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Feline calicivirus infection

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Category: Schede
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  • Disciplina: Malattie infettive
  • Specie: Gatto

Feline calicivirus (FCV), the aetiological agent of calicivirosis, is one of the pathogens most commonly associated with the group of upper respiratory tract diseases of the cat (Gaskell et al., 1994). FCV belongs to the family Caliciviridae, genus Vesivirus. It is a small, symmetrical icosahedral RNA virus with a diameter of 32-40 nm and without an envelope. The capsid is formed of 180 molecules of a single polypeptide named VP1. The complete genome of single-stranded RNA with positive polarity is 7690 bp long and has three open reading frames (ORF): (i) ORF 1 coding for non-structural proteins (putative 2C helicase, 3C protease, 3D RNA-dependent RNA polymerase); (ii) ORF 2 coding for the capsid protein VP1; (Carter et al., 1992) and (iii) ORF 3 coding for a small 12 kDa protein named VP2, which is essential for the production of the infectious particles (Sosnovtsev et al., 2005).

Nucleotide sequence analysis of the gene coding for the capsid protein and serological studies based on the use of seroneutralisation methods have shown that there are FCV strains which, although similar to the only known serotype, named F9, differ in pathogenic strength and antigenic structure from F9 (Buonavoglia et al., 2000). Being a virus without an envelope, FCV is resistant to the action of lipid solvents, while it is inactivated by  sodium hypochlorite and glutaraldehyde.

 

TRANSMISSION OF THE VIRUS

Feline calicivirus infection is acquired by direct contact with secretions from an infected cat in the acute phase of the infection. The virus can persist in the environment and remains infective for more than 1 month on damp surfaces at room temperature, and even longer in optimal conditions. Indirect transmission is also possible, especially in confined conditions, such as those in catteries, where the secretions can contaminate every surface and crevice. Indirect transmission occurs mainly for the systemic strains of the virus and in veterinary structures and hospitals.

In natural conditions, cats and leopards are receptive to infection by FCV. This infection has a cosmopolitan spread. The pathogenic agent is transmitted mainly through direct contact with cats during the acute phase of disease, or through contact with carrier animals. The prevalence is highest in animals aged between 2 and 12 months old. (Marsilio et al., 2005)  One particularly interesting aspect of the survival and diffusion of FCV in the environment is the capacity of this virus to persist in the tissues of asymptomatic cats. The main site of viral persistence is the epithelium of tonsils.

The shedding of FCV by persistently infected cats is continuous and, unlike what is seen with feline herpesvirus type 1 (FHV-1), is not influenced by stress. Studies carried out on this issue, (Dawson et al., 1991) showed that 50% of infected subjects shed the virus for about 75 days; furthermore, some cats can remain life-long carriers in the absence of clinical symptoms. The spread of the virus in catteries can also be favoured by manipulation by staff and by the sharing of bowls and cleaning equipment.

After recovering, many cats continue to shed virus: most do so for about 30 days, others for up to 75 days, but some for many years.

 

PATHOGENESIS

Following penetration through the oro-nasal route, FCV replicates in the tonsils and tissues of the respiratory apparatus; the oropharynx is the primary site of replication. The initial phase of transitory viraemia usually lasts about 3-4 days; a subsequent stage of viraemia can spread the virus to other viscera. In fact it has been shown that the virus can be shed not only via the nasal, conjunctival and oral routes, but also in the faeces and, sometimes, the urine. In asymptomatic carriers the virus remains localised in the tonsillar epithelium. The virus induces necrosis of epithelial cells: typically vesicles/ulcers form in the regions infected by the virus, especially the tongue. Less commonly the virus can spread to other organs causing pneumonia and lameness (from acute synovitis with thickening of the synovial membrane and increased synovial fluid).

 

CLINICAL SIGNS

 

Although subclinical forms of FCV infection occur, in most cases the infection is acute and causes upper respiratory tract symptoms. The most commonly occurring signs are a nasal discharge, which is initially serous, sneezing, and sometimes cough and dyspnoea. Ocular signs are also frequent, and include conjunctivitis, blepharospasm and chemosis (Fig. 1). In most cases the evolution of the infection is benign and any complications derive from concomitant infections with immunosuppressive viruses such as feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV), or secondary bacterial infections.

Feline calicivirus: a multifaceted virus

The clinical signs differ depending on the virulence of the strain involved and the age of the affected patient; sometimes there is fever, while loss of appetite is common when the oral cavity is involved. FCV has been isolated from aborted foetuses, demonstrating that transmission via the placental route is possible. (Van Vuuren et al., 1999) FCV infection has also been associated with forms of enteritis and severe disorders of the lower urinary tract in the cat. (Kruger et al., 1996)

Acute infection of the oral cavity

Hypersalivation often accompanies the appearance of the vesicles at the edge of the tongue, which rapidly transform into ulcers. These oral cavity ulcers can subsequently be associated with gingivitis and stomatitis, which may become chronic (Fig. 2 and Fig. 3) (Dawson et al., 1994). The acute erosions resolve within a few days, but can be so painful as to justify the use of systemic analgesics or low doses of corticosteroids.                                                      

Chronic stomatitis

 

Various studies have shown a correlation between FCV and the development of acute forms of gingivo-stomatitis; acute forms have also been induced experimentally, (Radford 2007) whereas chronic forms of gingivo-stomatitis have never been induced, nor has it been possible so far to demonstrate progression from the acute form to the chronic form. There are, however, numerous studies on the role of caliciviruses in causing or contributing to the development of chronic gingivo-stomatitis (Fig. 2). Although an indirect immunofluorescence assay for calicivirus can certainly demonstrate the local, chronic presence of the virus, the significance of such a finding is unclear. Other studies based on the use of immunohistochemistry or polymerase chain reaction analysis identified calicivirus in 85% of cats with chronic stomatitis and in 100% of cats with chronic inflammation of the oropharynx (Lommer 2003). However, despite these findings, it has not yet been possible to make a direct aetiological link between the disease and calicivirus; in fact, experimentally induced infection with the virus only seems to be able to cause mild forms of the disease. It is thought that the pathogenesis of chronic gingivo-stomatitis involves an  atypical immune response of unknown aetiology, associated with the presence of one or more viral co-factors. According to this hypothesis, calicivirus, like FIV, could be considered as a co-factor that acts together with alterations of the immune system. It is possible that the greater shedding of FCV seen in many cases is related to the stress caused by gingivo-stomatitis and the associated pain; the stress would suppresses local immune responses, thereby enabling greater viral replication.

Limping  syndrome

In sporadic cases, the clinical manifestations of FCV infection can be quite varied. Such manifestations include the ‘limping syndrome’, characterized by a stiff gait, hyperaesthesia and joint pain, as a result of a non-erosive, infectious polyarthritis. Affected cats usually develop fever and hyperaesthesia together with ulcers; the ulcers can occur concomitantly with the fever and hyperaesthesia or occur some days after (7-15 days). The limping syndrome can be associated with a naturally occurring infection or vaccination with live viruses (kitten limping syndrome). The clinical picture often resolves within 48-72 hours.

Inflammatory polyps

Calicivirus infection has also been associated with the development of rhinopharyngeal inflammatory polyps. It is certain that the virus causes a severe inflammatory reaction in the nasal and oropharyngeal mucosae; it is believed that the polypoid structures that tend to occlude the rhinopharynx are produced by the mucosa. There may also be otitis media, with development of inflammatory polyps in the tympanic bulla, but it is not yet clear whether the viral infection triggers the growth of the polyps or whether the infection develops in an already inflamed and, therefore, predisposed tissue.

Highly virulent systemic feline calicivirus disease

A more severe and systemic form of infection by FCV has recently been observed in both the USA and in Europe; this form mainly affects correctly vaccinated adult cats and causes severe, systemic signs. The currently available vaccines do, therefore, seem to provide only limited protection against this form of FCV infection, which, although uncommon, is often fatal. This disease is called highly  virulent systemic feline calicivirus disease,  although it was previously known as “haemorrhagic-like fever”. The causal strain is commonly called “systemic feline calicivirus”. The period of incubation of systemic FCV is 1–5 days in a nosocomial environment, but in the domestic setting can be as long as 12 days. The disease is more severe in adult animals than in kittens. The virulent strain of this FCV causes generalised vasculitis, multi-organ failure and death in more than 60% of affected subjects. The clinical signs in patients affected by virulent systemic FCV are initially the same as those of the classical forms of the disease caused by other strains of calicivirus, and include oral ulcers, fever and joint pain. However, as indicated by the term “systemic”, the disease is characterized by progressive worsening with the involvement of several organs.

Virulent systemic FCV is characterized by a systemic inflammatory syndrome, disseminated intravascular coagulation, multi-organ failure and death (mortality rate of about 67%).  The disease is more severe in normally vaccinated, adult cats.

 

Skin manifestations

There are also reports of calicivirus dermatitis, even though skin manifestations are more common during infections with feline herpesvirus. Some of the skin lesions of calicivirus dermatitis, such as those on the foot pads, are difficult to differentiate from lesions induced by other viruses and the differential diagnosis must, therefore, be made carefully. 

 

DIAGNOSIS

A presumed clinical diagnosis of calicivirus infection is based on the finding of respiratory signs such as conjunctivitis, runny eyes and nose, sneezing and hypersalivation. On inspection of the oral cavity, ulcers, predominantly on the palate and tongue, can be seen (Fig. 3 and Fig. 4); in young animals, these lesions can be considered specific.

A definite diagnosis cannot, however, be made only on the basis of the history and clinical findings, given that there are not pathognomonic clinical signs that enable FCV infection to be differentiated from infections caused by other micro-organisms responsible for respiratory tract diseases; specific laboratory examinations are needed to discriminate FCV infections from infections caused by feline herpesvirus(FHV-1), Chlamydophila felis and Bordetella bronchiseptica, which are frequently associated with each other during upper respiratory tract disease. (Marsilio et al., 2005).


   Fig. 3                                                                                                  Fig. 4

Diagnostic tests

Isolation of the virus from nasal, conjuctival or oropharyngeal swabs is easy to perform, although this test can sometimes give false negative results if, for example, there are few viruses present in the initial sample or if there are antibodies in the extracellular fluids which prevent replication of the virus in vitro.

Immunofluorescence studies for direct demonstration of the pathogen are considered less sensitive than viral isolation, particularly during chronic or recurrent infections, while they are reliable for the identification of viral strains grown on cell cultures (Gaskell, 1985).

Molecular biology techniques, such as polymerase chain reaction (PCR) and its variant, nested-PCR, which can be used directly on the conjunctival or oropharyngeal swabs, are currently the fastest methods with the greatest sensitivity (Marsilio et al., 2005).

Serological studies, aimed at detecting antibodies to FCV, are not a very reliable method for making a diagnosis of calicivirus infection both because of the widespread use of the vaccine and because of the variability in antibody titre depending on the degree of homology between the infecting viral strains and the antigen used in the test.

 

TREATMENT

In most cats, the respiratory manifestations associated with FCV infection are self-limiting. The ocular and nasal signs and the palatine ulcers tend to disappear in 48-96 hours even without treatment. Severe forms with nasal congestion, oral pain, anorexia and hypersalivation necessitate admission and supportive therapy, aimed above all at maintaining an adequate level of hydration and nutrition. It is very important to ensure that kittens receive the necessary nutrition, since many animals do not eat because of the pain related to the presence of ulcers on the tongue or because of severe nasal congestion, but also because of loss of the sense of smell. These subjects can be treated with topical decongestants for paediatric use, such as phenylephrine 0.25% or oxymetazoline 0.025% (Nelson and Couto, 1995). If necessary, a naso-gastric tube can be placed for forced feeding and the administration of analgesic drugs.

Antibiotic treatment is indicated in animals with severe clinical signs of secondary bacterial infections and in all cases in which there is a concomitant infection with C. felis or B. bronchiseptica.

Interferon-alpha2b or, more recently, feline interferon-omega, has been suggested as an adjuvant therapy. Although it does not seem to be able to act on already infected cells, it can be used to accelerate the course of the disease, preventing infection of healthy cells. Both types of interferon can be administered orally (30 IU day/cat) and topically (diluted in artificial tears to obtain 3000 units/ml of interferon-alpha2b  or 500,000 IU/ml of interferon-omega, applied three to five times a day, for 10 days). Positive results have been achieved even in cases of otherwise refractory disease.

It should be noted that low doses of interferon have a predominantly immunostimulatory effect, while high doses have effects that are directly and purely antiviral.

It has been shown that three doses of interferon-omega 2.5 MU/kg/day on alternate days, if injected (subcutaneously or intravenously) within the first 3-5 days after the onset of clinical manifestations, are effective at accelerating healing and preventing the development of chronic carriers.

The inflammation of the fauces and the periodontitis associated with chronic FCV infection is difficult to treat and the management of this syndrome is often palliative. Inflammation of the fauces can be partially mitigated by daily administrations of dexamethasone, starting at a dose of 2-3 mg/cat. If there is a clinical response after 2-3 weeks, the treatment can by continued, gradually tapering down the dose to reach 0.5-1.0 mg/cat on alternate days or even less if the clinical signs are controlled with very low doses. In these cases it is, however, almost always necessary to extract the teeth involved by the inflammatory process.

FCV: a constantly mutating pathogen. Variation in virulence and antigenicity
“Like most RNA viruses, FCV is a highly variable virus and constantly mutates. Numerous strains of FCV exist – and more may come up every day. This is also why we see a variation in virulence, antigenicity and post-infection immunity. Cats that have recovered from an FCV-associated disease probably do not have lifelong protection against further episodes of disease, particularly if caused by different strains.”(Dr. Alan Radford, University of Liverpool, member of the ABCD)
(From “FCV, the constantly mutating virus; the ABCD recommends annual boosters for high-risk cats”, ABCD Press Release).

 

PROPHYLAXIS

Direct prophylaxis against FCV infection is based on good disinfection of the environment, periodic laboratory controls aimed at identifying carriers and appropriate quarantine to prevent carriers from entering catteries.

Vaccination
Since it is virtually impossible to eliminate carriers from the environment, the control of FCV infections is largely dependent on vaccination. One of the factors complicating the control of these infections is that caliciviruses can exist in many populations of cats without causing serious clinical problems and it is, therefore, questionable whether animals in these circumstances need to be vaccinated. Over the last 15 years, prophylactic vaccination against FCV has been conducted predominantly with vaccines made from attenuated viruses of the F9 strain of FCV and administered parenterally. Despite the large scale use of these vaccines, FCV is still very widespread, and in any case, vaccinated animals can also become asymptomatic carriers. The ease with which vaccine-resistant strains of FCV develop in cat communities may indicate both that the serological differences found are more important than previously considered and that immunisation is less effective than was foreseen.

Various types of vaccines for FCV are currently available, in all cases associated with the vaccine for FHV-1: most are based on live attenuated viruses or inactivated viruses with or without adjuvants, and are administered systemically. Most of the vaccines are suitable for routine vaccination programmes and, in not previously exposed cats, produce a reasonable level of protection from the clinical manifestations of the infection. It should, however, be remembered that the vaccination does not protect against infection by either FCV or FHV-1. Vaccinated animals remain a potential source of field virus for other cats and, in particular for FCV, the biological diversity of the viruses implies than no single vaccine strain can protect equally well against all the field strains of the virus. This has practical implications for the choice of which of the currently available vaccines to use. However, like other rapidly evolving pathogens, FCV undoubtedly still holds many surprises under its capsid.

Although vaccination provides good protection against acute oral and respiratory manifestations of infection, it should be remembered that it does not protect against the infection and shedding of the virus into the environment. Furthermore, no single vaccine is able to protect equally well against all strains of FCV.

 

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