Causative agent
Avian influenza (AI) is caused by a type A Orthomyxovirus. Multiple serotypes (strains) of the AI virus exist and are classified based on relative numbers of hemagglutinin (H) and neuraminidase (N) surface antigens (e.g., H7N2, H5N1). Avian influenza viruses may be of low pathogenicity (LPAI) or high pathogenicity (HPAI) in birds. Most AI virus strains are LPAI and typically cause no to few clinical signs in infected birds. Low pathogenicity AI virus strains, however, are capable of mutating under field conditions into HPAI viruses, and some highly virulent strains of AI have evolved from milder strains after serial passage through poultry populations.

Natural distribution
Most domestic and wild bird species appear to be susceptible to AI. Waterfowl (including geese, ducks, swans, and sea and shore birds) throughout the world carry the virus, but clinical signs of disease are usually mild or not evident. Mortalities do occasionally occur. Infections in poultry may be more severe, and turkeys are more commonly infected than chickens. Pigs have been implicated in the epidemiology of infection in turkeys when production facilities are located in close proximity. An avian source of the H5N1 strain has been associated with severe human disease and death in Asia.

In addition to wild and domestic birds and poultry, pigs, and humans, we know that cats, dogs, palm civets, cynomolgus macaques, New Zealand white rabbits, stone martens, tigers, leopards, ferrets and rats can become infected with the H5N1 avian influenza virus. The avian influenza A (H5N1) virus that emerged in Asia in 2003-2004 is evolving and it is possible that other mammals may be susceptible to infection as well.

Transmission
Waterfowl serve as a reservoir of AI virus and may be a source for original introduction of the disease into poultry flocks. Another source may be from movement of infected poultry and poultry products. Infected birds shed the virus in oculonasal discharges and feces, and contaminated drinking water is commonly implicated as the source of infection. Once introduced into a flock, infected birds, contaminated equipment, insects, rodents, and personnel have all been implicated in the spread of the virus within the flock and between flocks. When birds are in close proximity and air movement is conducive, airborne transmission can occur. Although virus can be recovered from the yolk, shell, and albumin of eggs, vertical transmission has not been demonstrated. Incubation period is usually 3 to 7 days.

Exposure of poultry to migratory waterfowl and international movement of poultry, farm equipment, and people increase risk for introducing HPAI into U.S. poultry flocks. Live-bird markets are a reservoir of infection because they serve as a focal point for gathering and housing many species of birds.

Fortunately, transmission of H5N1 avian influenza virus to humans is rare. Bird-to-human transmission most often occurs when particles from contaminated feces are inhaled. Proper handling and cooking of meat and eggs provides protection against contracting avian influenza, as well as other viruses and bacteria such as Salmonella and Campylobacter. Although human-to-human transmission is theoretically possible, so far there are only a few cases where this is thought to have occurred. In those cases, human-to-human transmission did not continue beyond the immediate contacts of the primary case.

At the present time, natural transmission of H5N1 avian influenza to other mammals has been associated with outbreaks in wild or domestic birds and ingestion of raw infected meat. Cats in a laboratory setting were shown to be able to spread the virus to other cats, but it is not known whether this would occur under natural conditions. Dogs infected experimentally with the virus exhibited no associated disease. In late August 2006, a dog in Thailand was reported to have developed H5N1 HPAI after eating infected ducks. The details of the case have not yet been made available. Additional information will be provided as it becomes available.

Clinical signs
The clinical course of AI in birds ranges from mild disease to rapidly fatal, and depends on the age and species of the bird affected, husbandry practices, the pathogenicity of the virus strain, and environmental factors. In some flocks, the only evidence of infection is seroconversion (i.e., birds develop a detectable antibody titer to AI antigen).

Avian influenza can manifest as respiratory, enteric, reproductive, or neurologic disease. Associated clinical signs may include decreased egg production; soft-shelled or misshapen eggs; swelling of the head, eyelids, comb, wattles, and hocks; cyanosis of the wattles, combs, and legs; clear, mucopurulent, or blood-tinged nasal discharge; coughing; incoordination; diarrhea; ruffled feathers; depression; inappetence; petechiation (pinpoint hemorrhages) of the feet and shanks; and respiratory distress.

Because the clinical signs of AI are similar to those of other avian diseases, AI may be confused with infectious laryngotracheitis, infectious bronchitis, fowl cholera, E. coli and Newcastle disease.

Initial signs of H5N1 infection in people are usually similar to signs associated with seasonal influenza, including fever (usually greater than 100°F), malaise, nasal discharge, laryngitis, coughing, and body aches. Avian influenza H5N1 infection, however, differs in that there is generally a rapid onset of lower respiratory tract disease and almost all patients develop pneumonia that does not respond to antimicrobials. The spectrum of clinical signs observed in patients to date is broad and includes encephalitis, chest pain, bleeding from the nose and gums, and gastrointestinal signs (vomiting, watery diarrhea, and abdominal pain). The clinical course is aggressive and the fatality rate high.

Clinical signs in other mammalian species, such as cats and dogs, have not been well described.

Diagnosis
Whereas clinical signs may be suggestive of AI, diagnosis is confirmed through serologic testing and virus isolation and identification. When attempting to identify the disease in poultry flocks, serum samples from several birds should be submitted for serologic testing. Avian influenza virus may be isolated from tissue samples (trachea, lung, spleen, cloaca, and brain), tracheal or cloacal swabs, or fecal samples. Multiple specimens from multiple birds should be submitted to a qualified laboratory because many samples fail to yield virus. Determination of virulence for a particular strain requires virus isolation and subsequent controlled laboratory challenge of healthy chickens. Strains determined to be highly pathogenic (HPAI), as well as H5 and H7 subtypes that are not HPAI, must be reported to the U.S. Department of Agriculture.

Findings on necropsy vary with age of bird, species, and pathogenicity of the virus; however, typical lesions include subcutaneous edema of the head and neck, congestion and petechiation of the conjunctivae, excess mucous or hemorrhage in the trachea, congestion and ureate deposits in the kidneys, and petechiation of the keel, proventriculus, gizzard, intestines, abdominal fat, and peritoneum. The ovaries of laying hens may be hemorrhagic or necrotic, and the peritoneal cavity may be filled with yolk from ruptured eggs. The latter may lead to peritonitis and air sacculitis in birds that survive for longer periods. Often only dehydration and severe muscular congestion are found in young birds or those that die of peracute disease.

Prevention and control
Appropriate biosecurity practices are key to preventing infection with AI viruses. All-in, all-out flock management, with thorough cleaning and disinfection between flocks, can prevent spread of virus from one flock to another. Poultry flocks should not be allowed to come in contact with wild or migratory birds, and should be kept away from any source of water that may have been contaminated by wild birds. Personnel and equipment entering and leaving facilities must be appropriately disinfected on entry and exit, and should not be exchanged between facilities.

Producers and dealers utilizing live-bird markets must be especially cautious. Avian influenza can be introduced into these markets by infected birds or contaminated crates and trucks. Once the virus is established in the market, movement of birds, crates, or trucks from a contaminated market can spread the virus to other farms and markets. Protective measures that may prevent spread of AI include use of plastic, rather than wooden, crates; meticulous removal of manure, feathers and other debris from floors; appropriate cleaning and disinfection of equipment and vehicles; segregating birds by lots; and comprehensive cleaning and disinfection of premises after every day of sale. Birds not sold at the market should not be returned to the farm.

Mild forms of AI have been controlled in commercial chicken and turkey flocks through vaccination (autogenous) and strict quarantine. For HPAI, strict quarantine and rapid depopulation of infected flocks is the only approach found to be effective in stopping spread of the virus. Vaccination to control HPAI (H5N1) in Asia has been initiated.

In January 2006, the U.S. commercial chicken industry started a voluntary program where participating companies will test each flock on the farm before it is sent to slaughter. Any flock found to have avian influenza of the H5 or H7 type will be humanely euthanatized and not used for food. Additionally, active planning began for surveillance for avian influenza virus in zoos in the United States.

Treatment
Treatment for AI has not been effective and prognosis for flocks infected with HPAI is poor. Morbidity and mortality rates approach 100% within 2 weeks of onset of illness. Good husbandry and nutrition may assist birds in mounting an appropriate immune response and antibiotics may prevent secondary infections. Laying hens that survive infection with AI may not return to normal production for several weeks. Recovered flocks continue to intermittently shed virus and appropriate precautions and surveillance should be undertaken. Once an infected flock has been removed, the facility and equipment should be thoroughly cleaned and disinfected.

Adminstration of oseltamivir (Tamiflu) or zanamivir (Relenza) has been documented and approved for reducing duration of illness in human cases of influenza A; however, data regarding the efficacy of these antiviral agents against the H5N1 virus is limited.

Treatment for other species is symptomatic. Currently available antiviral drugs are approved for use in humans only and little is known about their use in other species. Veterinarians who use approved drugs in a manner that is not in accord with approved label directions (e.g., use of an antiviral drug only approved for use in humans) must follow the federal extralabel drug use regulations of the Animal Medicinal Drug Use Clarification Act (AMDUCA). Because of their potential importance in treating associated human disease, use of oseltamivir and zanamivir to treat avian influenza in non-human species has been discouraged and the FDA has banned extralabel use in poultry (chickens, turkeys, and ducks).

Decontamination
Avian influenza viruses are sensitive to most detergents and disinfectants, and heating and drying will readily inactivate them. Organic material, such as feces, will protect AI virus from inactivation, and active virus may be recovered from these sources for up to 105 days. Facilities and equipment should be cleaned and disinfected after infected flocks are removed, and poultry litter or manure should be composted before further use.

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