A (H7N7) infections among poultry workers and their families were confirmed in the Netherlands during an outbreak of avian flu among poultry. More than 80 cases of H7N7 illness were reported (the symptoms were mostly confined to eye infections, with some respiratory symptoms), and 1 patient died (in a veterinarian who had visited an affected farm). There was evidence of some human-to-human transmission.


2003: H9N2 infection was confirmed in a child in Hong Kong. The child was hospitalized but recovered. Diagnosis of Avian Influenza

Clinical signs and post-mortal lesions may be indicative of avian influenza infection. Virus isolation is needed for a definitive diagnosis. Laboratory Diagnosis Samples 1. Identification of the agent o Live birds – tracheal swabs and cloacal swabs or faeces o Dead birds – organs and faeces 2. Serology o Clotted blood samples or o serum Procedures Identification of the Agent Inoculation of 9-11-day-old embryonated chicken eggs followed by: 1. Haemagglutination immunodiffusion test to confirm the presence of influenza A virus 2. Subtype determination with monospecific antisera 3. Strain virulence evaluation: evaluation of the intravenous pathogenicity index (IVPI) in 4-8-week-old chickens Serology Tests available: ELISA: • • •

Detects antibodies to all AI virus, does not distinguish subtypes Only suitable for testing chicken and turkey serum Within 1 week of infection, antibodies are detected in more than half the specimens.


AGID (Agar Gel Immunodiffusion test) • •

As for ELISA does not distinguish AI subtypes Within 1 week of infection, antibodies are detected in more than half the specimens.

HI (Haemagglutination Inhibition test) • • • •

Serotype specific test Test available for each H subtype HI titres are positive a few days later than ELISA or AGID, titres persist long after infection Standard test for all avian species

IFT (Immunofluoresence test) • •

Able to detect antibodies to specific N-subtype Can be used to detect infection in vaccinated birds if a heterologous vaccine is used. Read more in Monitoring.

RT-PCR (Reverse-transcriptase polymerase chain reaction) • •

Able to detect influenza virus at very low levels The presence of subtype H5 or H7 can be confirmed by using H5 or H7 specific primers.

Transmission of Influenza A Viruses Between Animals and People Avian Flu: The Virus & its Spread Transmission Between Animal & People Influenza A viruses have infected many different animals, including ducks, chickens, pigs, whales, horses, and seals. However, certain subtypes of influenza A virus are specific to certain species, except for birds, which are hosts to all known subtypes of influenza A. Subtypes that have caused widespread illness in people either in the past or currently are H3N2, H2N2, H1N1, and H1N2. H1N1 and H3N2 subtypes also have caused outbreaks in pigs, and H7N7 and H3N8 viruses have caused outbreaks in horses. Influenza A viruses normally seen in one species sometimes can cross over and cause illness in another species. For example, until 1998, only H1N1 viruses circulated widely in the U.S. pig population. However, in 1998, H3N2 viruses from humans were introduced into the pig population and caused widespread disease among pigs. Most recently, H3N8 viruses from horses have crossed over and caused outbreaks in dogs. Avian influenza A viruses may be transmitted from animals to humans in two main ways: • •

Directly from birds or from avian virus-contaminated environments to people. Through an intermediate host, such as a pig.


Influenza A viruses have eight separate gene segments. The segmented genome allows influenza A viruses from different species to mix and create a new influenza A virus if viruses from two different species infect the same person or animal. For example, if a pig were infected with a human influenza A virus and an avian influenza A virus at the same time, the new replicating viruses could mix existing genetic information (reassortment) and produce a new virus that had most of the genes from the human virus, but a hemagglutinin and/or neuraminidase from the avian virus. The resulting new virus might then be able to infect humans and spread from person to person, but it would have surface proteins (hemagglutinin and/or neuraminidase) not previously seen in influenza viruses that infect humans. This type of major change in the influenza A viruses is known as antigenic shift. Antigenic shift results when a new influenza A subtype to which most people have little or no immune protection infects humans. If this new virus causes illness in people and can be transmitted easily from person to person, an influenza pandemic can occur. It is possible that the process of genetic reassortment could occur in a human who is coinfected with avian influenza A virus and a human strain of influenza A virus. The genetic information in these viruses could reassort to create a new virus with a hemagglutinin from the avian virus and other genes from the human virus. Theoretically, influenza A viruses with a hemagglutinin against which humans have little or no immunity that have reassorted with a human influenza virus are more likely to result in sustained human-to-human transmission and pandemic influenza. Therefore, careful evaluation of influenza viruses recovered from humans who are infected with avian influenza is very important to identify reassortment if it occurs. Although it is unusual for people to get influenza virus infections directly from animals, sporadic human infections and outbreaks caused by certain avian influenza A viruses and pig influenza viruses have been reported. (For more information see Avian Influenza Infections in Humans .) These sporadic human infections and outbreaks, however, rarely result in sustained transmission among humans. Avian Influenza: Introduction (Fowl plague)

Avian influenza (AI) viruses infect domestic poultry and wild birds. In domestic poultry, AI viruses are typically of low pathogenicity (LP), causing subclinical infections, respiratory disease, or drops in egg production. However, a few AI viruses cause severe systemic infections with high mortality. This highly pathogenic (HP) form of the disease has historically been called fowl plague. In most wild birds, AI viral infections are subclinical. Etiology: Avian influenza viruses are type A orthomyxoviruses characterized by antigenically homologous nucleoprotein and matrix internal proteins, which are identified by serology in agar gel immunodiffusion (AGID) tests. AI viruses are further divided into 15 hemagglutinin (H1-15) and 9 neuraminidase (N1-9) subtypes based on hemagglutinin inhibition and neuraminidase inhibition tests, respectively. Most AI viruses (H1-15 subtypes) are of LP, but some of the H5 and H7 AI viruses are HP for chickens, turkeys, and related gallinaceous domestic poultry.


Epidemiology and Transmission: LP viruses are distributed worldwide and are recovered frequently from clinically normal shorebirds and migrating waterfowl. Occasionally, LP viruses are recovered from imported pet birds and ratites. The viruses may be present in backyard flocks and other birds sold through live-poultry markets, but most commercially raised poultry in developed countries are free of AI viruses. The HP viruses arise from mutation of some H5 and H7 LP viruses and cause devastating epizootics. Depopulation and quarantine programs are used to quickly eliminate the HP viruses. The incubation period is highly variable and ranges from a few days to 1 wk. Transmission between individual birds is by ingestion or inhalation. Experimentally, cats have been infected with 1 strain of H5N1 Asian HP AI following respiratory exposure, ingestion of infected chickens, or contact with infected cats. Potentially, domestic house cats could serve as a transmission vector between farms, but the ability of other AI viruses, including other H5N1 strains, to infect cats is unknown. Transmission between farms is the result of breaches in biosecurity practices, principally by movement of infected birds or contaminated feces and respiratory secretions on fomites such as equipment or clothing. Airborne dissemination may be important over limited distances. Clinical Findings and Lesions: Clinical signs, severity of disease, and mortality rates vary depending on AI virus strain and host species. Low Pathogenicity AI Viruses: These AI viruses typically produce respiratory signs such as ocular and nasal discharge and swollen infraorbital sinuses. Sinusitis is common in domestic ducks, quail, and turkeys. Lesions in the respiratory tract typically include congestion and inflammation of the trachea and lungs. In layers and breeders, there may be decreased egg production or fertility, ova rupture (evident as yolk in the abdominal cavity) or involution, or mucosal edema and inflammatory exudates in the lumen of the oviduct. Some layer and breeder chickens may have acute renal failure and visceral urate deposition (visceral gout). The morbidity and mortality is usually low unless accompanied by secondary bacterial or viral infections or aggravated by environmental stress factors. 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 affected


birds, 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

Diagnosis: AI viruses can be readily isolated from tracheal and cloacal swabs. They grow well in the allantoic sac of embryonating chicken eggs and agglutinate RBC. The hemagglutination is not inhibited by Newcastle disease or other paramyxoviral antiserum. AI viruses are identified by demonstrating the presence of 1) influenza A matrix or nucleoprotein antigens using AGID or other suitable immunoassays, or 2) viral RNA using an influenza A specific RT-PCR tests. Differential Diagnosis: LP AI must be differentiated from other respiratory diseases or causes of decreased egg production including: 1) acute to subacute viral diseases such as infectious bronchitis, infectious laryngotracheitis, lentogenic Newcastle disease, and infections by other paramyxoviruses; 2) bacterial diseases such as mycoplasmosis, infectious coryza, ornithobacteriosis, turkey coryza, and the respiratory form of fowl cholera; and 3) fungal diseases such as aspergillosis. HP AI must be differentiated from other causes of high mortality such as velogenic Newcastle disease, peracute septicemic fowl cholera, heat exhaustion, and severe water deprivation. Prevention and Treatment: Vaccines can prevent clinical signs and death. Furthermore, viral replication and shedding from the respiratory and GI tracts may be reduced in vaccinated birds. Specific protection is achieved through autogenous virus vaccines or from vaccines prepared from AI virus of the


same hemagglutinin subtype. Antibodies to the viral neuraminidase antigens may provide some protection. Currently, only inactivated whole AI virus and recombinant fowlpox-AI-H5 vaccines are licensed in the USA. The use of AI vaccine requires approval of the state veterinarian. In addition, use of H5 and H7 AI vaccines in the USA requires USDA approval. Treating LP-affected flocks with broad-spectrum antibiotics to control secondary pathogens and increasing house temperatures may reduce morbidity and mortality. Treatment with antiviral compounds is not approved or recommended. Suspected outbreaks should be reported to appropriate regulatory authorities. Zoonotic Risk: Avian influenza viruses exhibit host adaptation and rarely infect humans, usually as isolated individual cases without human-to-human transmission. In the 1997 Hong Kong outbreak, the risk factor for human infection was direct contact with infected poultry, but not the handling, cooking, or consumption of poultry meat. In 2004, HP AI of strain H5N1 infected poultry and wild birds in 9 Asian countries. In Thailand and Vietnam, 37 human cases were confirmed, with a case fatality rate of 68%. THE DISEASE IN BIRDS 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. THE ROLE OF MIGRATORY BIRDS 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. COUNTRIES AFFECTED BY OUTBREAKS IN BIRDS 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. THE DISEASE IN HUMANS History and epidemiology. 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 freeranging 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. Assessment of possible cases. 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. Clinical features 1. 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)

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