Update on viral diseases in cats (Proceedings)

Feline herpesvirus

Feline herpesvirus (FHV) is a common pathogen of domestic cats. The virus is a ds DNA virus with a lipid envelope. The virus primarily targets epithelia of the upper respiratory tract and conjunctiva, and only rarely spreads beyond these regions to cause disease. As with all herpesviruses, after acute infection it enters a latent state in innervating sensory nerves. In cats, this most commonly occurs in the trigeminal ganglion. From this latent state, the virus can be reactivated leading to replication in the epithelia, virus shedding, and in a minority of cats, disease. Termed recrudescence, it can be stimulated by any stressor, including trauma, concurrent disease, parturition, boarding, or changes in social hierarchy.

The typical presentation of FHV infection is that of upper respiratory tract disease: sneezing, nasal and/or ocular discharge, depression, and decreased appetite. Conjunctivitis is not uncommon, and can progress to severe hyperemia and chemosis, with mucopurulent ocular discharge. Infection may lead to corneal ulceration. Less common manifestations of FHV are ulcerative dermatitis and stomatitis.

Diagnostics for FHV infection primarily involves virus detection, as most cats are seropositive from either natural exposure or vaccination. Antigen detection using immunofluorescence is fast and inexpensive; however, sensitivity is relatively low, especially in chronic infections. Virus isolation remains the gold standard. However, in chronic infections, notably chronic conjunctivitis or other ocular disease, the virus may be neutralized by locally-produced antibody leading to false negative results. Genetic detection using polymerase chain reaction (PCR) has high sensitivity, such that subclinical, and even latent infections may be detected. Thus, positive results must be interpreted in light of other clinical information.

Advancements have been made in the treatment of FHV infection in cats. Nucleoside analogs developed for human herpesvirus infections have shown some efficacy against feline herpesvirus, at least in vitro. Toxic side effects have been reported with some, such as acyclovir, but others, such as ganciclovir may prove to be useful clinically. Topical administration of antiviral medications has been used with some success, and include trifluridine and idoxuridine. Interferon (IFN) has been used with some success, and has been shown to be efficacious in vitro (human alpha IFN – US; and feline omega IFN – Europe). L-lysine given orally inhibits viral protein synthesis and restricts virus replication. It is optimal when used early in infection, or as a means to prevent recrudescence during stress. Experimentally, lactoferrin has been shown to inhibit virus attachment and entry, and may be eventually be available as an antiviral treatment for FHV.

Protection following recovery is not long-lived, and reinfections may occur. Antigenic variation is not a significant problem with feline herpesvirus, thus, the antigenic coverage of vaccines is adequate. Non-adjuvanted modified live vaccines are recommended. Vaccines do not prevent infection, nor production of the carrier state. They do offer protection from disease, however.

Feline calicivirus

Feline calicivirus (FCV) continues to be an important respiratory pathogen of cats. It is a nonenveloped virus making it very hardy in the environment, and easily spread by fomites. It is a ss RNA virus with a significant mutation rate. This may lead to changes in antigenicity (many strains that vary antigenically exist) as well as virulence.

Clinical presentations with FCV infection can vary from mild upper respiratory tract disease to viral pneumonia to lethal systemic disease. The typical presentation is similar to FHV infection, though the ocular discharge generally remains serous, corneal ulcers do not occur, and oral ulcers are common. The majority of infections are mild and self-limiting. However, following recovery, infection with shedding in oropharyngeal secretions may persist for periods of week to months, even in the face of vaccination. Lameness, ulcerative dermatitis, and gingivitis have also been associated with FCV, though the pathogenesis is unclear.

Currently, no specific antiviral medication for FCV exists. A recent study showed efficacy of virus-specific compounds in blocking FCV replication in vivo. It was safe, reduced disease development, virus shedding, and mortality.

Persistent infections following recovery from acute disease are not uncommon. Infected cats may continue to shed the virus throughout their lifetime, but most shed for periods of weeks to a few months. Vaccination is the main means of control, and as with FHV, prevents disease, but not infection nor the carrier state. Most vaccines contain a single strain. Manufacturers are investigating the utility of and including additional strains in vaccines to increase the spectrum of protection. Newer vaccinal strains appear to induce neutralizing antibodies against a higher proportion of caliciviral field strains. However, because of the strain variability, it will be difficult to achieve a vaccine that provides protection to all strains in circulation. In addition, it is important to bear in mind that inclusion of two or more strains isolated from different disease manifestations does not necessarily insure broad protection against the varied pathogenic phenotypes.

Environmental decontamination is also important for control in multi-cat situations. During outbreaks of VSD due to FCV, strict quarantine measures and barrier nursing is required to prevent the spread.

Virulent systemic calicivirus

In 2000, an isolated epizootic of a virulent systemic disease (VSD) attributed to feline calicivirus (FCV) was described by Pedersen and others. Since then, additional outbreaks in the US and UK have been described. The symptoms have included a high fever, oral ulcers, subcutaneous edema, and ulcerative dermatitis. Interstitial pneumonia, as well as hepatic, splenic and pancreatic necrosis have also been described. The disease has a significant mortality, even in vaccinated cats.

Mutations in the viral genome are believed to be responsible for the change in phenotype of the virus, but each variant from the different outbreaks have been distinct. In fact, no consistent genetic motif has been associated with this disease manifestation. Most have arisen from a shelter or rescue facility, and have "burned out" almost as quickly as they started. This last fact is likely due to the lack of subclinical infection, and the strict quarantine and other control measures implemented in these outbreaks. Host and immune factors are also speculated to play a role in this disease syndrome. Alterations in certain cytokines have been found in affected tissues, suggesting an immunopathogenicity.

Diagnosis of VSD associated with calicivirus involves clinical signs, history, identification of calicivirus in lesions (e.g. swabs of oral ulcers, blood, epidermal biopsies), and elimination of other potential causes. As stated above, no specific viral assay for the FCV of VSD currently exists. At least one commercial vaccine has been released that contains two FCV strains, including one associated with VSD. Since antigenicity does not correlate with disease syndrome, inclusion of two or more strains isolated from different disease manifestations does not necessarily insure broad protection against the varied pathogenic phenotypes. Synergy with the combination of isolates must be demonstrated to substantiate claims of broad antigenic protection.

Feline leukemia virus (FeLV)

Feline leukemia virus (FeLV) remains a significant threat to cats. Infection with FeLV may lead to lifelong persistence of the virus, and causes immunosuppression, degenerative conditions such as anemia, and/or proliferative diseases such as lymphoma and leukemia. Investigations of FeLV infection using molecular detection techniques have identified four stages of infection.

In this study, a small % of cats positive by genetic detection were negative by antigen (p27) detection using ELISA. Other studies detecting proviral DNA in whole blood found ~5% were negative by antigen ELISA. It is not know if this is a stage in clearance of the virus, or if the provirus remains. A recent study evaluating risk factors for FeLV infection found that adults, sexually intact males, and outdoor cats were at higher risk for infection.

Vaccines for FeLV were developed many years ago, and are commonly used in veterinary practices. Most are inactivated vaccines with adjuvant. Recently, a recombinant canarypox incorporating the env and gag genes of FeLV has been developed. This vaccine is nonadjuvanted, is administered intradermally, and has been shown to induce comparable immunity to the subcutaneous vaccine. Immunity with FeLV vaccines appears to be nonsterilizing, and in fact, provirus can be found in immunized cats following challenge. The significance of the "latent" virus is not known. As stated in a report by Hoffman-Lehmann and others (2007) vaccines "protect cats from persistent antigenaemia and thus from FeLV-associated fatal disease. They significantly prolong the life expectancy of vaccinated cats. Nonetheless, the search for improved vaccines, which prevent FeLV proviral integration, should continue."

Feline immunodeficiency virus

Feline immunodeficiency virus (FIV) also continues to threaten cats worldwide. The risk factors noted above for FeLV also apply to FIV. Infection with FIV is lifelong, thus accurate diagnosis is imperative. Currently, diagnostic assays rely on antibody testing.

FIV isolates are classified into 5 subtypes (A-E) based on genetic sequence of the envelope glycoprotein. Many endemic FIV isolates in Europe, Japan and the US are subtype B, and emerging isolates within this subtype have been documented. A vaccine containing subtypes A and D became available for cats in 2002., and this vaccine has shown efficacy against heterologous subtypes including subtype B. However, other studies have shown less cross protective capabilities. The extreme genetic variation of FIV isolates would seem to indicate that protection against all strains is not feasible. The vaccine is inactivated virus with adjuvant, and is recommended primarily for those cats at high risk, such as outdoor male cats or cats that reside with FIV-infected cats. While protection is afforded, vaccination results in the production of antibodies indistinguishable from that induced by natural infection. Thus, vaccinated cats will test positive with current diagnostic assays. Kittens from vaccinated dams will also possess passively-acquired antibodies.

To circumvent this problem, genetic detection of the virus has been used to diagnose active infection with FIV. However, because of the genetic variation of the virus, false negative results are not uncommon. In addition, false positive results have been found in vaccinated cats. The results from one study by Crawford and others (2005) are shown in this table:

Thus, reliable and accurate detection of FIV infection by molecular assays is difficult. Recently, a report by Levy and others (2008) has shown promising results with an antibody assay able to distinguish vaccinal response from that of natural infection. This discriminant ELISA may prove to be useful for accurate testing of vaccinated cats.

Avian influenza

The emergence and spread of the H5N1 strains of avian influenza in recent years has caused concern over a future pandemic in the human population. The virus, a particularly virulent and contagious strain, has affected waterfowl and domestic poultry in Asia, Europe, the Middle East and Africa. In addition, it has successfully infected humans in contact with infected birds, leading to severe disease, and death in over 50% of cases. Thusfar, efficient human-to-human spread has not occurred.

Infection has also occurred in domestic cats and dogs. Seropositive dogs and cats have been found in Thai villages. Natural infection of dogs has occurred from ingestion of infected carcasses. In some cases, systemic disease and death have occurred. Cats also may be infected by consumption of carcasses of infected birds. During an outbreak in Germany among waterfowl, infection of several domestic cats occurred. Infections were fatal, and pneumonia and hepatic necrosis was found. Experimental studies in cats have produced lethal infections, and spread to in-contact cats. Shedding was documented in both respiratory secretions and feces of infected cats. Inoculation studies in dogs have shown susceptibility of dogs to infection with H5N1, and shedding may occur from the nose with no signs of disease. This study also showed receptors for the avian influenza exist in both the upper and lower respiratory tracts of dogs.

Because these animals live in close contact with humans, concern exists over the risk of transmission from these animals. This possibility also brings questions from owners regarding risks to their pets, and themselves. Currently, it is unlikely that cats and dogs play any role in the natural transmission of avian influenza. No direct transmission has been reported, and the level of shedding by these animals appears to be lower than that of birds. However, monitoring of domestic pets during an H5N1 outbreak is warranted.

Rabies

Rabies virus continues to be a threat to domestic pets worldwide. Recently, it was announced by the CDC that the canine strain of rabies has been eliminated from the US. However, the virus remains present in wildlife in the US, posing a risk for domestic pets, as well as people. Lyssaviruses continue to emerge in other parts of the world, and genetic variants of rabies virus do exist. New variants of rabies virus in North America could occur and pose an emerging threat. Rabies infections in raccoons are of particular concern due to the increased likelihood of raccoon contact with pets as well as people in suburban areas. In addition, importation of dogs poses a risk for introduction of foreign variants. Data indicates an increasing number of unvaccinated puppies are being imported into the US, and since 2004, infection has been documented in at least two imported puppies. Federal regulations are under review to address these risks.

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