Feline calicivirus infection
edited November, 2020
The Feline Calicivirus infection guidelines were first published in the J Feline Med Surg 2009; 11: 538-546 and updated in J Feline Med Surg 2015; 17:570-582; the present update has been authorised by Regina Hofmann-Lehmann.
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Feline calicivirus (FCV) is a highly contagious pathogen with a widespread distribution in the feline population. It belongs to the Caliciviridae family, genus Vesivirus; caliciviruses include important pathogens of humans (such as the Norwalk virus, one of the commonest causes of infectious gastroenteritis in people) and animals, including the European brown hare syndrome virus and rabbit haemorrhagic disease virus (Green et al., 2000).
Calicivirus particles are hexagonal or star-shaped and show cup-shaped depressions in electron microscopic preparations; the name is derived from Greek calyx meaning cup or goblet (Fig. 1).
The virus has a small single-stranded RNA genome of positive (messenger) polarity, which allows it to evolve quickly. It is enclosed by multiple copies of the major capsid protein, the most variable, probably immunodominant protein domain (principally targeted by the host's immune response) (Tohya et al., 1997; Radford et al., 1999; Geissler et al., 2002). There are antigenic differences between different FCV isolates , which create some difficulties when trying to maximise vaccine cross protection. Nonetheless, most strains of FCV are closely related enough antigenically to induce some degree of cross protection and this has been utilized in developing vaccines. Genetically, most FCVs belong to a single diverse genogroup (Geissler et al., 1997; Glenn et al., 1999; Coyne et al., 2012); however, a second genogroup has been described in Japan (Ohe et al., 2006; Sato et al., 2017). In investigation of the spatial and temporal distribution of FCV strains a very high genetic and antigenetic FCV strain complexity has been described, with many different FCV strains circulating within a cat population and no given field strain dominate it (Coyne et al., 2012; Spiri et al., 2016). Based on this observation, it was suggested that FCV evolution is not associated with selective competition among different strains in the cat population (Coyne et al., 2012). No association has been demonstrated between FCV capsid gene sequences and or antigenic characteristics and different disease manifestations (Geissler et al., 1997; Pereira et al., 2018; Spiri et al., 2019).
There are no known reservoirs or alternative hosts for FCV, apart from wild felids, and humans are not susceptible to infection. Apart from the existence of a proper canine calicivirus, FCV-like viruses have been isolated from dogs (Hashimoto et al., 1999; Roerink et al., 1999; Martella et al., 2002; Di Martino et al., 2009). The role of FCV-like viruses in the epidemiology in both dogs and cats is uncertain (Binns et al., 2000; Helps et al., 2005), but is probably not significant.
FCV is shed by cats with acute disease predominantly via oral and nasal secretions but is also detected in blood, urine and faeces of infected cats. On recovery, many cats continue shedding, most of them for at least 30 days post-infection, and a few for several years up to life-long (Wardley 1976). A small proportion of cats was found to be non-shedders, although continuously exposed to FCV over long periods; these cats were thought to be resistant to infection, probably dependent on immune-mediated mechanisms or genetic host factors (Coyne et al., 2006a).
FCV infection is widespread in the general cat population. The prevalence is broadly proportional to the number of cats in a household. It is low in household cats kept in small groups (~10%; (Wardley et al., 1974)), and higher in groups of four or more cats (Berger et al., 2015b; Kratzer et al., 2020). The prevalence within individual colonies and shelters is variable, ranging from low to high (50-90%) values (Radford et al., 2001a; Radford et al., 2003; Bannasch and Foley 2005; Helps et al., 2005; Coyne et al., 2006a). No association was found in an Australian study between socioeconomic status and the prevalence of FCV infection, which contrasted with findings for feline immunodeficiency virus (FIV) infection (Tran et al., 2019). A recent antibody study in stray cat colonies in Italy found that 85% of the cats were antibody-positive for FCV (Dall'Ara et al., 2019).
High FCV prevalence within a colony is associated with high FCV strain diversity, related to a small number of persistently infected cats and reinfection of other members of the cat population with either a variant of the same FCV strain or with a different strain (Radford et al., 2003; Coyne et al., 2007b). Each cat colony or group is usually infected with distinct viruses that evolve from distinct ancestors (Radford et al., 2001b; Radford et al., 2003). At the same time, individual cats can be infected with more than one FCV strain (Radford et al., 2000; Coyne et al., 2007b). Introduction of new strains into a cat colony and infection of individual cats with more than one strain can lead to recombination events, increasing genetic variability; the latter might be associated with the selection of antigenic variants in a cat that escape the collective immune response, thereby enabling endemic infection in a cat population (Coyne et al., 2006c; Coyne et al., 2007b). In shelter environments with a high turnover of cats and, in turn, with frequent introductions of new FCV strains, particularly high genetic variability of FCV has been demonstrated (Pereira et al., 2018). In comparison, a low level of viral diversity of FCV was found within stable multicat households (Pereira et al., 2018). The spread of FCV within cat shelters might be reduced by good hygiene and biosecurity measures (Coyne et al., 2007a). Infection generally occurs through direct contact with secretions from acutely infected and carrier cats (Wardley and Povey 1977). However, the virus survives in the environment and remains infectious for up to one month on dry surfaces at room temperature, and even longer under colder conditions (Doultree et al., 1999; Duizer et al., 2004; Clay et al., 2006). The virus also persists longer in damp compared to dry environments, and aerosol spread has been detected in facilities with FCV-shedding cats (Spiri et al., 2019). Indirect transmission can occur, especially within the close confines of a cattery, where secretions can contaminate cages, feeding and cleaning tools or personnel. Moreover, indirect transmission via fomites or people must also be expected in facilities, as has been described for virulent-systemic FCV (VS-FCV) variants (Pedersen et al., 2000; Schorr-Evans et al., 2003; Reynolds et al., 2009). In one study, a primary role of caregivers’ hands in the spread of a VS-FCV outbreak was reported; although washing and disinfecting procedures had been in place, it is assumed that one student infected up to ten cats during physical examination or oral medication of cats (Deschamps et al., 2015). The virus can also remain infectious in flea faeces for up to 8 days, and kittens can be experimentally infected with FCV by contact with infected fleas or their faeces (Mencke et al., 2009).
Cats can be infected with FCV via the nasal, oral or conjunctival routes. The oropharynx is the primary site of replication. Transient viraemia occurs 3 to 4 days after infection, at which time the virus is detected in many other tissues. The virus induces necrosis of epithelial cells: vesicles, typically on the tongue, develop into ulcers; in the affected regions, the mucosa is infiltrated with neutrophils. Healing usually takes place over a period of 2 to 3 weeks (Gaskell et al., 2006), but can last significantly longer in individual cases.
FCV less commonly affects other tissues, such as the lungs or joints, leading to pneumonia (focal alveolitis, progressing to areas of acute exudative pneumonia and then to proliferative, interstitial pneumonia) and lameness, the so called limping kitten syndrome (Fig. 2). Co-infections of feline herpesvirus (FHV) and FCV are generally very common and have been described in kittens with pneumonia; FHV infection leads to airway damage, which might facilitate secondary infection with FCV due to reduced mucociliary clearance and impaired immune defences (Monne Rodriguez et al., 2018). Acute synovitis with thickening of synovial membranes and increased synovial fluid have been noted in cats with limping kitten syndrome (Dawson et al., 1994). The pathogenesis of the limping syndrome is not clear, although immune complexes are thought to play a role (Bennett et al., 1989), and FCV can be isolated from affected joints (Dawson et al., 1994). Limping kitten syndrome can also occur after FCV vaccination with some modified live virus vaccines.
The pathogenesis and clinical presentation of systemic disease caused by VS-FCV differ considerably from the typical picture described above. These VS-FCV strains cause widespread vasculitis, multi-organ involvement and death in up to two thirds of infected cats (Pedersen et al., 2000; Hurley and Sykes 2003; Schorr-Evans et al., 2003; Coyne et al., 2006b). The pathogenesis of VS-FCV infection is unknown and might include viral evolution and/or immune-mediated components as well as environmental and management factors (Hurley 2006). The virulent strains display a different cell tropism and grow more rapidly in cell culture compared to less virulent isolates (Pesavento et al., 2004; Ossiboff et al., 2007). The faster in vitro growth was associated with the capsid protein gene (Lu et al., 2018). The authors of the latter study suggested that conserved surface residues on the P2 subdomain of the capsid are important for the virus-receptor interaction and subsequent conformational changes that likely influence the in vitro infection kinetics and the virulence of different FCV isolates in vivo (Lu et al., 2018).
Healthy cats can be FCV carriers (Coutts et al., 1994; Coyne et al., 2006a; Berger et al., 2015b); in these cats the virus can be localised to the epithelium of the tonsils. However, in an experimental setting tonsillectomy did not eliminate the carrier state, suggesting that virus is also located in other sites. It is believed that evolution of the variable capsid protein allows FCV to escape the host immune response and to persist in carrier cats (Johnson 1992; Kreutz et al., 1998; Radford et al., 1998; Coyne et al., 2007b); although some structural restrictions might prevent substantial antigenic evolution of the FCV capsid (Smith et al., 2020). Indeed, it has been shown that certain residues of the capsid are required for binding of FCV to its cellular receptor (feline junctional adhesion molecule A, fJAM-A) and for subsequent events after binding (Lu et al., 2018; Conley et al., 2019).
Maternally derived antibodies (MDA) are important for protection during the first weeks of life and can interfere with vaccination. There are only few data on the extent and longevity for FCV MDA in cats. In general, their levels are higher and persist for longer than for FHV. In an experimental study, the average half-life of FCV MDA was determined to be 15 days and their persistence as 10-14 weeks (Johnson and Povey 1983). However, in a field study, 20% of kittens at only six weeks of age had no detectable antibodies against a widely used vaccine strain (Dawson et al., 2001).
Virus neutralising antibodies appear by approximately 7 days post infection (Kahn et al., 1975). In general, FCV neutralising antibody titres are higher than for FHV infection and their levels correlate well with protection against homologous challenge (Povey and Ingersoll 1975). Prior infection with one strain can still significantly reduce the acute clinical signs upon exposure to a heterologous strain, and in some cases oral shedding can be reduced (Povey and Ingersoll 1975; Knowles et al., 1991; Spiri et al., 2019). In general, the level of heterologous protection will depend on the virus strains involved. Cats can be protected also in the absence of detectable virus neutralising antibodies (Knowles et al., 1991; Poulet et al., 2005; Lesbros et al., 2013), suggesting a role for other immune mechanisms, and indeed, cellular responses have been demonstrated in vaccinated cats (Tham and Studdert 1987). Also, FCV-specific IgG and IgA antibodies have been demonstrated in the saliva during the course of infection (Knowles et al., 1991), although their significance in protection is unknown.
FCV infection can cause acute oral and upper respiratory signs but also has been associated with chronic stomatitis, which is considered an immune-mediated condition. Moreover, the “foot and paw” and VS-FCV disease have been described.
Acute oral and upper respiratory tract disease
Clinical findings can differ, depending on the FCV strain, the age of the affected cats and husbandry factors. While in some cases infection is subclinical, in many others, there is a typical syndrome of lingual ulceration (Fig. 3, 4) and a relatively mild acute respiratory disease. More severe signs can resemble the respiratory disease caused by FHV; however, frequently occurring co-infections with FHV, Chlamydia felis or Mycoplasma felis might be responsible for some of the respiratory signs rather than FCV itself (Berger et al., 2015b).
Acute oral and upper respiratory disease signs are mainly seen in kittens. The incubation period is 2 to 10 days (Hurley and Sykes 2003). Oral ulcerations, sneezing and serous nasal discharge are the main signs (Gaskell et al., 2006). Fever is also commonly observed. Anorexia, sometimes accompanied by hypersalivation due to oral erosions (located mainly on the tongue), is often more prominent than signs of rhinitis (Berger et al., 2015a). Signs usually resolve after a few days with only symptomatic treatment (Ballin et al., 2014; Friedl et al., 2014). In some severe cases, pneumonia, manifested by dyspnoea, coughing, fever and depression can occur, particularly in young kittens. Moreover, cases of corneal ulcers have been reported in FCV-infected cats (Gerriets et al., 2012). In rare cases, cats with corneal ulcers had high viral FCV RNA loads in the absence of other pathogens including FHV, Mycoplasma felis and Chlamydia felis (C.B. personal communication). It is unclear what the role of FCV is in these cases.
Feline chronic gingivostomatitis (FCGS)
An excellent review on periodontal disease and feline chronic gingivostomatitis (FCGS) has been published (Perry and Tutt 2015), and this cautions that severe gingivitis in a cat infected with FCV does not automatically provide for a diagnosis of FCGS. The inflammation in FCGS, by definition, extends beyond the mucogingival junction to encompass the alveolar mucosa and other soft tissues. If the inflammation is confined to gingival tissues, by definition a diagnosis of FCGS cannot be made. The aetiology of FCGS remains uncertain and several infectious agents can be associated with FCGS. In a prospective study, FCV was more significantly more commonly detected by RT-PCR in 52 cats with FCGS (54%) than in 50 healthy age-matched control cats (24%) (Belgard et al., 2010). Similar results were found in a study investigating 42 oral biopsies of cats with FCGS (40% RT-PCR positive versus none of the 19 controls (Dowers et al., 2010)). More recent studies confirmed these observations also in a larger population of cat in Spain (n = 260 cats with FCGS, 59% FCV-positive versus 98 controls, 15% FCV-positive; (Fernandez et al., 2017) and in a study in Japan (Nakanishi et al., 2019). However, in FCV-positive cats with FCGS, the viral FCV RNA loads were not associated with severity of disease (Druet and Hennet 2017), and a recent study in 26 cats failed to find FCV in FCGS lesions by immunohistochemistry (Rolim et al., 2017). It has been suggested that FCGS is an immune-mediated reaction to FCV (and potentially other oral antigens). The disease has not been reproduced experimentally using two different FCV isolates from cats with FCGS and oronasal infection (Knowles et al. 1991). FCV does not appear to play a role in feline odontoclastic resorptive lesions (FORLs) (Thomas et al., 2017).
An acute transient shifting lameness (Fig. 2) with fever can be associated with FCV infection (Pedersen et al., 1983; Dawson et al., 1994; TerWee et al., 1997) and also occur after FCV vaccination. Experimental oronasal infection with the FCV vaccine strain 255 led to mostly mild lameness in a small number of cats (3/10) (TerWee et al., 1997). Some cases develop following vaccination with modified live FCV vaccines using different strains; not always it’s the vaccine strain that is accountable for the limping, since in some cases FCV field strains, different to vaccine strains were detected and vaccination was incidental. In natural infection, it can occur a few days or weeks after the acute oral or respiratory signs (Pedersen et al., 1983; Bennett et al., 1989). The lameness can be severe and can shift quickly from one limb to another. Full recovery usually occurs within 24-48 hours without treatment, but NSAIDs can be useful to reduce inflammation and pain.
Paw and mouth disease
Paw and mouth disease has been reported in Australia (Cooper and Sabine 1972) prior to the description of VS-FCV infections in the US and Europe. It resembles initially very much VS-FCV disease but high mortality and epizootic spread has not been observed (Cooper and Sabine 1972; Love and Zuber 1987). Characteristic clinical signs include cutaneous oedema and ulcerative lesions on the skin of paws and on the head, in and around the mouth, and in the perianal region; as well as fever, depression and anorexia (Cooper and Sabine 1972; Love and Zuber 1987). Oedema is located mainly on the head and limbs. Organ involvement and jaundice has been observed in some cases (Willi et al., 2016). Usually, mortality is not high, but fatal cases have also been described (Meyer et al., 2011; Willi et al., 2016). In contrast to VS-FCV, “paw and mouth” disease is seen in single or very few cats and no epizootic spread of the disease is observed (Cooper and Sabine 1972; Love and Zuber 1987; Meyer et al., 2011; Battilani et al., 2013; Willi et al., 2016). It is unclear whether this was a distinct syndrome or whether these were also mild outbreaks of VS-FCV disease.
Virulent systemic feline calicivirus (VS-FCV) infection
Outbreaks of highly virulent and often lethal FCV infection in domestic cats have been described in the United States (Pedersen et al., 2000; Hurley and Sykes 2003; Schorr-Evans et al., 2003; Hurley et al., 2004; Pesavento et al., 2004), China (Guo et al., 2018) as well as in several European countries: France (Deschamps et al., 2015), Germany (Schulz et al., 2011), Italy (Caringella et al., 2019), Switzerland (R.H.L. personal communication), and the UK (Coyne et al., 2006b; Reynolds et al., 2009). A single outbreak has also been described in exotic captive felids in the United States (Harrison et al., 2007). The disease was initially named “hemorrhagic-like fever” (Pedersen et al., 2000) but subsequently “highly virulent feline calicivirus disease” was suggested, since haemorrhages were seldom observed (Schorr-Evans et al., 2003; Hurley et al., 2004). The causative virus strains are most commonly referred to as “virulent systemic feline calicivirus” (VS-FCV).
The incubation period in natural cases of VS-FCV infection in cats exposed in hospitals is usually 1-5 days; in the home environment it can extent up to 12 days (Hurley and Sykes 2003). The disease appears to be more severe in adults than kittens. Vaccination did not protect cats against field infections in many VS-FCV outbreaks (Hurley and Sykes 2003; Schorr-Evans et al., 2003; Hurley et al., 2004), although experimentally, some protection has been shown and prior vaccination resulted in a milder form of the disease (Pedersen et al., 2000; Brunet et al., 2005; Poulet et al., 2008; Lesbros et al., 2013). It is unknown whether this lack of or insufficient vaccine protection is due to inherent characteristics of hypervirulent strains or simply that vaccine-“susceptible” strains are unlikely to cause outbreaks since vaccination is so widely practiced (Pedersen et al., 2000; Hurley 2006). However, at least in one study it was recognized that many of the affected cats had not been, or had been insufficiently, vaccinated against FCV and that, according to in vitro neutralisation patterns, some cases might have potentially been prevented by vaccination (Willi et al., 2016). Moreover, in a large VS-FCV outbreak at the University Animal Hospital of Zurich, Switzerland, in 2016, most of the affected cats (approx. 80%) had not been FCV-vaccinated or had been vaccinated insufficiently (R.H.L. personal communication).
In contrast to the common strains, VS-FCV strains cause systemic disease characterized by severe systemic inflammatory response syndrome, disseminated intravascular coagulation (DIC), multi-organ failure, and commonly death. Mortality is high (~30-70%) (Schorr-Evans et al., 2003; Foley et al., 2006); in one outbreak, 79% (11/14) of the cats had to be euthanized or died with FCV associated virulent systemic disease (Deschamps et al., 2015).
The clinical signs of VS-FCV infection are variable. The initial findings are frequently typical of a severe acute upper respiratory tract disease. Characteristic signs are cutaneous oedema and ulcerative lesions on the skin and paws (Hurley and Sykes 2003). Oedema is located mainly on the head and limbs (Fig. 5). Crusted lesions, ulcers and alopecia can be seen on the nose, lips, and ears, around the eyes (Fig. 6) and on the footpads (Fig. 7). Not all affected cats show all the typical clinical signs, which makes it difficult to recognize all infected cats early during infection. Moreover, paw and mouth disease associated with FCV infection is characterized by similar initial clinical signs, including oedema, mouth and skin ulceration and fever (Cooper and Sabine 1972; Willi et al., 2016). Some of the cats with VS-FCV disease are jaundiced (e.g. due to hepatic necrosis, pancreatitis); some can show severe respiratory distress (e.g. due to pulmonary oedema). Thromboembolism and coagulopathy caused by disseminated intravascular coagulopathy can be observed, including petechiae, ecchymoses, epistaxis or bloody faeces (Hurley and Sykes 2003; Coyne et al., 2006b). Typically, VS-FCV outbreaks start in multicat environments, such as animal shelters or veterinary clinics, and they are characterized, apart from the clinical signs listed above, by epizootic spread and a high mortality.
FCV has also been implicated in other diseases like polyps and cystitis, but evidence for these associations is lacking (Klose et al., 2010; Larson et al., 2011). Most recently FCV was isolated from faeces of cats with enteritis lending support to the hypothesis that some FCV strains might acquire enteric tropism and act as enteric pathogen (Di Martino et al., 2020). However, currently there is insufficient data to determine whether FCV can act as a primary causative agent of gastrointestinal disease, whether it can trigger mechanisms of synergism in co-infections with other enteric pathogens, or whether it is passively shed into the gastrointestinal tract of FCV-infected cats.
Because of the asymptomatic carrier phase, and the fact that viruses in modified live virus vaccines are occasionally shed post-vaccination (Ruch-Gallie et al., 2011), caution should be taken when interpreting any FCV reverse-transcriptase PCR (RT-PCR)-positive result because of the poor correlation between the presence of virus and clinical signs (Sykes et al., 1998). However, in a cat that has typical clinical signs and a positive RT-PCR result, a causal relationship is likely.
The diagnosis of VS-FCV outbreaks relies on clinical signs, high contagiousness and high mortality rate and the isolation of the same strain from the blood of several diseased cats, assessed by sequencing hypervariable regions of the capsid gene.
Conventional, nested and real-time RT-PCR assays have been developed to detect FCV RNA in conjunctival and oral swabs, blood, cutaneous scrapings or lung tissue, depending on the clinical form and the outcome of the disease. The diagnostic sensitivity of RT-PCR depends on both the primers used in the PCR and the detected strain, because of the high variability of the viral genome; therefore, molecular assays should be optimised using a large panel of strains to minimize false negative results (Helps et al., 2002; Scansen et al., 2004; Wilhelm and Truyen 2006). Despite this, neither of two well-established FCV RT-PCR systems was able to amplify all isolates in a recent field study (Meli et al., 2018). Multiplex PCR assays have also been developed that detect FHV and FCV (and sometimes also Chlamydia felis) at the same time (Sykes et al., 2001), but such assays might be less sensitive. As well as having the potential to diagnose FCV infection, RT-PCR can provide the means of identifying uniquely the virus strain involved and has proven useful in molecular epidemiology and outbreak investigations. Generally real-time RT-PCR is recommended over conventional RT-PCR assays for diagnostic purposes due to a higher sensitivity, and – if available – quantitative assays are preferred since they also provide information on the virus load in positive samples. The result of diagnostic FCV RT-PCR must always be interpreted in conjunction with the clinical signs. A negative RT-PCR result does not rule out FCV infection. Factors, other than the sensitivity and specificity of the assay, that influence the result of the RT-PCR include the time of sampling, storage and transport (Meli et al., 2018). The detection of FCV by RT-PCR was significantly more likely in swabs from the oropharynx and tongue compared to conjunctival swabs (Schulz et al., 2015). Since there was no difference for the detection of FHV and Chlamydia felis among the different sampling sites, it was recommended to use the oropharynx as the preferred sampling site for detection of all three pathogens, but ideally multiple swabs are collected or multiple sites are collected with the same swab (sequentially starting with the conjunctiva), to maximise the likelihood of detection (Schulz et al., 2015).
Virus isolation is a useful method for detecting FCV infection; it indicates the presence of replicating virus and has the advantage of being less influenced by the effect of strain variation than RT-PCR. FCV replicates in cell lines of feline origin; its rapid growth in tissue culture can compromise identification of concurrent FHV infection (Pedersen 1987). Virus can be isolated from nasal, conjunctival or oro-pharyngeal swabs (Gaskell and Dawson 1998), but virus isolation can fail due to low numbers of virions in the sample, virus inactivation during transit, or to the presence of antibodies in extracellular fluids that prevent virus replication in vitro (Meli et al., 2018). The likelihood of successful virus isolation is maximised if swabs from both conjunctiva and oropharynx are collected (Marsilio et al., 2005). Moreover, combined FCV detection by RT-PCR directly from swabs and after virus isolation further increased sensitivity; neither of the methods alone, RT-PCR nor virus isolation, were able to detect all FCV-positive samples (Meli et al., 2018). Therefore, a negative FCV test result in a cat suspected to be infected with FCV does not exclude FCV infection.
FCV antibodies can be detected by virus neutralisation or ELISA (Lappin et al., 2002). The antibody prevalence is generally very high in cat populations as a result of natural infection and vaccination (Hellard et al., 2011; Bergmann et al., 2019). Consequently, the presence of specific antibodies is not useful to diagnose infection ((Gaskell and Dawson 1998); EBM grade I). Levels of virus neutralising antibodies can be used to predict whether a cat is protected or not, but must be interpreted with care, as false negative results can be obtained if virus neutralising antibodies do not cross-react with the laboratory strains used in the test. In addition, titres can appear higher when homologous rather than heterologous virus-antibody pairs are used. When the strain used is not defined, it makes interpretation of the results difficult (Scott and Geissinger 1997; Scott and Geissinger 1999; Dawson et al., 2001; Gore et al., 2006). The value of FCV antibody testing in predicting protection from FCV infection is limited (Radford et al., 2009; Bergmann et al., 2019).
Diagnosis of VS-FCV infections
Consistent genetic markers associated with virulence, specifically hypervirulent strains involved in VS-FCV, have yet to be identified (Abd-Eldaim et al., 2005; Foley et al., 2006; Ossiboff et al., 2007; Spiri et al., 2016), although a recent study found that the capsid gene of a virulent FCV isolate was responsible for more rapid in vitro growth kinetics (Lu et al., 2018). Moreover, analysis of the amino acid properties of the E region of VP1 built by the coding sequences of different VS-FCV strains was able to differentiate the latter and classical FCV strains (Brunet et al., 2019). Seven residue positions of region E were identified that were different between different pathotypes, and a structural analysis suggested an interaction of these residues with fJAM-A or VP2, which can lead to different post-binding events of the virus and conformational changes, which in turn might explain the differences in pathogenesis between different pathotypes (Brunet et al., 2019). Nonetheless, currently there are still no diagnostic assays that specifically detect VS-FCV. The diagnosis of VS-FCV infections is based on the typical clinical appearance, often the occurrence in multicat environments, the epizootic spread and the detection of FCV in the diseased cats by RT-PCR from oropharyngeal swabs, cutaneous scrapings from ulcerated lesions or from blood. What is mentioned above for FCV is true also for VS-FCV: One negative FCV RT-PCR result does not rule out a VS-FCV infection. It is important to consider adequate hygienic measures as soon as clinical signs compatible with VS-FCV infection are seen in a cat, although severe, non-epizootic forms of FCV infections exist (paw and mouth disease) with clinical presentations initially similar to FCV associated virulent systemic disease (Meyer et al., 2011; Battilani et al., 2013; Willi et al., 2016).
Treatment of acute upper respiratory tract or oral disease
Cats severely affected by FCV infection need intensive nursing care and supportive therapy. The resolution of dehydration and restoration of electrolyte disturbances, by intravenous fluid administration if required, is needed for cats with severe clinical signs. Food intake is extremely important. Many cats with FCV infection do not eat mainly because of fever and/or pain from ulcers in the oral cavity, sometimes also because of their loss of smell due to nasal congestion. Food can be blended to cause less pain when eating, should be highly palatable, and can be warmed up to increase the smell. Tempting the cat to eat by hand feeding of warm smelly blended foods can be sufficient in mild cases but appetite stimulants (e.g. mirtazapine; 1.88-2 mg/cat PO, SID if renal and hepatic function is not compromised, give EOD if it is). Alternatively, commercial fluid high-energy diets can be used for hand feeding. If the cat is not eating for more than three days, placement of a feeding tube and enteral nutrition is indicated. One option is to use naso-oesophageal tube (NOT) feeding; these usually require no sedation for placement but cats with FCV might resent the presence of the tube around the nose and sometimes intermittent placing of the NOT for each feed can work better than leaving one in place, but softer silicone tubes are now available that can be used for cats with soreness of the nose and/or pharynx. In more severe cases and in cats that are expected to eat within a few days, oesophagostomy tube feeding can be used but these need short general anaesthesia for placement but do allow for medicating and easier feeding via the wider bore tubes which are away from the cat’s face.
Non-steroidal anti-inflammatory drugs can be used to decrease fever and oral pain, but only once dehydration is corrected, and ideally when there is food intake. Maropitant is sometimes used in cats with upper respiratory symptoms, but there is no study proving its efficacy in these conditions, and moreover there is no indication to use it in cats with FCV infection.
Cheap small nebulisers can be purchased for use in the veterinary clinic (or loaned to owners to use at home) for regular nebulisation therapy with saline (q 4-6 hours if possible for 15 mins at a time) – in the hospital setting this can be applied close to the cat’s face by placing the cat in an igloo and covering the igloo for example. This can rehydrate the upper respiratory tract, loosen secretions, reduce congestion and increase comfort. If a nebuliser is not available, an alternative is to provide steam therapy. Owners can do this at home by sitting with their cat with care in a bathroom with hot running water/shower. Adequate humidity will be present when the bathroom mirror becomes ‘foggy’ and the time this takes will depend on the size of the bathroom.
If there is a nasal discharge, this should be cleaned away several times a day with physiological saline solution, and ointment should be applied locally. If the nose is congested, nasal flushing with saline is recommended to remove the congestion. If there is a mucous nasal discharge, drugs with mucolytic effects (e.g. bromhexine) may be helpful.
At the clinician’s discretion, antibiotics should be given to cats with severe disease and suspected secondary bacterial infection. An empirical choice is usually made initially, as diagnostic tests are unlikely to be indicated or performed in acute infection. It is crucial to use antibiotics with good penetration in the respiratory tract and/or oral cavity. Oral doxycycline (10 mg/kg q12h) for 7-10 days is recommended as a 1st line treatment in the ISCAID guidelines (Lappin et al., 2017).
Most antivirals used in veterinary medicine only inhibit replication of DNA viruses or retroviruses, and antivirals for the specific treatment of FCV infections are not available. Ribavirin is one of the few antiviral agents able to inhibit FCV replication in vitro. However, it appears to be very toxic to cats and side effects have precluded its systemic use ((Povey 1978) EBM grade III). Feline interferon-ω (licensed for the treatment of canine parvovirus and feline leukaemia virus infections in some European countries) has been shown to inhibit FCV replication in vitro ((Fulton and Burge 1985; Mochizuki et al., 1994; Taira et al., 2005); EBM grade IV). There is some suggestion that strains can vary in their sensitivity to interferon (Ohe et al., 2008). One prospective, randomised, placebo-controlled, double-blinded clinical study investigated whether administration of feline interferon-ω using an owner-friendly protocol (one injection, afterwards topical administration) improved clinical signs in cats with acute feline upper respiratory tract disease caused by FCV and/or FHV and whether this treatment reduced shedding of FCV. Thirty-seven cats affected with acute clinical signs caused by FCV and/or FHV were randomly assigned to treatment groups, receiving either placebo or feline interferon-ω (2.5 MU/kg subcutaneously, followed by 0.5 MU topically at 8-h intervals via the conjunctiva, intranasally, and orally for 21 days). All cats received additional symptomatic treatment. All cats showed rapid improvement of clinical signs, but treatment with feline interferon-ω was not more effective in ameliorating clinical signs compared to placebo (Ballin et al., 2014). PSSNa polymers (polysodium 4-styrenesulfonates) have been suggested as potent FHV and FCV inhibitors for topical use (Synowiec et al., 2019). Anti-FCV-specific F(ab')2 fragments elicited in horses immunized with inactivated FCV showed efficient FCV neutralising activity in vitro and had therapeutic and prophylactic effects in FCV-infected cats (Cui et al., 2019). Moreover, adenosine analogue NITD008 were found effective against FCV replication in vitro (Enosi Tuipulotu et al., 2019) but its effectiveness has not been determined in vivo.
A commercially available product, Feliserin (hyperimmune serum available in Germany only to the author’s knowledge) which contains antibodies against FCV, FHV and FPV is marketed for the treatment of acute viral feline upper respiratory tract disease (FURTD) disease. One study evaluated its efficacy, versus placebo, for acute viral FURTD due to FCV and/or FHV infection (Friedl et al., 2014). Feliserin was given for 3 days, subcutaneously once daily and topically into eyes, nostrils, and mouth every 8 hours. Clinical signs and health status in both groups improved significantly over time. Cats receiving hyperimmune serum significantly improved in terms of clinical signs by day 3, while cats in the placebo group only improved significantly by day 7. Thus, administration of hyperimmune serum led to a more rapid improvement of clinical signs in cats with acute FURTD, but by day 7, clinical signs had improved equally in both groups, so the value of the treatment may not be great enough to warrant its use.
Treatment of FCGS
A full description of the treatment of chronic stomatitis is beyond the scope of these guidelines. However, several modalities have been used to treat chronic ulceroproliferative stomatitis. Recommended options depend on the disease severity and stage and include antibiotics plus rigorous dental cleaning, daily chlorhexidine application, corticosteroids and/or other immunosuppressant or immunomodulatory drugs (chlorambucil and cyclosporine; (Vercelli et al., 2006); EBM grade IV) and in severe cases, full teeth extractions ((Hennet 1994); EBM grade III). Two recent studies investigated treatment of FCGS using intravenous injections of fresh adipose-derived mesenchymal stem cells; autologous cells were found to be more efficient than allogenic cells (Arzi et al., 2016; Arzi et al., 2017). Five of seven cats completing the study responded to treatment by either complete clinical remission (n=3) or substantial clinical improvement (n=2) (Arzi et al., 2016).
Anecdotal and clinical case reports and few studies have suggested the use of both feline interferon-ω and human interferons to treat cats with chronic stomatitis associated with FCV shedding, by intra-lesional or combined systemic plus intralesional application (Southerden and Gorrel 2007). A cat with chronic gingivostomatitis which had not responded to tooth extraction completely responded to treatment with feline interferon-ω within 6 weeks (Southerden and Gorrel 2007). Feline interferon-ω was initially administered daily, and then switched to 105 IU/cat q 24 h PO (in 2 mL of isotonic saline solution) for 2 months and then every other day (Southerden and Gorrel 2007). In a randomised, double-blinded study of 39 FCV-infected cats with stomatitis, treatment with oral feline interferon-ω at 105/cat q 24 h for 90 days was compared to treatment with prednisolone at 1 mg/kg q 24 h PO for 7 days, followed by 1 mg/kg q 48 h PO for 7 days, and finally 0.5 mg/kg q 48 h PO for 7 days (Hennet et al., 2011). There was no significant difference between the two groups for most of the parameters, except for the pain score that was significantly lower in cats treated with feline interferon-ω after 2 and 3 months (Hennet et al., 2011). In another much shorter duration study, 17 FCV-infected cats with chronic gingivostomatitis were treated with either feline interferon-ω SC at days 1, 2, 3, 7, 8, 14, and 21 (n=13) or 1 mg/kg prednisolone q 24 h SC (n=4) at the same time points (Matsumoto et al., 2018). There was a significant improvement in the clinical and salivation scores of the cats treated with feline interferon-ω, but not in the pain upon opening the mouth, nor in the presence of halitosis or mandibular lymphadenopathy (Matsumoto et al., 2018). Oral administration of feline interferon-ω led to clinical improvement of lesions in two cats with type II diabetes mellitus and concurrent chronic gingivostomatitis, and the required insulin dose could also be decreased (Leal et al., 2013). Thus, feline interferon-ω might be a good alternative to glucocorticoid treatment especially in cats in which full teeth extraction is not an option and in those, which cannot be treated with glucocorticoid, such as those with diabetes.
Other management considerations
- Avoid stress, consider environmental enrichment and management of the multicat households. A recent study looked at the effect of a synthetic feline facial pheromone (Feliway [CEVA]) in two shelters in the USA (Chadwin et al., 2017) in reducing stress scores and/or the incidence of infections associated with FURTD, compared to placebo. No evidence was found that the pheromone product had any effect on stress scores or incidence of infections associated with FURTD in the shelter-housed cats.
- Consider hygiene, partitions, grouping, order of cleaning (ill cats last) etc. Effective barrier nursing is essential for hospitalised patients being treated with acute infections associated with FURTD. However, staff should be mindful that outwardly normal cats could be shedding FCV.
- Care with introduction of new cats into a household, if you have a FCV free household - quarantine for 3 weeks with the option to swab for FCV before introduction into the household.
- If there are recurrent problems with FCV in a multicat environment, reduce the number of cats within the individual group (see also “Managing FCV outbreaks in multi-cat communities”(ABCD 2019)).
Treatment of VS-FCV infection
In outbreaks of VS-FCV, severely affected cats have been treated with intensive care supportive treatment (e.g. fluid therapy, antibiotics) as well as with glucocorticoids, feline interferon-ω, and specific antibody preparations; and clinical improvement has been reported anecdotally in some cats. However, controlled clinical studies have not been published; so specific treatment for the disease is not currently known ((Hurley 2006); EBM grade III).
FCV infection is ubiquitous and can induce severe disease. ABCD therefore recommends that all cats should be vaccinated against FCV (ABCD 2020). Recent European surveys of vaccine history in cats and owners’ attitudes to vaccination have shown that 78% of German cats had been vaccinated during the last three years (Gehrig et al., 2018) and 69% of the cats in the UK had been vaccinated during the last 12 months (Habacher et al., 2010). Although vaccination provides good protection against acute oral and upper respiratory tract disease in most cases, it does not prevent cats from becoming infected or from shedding FCV following infection (Radford et al., 2006).
Currently, FCV is combined with FHV in divalent vaccines (only in some countries) or, more commonly, with other antigens. Both modified live and inactivated parenteral vaccines are available. Modified live intranasal vaccines are still current in the USA, but unfortunately are no longer available in Europe. In a recent study, intranasal administration of an experimental inactivated, non-adjuvanted FCV vaccine has been shown to be better than a subcutaneous vaccine in terms of reducing clinical scores and virus shedding following exposure (Sato et al., 2017). Moreover, cats that had received an intranasal vaccine did not develop detectable antibodies against feline renal cells induced by vaccine components (Lappin et al., 2005).
There is currently no vaccine available that protects equally well against all FCV field strains and vaccine companies are seeking to identify newer strains that potentially provide wider cross protection. The most commonly used vaccine strains are F9, which is the oldest, isolated in the 1950s, FCV 255, and two newer strains G1 and 431 (Poulet et al., 2000; Poulet et al., 2005). Some vaccine companies do not state the strain of virus used in their vaccine. One manufacturer has introduced a hypervirulent strain into its vaccine in the USA (Huang et al., 2010), and a Japanese research group has developed a triple strain vaccine (Masubuchi et al., 2010); however, at the time of writing (2020) these are not available in Europe. As FCV can mutate quickly, field strains could evolve resistance to any vaccine-induced immune response, particularly if a vaccine is used for a prolonged period of time in the population (Lauritzen et al., 1997).
FCV vaccines provide protection mainly by inducing humoral immunity (virus neutralising antibodies). However, it is difficult to make a general recommendation about which vaccine strain or strains to use based on results from in vitro neutralisation studies as conflicting results have been published from studies testing the susceptibility of field strains of FCV to neutralisation by sera raised by different vaccine strains. Two studies suggest that the oldest vaccine strains still effectively cross neutralise current field strains (Porter et al., 2008; Afonso et al., 2017), whereas other studies demonstrated that antisera raised against newer vaccine strains effectively cross-neutralised a larger proportion of field strains compared to antisera raised against the oldest vaccine strain (Addie et al., 2008; Poulet et al., 2008; Wensman et al., 2015). The different outcomes of these studies likely reflect both the different populations of cats that were sampled in order to isolate field strains as well as the different methodologies adopted to prepare antisera against the vaccine strains.
Several studies were conducted to obtain more information about the field strains circulating in Europe (Coyne et al., 2012; Hou et al., 2016; Spiri et al., 2016; Afonso et al., 2017). A recent field study addressed the hypothesis as to whether the decade-long use of the FCV vaccine strain F9 drove the emergence of vaccine-resistant viruses in the UK (Afonso et al., 2017; Smith et al., 2020). The authors concluded that this was not the case as there was no evidence of progressive phylogenetic or antigenic divergence from the vaccine strain F9 of geographically representative field isolates collected in 2001 and 2013/2014 (Afonso et al., 2017; Smith et al., 2020). Recent epidemiological and phylogenetic studies in Switzerland also indicated that the oldest vaccine strain clusters with contemporary FCV field isolates and provides protection against FCV infection under field conditions (Berger et al., 2015a; Spiri et al., 2016; Kratzer et al., 2020). Moreover, a recent comparative in vivo study found no evidence of reduced protection against a European FCV field strain of a FCV F9 strain based vaccine in comparison with a FCV vaccine containing the newer G1 and 432 FCV strains (Almeras et al., 2017).
Independent of the vaccine strains used, if FCV-associated disease is found to be occurring in fully vaccinated cats then changing to a different FCV vaccine antigen should be considered.
The onset of immunity was determined to be within 7 days after vaccination for a non-adjuvanted inactivated FCV vaccine: Kittens were protected from severe clinical signs and vaccine efficacy was similar 7 days and 4 weeks after vaccination (Jas et al., 2009). The duration of immunity for the same vaccine was reported to be 3 years (Jas et al., 2015).
The impact of vaccination on the shedding of field viruses is controversial, with some studies showing a moderate reduction (Poulet et al., 2005; Jas et al., 2009; Almeras et al., 2017) whilst others show that vaccination might actually extend the period of virus shedding after infection (Dawson et al., 1991; Pedersen and Hawkins 1995; Spiri et al., 2019). One study reported that the impact of vaccination on shedding of FCV field strains depended on the timepoint after vaccination at which this was measured; whilst a reduction in FCV shedding was observed when FCV infection occurred a few weeks or one year after vaccination, viral shedding was not reduced anymore with FCV infection 3 years after vaccination (Jas et al., 2015).
Live parenteral and intranasal FCV vaccine strains can be shed following vaccination, although this seems to be uncommon (Pedersen and Hawkins 1995; Radford et al., 1997; Radford et al., 2000; Radford et al., 2001a; Coyne et al., 2007b; Ruch-Gallie et al., 2011).
Live vaccines retain some pathogenic potential and can induce disease especially if administered incorrectly, e.g. when such a vaccine is accidentally aerosolised or spilled onto the cat’s skin or fur and ingested during grooming (Dawson et al., 1993; Pedersen and Hawkins 1995; Radford et al., 1997; Radford et al., 2000).
Cats that have recovered from FCV disease are probably not protected for life against further episodes of disease, particularly those caused by different strains. Therefore, vaccination of recovered, healthy cats is generally recommended, even in situations where FCV is endemic, and vaccination should be applied as soon as the clinical signs have resolved to potentially induce immunity against a broader spectrum of strains.
In contrast to FPV, the value of antibody testing in predicting protection is limited, because antibodies to the FCV strain used in a laboratory test might not necessarily protect against the FCV strains to which the cat will subsequently be exposed in the field. Accordingly, a field study came to the conclusion that measuring FCV antibodies cannot replace routine vaccination against FCV (Bergmann et al., 2019).
Kittens: ABCD recommends that all kittens should be vaccinated against FCV (ABCD 2020). Because MDA can interfere with the response to vaccination, the primary course of vaccination is usually started at around 9 weeks of age, although some vaccines are licensed for use at an earlier age. Kittens should receive a second vaccination 2 to 4 weeks later, but not earlier than at 12 weeks of age. This protocol has been developed to ensure optimal protection. However, due to a longer persistence of MDA, some kittens might fail to respond to this protocol ((Dawson et al., 2001); EBM grade I)(Poulet 2007). Therefore, in high-risk situations, particularly where FCV has been shown to cause disease in vaccinated kittens, a third vaccination at 16 weeks should be considered. After the kitten primary vaccination course, all cats receive an additional vaccine dose at 10 to 16 months of age: This will ensure adequate vaccine induced immunity for cats that might not have adequately responded to the primary course. It is recommended using the same vaccine brand or at least the same vaccine strains for the entire primary vaccination course.
Older cats of uncertain FCV vaccination status should also receive two injections with an interval of 2 to 4 weeks, and a boost 1 year later, using vaccines containing the same virus strains. This applies even if the vaccine contains modified live virus.
The issue of recommended intervals between boosters is still controversial. However, based on study results published by several independent groups, ABCD recommends that boosters should be given at triennial intervals to protect individual cats against FCV field infections (EBM grade II) for cats in low-risk situations, such as mainly indoor-only cats with little or no contact to others. However, owners should be made aware that as time since the last vaccination increases, the degree of clinical protection decreases.
However, cats in crowded high-risk situations (e.g. boarding catteries) should be revaccinated at yearly intervals. For other cats, an informed decision should be made on the basis of a risk-benefit analysis. The ABCD recommends a single injection if the interval since the last vaccination is not more than three years. Even if the interval exceeds three years, usually one vaccination would ensure protection, especially if a modified live vaccine is used. When switching FCV vaccines to different vaccine strains for boosters, then one vaccine is sufficient if the new vaccine contains a modified life strain; however, two vaccines are recommended to ensure optimal protection if switching to an inactivated vaccine, when the inactivated vaccine contains different strains to the previous vaccine. The ABCD realizes that unfortunately single-component FCV vaccines are currently unavailable. Annual boosters that protect against other antigens might in practice entail more frequent boosters than triennially.
In multicat environments, FCV is frequently a problem and it is rather a question of how much FCV-associated disease is tolerable. To reduce FCV-associated clinical problems in multicat environments, special measures are necessary, such as decreasing cat group sizes, reducing introductions of new cats and quarantining newly introduced cats, separating sick cats, hygienic measures using disinfection effective against FCV and washing clothes at temperatures ≥ 60°C and augmenting vaccination to annual boosters and changing vaccine antigen if disease persists (ABCD 2020). ABCD has developed a factsheet aimed at veterinary surgeons responsible for the health and wellbeing of groups of cats that helps develop structured healthcare discussions with clients and locate weak points that can be improved to reduce FCV problems within the facility (ABCD 2019).
FCV is often a problem in cat shelters. Management to limit or even prevent virus transmission is as important as vaccination in control. Shelter design and management should be aimed at avoiding cross infection of cats. Cats should be housed individually unless they are known to originate from the same household. Dogs and cats should be housed separately, and flea control should be implemented to minimise the risk of transmission of FCV and other diseases. If acute respiratory disease occurs in a shelter, identification of the agent involved (with differentiation of FCV from FHV, Chlamydia felis, Bordetella bronchiseptica, and Mycoplasma spp.) is useful in deciding on the appropriate preventative measures and treatment. In case of an FCV outbreak, it should be considered that FCV can persist in the environment for about 1 month and is resistant to many common disinfectants. Effective substances include sodium hypochlorite (5% bleach diluted at 1:32), potassium peroxy-monosulfate, chlorine dioxide and commercial products that have been approved for their virucidal activity. Any clothing or cat bedding etc. should be washed at ≥ 60°C. New healthy cats should be vaccinated as soon as possible (ABCD 2020). Modified live virus vaccines are preferred in shelters because of the earlier onset of protection.
FCV can be a major problem for cat breeders. Infection most often appears as FURTD in young kittens, typically at around 4-8 weeks as MDA wanes. Disease in such young kittens can be severe and frequently involves all the kittens in the litter; some kittens can die. Vaccination of the queen will not prevent virus shedding but can be beneficial in ensuring that the kittens benefit from higher levels of MDA through the colostrum and milk, providing protection for the first month or so of life.
Revaccinations should take place prior to mating. Vaccination during pregnancy is not recommended. Modified live virus vaccines are not licensed for use in pregnant cats and if considered at all, an inactivated vaccine must be used. Queens should kitten in isolation, and in order to avoid the risk of exposure to potential carrier cats, the litter should not mix with other cats until it has been fully vaccinated. Early vaccination should be considered for litters from queens that had infected litters previously or for which there is concern of infection (ABCD 2020). The earliest age for which FCV vaccines are licensed is six weeks, but vaccination could be considered even earlier in kittens deemed to be at risk. When levels of MDA might be too low to protect, vaccination should be repeated every 2 weeks until the primary vaccination course is concluded at 12 weeks.
When all other control strategies have failed, early weaning into isolation from around 4 weeks of age has been suggested, is an alternative approach to protect kittens against infection from their mothers. However, the stress and behavioural problems that arise from early weaning are huge and it was not demonstrated to be effective; therefore, ABCD does not recommend this for FCV problems.
If VS-FCV outbreaks are encountered, this usually happens in multicat environments, such as cat shelters or veterinary facilities. Controlling a VS-FCV outbreak is very challenging; all exposed cats must be considered at risk for transmitting severe disease to others; there is no clearly defined “quarantine period” after which we know cats are safe; and it cannot be assumed that vaccination is protective. Moreover, indirect transmission must be considered through persons and fomites. It is important to create an immediate and complete break between exposed cats and newly admitted cats to the shelter or veterinary facility. Veterinary practices/clinics have been completely closed for cats following an outbreak for at least four weeks to achieve this which was very effective in controlling the outbreaks. The exposed cats should be isolated/quarantined. Hygiene and disinfection are very important, including thoroughly cleaning of all surfaces, followed by application of a disinfectant active against unenveloped viruses, e.g. accelerated hydrogen peroxide (RescueTM), potassium peroxymonosulfate (Trifectant®, Virkon-S®), and sodium hypochlorite (bleach) are all effective. Pre-cleaning with a detergent to remove all organic matter is especially important when using bleach as a disinfectant, as bleach is substantially inactivated by organic matter so will not work unless cleaning before its use is thorough. It is important to allow the disinfected area to dry thoroughly and disinfection should be repeated once. For outbreaks in shelters, helpful online resources are available (UCDavis 2018).
ABCD Europe gratefully acknowledges the support of Boehringer Ingelheim (the founding sponsor of the ABCD) and Virbac.
ABCD (2019): European Advisory Board for Cat Diseases (ABCD): Managing FCV outbreaks in multi-cat communities. Accessed 11.11.2020. http://www.abcdcatsvets.org/wp-content/uploads/2020/02/FCV-in-multi-cat-communities.pdf.
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