Avian influenza: An emerging feline threat?

Many researchers and health officials are concerned about the potential for an influenza pandemic caused by avian influenza virus. Outbreaks of a highly pathogenic strain of influenza have occurred recently in domestic and wild-bird populations in several Asian countries. Incidents of transmission of avian influenza to people have been associated with these outbreaks. In July, the disease arrived in Russia and Central Asia, leaving health officials concerned about the spread of avian influenza to western Europe.1 Avian influenza also has been transmitted to a few domestic and nondomestic cats in Thailand, generally through contact with and ingestion of carcasses of infected poultry.

Margaret C. Barr, DVM, PhD

THE ORIGINS OF A POSSIBLE PANDEMIC

The three major human influenza pandemics of the 20th century have been associated with avian influenza cross-overs into the human population.2 The Spanish flu of 1918 killed between 20 and 50 million people worldwide. The virus responsible for the pandemic appears to have been an avian influenza virus that mutated to become highly pathogenic and easily transmitted from person to person. The 1957 Asian flu outbreak was caused by a virus carrying both avian and human influenza genes. The Hong Kong flu pandemic of 1968 was similarly caused by a virus with a combination of avian and human influenza genes.2

Since 2003, a strain of virus known as H5N1 has been responsible for outbreaks of avian influenza in domesticated poultry and wild ducks in southeastern and central Asia, resulting in high morbidity and mortality. An estimated 100 million birds have been affected in these outbreaks, and standard control procedures have not effectively controlled the spread of disease.3 A particular cause for alarm is that the H5N1 virus has infected several people who had contact with sick birds, including a disproportionate number of children. Of 89 confirmed cases in people in 2004 and the first three months of 2005, 52 resulted in death.4 The extent of milder infection and disease in the human population is unknown, but current evidence suggests that this influenza strain is highly pathogenic in people. A recent report also suggests that person-to-person spread of the virus has occurred in at least one instance.5 The virus appears to be resistant to two major anti-influenza therapeutic drugs, amantadine and rimantadine.4

If the current circulating avian influenza virus undergoes mutations that allow it to infect people easily or if it recombines with human influenza virus, the likelihood of another influenza pandemic is great. People have no immunologic memory of this influenza virus strain, so the entire world population would be at risk in an outbreak. This is also true for other mammalian species susceptible to influenza virus infections, including pigs, horses, some marine mammals, and cats.

THE VIROLOGY OF INFLUENZA

Influenza viruses belong to the Orthomyxoviridae family. An understanding of their genetic composition is critical for understanding how pandemics—or panzootics—occur.

Structure and classification

Influenza viruses are enveloped, single-stranded RNA viruses. Their genome is composed of eight segments, with each segment encoding one or occasionally two proteins. The segments that get the most attention are the hemagglutinin (HA) and neuraminidase (NA) genes that encode proteins found on the viral envelope.2,6 The HA protein is responsible for cell receptor binding and determines the type of cells that can be infected, while the NA protein is involved in the release of nascent virus from infected cells. Fifteen different HA antigens, designated H1 through H15, and nine different NA antigens, designated N1 through N9, have been characterized.

Influenza virus strains are usually identified by their HA and NA subtypes. For example, the Spanish flu virus of 1918 was an H1N1 virus. Different species of animals tend to harbor different influenza virus strains. Equine influenza viruses are usually H3N8 or H7N7 derivatives, human and swine influenza viruses are often H3N2 subtypes, and H2N2 is a common avian influenza virus.2,6

Antigenic drift and shift

Influenza viruses are famous for their ability to change quickly and evade the collective immunity of a population of animals or people. This rapid evolution is accomplished in two main ways: antigenic drift and antigenic shift.

Antigenic drift refers to point mutations that occur during virus replication that result in changes in the encoded protein sequences. These changes can result in an inability of an animal's immune system to recognize the protein, even if the animal was previously exposed to the parent virus. In this case, the progeny virus is still considered to have the same subtype (e.g. H3N8), but it has changed enough to infect previously immune animals or even animal species that were not susceptible to infection with the parent virus. Antigenic drift within an avian influenza virus was likely responsible for the 1918 human influenza pandemic.2,6

Antigenic shift refers to gene segments from one influenza virus recombining with gene segments from another influenza virus. For this to occur, a single host cell in an animal must be infected by two different strains of virus. After dual infection of the cell occurs, both viruses begin to replicate, and gene segments from both viruses are packaged in various combinations in virus particles. This process is called genetic reassortment.2,6 Pigs are susceptible to both avian and human influenza virus infections, so they can serve as intermediate hosts for the formation of new viruses containing both avian and human influenza genes (Figure 1). Reassortment of avian and human influenza virus genes, and the resulting antigenic shift, accounted for the 1957 and 1968 human influenza pandemics.

Figure 1. Genetic reassortment of human and avian influenza viruses has occurred in pigs and is thought to have caused influenza pandemics in 1957 and 1968. It is unclear whether cats might also serve as a vessel for reassortment.

A recent news report in Nature stated that a large proportion of the pig population in Indonesia is infected with avian influenza virus H5N1 without signs of disease.7 Concurrent introduction of a human influenza virus into Indonesian swine could set up the ideal situation for genetic reassortment. This type of reassortment can occur anywhere in the world. In the United States, recent outbreaks of respiratory disease in pigs have been caused by influenza viruses formed through genetic reassortments of avian, swine, and human influenza viruses.8

WHAT DOES THIS MEAN TO FELINE PRACTITIONERS?

Historically, cats have been considered to be resistant to influenza virus infections. Cats can be experimentally infected with human H3N2 virus, but the infection is usually subclinical.9 Although cats live in close contact with people, feline influenza outbreaks have not been recognized. Whether human-to-cat transmission is possible is unknown, but it clearly has not been associated with disease in the past. During 2003 and 2004, however, several events occurred that suggested that cats can—and do—become infected with the H5N1 strain of avian influenza virus.

Outbreaks in nondomestic and domestic cats in Thailand

In December 2003, two tigers and two leopards in a zoo in Thailand died after exhibiting signs of fever and respiratory distress.10 The animals had been fed fresh poultry carcasses from a local slaughterhouse. Although the diagnosis had not been made at the time, chickens in the area were dying of H5N1 influenza virus infections. Postmortem examination of tissues from the tigers and leopards revealed fibrinous pneumonia, multifocal hemorrhage in internal organs, and encephalitis. Immunohistochemistry, reverse transcriptase-polymerase chain reaction testing, and virus isolation confirmed a diagnosis of H5N1 avian influenza virus infection. The virus was virtually identical to the strain that was circulating in chickens at the time of infection. All the animals had been vaccinated with an attenuated feline panleukopenia virus vaccine two weeks before their illness. Although there was no evidence of panleukopenia virus-induced disease, immunosuppression associated with the vaccine may have contributed to the severity of the influenza in these cats.10

Domestic cats in Thailand have also been infected with the H5N1 virus.11,12 In February 2004, a group of 15 cats living near an affected poultry farm became ill. According to news reports, three of the cats had been tested for avian influenza by researchers at Thailand's Kasetsart University, with two cats having positive results at that time. Fourteen of the 15 cats had died, and the last cat was very ill. The method of influenza transmission in these cats was unknown.

Influenza in greyhounds: A cautionary tale

A second outbreak of H5N1 avian influenza in nondomestic cats occurred in October 2004 in a tiger zoo in Thailand.13 Initially, the cats likely became infected by ingesting raw infected bird carcasses. Tigers infected later in the outbreak were probably infected by cat-to-cat transmission because they were fed cooked poultry beginning a few days after the first tigers became ill. Clinical signs in affected tigers included respiratory distress, a serosanguineous nasal discharge, neurologic signs, and high fever. Leukopenia, thrombocytopenia, and elevated liver enzyme activities were common laboratory findings. Most of the animals had severe lung congestion and hemorrhage. Infection with H5N1 avian influenza virus was confirmed in several animals by using immunohistochemistry, virus isolation, or both techniques. Twenty-nine tigers died during the first week of the outbreak, and a total of 147 of the zoo's 441 tigers either died or were euthanized during the three weeks after the first tigers became ill.

Experimental inoculation of domestic cats

In addition to these outbreaks, researchers have demonstrated the susceptibility of domestic cats to H5N1 avian influenza virus.14 Unlike in previous studies with other influenza virus strains, cats developed severe respiratory disease after exposure to H5N1 virus by ingestion, intratracheal inoculation, or contact with experimentally infected cats. Intratracheal inoculation of three cats resulted in fever beginning Day 1 after exposure and in decreased activity, conjunctivitis, and labored breathing by Day 2 after exposure. One cat died on Day 6. Pathologic findings included focal pulmonary consolidation and diffuse alveolar damage. Two cats housed with these infected cats and three cats fed virus-infected chicks also developed similar clinical signs and pathology. Infection with H5N1 avian influenza virus was confirmed in all these cats by virus isolation from pharyngeal swabs and by immunohistochemistry on lung tissue.

THE VETERINARIAN'S ROLE IN INFLUENZA SURVEILLANCE

The H5N1 outbreaks in domestic and nondomestic cats in Thailand emphasize the potential of this virus as a feline pathogen. Although poultry and wild ducks are the primary reservoir of the virus, several species of songbirds are also susceptible to infection.15 These bird populations could serve as a conduit of human infection through feline intermediaries. With each genetic reassortment of the influenza viruses, species barriers become less effective (Figure 2). Many influenza viruses can no longer legitimately be categorized as equine, avian, human, or swine viruses. It seems reasonable for veterinarians to consider including influenza as a differential diagnosis in cats with respiratory and neurologic disease. Prompt recognition of avian influenza in any susceptible population of animals will help control its spread and decrease the chance of another devastating influenza pandemic.

Figure 2. Genetic reassortment of influenza viruses may lead to additional species being involved in transmission.

If you suspect avian influenza in any species, contact the Animal Health Diagnostic Center, College of Veterinary Medicine, Cornell University (phone: 607-253-3900; e-mail: diagcenter@cornell.edu) for testing information. Report cases of avian influenza to local or state public health departments or the county veterinarian. Although guidelines for handling infected pets have not been established, human infection-control precautions recommended by the CDC can be adapted for use in companion animals. Use stringent hygienic care (including using gloves, gowns, and masks) when handling potentially infected animals, and maintain these animals under isolation conditions until testing is completed or for 14 days after the onset of clinical signs. Treatment of influenza virus infection in cats would probably be based on supportive care. Influenza antiviral agents have not been tested in cats, so their safety and efficacy are unknown.

Margaret C. Barr, DVM, PhD

College of Veterinary Medicine

Western University of Health Sciences

Pomona, CA 91766.

Dr. Barr lectured on this topic at the 2005 Central Veterinary Conference. Her paper originally appeared in the conference proceedings.

REFERENCES

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11. Care urged after bird flu infected feline found. China Daily. Available at: www2.chinadaily.com.cn/english/doc/2004-02/20/content_307975.htm. Accessed March 29, 2005.

12. The World Health Organization Communicable Disease Surveillance & Response (CSR). Avian influenza (H5N1)—update 28: reports of infection in domestic cats (Thailand), situation (human) in Thailand, situation (poultry) in Japan and China. 20 February 2004. Available at: www.who.int/csr/don/2004_02_20/en/. Accessed Sept. 15, 2005.

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