The most prevalent infectious problem of cats is upper respiratory tract infection (URI), with morbidity in many shelters and breeding catteries approaching 100%. Of the five well recognized pathogens associated with feline URI (Bordetella bronchiseptica, Chlamydophila felis, Mycoplasma spp., feline calicivirus (FCV) and feline herpesvirus (FHV)), all of the bacteria are relatively uncommon, specific antimicrobial therapies with variable efficacy are available for all except FCV, and few are associated with frequent fatal infection except FCV. Thus the focus of this talk will be a brief overview of FCV in the specific context of URI, followed by the extension of clinical FCV-disease as a complication of uncontrolled infection with virulent strains and in susceptible host individuals.
Caliciviruses of cats have high rates of infectivity, morbidity and death. The ability of FCV to induce disease is due directly to the virus and also to immune-mediated complications. FCV is an RNA virus with high rates of mutation and high antigenic and genetic diversity. The name comes from a calyx-like depression in the virus surface on electron microscopy. The virus has two large and one small open reading frames, one coding for a structural capsid protein which functions in RNA and host cell attachment. The virus has numerous arch-like capsomeres, each of which is a capsid protein dimer.
FCV infection is usually transmitted by aerosol via oral and nasal routes. Subsequently, the virus spreads systemically and is secreted in saliva, respiratory secretions, faeces and urine. Shedding occurs for approximately 2 weeks but may last for months to years. Typically, cats develop lymphopenia and neutropenia, potentially with fever, conjunctivitis, rhinitis and vesicular stomatitis. Because vesicles rupture within hours to days, small inflamed, painful erosions are more typical. Co-infections tend to exacerbate disease severity.
About 25% of FCV-infected cats develop chronic infection. Possible mechanisms for chronic infection are inadequate immunity, reinfection with antigenically dissimilar strains of FCV, or emergence of genetic variants of virus. An important complication of mild upper respiratory tract infection is lower respiratory disease either with FCV alone or with secondary bacteria such as B. bronchiseptica, Escherichia coli or others.
Polyarthritis and stomatitis are immune-mediated complications of infection. It is common on about the second day of FCV infection for a cat to have transient fever and shifting-leg limping. These cats usually have oral lesions and are better within 3-4 days. The joints have thickened synovium and increased synovial fluid. A different polyarthritis scenario occurs 10 days to 3 weeks after infection in which immune-complex polyarthritis may occur. This syndrome may occur after URI lesions have resolved. Anecdotally, this syndrome also may occur in cats that have been vaccinated recently. There is FCV immunoglobulin and complement within synovial macrophages, which suggests immune complex deposition.
Immune complex, chronic 'lymphocytic/ plasmacytic' stomatitis occurs in some cats with previous or ongoing URI. This condition can be severe, resistant to management and may eventually require euthanasia. Affected cats may have ptyalism, halitosis, dysphagia, poor grooming and weight loss. The gums are swollen, sometimes with faucitis and glossitis. Hypergammaglobulinaemia may be present and interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, IL-12 and interferon (IFN)-γ may be increased. Histopathologically there are plasma cells and lymphocytes predominantly but also sometimes neutrophils and anaerobic bacteria. Cats with chronic, high-titre FCV infection can develop progressive immune complex-induced glomerulonephritis, with renal failure characterised by high urine protein concentrations and high urine protein:creatinine ratios.
A recently emerging syndrome in cats in the USA appears due to a particularly pathogenic series of FCV infections where cats developed facial and limb oedema similar to the haemorrhagic fever syndrome observed in rabbit haemorrhagic calicivirus infection. This 'virulent systemic feline calicivirus' (VS-FCV) can be associated with up to 67% mortality even in healthy adult cats and has erupted in at least six epidemics since 1998. In all outbreaks, there was a rapid onset and spread, with enigmatic, gradual or abrupt conclusion.
VS-FCV has a tropism for epithelial and endothelial cells. Infection appears to be clinically very severe with multisystemic attack, systemic vascular compromise and frequent signs of fever, oedema, multiple-organ failure, haemorrhage, shock and death. On pathology, cats may have subcutaneous oedema, ulceration and segmental to full-thickness epithelial necrosis of the stratum basale, stratum spinosum and follicles, pulmonary oedema and liver or pancreatic compromise. Immunohistochemical staining shows virus potentially in skin, nasal mucosa, tongue, buccal mucosa, pinna, paw pads and lungs. Transmission electron microscopy documented viral antigen within endothelial and epithelial cells in affected skin. The pathogenesis of virulent systemic caliciviral disease appears to be at least partly immune mediated. Affected tissues of cats with VS-FCV infection have up-regulated IL-10, TNF-α and macrophage inflammatory protein (MIP)-1α, but no differences compared with control tissues in the cytokines IL-1β, IL-2, IL-4, IL-6, IL-12p40, IL-18, IFN-γ, IFN-α and 'regulated upon activation, normal t-cell expressed, and secreted' (RANTES).
The rapid emergence of the novel VS-FCV-associated clinical syndrome suggests that new genetic FCV variants could be responsible. For example, in the Los Angeles outbreak, all VS-FCV strains obtained from case cats clustered very closely together and contained a characteristic deletion of three nucleotides (nt). However, when 235 nucleotide amplicons in the viral capsid hypervariable region from northern and southern California VS-FCV outbreak strains were compared with North Carolina and Florida VS-FCVs, this three nt deletion was missing from some strains. VS-FCVs are not all members of a single clade; rather these mutant viruses are emerging from several different lineages intermixed with other field strain FCVs. If the disease pathogenesis is immune-mediated, the initial virus-host interaction could initiate immune sequelae that are similar among cats and outbreaks even if the original viral genotype differs.
Management of FCV-associated disease is a serious challenge. Often the problem is a herd-health problem best attacked through population management strategies such as quarantine and movement control. Because there are no specific antiviral drugs effective against FCV, management of individual sick cats requires treatment of complications of infection. Kittens of vaccinated or naturally infected queens have some minimal protection against FCV. Maternal immunity lasts 3-9 weeks. After infection with one strain, there may or may not be protection against other strains. As cats mature to about 3 years of age, their innate protective mechanisms generally develop sufficiently for relatively complete protection against many field strains.
Vaccination for FCV does not completely prevent infection but may reduce signs of severe disease. Some of the modified live vaccines induce mild to moderate URI. Subcutaneous vaccines can induce oropharyngeal shedding of vaccine-strain virus. A killed virus vaccine is commercially available that will reduce vaccine-associated morbidity. However, this vaccine must be given at least twice (at least 2-4 weeks apart) before effective immunity is produced; the adjuvant may be locally irritating and predispose cats to later vaccine-associated sarcoma; and the cat is not protected for 2 weeks or longer after the first vaccination.
The most important components of care for cats with URI are nursing care and maintenance of hydration. Cats with plugged noses, sore mouths, or any indication of inappetence may need to be encouraged to eat, especially if they are young kittens. The nose should be cleaned gently and warmed all-meat baby food (with no onion powder) offered. Antibiotics should be reserved for cases with green purulent discharge, a concern of sepsis, or a strong suspicion of secondary bacterial infection (because antibiotic use affects normal flora adversely and promotes antibiotic resistance and susceptibility to further infection).
Immunosuppressive therapy is the mainstay for cats with immune complex complications of FCV. Treatment for FCV-induced polyarthritis typically consists of immunosuppressive steroid treatment. If there is no improvement in clinical signs and resolution of acute inflammation, additional immunosuppression with drugs such as azathioprine may be beneficial, although this treatment increases the risk of exacerbating frank URI. Treatment for chronic FCV-associated stomatitis is extraordinarily difficult. Some recommendations are broad-spectrum antibiotics with particular efficacy for anaerobic bacteria, dental disinfectant rinses, steroid administration and full-teeth extractions, but cases are often refractory to treatment, progressive and severely debilitating. Administration of aggressive immunosuppression must be performed cautiously, especially in cats with both FCV and FHV infection. However, the cat's quality of life with active stomatitis is so poor that the risk of immunosuppression is warranted. Nevertheless, some cases of stomatitis and glomerulonephritis are essentially untreatable.