Feline Infectious Peritonitis Guideline

The Feline Infectious Peritonitis guidelines were first published by Addie et al. in 2009 in Journal of Feline Medicine and Surgery 11 (7) 594-604, and again by Tasker et al. in 2023 in Viruses 15 (9) 1847. The present update has been written by Séverine Tasker and ABCD members. ABCD FIP Diagnostic Approach Tools are also available.

Update March 28, 2024

Key Points

• Feline coronavirus (FCoV) is a ubiquitous RNA virus of cats, which is transmitted faeco-orally.
• FCoV is primarily an enteric virus and most infections do not cause clinical signs, or result in only enteritis, but a small proportion of FCoV-infected cats develop FIP.
• The pathology in FIP comprises a perivascular phlebitis that can affect any organ.
• Cats under two years old are most frequently affected by FIP. Most cats present with fever, anorexia, and weight loss; many have effusions, and some have ocular and/or neurological signs.
• Making a diagnosis is complex and ABCD FIP Diagnostic Approach Tools are available to aid veterinarians. Sampling an effusion, when present, for cytology, biochemistry, and FCoV RNA or FCoV antigen detection is very useful diagnostically. In the absence of an effusion, fine-needle aspirates from affected organs for cytology and FCoV RNA or FCoV antigen detection are helpful.
• Definitive diagnosis usually requires histopathology with FCoV antigen detection.
• Antiviral treatments now enable recovery in many cases from this previously fatal disease; nucleoside analogues (e.g., oral GS-441524) are very effective, although they are not available in all countries. Details on antiviral treatment protocols are given in Table 2 of these guidelines.

1. Introduction

Feline coronavirus (FCoV) is a ubiquitous RNA virus present in many cat populations around the world. FCoV is primarily an enteric virus, and infection does not usually result in clinical signs or causes only enteritis (Pedersen et al., 1981; Hayashi et al., 1982; Addie and Jarrett 1992; Kipar et al., 1998; Addie and Jarrett 2001) or failure to gain weight normally (Addie and Jarrett 1992). However, a small proportion of FCoV-infected cats go on to develop a serious disease mediated by a vasculitis (Kipar et al., 2005), called feline infectious peritonitis (FIP). Coronaviral genomes possess a high level of genetic variation due to the error rate of RNA polymerase, leading to multiple mutations. Although FCoV infections can undergo a systemic phase within monocytes in healthy cats (Kipar et al., 2010; Mustaffa-Kamal et al., 2019), mutations occurring in an individual cat are believed to allow a switch of cell tropism from enterocytes to monocytes to enable the subsequent development of highly pathogenic FIP-inducing FCoV (Pedersen 2014b), as discussed later in this review. However, an individual critical mutation has not been identified and likely does not exist (Zehr et al., 2023).

FIP disproportionately affects pedigree cats (Robison et al., 1971; Rohrbach et al., 2001; Norris et al., 2005; Pesteanu-Somogyi et al., 2006; Worthing et al., 2012; Soma et al., 2013; Coggins et al., 2023) and those under two years old (Rohrbach et al., 2001; Norris et al., 2005; Pesteanu-Somogyi et al., 2006; Riemer et al., 2016; Katayama and Uemura 2021; Yin et al., 2021). Most cases present with effusions (typically abdominal and/or pleural, occasionally pericardial, or scrotal) alongside fever, anorexia, and weight loss (Sparkes et al., 1991; Pedersen 2009; Tsai et al., 2011; Riemer et al., 2016; Baek et al., 2017; Felten and Hartmann 2019; Jones et al., 2021; Krentz et al., 2021; Yin et al., 2021; Sweet et al., 2022; Coggins et al., 2023). Abdominal lymphadenopathy is also reported (Lewis and O’Brien 2010; Dunbar et al., 2019; Yin et al., 2021; Coggins et al., 2023), especially in cats without effusions (Katayama and Uemura 2023). Ocular (e.g., uveitis) (Ziolkowska et al., 2017; Katayama and Uemura 2023) and neurological (e.g., ataxia) (Kline et al., 1994; Foley et al., 1998; Crawford et al., 2017; Katayama and Uemura 2023) signs can also occur.

Sampling an effusion, when present, for cytology, biochemistry, and FCoV antigen or FCoV RNA analysis is the most useful diagnostic step for FIP, while fine-needle aspirates (FNAs) from affected organs for cytology and FCoV RNA analysis are helpful if effusions are absent (Thayer et al., 2022). However, definitive diagnosis usually requires consistent histopathological changes in affected tissues with positive FCoV antigen immunostaining (Felten and Hartmann 2019).

If prompt treatment with antivirals, typically the nucleoside analogue GS-441524, is not given, FIP has a very poor prognosis with a short survival time (Ritz et al., 2007; Tsai et al., 2011). The recent development and availability of curative antiviral treatments (Pedersen et al., 2019; Addie et al., 2020b; Dickinson et al., 2020; Katayama and Uemura 2021; Krentz et al., 2021; Yin et al., 2021; Addie et al., 2022; Bohm 2022; Nekouei et al., 2022; Roy et al., 2022; Coggins et al., 2023; Green et al., 2023; Katayama and Uemura 2023) have revolutionised the approach to, and outcome of, FIP, although these treatments are often expensive and not legally available in all countries. Clinicians are now in need of diagnostic tools to help determine the likelihood of a diagnosis of FIP quickly (Thayer et al., 2022) so that effective antivirals can be used as soon as possible in countries in which antivirals are available.

These current guidelines contain minor updates to the previous ABCD FIP guidelines, published in 2023 (Tasker et al., 2023b). Some repetition is present in the sections of these guidelines as they have been designed to be readable in isolation, without needing to refer to other sections. However, the resulting guidelines are very long, and thus non-referenced boxed summaries are included at the end of each section (and subsections when needed) to provide an overview of essential facts in that area to allow access to information quickly.

2. Agent Properties

2.1. Virus Classification

Feline coronavirus (FCoV) (Owens et al., 2012) is a large, pleomorphic spherical, enveloped virus particle classified in the order Nidovirales; family Coronaviridae; subfamily Coronavirinae; genus Alphacoronavirus; species Alphacoronavirus 1, which also includes the enteritis-causing canine coronavirus (CCoV), transmissible gastroenteritis virus (TGEV) and porcine respiratory coronavirus (PRCoV) (De Groot et al., 2012; Jaimes et al., 2020). The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is very distinct and different from FCoV, belonging to a different genus: the genus Betacoronavirus (Haake et al., 2020). Separate guidelines on SARS-CoV-2 in cats are available (Hosie et al., 2021).

2.2. Virus Genome and Structure

Being an enveloped virus, FCoV is readily inactivated by most disinfectants, steam, and washing at 60°C (Addie et al., 2015a). It has been suggested it might preserve its infectivity for days to a few weeks (Scott 1988), depending on environmental conditions and protection by faecal matter. A more comprehensive study (Reissner et al., 2023) evaluated the stability of FCoV as a surrogate for SARS-CoV-2. It found that airborne FCoV remained infectious for over seven hours; its stability being higher at relative humidities of around 40% and 70%. Additionally, FCoV remained infectious for several months on stainless steel surfaces, especially at cool (4⁰C compared to 20⁰C) temperatures and in the presence of organic material.

A schematic diagram of the FCoV genome is shown in Figure 1.

Figure 1. Schematic diagrams of type I FCoV, not drawn to scale. (a) Schematic FCoV genome. FCoV is a positive-sense single-stranded RNA virus. The FCoV genome of 27–32 kilobases encodes a replicase polyprotein, four structural proteins (spike [S], membrane [M], nucleocapsid [N] and envelope [E]) and non-structural accessory proteins 3a, 3b and 3c and 7a and 7b. UTR indicates an untranslated region. Image Emi Barker, Langford Vets, University of Bristol, UK (Barker and Tasker 2020b). (b) Schematic FCoV spike protein (based on (Millet and Whittaker 2015; Healey et al., 2022; Shi et al., 2023)) sequence showing the division into the S1 and S2 subunits representing the receptor-binding and fusion domains, respectively, with N- and C-terminals shown. The S1/S2 and S2′ sites represent cleavage sites (in red), and the fusion peptide domain is also shaded in red. The positions of the M1058* and S1060* amino acid residues (blue lines) are shown because these correspond to the FCoV nucleotide sequences in specific spike gene mutations that are evaluated in some commercially available molecular assays. * Convention is to label amino acid substitutions by initials surrounding the numbered amino acid residue location (e.g., M1058L indicates that methionine is replaced by leucine at position 1058; similarly, S1060A indicates that serine is replaced by alanine at position 1060). Image Séverine Tasker, University of Bristol, UK.

The 5′ two-thirds of the positive-sense coronavirus (CoV) genome consist of two overlapping open reading frames (ORFs), 1a and 1b, that encode non-structural polyprotein (pp) 1 (pp1a and pp1b) (Figure 1a). The polyproteins are cleaved into individual non-structural proteins (nsps), including RNA-dependent RNA polymerase that plays a role in viral replication. ORF 1a also encodes for viral proteases, including the viral 3C-like protease, which is a target for antiviral therapy (see Section 10 on Treatment of FIP). The other third of the genome consists of ORFs encoding structural proteins, a spike [S] (a protein found on the FCoV surface—see Figure 1b), a membrane (in the FCoV membrane), a nucleocapsid (the protein wrapped around the FCoV genome), an envelope (also in the FCoV membrane) (see Figure 2) and non-structural accessory proteins 3a, 3b, 3c, 7a and 7b (see Figure 1a) (Horzinek and Lutz 2000; Terada et al., 2014). Non-structural proteins are involved in the replication of the virus and modification of the host immune response but are not incorporated into the mature virus particle. More information on the function of the structural proteins is found in Section 2.4 on FCoV pathotypes and genome mutations.

Figure 2. Schematic diagram of FCoV structure showing single-stranded (ss) RNA and the structural proteins: spike, envelope, membrane and nucleocapsid proteins. The spike protein is the part of the virus particle that interacts with the host-cell receptor. The spikes on the surface present a coronal (i.e., crown-like) appearance under electron microscopy (Jaimes and Whittaker 2018). Image Emi Barker, Langford Vets, University of Bristol, UK (Barker and Tasker 2020b).

2.3. FCoV Types I and II and Replication

FCoV is divided into types I and II, based on growth in vitro, genomic properties, and antigenicity (Shiba et al., 2007). The biology of the two FCoV types (in particular with regard to receptor usage and cell culture adaptation) differs greatly with type II FCoV, although it is less common in the field, being the most easily isolated and grown in cell cultures in vitro (Jaimes et al., 2020).

Type II FCoV strains arise from recombination between type I FCoV and CCoV (Figure 3), usually including the spike of CCoV, varying amounts of adjacent 3a, 3b and 3c genes, and envelope genes, but not the nucleocapsid gene, which remains of FCoV origin (Herrewegh et al., 1998; Le Poder et al., 2013; Terada et al., 2014). Both type I and type II FCoV can occur as less-virulent FCoV and as FIP-associated FCoV (Pedersen 2014b). Type I FCoV is more prevalent in most parts of the world (Hohdatsu et al., 1992; Addie et al., 2003; Duarte et al., 2009; Lin et al., 2009; An et al., 2011; Amer et al., 2012; Soma et al., 2013; Terada et al., 2014; Wang et al., 2014a; Decaro et al., 2021; Zhou et al., 2021a; Lin et al., 2022; Xu et al., 2023; Dong et al., 2024); a prevalence of type I of 80–95% has been reported (Benetka et al., 2004; Kummrow et al., 2005).

Most laboratory research has focused on type II FCoV strains since they, unlike type I FCoV, can be readily propagated in vitro (Pedersen et al., 1984) (facilitating experimental studies), despite most field infections being type I FCoV. Experimental studies have tried to develop culture methods for type I FCoV using both permanent feline intestinal epithelial-cell cultures of ileocyte and colonocyte origin (Desmarets et al., 2013) and colonic organoid preparations (Tekes et al., 2020), but neither are currently routinely available for use.

A novel FCoV, termed FCoV-23, has been described (Attipa et al., 2023a; Attipa et al., 2023b; Warr et al., 2023), which has arisen due to recombination of type I FCoV and a highly pathogenic pantropic CCoV. Further details are provided in Section 4. Pathogenesis.

The RNA-dependent RNA polymerase makes a full-length negative-strand RNA copy of the genome as well as a nested set of smaller subgenomic RNAs with a common 3′ end (Lai and Cavanagh 1997). These negative-strand RNAs serve as templates for new positive-sense genomes and positive-sense subgenomic mRNAs. The subgenomic mRNAs have a nested-set structure with sequences starting at the 3′ terminus and extending to various distances toward the 5′ end. If a real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay is designed to amplify 3′ subgenomic mRNAs, this can influence the quantitative results for apparent FCoV load (Barker and Tasker 2020b) (see Section 7.5.2 on Detection of FCoV RNA by RT-PCR). In general, only the 5′ most ORF of each subgenomic mRNA is used for encoding the proteins, even though the subgenomic mRNAs have more than one coding sequence (except the smallest one).

Figure 3. Origin of feline coronavirus (FCoV) type II; Image Peter Rottier, University of Utrecht, The Netherlands. Schematic diagram showing how type II FCoV arises from recombination of FCoV type I (shown in white) with CCoV (shown in brown).

2.4. FCoV Pathotypes and Genome Mutations

FCoVs have been assigned to two pathotypes (biotypes) (Poland et al., 1996; Gao et al., 2023), which can be referred to as feline enteric coronavirus (FECV), which mainly replicates in the enteric epithelial cells, and feline infectious peritonitis virus (FIPV), which results in a mostly lethal infection with efficient systemic replication in monocytes or macrophages (Barker and Tasker 2020b; Gao et al., 2023). Both types I and II can exist as each pathotype (Gao et al., 2023). However, it is not only FIPVs that can replicate systemically, as FECVs have also been shown to replicate systemically in healthy cats and those without FIP (Meli et al., 2004; Kipar et al., 2006; Fish et al., 2018). In this review, we use the taxonomic term FCoV (as defined in virus nomenclature (Owens et al., 2012)), but distinguish viruses as a ‘less-virulent FCoV’ and an ‘FIP-associated FCoV’ when needed, to stipulate differences in biological behaviour between the two FCoV pathotypes.

FCoV genomes, like all coronaviral genomes, possess a high level of genetic variation due to the high error rate of RNA polymerase leading to different types of mutations, including point mutations, deletions, introduction of stop codons and recombinations (Herrewegh et al., 1998; Bank-Wolf et al., 2014; Borschensky and Reinacher 2014; Xia et al., 2020; Paltrinieri et al., 2021).

The widely accepted hypothesis is that genetic variation and subsequent selection facilitate the switching of cell tropism from enterocytes to systemic monocytes/macrophages within an FCoV-infected cat that develops FIP (Pedersen 2014b). This occurs when a less-virulent FCoV converts to an FIP-associated FCoV (Pedersen et al., 2009; Chang et al., 2012; Barker et al., 2013) via the so-called ‘internal mutation’ theory. This ‘internal mutation’ theory is supported by several studies showing a close genetic relationship between the FIP-associated FCoV and FCoV from faecal samples of cats without FIP living in the same environment (Chang et al., 2011; Barker et al., 2013; Decaro et al., 2021; Meli et al., 2022), which is much closer than their relationship to FCoV collected from cats of other environments. However, the theory was questioned based on the results of a study that indicated that ‘FECV’ and ‘FIPV’ (the terms used in the study) were two distinct types of FCoV circulating independently in the cat population (Brown et al., 2009), leading to the ‘circulating virulent and avirulent FCoV’ theory. However, in that study, samples were derived from a population of shelter cats, a population in which the introduction of different genetically unrelated FCoV can be expected because of their different geographic origin (Pedersen 2014b). One other study has provided some support for the ‘circulating virulent and avirulent FCoV’ theory in a small outbreak of FIP in shelter cats (Healey et al., 2022). This ‘circulating virulent and avirulent FCoV’ theory may better explain the occasional FIP outbreaks reported in multi-cat environments (Graham et al., 2012; Barker et al., 2013; Wang et al., 2013; Terada et al., 2014; Healey et al., 2022; Attipa et al., 2023a).

Although the genes involved in the FCoV virulence genetic shift are still unknown, mutations in different genes have been postulated to be associated with the switch of the less-virulent (primarily intestinal) FCoV into the virulent (primarily systemic) FIP-associated FCoV, including the spike gene and accessory genes 3c and 7b (Pedersen et al., 2012; Gao et al., 2023) (see Figures 1b and 2).

The spike protein comprises two subunits, S1 and S2 (Figure 1b); feline host-receptor recognition is mediated by S1 and membrane fusion by S2 (Bosch et al., 2003; Li 2016; Zehr et al., 2023). The main receptor for type II FCoV is feline aminopeptidase N (fAPN) (Tusell et al., 2007; Tekes et al., 2010), but the main receptor for type I FCoV remains unknown (Dye et al., 2007; Tekes et al., 2010). Following receptor recognition (Belouzard et al., 2012), the spike protein is activated by feline host-cell proteases, such as furin (Millet and Whittaker 2015). Type I FCoV has two cleavage sites, called S1/S2 and S2′; the S1/S2 is cleaved by furin and referred to as the furin cleavage site (Millet and Whittaker 2015). Type II FCoV contains only the S2′ site (Millet and Whittaker 2015). Viral-cell-membrane fusion then occurs via the S2 subunit fusion domain (Jaimes et al., 2020). As well the fusion domain, the S2 subunit (Figure 1b) contains two heptad repeats (HR1 and HR2) areas, also involved in viral membrane fusion (Bosch et al., 2003).

Two alternative amino acid differences in the S2 fusion domain of the S protein, namely M1058L and S1060A (nomenclature based on position and nature of the amino acid change, i.e., methionine [M] to leucine [L] at position 1058 and serine [S] to alanine [A] at position 1060) (Figure 1b), have been detected. Together they distinguished FIP-associated FCoV in tissues from less-virulent FCoV in faeces (Chang et al., 2012; Decaro et al., 2021; Meli et al., 2022), suggesting they were likely to be associated with the development of FIP. However, other studies (Porter et al., 2014; Barker et al., 2017), evaluating both faecal and tissue samples from cats with and without FIP, found these mutations in the viral genomes detected in the tissues of cats without FIP, suggesting their association with systemic FCoV infection, rather than FIP per se. A novel mutation (M1058F, where F represents phenylalanine) in this region has also been reported in association with FIP (Meli et al., 2022). Clearly, the situation is complex, and it is likely, as has been suggested (Zehr et al., 2023), that multiple mutations are involved in the development of FIP. More information on spike gene mutations is found in Section 7.5.3 on Molecular Techniques Characterising FCoV Spike (S) Gene Mutations following Positive RT-PCR for FCoV RNA.

The furin cleavage site (S1/S2) at the junction of the receptor binding (S1) and the fusion (S2) subunits of the spike protein, is another genomic region associated with FIP (Licitra et al., 2013). While all less-virulent FCoV had a conserved furin cleavage site, in most FIP-associated FCoV at least one substitution was found (Licitra et al., 2013). Other mutations in the S1/S2 cleavage site have been reported (Millet and Whittaker 2015; Andre et al., 2019; Healey et al., 2022; Ouyang et al., 2022).

Mutations in the HR1 region of the S gene (Bank-Wolf et al., 2014; Lewis et al., 2015) have been said to be associated with FIP.

The ORF 3 gene encodes for a protein for which the exact function is still unknown. Interestingly, mutations leading to a truncated protein were detected in (up to approximately two-thirds of) the 3c genes of FCoV found in tissues of cats with FIP (Pedersen et al., 2009; Chang et al., 2010; Hsieh et al., 2013; Borschensky and Reinacher 2014), while the ORF 3 gene was intact in all FCoV detected in faecal samples. This suggests that an intact 3c is an absolute requirement for the infection of the gut epithelial cells (Chang et al., 2010; Pedersen et al., 2012), but is not necessary for replication in monocytes. No association between 3c sequences and FIP was found in one extensive study (Zehr et al., 2023).

Research has also evaluated the non-structural glycoprotein 7b, encoded by ORF 7b, for an association with FCoV virulence. Some suggested an association was present (Vennema et al., 1992), whilst others disputed this (Borschensky and Reinacher 2014; Myrrha et al., 2019).

There is no evidence that specific mutations in the 3a, 3b and 7a genes mediate the development of FIP (Bank-Wolf et al., 2014). It has been shown that ORF7b deletions occur readily in vitro, correlating with loss of virulence (Herrewegh et al., 1995b)

One novel study (Zehr et al., 2023) evaluated natural selection differences between less-virulent FCoV and FIP-associated FCoV using molecular evolutionary genetic statistical techniques, focusing on the S, ORF3abc and ORF7ab genes. It found that there were two sites that showed differences in natural selection pressure between less-virulent FCoV and FIP-associated FCoV,—one within the S1/S2 furin cleavage site and the other within the fusion domain of S. The authors deduced that a combination of mutations in non-pathogenic FCoV likely contributes to FIP development and that it was unlikely to be one singular ‘switch’ mutational event (Zehr et al., 2023).

3. Epidemiology

3.1. Transmission of FCoV

FCoV is a contagious virus. Faeces are the main source of FCoV infection, with litter trays representing the principal source of infection in groups of cats. Cats are most likely to be infected orally, with transmission being mainly indirect following contact with objects contaminated with faeces (e.g., via litter trays, cat litter fomites and scoops, brushes, vacuum cleaners, shoes) and by grooming paws contaminated during litter tray use. Thus, the major route of transmission is faecal-oral.

A case report (Andre et al., 2020), documenting FIP-associated rhinitis, suggested that the respiratory tract might be a place of entry for the transmission of FCoV. Since the virus is found only rarely in the saliva of healthy cats, close contact or sharing feeding bowls are not major routes of infection (Addie and Jarrett 2001).

Transplacental transmission has been described from a queen that developed FIP during pregnancy (Pastoret and Henroteaux 1978), but this phenomenon is extremely rare (Addie and Jarrett 1990). A study (Stranieri et al., 2020a) evaluated testicular tissue and semen for FCoV RNA by RT-PCR in male cats to evaluate the risk of venereal transmission of FCoV. FCoV RNA was amplified from around 15% (6 of 39) of testicles in the study and none of the 17 semen samples tested, suggesting venereal transmission of FCoV would be unlikely.

The transmission of FCoV via blood transfusion has not been reported.

The possibility of mechanical vectors being involved in the transmission of a highly virulent strain of FCoV was suggested during the early investigation of a large outbreak of FIP in Cyprus (Attipa et al., 2023a), similar to discussions around the transmission of SARS-CoV-2 by cat fleas (Villar et al., 2020) (although more recent work on the Cyprus outbreak suggests possible cat to cat transmission (Attipa et al., 2023b; Warr et al., 2023); see Section 4. Pathogenesis). However, further research is required to confirm this, and vector transmission for FCoV has not yet been confirmed.

In FCoV-infected breeding catteries, kittens commonly become infected when young, within a few weeks of age (Lutz et al., 2002) (see also Section 4 on Pathogenesis and Section 5 on Immunity). Results from multivariable analysis suggested that young age (less than one year) was significantly associated with FCoV shedding in one study of German breeders (Klein-Richers et al., 2020), but in another study, evaluating a similar group of cats from these breeders, age was not significantly associated with FCoV shedding (Felten et al., 2023).

After natural infection, cats begin to shed the virus in the faeces in as early as two days (Stoddart et al., 1988a; Meli et al., 2004) and continue to shed for days, weeks, months, and a few even for life (persistent infection) (Stoddart et al., 1988a; Herrewegh et al., 1997; Horzinek and Lutz 2000; Addie and Jarrett 2001; Addie et al., 2003; Meli et al., 2004; Pedersen et al., 2008). Shedding typically lasts a few weeks to months, then stops, or occurs intermittently, and can recur due to re-infection in an endemic environment, as immunity is short-lived (Foley et al., 1997b; Addie and Jarrett 2001; Addie et al., 2003; Meli et al., 2004; Pedersen et al., 2008; Kipar et al., 2010; Vogel et al., 2010; Bubenikova et al., 2020; Meli et al., 2022; Vojtkovska et al., 2022). In breeding catteries in one study (Felten et al., 2023), 19% of cats were categorised as being intermittent shedders, with the variable detection of FCoV RNA in four faecal samples collected at intervals of between five and 28 days. In another study of pet cats, 31% were deemed to be either intermittent shedders or to have recovered and then been re-infected (Addie and Jarrett 2001); this study was unique in terms of the very long (up to five years) follow-up of the cats.

However, it has been suggested that the true intermittent shedding of FCoV does not occur, but a cat can appear to intermittently shed due to the following (Addie et al., 2023):

• Cycles of re-infection.
• Faecal FCoV RNA levels around the limit of detection of the RT-PCR assay being used such that positive and negative results occur interchangeably.
• The presence of faecal or cat litter RT-PCR inhibitors affecting RT-PCR sensitivity, giving false-negative results.

A few cats (3–9%) never shed FCoV following infection (Foley et al., 1997b; Addie and Jarrett 2001); these cats may be resistant to FCoV infection. In the study of breeding catteries (Felten et al., 2023), 24% of cats were negative for FCoV RNA in all four faecal samples collected at intervals of between five and 28 days; it is not known if these cats were resistant to infection, as they were only followed for around four months and could have shed FCoV before testing started or after it was stopped.

Some cats develop persistent virus shedding; around 13% in natural infection (with positive FCoV shedding identified for at least eight consecutive months) (Addie and Jarrett 2001) and 22% in experimental infection (Pedersen et al., 2008). However, a standard definition of a persistent FCoV shedder cat does not exist. One method involves testing four faecal samples, each one week apart, as this resulted in the same identification of FCoV shedders as samples collected weekly for 24 weeks (Rohner 1999; Horzinek and Lutz 2000). In a study of breeding catteries (Felten et al., 2023), cats were regarded as being persistent shedders if they gave positive results for FCoV RT-PCR on at least three of the four faecal samples collected from each cat in the study; using this definition, 56% were deemed to be persistent shedders, with the majority (89%) of these cats giving positive results on all four faecal samples. Such cats are likely to play a major role in the transmission of FCoV within households.

Persistent virus shedding may be influenced by the dose of virus received at inoculation (Vogel et al., 2010), although in one study of naturally infected cats, the virus was remarkably conserved over a period of years, suggesting that it had found an antigenic niche not detectable by the host’s immune system (Addie et al., 2003).

Faecal excretion reaches high levels, especially in kittens (Addie and Jarrett 2001; Pedersen et al., 2008; Vogel et al., 2010). The higher the FCoV antibody titre, the greater the chance of the cat shedding FCoV (Addie and Jarrett 2001; Lutz et al., 2002; Pedersen et al., 2008; Addie et al., 2015b; Felten et al., 2020), as well as the greater the frequency of faecal FCoV shedding, and the higher the FCoV virus load present (Felten et al., 2020). The identification of patterns of faecal shedding based on RT-PCR will rely on, in part, the sensitivity of the RT-PCR being used to detect the FCoV RNA, as mentioned above, and the frequency of faecal RT-PCR testing. Due to the suspected short duration of any immunity following infection, failure to separate out cats that are FCoV shedders could favour the spread and persistence of FCoV in a household (Horzinek and Lutz 2000), which could account for the high antibody prevalence in the multi-cat environment.

The horizontal transmission of FIP-associated FCoV, in contrast to less-virulent FCoV, is believed to occur only rarely (see Section 4 on Pathogenesis, including discussion on the 2023 outbreak of FIP in Cyprus stray cats, Section 5 on Immunity, and Section 8.1 on Does a Cat with FIP Pose a Threat to Other Cats in its Household?), such as in shelters, as proposed in the ‘circulating virulent and avirulent FCoV’ theory. Indeed, horizontal transmission has been described as ‘the exception rather than the rule’ (Horzinek and Lutz 2000). FIP can be induced experimentally by the inoculation of an FIP-associated FCoV intraperitoneally (Kim et al., 2016)—a route that bypasses the natural faecal-oral transmission pathway.

Although FCoV and CCoV are closely related, contact with dogs does not appear to be a major predisposing factor for CoV infection in cats (Le Poder et al., 2013). However, one study (Benetka et al., 2006) found feline/canine CoV recombinant viruses in cats of a rescue shelter that housed both cats and dogs. In the M protein gene, these strains were more closely related to FCoV-like CCoV than to FCoV, suggesting that infection with CCoV and subsequent recombinations with FCoV had occurred within this environment. Feline/canine CoV recombination is believed to be behind the emergence of a novel FCoV strain, FCoV-23, behind the FIP outbreak in Cyprus (Attipa et al., 2023b; Warr et al., 2023).

3.2. Prevalence of FCoV

With the exception of a few islands of isolated feline populations (e.g., the Falkland Islands) (Horzinek and Osterhaus 1979; Levy et al., 2008; Addie et al., 2012), FCoV infection has been reported worldwide. In a meta-analysis study (Marzok et al., 2023), FCoV infection was regarded as being widespread globally; in the final 54 selected studies, the overall prevalence of FCoV infection was 32% (13,639 cats out of 42,076); however the methods used to determine FCoV infection varied e.g. serum FCoV antibodies, FCoV RNA in faeces, electron microscopy on faeces, and some of the studies comprised only cats with FIP, likely influencing the results.

The prevalence of FCoV, determined by the detection of serum FCoV antibodies and/or FCoV RNA in faeces, in studies from various countries, is given in Table 1.

Table 1. Prevalence of FCoV in various countries from selected studies using either serum FCoV antibody or faecal FCoV RNA detection.

Country	Method Used for Prevalence Determination *	Number of Cats	Prevalence	Reference
Australia	Antibodies	49 feral cats 306 owned cats	0% 34%	Bell et al., (2006b)
Australia	FCoV RNA in faeces	289 cats with diarrhoea including: 80 shelter cats with diarrhoea	40% 54%	Paul and Stayt (2019)
Austria	Antibodies	159 cats without FIP	71%	Posch et al., (2001)
China	FCoV RNA in faeces	112 cats treated in vet hospitals or from catteries	68%	Dong et al., (2024)
Croatia	Antibodies	106 pet cats	42%	Raukar (2021)
Czech Republic	FCoV RNA in faeces	70 shelter cats	63%	Vojtkovska et al., (2022)
Falkland Islands	Antibodies	10 feral cats 95 pet cats	0% 0%	Addie et al., (2012)
France	FCoV RNA in faeces	88 healthy cats	17%	Le Poder et al., (2013)
Galapagos Islands	Antibodies	34 pet and 18 feral cats	0%	Levy et al., (2008)
Germany	FCoV RNA in faeces	82 cats from 19 breeding catteries	71%	Felten et al., (2020)
Germany	Antibodies	82 cats from 19 breeding catteries	78%	Felten et al., (2020)
Germany	FCoV RNA in faeces	179 cats from 37 breeding catteries	77% †	Klein-Richers et al., (2020)
Germany	FCoV RNA in faeces	12 cats in contact with FIP cats 18 cats with FIP	66% 33% ‡	Meli et al., (2022)
Germany	FCoV RNA in faeces	All pedigree breeding catteries: 211 cats without diarrhoea 23 cats with diarrhoea 234 total cats	59% 87% 62%	Felten et al., (2022)
Greece	Antibodies ¥	267 client-owned cats 156 stray cats 21 cattery cats	10% 15% 19%	Kokkinaki et al., (2023)
Iran	Antibodies	248 pet cats presenting to a referral hospital	7%	Avizeh et al., (2012)
Israel	Antibodies	68 feral cats 54 shelter cats 33 pet cats	60% 83% 21%	Baneth et al., (1999)
Italy	Antibodies	24 healthy pet cats 11 FCoV exposed cats 32 cats with FIP	25% 36% 91%	Giordano et al., (2004)
Italy	Antibodies	120 cattery or shelter cats	82%	Pratelli (2008)
Italy	Antibodies	82 stray colony cats	39%	Spada et al., (2016)
Italy	Antibodies	81 stray colony cats 60 shelter cats 77 owned cats	19% 30% 51%	Spada et al., (2022)
Japan	Antibodies	2815 pedigree cats 14,577 non-pedigree domestic shorthair cats	67% 31%	Taharaguchi et al., (2012)
Republic of Korea	Antibodies	212 (107 pet and 105 feral cats), both sick and healthy in nature	14%	An et al., (2011)
Republic of Korea	FCoV RNA in faeces	212 (107 pet and 105 feral cats, both sick and healthy in nature)	7%	An et al., (2011)
Malaysia	Antibodies	24 cats in 4 breeding catteries	100%	Arshad et al., (2004)
Malaysia	FCoV RNA in faeces	24 cats in a Persian cattery 20 cats in a rescue cattery	96% 70%	Sharif et al., (2009)
Malaysia	Antibodies	22 cats from shelters and 5 privately owned cats; all had respiratory clinical signs	100%	(Aslam et al., 2023)
The Netherlands	Antibodies	21 FIP cases 45 in-contact cats 69 cats presented for Non-FIP conditions 109 specific pathogen-free cats	100% 91% 16% 0%	Osterhaus et al., (1977)
The Netherlands	FCoV RNA in faeces	17 FIP cats 170 apparently healthy	35% 16%	Chang et al., (2010)
The Netherlands	Antibodies	137 cats using samples from laboratory serum bank	57%	Zhao et al., (2019)
The Netherlands	Antibodies	407 stray rural cats	34%	Duijvestijn et al., (2023)
Sweden	Antibodies	142 non-pedigree domestic cats 64 pedigree cats	17% 65%	Ström Holst et al., (2006)
Switzerland	Antibodies	95 cats in 8 breeding households	99%	Rohner (1999)
Switzerland	Antibodies	Cats presented to vets: 561 healthy 860 sick	21% 36%	Lutz et al., (1990)
Taiwan	Antibodies	760 healthy cats 73 cats with FIP	28% 100%	Wang et al., (2014a)
Turkey	Antibodies	100 healthy cats comprising 79 pet and 21 shelter cats	21%	Pratelli et al., (2009)
Turkey	Antibodies	169 ill cats	37%	Tekelioglu et al., (2015)
Turkey	Antibodies	20 outdoor cats 33 indoor cats	70% 70%	Oguzoglu et al., (2010)
UK	Antibodies	136 of 155 pet cats	88%	Addie and Jarrett (2001)
UK	FCoV RNA in faeces	136 cats from 20 multi-cat and 9 single-cat households known to have endemic FCoV	Viral RNA detected in 97% cats at least once	Addie and Jarrett (2001)
UK	Antibodies	2207 cats in rescue shelters including: 1173 that were tested within 5 days of admission to the shelter	26% 24%	Cave et al., (2004)
UK	Antibodies	131 pedigree cats at cat shows	84%	Sparkes et al., (1992)
UK	Antibodies	516 stray cats	22%	Muirden (2002)
UK	FCoV RNA in faeces	48 cats with FIP 35 cats without FIP	65% 20%	Barker et al., (2017)
UK	FCoV RNA in faeces	1088 cats with diarrhoea 437 pedigree cats 631 domestic cats	57% 79% 42%	Paris et al., (2014)
UK	FCoV RNA in faeces	16 cats with FIP 10 cats without FIP	81% 60%	Porter et al., (2014)
UK	FCoV RNA in faeces	8 cats with FIP 3 cats without FIP	100% 33%	Addie et al., (1996)
USA	FCoV RNA in faeces	50 healthy shelter cats	56%	Fish et al., (2018)
USA	FCoV RNA in faeces	34 shelter cats	18%	Chen et al., (2023)

* Antibodies indicate serological assay for FCoV antibody detection in blood (serum). The faecal collection method for FCoV RNA detection by reverse-transcriptase polymerase chain reaction (RT-PCR) is not specified, but it is known that faecal samples have higher FCoV loads than rectal swabs (Meli et al., 2022) the so collection method may influence the prevalence figures obtained. Only studies on faecal samples are included, and an analysis of samples collected directly from the intestines (e.g., at post-mortem examination) is not included. † 77% derived when all four faecal samples that were analysed per cat were included; in contrast, when only the last single, only the last two, or only the last three faecal samples analysed per cat were included, the percentage of FCoV RT-PCR-positive results dropped to 62%, 69%, and 74%, respectively. ‡ 33% represents six of 18 cats with FIP that were FCoV RT-PCR-positive in faeces on day 0 before starting treatment for FIP; however, when samples from the first three days of the treatment study were included in the analysis (i.e., days 0–2), 11 of the 18 cats (61%) were faecal FCoV RT-PCR-positive. ¥ In this study, only 15 of the 438 cats for whom the breed was known were pedigree.

FCoV, and therefore FIP, is particularly common where conditions are crowded (Sharif et al., 2009; Felten et al., 2020) and less common in individually housed, stray or feral cats (Addie and Jarrett 1992; Herrewegh et al., 1995a; Addie 2000; Cave et al., 2004; Bell et al., 2006b; Oguzoglu et al., 2010; Taharaguchi et al., 2012; Tekelioglu et al., 2015; Spada et al., 2022; Kokkinaki et al., 2023). In one study using multivariable analysis (Kokkinaki et al., 2023), cats adopted as strays were more likely to be FCoV antibody-positive, as were cats that had contact with other cats.

Wild felids, especially those in zoos, can also be FCoV-infected (Kennedy et al., 2002) .

FCoV is highly contagious, and in households where it is present, the prevalence of serum FCoV antibodies indicating exposure is often high (see Section 5 on Immunity).

Cats who spent over 60 days in UK shelters were five times more likely to have FCoV antibodies than the same population on the day of entry to the shelter (Cave et al., 2004). This may be due to increased transmission and exposure within shelters, but the stress of admittance to a shelter may also play a role in the increased FCoV antibody prevalence.

In an Italian study (Spada et al., 2022) using multivariable analysis, domestic shorthair cats were less likely to be FCoV antibody-positive compared to some pedigree breeds. Another study that used multivariable analysis, from Turkey (Tekelioglu et al., 2015), reported that FCoV antibody-positive status was associated with age (interestingly aged 3-years being increased risk compared to young kittens), positive FIV serological status and living with other cats.

In a Japanese study including 17,392 cats, the FCoV antibody prevalence was 67% in purebred cats and 31% in non-pedigrees (Taharaguchi et al., 2012). In purebred cats, seroprevalence increased rapidly in early life, reaching around 80% by three months of age, and remaining at this level until around two years of age. Seroprevalence thereafter progressively decreased, reaching around 30% in cats aged 14 years or more. In contrast, in the non-pedigree cats, there was little fluctuation in seroprevalence, with levels remaining at around 30% at all ages. The authors suggested that this could be due to the multi-cat environments that the pedigree cats were likely to be kept in, leading to the high seroprevalences in younger cats (Taharaguchi et al., 2012). Among the purebred cats in this study in Japan, the American shorthair, Himalayan, Oriental, Persian, and Siamese breeds showed low antibody prevalence, while the American curl, Maine coon, Norwegian Forest cat, Ragdoll and Scottish fold breeds had high antibody prevalence (Taharaguchi et al., 2012).

In a German study of breeding catteries (Felten et al., 2023), the Persian breed was associated with persistent high FCoV shedding (i.e., FCoV RNA detection in faeces), whereas the Birman and Norwegian Forest breeds were more likely to be non-FCoV shedders. It is not known if these results were due to genetic susceptibility or resistance, or whether they were related to husbandry factors within those breeds’ households.

In a study in the Netherlands sampling stray rural cats, 34% of the cats were FCoV antibody seropositive, positive results significantly associated with being three years or older and being unhealthy (Duijvestijn et al., 2023).

It has been found that the feline AB blood group phenotype is not associated with FCoV antibody-positive status, i.e., there is no association between blood types A, B or AB and FCoV antibody presence (Spada et al., 2022). Other feline blood groups, such as Mik, have not been investigated.

3.3. Prevalence and Risk Factors for FIP

The prevalence of FIP within a cat population as a whole was 0.5% (60 of 11,535) of all the cats examined at the North Carolina State University College of Veterinary Medicine (1986–2002), a tertiary referral centre (Pesteanu-Somogyi et al., 2006). A retrospective database study of 24 American veterinary teaching hospitals revealed a diagnosis of FIP in 1420 cats from 397,182 (0.4%) feline consultations over a 10-year period (Rohrbach et al., 2001). The percentage of FCoV-infected cats that develop FIP is small (usually less than 10%), but it is variable in different studies and populations (Thayer et al., 2022). In one study, FIP mortality in 282 FCoV antibody-positive kittens was 8% (Addie et al., 1995a). The incidence of FIP in a household or cattery increased with the number of cats present in one study (Kass and Dent 1995) but was not associated with mean cat number in another (Foley et al., 1997a). A seasonal variation has been noticed, with the lowest number of recorded FIP diagnoses in July and increased diagnoses in January to April (winter) in one study (Rohrbach et al., 2001), and an increased number in autumn and winter in another (Foley et al., 1997a); both of these studies were derived from data collected from the Northern Hemisphere.

FIP disproportionately affects pedigree cats (Robison et al., 1971; Rohrbach et al., 2001; Norris et al., 2005; Pesteanu-Somogyi et al., 2006; Worthing et al., 2012; Soma et al., 2013; Coggins et al., 2023) and those under two years of age (Rohrbach et al., 2001; Norris et al., 2005; Pesteanu-Somogyi et al., 2006; Riemer et al., 2016; Katayama and Uemura 2021; Yin et al., 2021). In some studies, cats less than one year of age were particularly represented (Rohrbach et al., 2001; Tsai et al., 2011; Worthing et al., 2012; Soma et al., 2013; Yin et al., 2021; Coggins et al., 2023; Taylor et al., 2023). In Germany, 39% of 222 cats with FIP were under one year old, and thereafter, the age of cats with FIP was evenly distributed except between seven and 11 years of age, when the incidence was about half that of other age groups (Riemer et al., 2016).

In a North Carolina study (Pesteanu-Somogyi et al., 2006), pedigree cats were also over-represented for FIP; FIP was present in nearly 1.3% of the pedigree cats compared to 0.35% in mixed breed cats, and breed predisposition was statistically significant in the Abyssinian, Bengal, Birman, Himalayan, Ragdoll and Rex breeds. In Australia (Worthing et al., 2012), 71% of cats with FIP were purebred (Norris et al., 2005), and in a different Australian study, domestic crossbreeds and Persian and Himalayan cats were significantly under-represented in the FIP cohort, while several other breeds were over-represented, including British shorthair, Devon Rex and Abyssinian.

The percentage of effusions that were found to be positive by FCoV RT-PCR varied with the cat’s breed and age in a Japanese study (Soma et al., 2013) and with age in a study in China (Lin et al., 2022). In Japan, 210 (56%) of 377 FCoV RNA RT-PCR-positive ascitic samples were from cats of one year of age or less (Soma et al., 2013), and in the Chinese study, only one of 127 cats with suspected FIP was over seven years old (Yin et al., 2021). In the Japanese study, in cats up to one year of age, 95% of effusions of pedigree cats were RT-PCR-positive compared to 79% of the effusions of non-pedigree cats (Soma et al., 2013). However, in these studies, FIP was not confirmed as a diagnosis; the study used a positive FCoV RT-PCR result on an effusion to indicate that a diagnosis of FIP was likely.

Some authors have noted a predisposition for FIP in male over female cats (Rohrbach et al., 2001; Benetka et al., 2004; Norris et al., 2005; Worthing et al., 2012; Soma et al., 2013; Riemer et al., 2016; Lv et al., 2022; Coggins et al., 2023; Taylor et al., 2023; Dunbar et al., 2024), while others found no sex predisposition (Pedersen 1976; Pedersen et al., 2014; Yin et al., 2021), although neutered status was associated with FIP in one study (Yin et al., 2021). Pedigrees of cats that die of FIP can often be traced back to the stud cat, rather than the queen (Foley and Pedersen 1996), but, unexpectedly, breeding intentionally for FIP resistance led to more, rather than less, FIP occurring in the offspring (Pedersen et al., 2016), which is of note. In one study of multi-cat households (Foley et al., 1997a), the number of cats in the household was not associated with the development of FIP, but the number of cats shedding FCoV, as well as the proportion of cats that were chronically shedding FCoV, were associated with FIP. Occasionally, there are reports of several littermates all developing FIP, possibly suggesting a genetic predisposition in those siblings (Krentz et al., 2022).

Wild felids can also develop FIP and it has been described in cheetahs, European wildcats, a tiger, a mountain lion, lion and sand cats (Evermann et al., 1988; Stout et al., 2021; Aplasca et al., 2023). FCoV-infected cheetahs are said to be predisposed to develop FIP (Evermann et al., 1988). In the reports on sand cats, siblings were found to be affected by FIP, possibly suggesting a predisposition (Aplasca et al., 2023).

4. Pathogenesis

As noted above, the major route of FCoV infection is faecal-oral. Following ingestion, the virus first enters and replicates within the epithelial cells of the small intestinal villi (Pedersen et al., 1981). Type II FCoV uses the fAPN present on the intestinal villi and the monocytes (Tusell et al., 2007; Tekes et al., 2010), whilst the receptor for type I FCoV remains unknown (Dye et al., 2007; Tekes et al., 2010).

FCoV shedding occurs in the faeces from as early as two days post-infection (Stoddart et al., 1988a; Meli et al., 2004; Kipar et al., 2010). This infection is not usually associated with clinical signs but sometimes can be accompanied by enteritis (Pedersen et al., 1981; Hayashi et al., 1982; Addie and Jarrett 1992; Addie and Jarrett 2001; Sabshin et al., 2012) and/or upper respiratory tract signs (Addie and Jarrett 1990). Indeed, in one study (Curtis et al., 2024) which performed proteomic analysis on plasma samples from cats without FIP that were either positive, or negative, for both serum FCoV antibody and FCoV faecal shedding, no proteins were found that were significantly different between these two groups, in contrast to the finding of many (442) proteins that differed significantly between cats with FIP and those that were negative for both serum FCoV antibody and FCoV faecal shedding, as well as many (455) proteins that differed significantly between cats were FIP and those that were positive for both serum FCoV antibody and FCoV faecal shedding. The authors concluded that these findings (Curtis et al., 2024) were consistent with a clinically silent presentation of FCoV infection in the absence of FIP in this group of naturally infected cats, where FCoV replication occurred without stimulating a systemic host response. Occasionally, very severe, indeed fatal, coronavirus enteritis has been reported (Kipar et al., 1998). As described earlier, the virus shedding of type I FCoV in faeces can follow different patterns (Bubenikova et al., 2020). Most cats infected with type I FCoV shed the virus for two to three months (Addie and Jarrett 2001), either continuously or possibly intermittently (Addie et al., 2023), and then stop; immunity is short-lived because these cats can be re-infected by the same or different strain of FCoV within a few weeks (Addie et al., 2003). Conversely, around 13% of cats infected with type I FCoV become persistently infected carriers (Addie and Jarrett 2001) and shed FCoV in their faeces persistently. However, cats experimentally infected with type II FCoV shed the virus for around two weeks (Stoddart et al., 1988a), and no type II carrier cat has been reported yet.

Fortunately, only a small proportion of FCoV-infected cats go on to develop FIP (Pedersen 1987; Addie et al., 1995a; Kipar et al., 2005).

From two weeks post-infection, the virus is found in the colon (Kipar et al., 2010). In persistently infected carrier cats without clinical signs, the ileum, and especially the colon, are the main sites of persistent viral replication (Herrewegh et al., 1997; Kipar et al., 2010).

The mesenteric lymph nodes (MLNs), as the most likely first site of FCoV spread from the intestine regardless of subsequent viraemia, have been evaluated for mediators of the innate immune response, and evidence of toll-like receptor involvement has been found in the response to FCoV infection (Malbon et al., 2019).

Efficient FCoV replication in activated monocytes and macrophages is a key event in FIP pathogenesis (Malbon et al., 2020a), governing:

• Whether or not the cat will go on to mount a successful immune response and eliminate the virus.
• Whether the cat will mount a semi-successful immune response, remaining clinically well, but shedding FCoV in the faeces for months to years.
• Whether the cat will mount a deleterious immune response (sometimes the pathology has been described as being immune-mediated in nature (Horzinek and Lutz 2000)), resulting in a widespread pyogranulomatous vasculitis and ultimately premature death without effective antiviral treatment.

The outcome of infection of the monocytes and macrophages is partially dependent on the host cell; however, virulent strains do replicate more efficiently within permissive monocytes and macrophages (Dewerchin et al., 2005). Monocytes from an outbred population of cats varied in their ability to sustain FCoV replication regardless of whether the strain of FCoV was deemed very virulent or relatively avirulent, with the monocytes of some cats not sustaining replication of either FIP-associated FCoV or less-virulent non-FIP-associated laboratory strains of FCoV (Dewerchin et al., 2005). What happens in monocytes and macrophages following FCoV infection in FIP is quite extraordinary: usually, an infected cell will display viral antigens in association with a feline leucocyte antigen (the feline version of the major histocompatibility complex) on its surface to enable antibody-mediated, or cell-mediated, lysis, but in cats with FIP, infected macrophages lack the surface expression of viral antigens, helping escape cell lysis (Cornelissen et al., 2007).

FCoV viraemia, when it occurs, is short-lived, peaking about seven to 14 days post-infection and declining thereafter (Kipar et al., 2010; Mustaffa-Kamal et al., 2019); thus, by the time clinical signs of FIP appear, viraemia cannot always be detected, and RT-PCR tests on blood samples to detect FCoV RNA have been negative. However, this pattern of negative RT-PCR results on blood samples in FIP has not been observed in recent studies, which have found that a high percentage of cats with FIP have detectable FCoV in their blood by RT-PCR at diagnosis (Katayama and Uemura 2021; Krentz et al., 2021; Katayama and Uemura 2023) (see Section: FCoV RT-PCR on Blood Samples). This suggests that FCoV viraemia might last longer than previously thought.

The virulence of the virus, the viral load and the cat’s immune response determine whether or not FIP will develop. Thus, both viral genetics and host immunity are likely to play a role in the development of FIP (Addie and Jarrett 1995; Dewerchin et al., 2005; Rottier et al., 2005; Hsieh and Chueh 2014; Pedersen et al., 2014; Mustaffa-Kamal et al., 2019; Malbon et al., 2020b). Resistance, in terms of the ability of the host to ‘fight off’ FCoV infection, likely increases between six and 12 months of age (Pedersen 2014b), although FIP can occur at any age (Riemer et al., 2016).

In those cats in which FCoV is able to replicate freely within the monocytes, the monocytes attach to the walls of small- and medium-sized veins, releasing matrix metalloproteinase-9, which destroys the collagen of the basal lamina of affected vessels (Kipar et al., 2005). This event permits the extravasation of the monocytes, where they differentiate into macrophages. The breakdown of the endothelial tight junctions allows plasma to leak out of the vessels (Kipar et al., 2005). It is believed that the death of virus-laden macrophages (apoptosis) plays a key role in FCoV dissemination (Watanabe et al., 2018). Markers of intestinal and epithelial surface injury are higher in cats with FIP (especially in those with thoracic compared to abdominal effusions for some markers) compared to FCoV-infected cats without FIP (Gulersoy et al., 2023). In more acute forms of FIP, many blood vessels are affected, and this plasma leakage becomes apparent clinically as an effusion in the abdominal, thoracic and/or pericardial cavities. Within this process, the deposition of immune complexes and subsequent complement activation is thought to cause an intense inflammatory response that may extend across blood vessel walls, rendering them more permeable (Horzinek and Lutz 2000). However, vascular endothelial growth factor protein levels are elevated in cats with FIP and effusions compared to FIP cats without effusions, and this protein may be key in the progression from vasculitis without effusion to the development of effusions (Curtis et al., 2024). In more chronic forms of FIP, fewer blood vessels are affected, but the perivascular pyogranulomata on affected organs can become quite large and is even easy to mistake for a tumour upon gross examination, exploratory laparotomy or post-mortem examination. FCoV-infected macrophages release cytokines, such as tumour necrosis factor-alpha (TNF-α) (Takano et al., 2007b), which upregulates fAPN (Takano et al., 2007b), causes lymphopenia via lymphocyte apoptosis (Dean et al., 2003; Takano et al., 2007a; Curtis et al., 2024) and inhibits neutrophil apoptosis (Takano et al., 2009). The role of TNF-α is important in the development of FIP, such that anti-TNF-α antibodies have been used as a possible therapy (Doki et al., 2013; Doki et al., 2020b).

As described above, FIP arises only in a small percentage of FCoV-infected cats following FCoV infection, and the horizontal transmission of FIP via an FIP-associated FCoV strain is believed to be a very unlikely occurrence. Indeed, several experimental and field observations support the assumption that cats do not become infected with FIP-associated FCoV orally. FIP-associated FCoV strains from different cats of the same household show mostly unique genetic characteristics, suggesting that these viruses developed independently in individual cats (Chang et al., 2012; Barker et al., 2013; Licitra et al., 2013). Additionally, only a very small percentage of cats with FIP shed FIP-associated FCoV, most likely because the mutated viruses cannot replicate in enterocytes due to deletions in the 3c gene (Pedersen et al., 2009; Pedersen et al., 2012; Wang et al., 2013; Porter et al., 2014). Furthermore, faecal samples of cats with FIP do not cause disease after oral inoculation (Pedersen et al., 2012). Also, in multi-cat households, FIP cases are often limited to a single cat (or occasionally, at most, a few cats) and additional cases might not occur for several years.

However, a few reports exist in which a higher number of cats (greater than 10%) developed FIP in multi-cat environments (Graham et al., 2012; Barker et al., 2013; Wang et al., 2013; Terada et al., 2014; Healey et al., 2022; Taylor et al., 2023). Although such outbreaks (referred to as epizootics) are rare, they certainly occur. Several factors might contribute to these outbreaks, such as increased population stress (usually due to overcrowding or high kitten production), unintentional use of genetically predisposed cats, introduction of a new FCoV strain (such as one that has a high chance of becoming an FIP-associated FCoV) (Attipa et al., 2023a), or possible horizontal transmission (Pedersen 2009), in line with the previously mentioned ‘circulating virulent and avirulent FCoV’ theory.

The reports of very large numbers of stray cats in Cyprus succumbing to FIP emerged in 2023 when a 40-fold increase in FIP cases was reported. This led researchers to investigate the origins of the outbreak (Attipa et al., 2023a; Attipa et al., 2023b; Warr et al., 2023) and virus sequencing revealed the presence of a novel FCoV, termed FCoV-23. FCoV-23 has arisen due to recombination, and comprises a type I FCoV with the spike gene of a highly pathogenic pantropic CCoV. The similarities across multiple FCoV-23 sequences from different cats led the researchers to conclude that FCoV-23 is likely transmitted cat to cat, although further research on asymptomatic carrier cats and transmission studies are required to confirm this (Attipa et al., 2023b; Warr et al., 2023). The FIP disease resulting from FCoV-23 develops very rapidly and does not appear to affect predominantly young cats, as is usually seen with FIP. Neurological signs may also be more common with FIP due to FCoV-23. FCoV-23 was found to be the cause of FIP in a cat imported to the UK from Cyprus (Warr et al., 2023). Until further research has confirmed cat to cat transmission of FIP due to FCoV-23, veterinarians should be aware of the need to isolate suspected cases of FCoV-23 (i.e. involving travel to Cyprus) to avoid transmission to other cats. Cats affected with FIP due to FCoV-23 do respond to antiviral treatments (GS-441524 and molnupiravir have been used; see Section 10.1 Antiviral Treatments for FIP).

5. Immunity

The development of FIP is associated with the severe suppression of natural killer cells and regulatory T cells—central players in the innate and adaptive cell-mediated immunity (CMI), respectively (Vermeulen et al., 2013). Until the study on FCoV replication in monocytes was conducted by Dewerchin et al. (Dewerchin et al., 2005), the outcome of FCoV infection had been mainly attributed to virulence factors (mutations, deletions) in the virus (Pedersen 2014b), although host factors obviously played a role in pathogenesis. An effective early T cell response is believed to critically determine the outcome of infection with FCoV (de Groot-Mijnes et al., 2005).

One of the most investigated cytokines important in FCoV infection has been interferon (IFN) gamma (IFN-γ), which is an important modulator of CMI. The expression of IFN-γ mRNA by leucocytes in the circulation or in tissues has been investigated in many studies using RT-PCR and immunohistochemistry (IHC) (Gunn-Moore et al., 1998; Dean et al., 2003; Kiss et al., 2004; Berg et al., 2005; Gelain et al., 2006) and in plasma by proteomic analysis (Curtis et al., 2024). Some studies (Gunn-Moore et al., 1998; Kiss et al., 2004; Gelain et al., 2006) found high IFN-γ mRNA expression in the peripheral blood leucocytes of clinically normal cats with FCoV infection, but low expression in cats with FIP. In contrast, IFN-γ mRNA is abundant within FIP lesions (Berg et al., 2005). Giordano et al. Giordano and Paltrinieri (2009) concluded in their study that although cats resistant to FIP have strong CMI, which can be measured by high serum IFN-γ production, CMI is also likely to be involved in the pathogenesis of FIP, albeit at a tissue level, as evidenced by high IFN-γ concentration in FIP effusions. These findings could be the basis of further studies into the mechanisms through which IFN-γ production could prevent the onset of FIP. The importance of CMI in the resistance to FIP was further investigated in an experimental study (Mustaffa-Kamal et al., 2019) in which the antiviral T cell responses were measured during primary and secondary exposure to FIP-associated FCoV. Definitive adaptive T cell responses, predictive of disease outcome, were not detected during the early phase of primary infection with FIP-associated FCoV, but recovery antiviral T cell responses were seen later in primary infection for a subset of cats showing slow progression to FIP or resistance to FIP compared to those showing a fast progression of FIP. The emergence of antiviral T cell responses after secondary exposure (re-challenge) to FIP-associated FCoV in cats that were resistant to FIP after primary infection also suggested a role of CMI in the later control of infection with FIP-associated FCoV and disease progression.

Hsieh et al. (Hsieh and Chueh 2014) investigated whether single-nucleotide polymorphisms (SNPs) in the feline IFN-γ gene were associated with the outcome of FCoV infection. Some ‘FIP-resistant’ and ‘FIP-susceptible’ alleles were suggested, and a subsequent study found an increased frequency of documented feline IFN-γ SNPs in pedigree cats, but small numbers limited statistical analysis (Kedward-Dixon et al., 2020). A larger study (Barker et al., 2020) published on the prevalence of feline IFN-γ SNPs in non-pedigree cats did find a statistical association between the presence or absence of FIP and genotype; however, the strength of this association (presence of the ‘protective’ genotype in 16% of the cats with FIP and its absence in 66% of the cats without FIP) limits its use in individual cats or to guide breeding. Another study found associations between FIP and SNPs in the TNF-α and the dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin (DC-SIGN) genes (Wang et al., 2014b), although no such associations were found in a subsequent study (Kedward-Dixon et al., 2020). A proteomic study by Curtis et al., (2024) has found significantly increased DC-SIGN-related proteins in in cats with FIP.

The role of humoral immunity in protecting against FIP is ambiguous. Maternally derived antibodies have been suggested to provide protection until about five to six weeks of age (Addie and Jarrett 1992) until they decline and become undetectable by six to eight weeks of age. However, infection at two weeks of age has also been detected rarely (Lutz et al., 2002), questioning protection by maternally derived antibodies. On the other hand, cats with active enteric FCoV infections have strong systemic IgG and mucosal secretory IgA responses that wane after FCoV clearance, with no evidence of a mucosal IFN-γ T cell response, suggesting that humoral responses can control infection (Pearson et al., 2019).

Seroconversion (i.e., antibody production) to FCoV takes seven to 28 days post-infection (Stoddart et al., 1988b; Horzinek and Lutz 2000; Meli et al., 2004; Vogel et al., 2010). Following natural infection, antibody titres can decline to zero over a period of several months to years, as demonstrated by more than half the serum antibody-positive cats in 24 of 73 households with endemic FCoV infection becoming serum antibody-negative (Addie et al., 1995a). In other longitudinal studies of multi-cat households (Addie et al., 2003), FCoV antibody titres were variable (i.e., increased and decreased), believed to be due to cycles of infection and re-infection, but they can decrease when maintaining closed households (Addie et al., 2000) or with the segregation of serum antibody-positive and -negative cats (Addie and Jarrett 2001).

The clearance of natural infections has been associated with antibodies directed against the FCoV S protein (Gonon et al., 1999). Conversely, in experimental infections, antibodies directed against the S protein can be detrimental (Vennema et al., 1990). In cats with pre-existing antibodies, ‘antibody-dependent enhancement’ (ADE) has been observed experimentally, resulting in a more rapid disease course and earlier death (Horzinek and Lutz 2000). This enhancement was observed irrespective of whether cats had acquired antibodies through passive or active immunisation using experimental vaccines (Weiss and Scott 1981; Vennema et al., 1990; De Groot and Horzinek 1995). However, in field studies, cats developed FIP on first exposure to FCoV (and thus did not have pre-existing antibodies), and some cats experienced repeated FCoV infections without developing FIP, leading to the conclusion that ADE is likely an experimental phenomenon, which is not believed to be important in natural infection (Addie et al., 1995b; Addie et al., 1995a; Addie et al., 2003). Additionally, an experimental study (Mustaffa-Kamal et al., 2019) documented that nine of 10 cats that had not developed FIP following primary infection with an FIP-associated FCoV strain resisted the development of the disease following re-challenge. However, the phenomenon of ADE still remains a major concern in vaccine development for FIP.

6. Clinical Signs

6.1. Clinical Signs Associated with FCoV Infection

FCoV infection does not often cause clinical signs sufficient for a cat owner to seek veterinary attention following infection, although FCoV-infected littermates tend to have poorly grown kittens amongst them and a more frequent history of diarrhoea and upper respiratory signs than uninfected kittens (Addie and Jarrett 1990). Occasionally, FCoV infection causes enteritis (Pedersen et al., 1981; Hayashi et al., 1982; Addie and Jarrett 1992; Addie and Jarrett 2001; Sabshin et al., 2012; Addie et al., 2023) with clinical signs of diarrhoea and/or vomiting. FCoV infection was significantly associated with diarrhoea in a study of 234 cats from 37 breeding catteries in Germany, although faecal FCoV load was not correlated with faecal consistency scoring (Felten et al., 2022). Although co-infections with potential enteropathogens were also common in this study, their presence in cats with FCoV infection was not associated with diarrhoea (Felten et al., 2022). FCoV infection was also significantly associated with diarrhoea in cats from home-based foster care, but not in cats from shelters, sanctuaries, or trap-neuter-return programs in the USA (Andersen et al., 2018). Occasionally, very severe, even fatal, coronavirus enteritis has been reported (Kipar et al., 1998), and chronic diarrhoea was reported in FCoV carrier cats (Addie and Jarrett 2001; Addie et al., 2023).

6.2. Clinical Signs Associated with FIP

6.2.1. General Clinical Signs of FIP

The clinical picture of FIP varies considerably, reflecting the variability in the distribution of the vasculitis and (pyo)granulomatous lesions. The vasculopathy can result in effusions (‘wet FIP’), whilst granuloma formation alone results in ‘dry’ or ‘non-effusive FIP’ mass lesions. The clinical presentation that includes the development of effusions is regarded as being most common (Sparkes et al., 1991; Pedersen 2009; Tsai et al., 2011; Riemer et al., 2016; Felten and Hartmann 2019; Jones et al., 2021; Krentz et al., 2021; Yin et al., 2021; Sweet et al., 2022; Green et al., 2023): 78% of 224 cases of FIP had effusions (Riemer et al., 2016) in one study. The distinction between so-called ‘effusive’ and ‘non-effusive’ forms of FIP is important for diagnostic purposes because the analysis of an effusion is so useful. However, there is a considerable overlap between the two forms and, indeed, FIP cases with effusions also have pyogranulomatous lesions visible at post-mortem examination or can evolve to a more non-effusive disease, and, similarly, cats without effusions can develop effusions (Addie et al., 2022). Clinical signs of FIP can also change over time, and therefore repeated physical examinations are important to detect newly apparent clinical signs; for example, an effusion can develop, or ocular changes can become visible on ophthalmoscopic examination. ABCD FIP Diagnostic Approach Tools (Tasker et al., 2023a) are available to help the veterinarian assess clinical signs for FIP.

Non-specific clinical signs can occur in both cats with effusions or without effusions and include fever, lethargy, anorexia and weight loss (Cerna et al., 2022; Green et al., 2023; Muller et al., 2023; Taylor et al., 2023) (or failure to gain weight/stunted growth in kittens), although occasionally some cats remain bright and retain good body condition. Fever is commonly present, and it can fluctuate and is refractory to many drugs and non-responsive to antibiotics. One study describing referral cats with a history of fever found that FIP was the most common diagnosis made, highlighting its importance as a differential diagnosis for fever even at referral level (Spencer et al., 2017). Another study (Riemer et al., 2016), which described the clinical features of FIP, documented fever in 56% of FIP cases. Fever was shown to be more common in cats with effusion than in cats without effusion (Riemer et al., 2016). Fever was also more severe in cats with thoracic (10 cats) than abdominal (30 cats) effusions in one study (Gulersoy et al., 2023).

FIP can be associated with effusion formation in one or more body cavities. Abdominal effusions leading to a clinical presentation of ascites, sometimes with abdominal distension, are the most common effusions seen with FIP (Riemer et al., 2016; Lv et al., 2022; Coggins et al., 2023; Green et al., 2023; Taylor et al., 2023) (Figure 4).

Figure 4. Ascites in a young Sphinx cat presenting with FIP. Image Hannah Dewerchin, Ghent University, Belgium (Addie et al., 2009).

Pleural effusion can be present concurrently to abdominal effusion. In some cats, the effusion is restricted to the thorax; cats with pleural effusion can present with dyspnoea (Pedersen 2009; Beatty and Barrs 2010; Spencer et al., 2017; Green et al., 2023; Gulersoy et al., 2023). In a retrospective study (Konig et al., 2019) including 306 cats diagnosed with pleural effusion of established aetiology, FIP was only diagnosed in 9% of cats, while cardiac disease was the most common aetiology (35%), followed by neoplasia (31%), pyothorax (9%) and chylothorax (5%). Cats with FIP were significantly younger than those with cardiac disease and neoplasia, and cats with cardiac disease had a significantly lower body temperature, higher serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activity, and lower protein concentrations and nucleated cell counts in the effusion than cats with FIP (Konig et al., 2019).

Pericardial effusions (Fischer et al., 2012b; Baek et al., 2017; Cosaro et al., 2023), with or without effusions in other body cavities, are also occasionally reported. Rarely, effusion in the scrotum is present in intact male cats due to a serositis involving the tunica vaginalis of the testes, leading to scrotal enlargement. When effusions form in FIP, the disease progression is often quite acute in nature, progressing within a few days or weeks and severely limiting survival (Ritz et al., 2007).

FIP is often more difficult to diagnose when effusions are not present because fever, anorexia, lethargy, and weight loss (or failure to gain weight in kittens) can be the only clinical signs, particularly in the early stages of disease. FIP presenting without effusions also tends to be more chronic than FIP associated with effusions, progressing over a few weeks to months. Additional signs of FIP without effusions depend on the organs affected by the pyogranulomatous lesions and can include the central nervous system (CNS) (Kline et al., 1994; Foley et al., 1998; Crawford et al., 2017; Katayama and Uemura 2023), eyes (Ziolkowska et al., 2017; Katayama and Uemura 2023) and/or abdominal organs (such as the liver, abdominal lymph nodes, kidney, pancreas, spleen and/or gastrointestinal tract) (Norris et al., 2005), and such signs can also occur in cats with effusions.

Renomegaly (Muller et al., 2023), but also occasionally a reduction in kidney size, can occur . A pyogranulomatous pneumonia can occur (Trulove et al., 1992; Macdonald et al., 2003), causing respiratory signs. Abdominal lymphadenomegaly and lymphadenopathy are common (Dunbar et al., 2019; Addie et al., 2023; Coggins et al., 2023; Zwicklbauer et al., 2023). In one retrospective study of suspected cases of FIP (Yin et al., 2021), 41% of cats had a palpable abdominal mass on palpation, believed to be either mesenteric lymphadenomegaly or an intestinal mass. Mesenteric lymphadenomegaly and abdominal organomegaly were noted in 27% and 25% of 28 cats with FIP, respectively, in one report (Coggins et al., 2023). In another study of suspected FIP in cats without effusions or with ‘mixed’ signs of both effusive and non-effusive FIP (‘mixed’ was the terminology used by the authors to describe cases with signs of both) (Katayama and Uemura 2023), 31% of cats had abdominal lymphadenopathy, but the size of the lymph nodes was not described. Jaundice can occur (Figure 5), more commonly in cats with effusions; although hyperbilirubinaemia is common, levels are often not high enough to result in clinical jaundice (Pedersen 2009; Riemer et al., 2016; Green et al., 2023; Taylor et al., 2023). For example, in a large study of cats with FIP (Taylor et al., 2023), 120-286 (42%) were hyperbilirubinaemic but only 58/306 (19%) were jaundiced.

Figure 5. Icterus can occur in cases with FIP, particularly in cats with effusive FIP. Image Séverine Tasker, Bristol Veterinary School, University of Bristol, UK.

6.2.2. Clinical Signs of FIP Associated with the Intestinal Tract

FIP can also manifest in the intestinal tract and/or regional lymph nodes (sometimes called a ‘focal form of intestinal FIP’ (Harvey et al., 1996)), presenting typically as a palpable abdominal mass due to primary involvement of the MLNs and/or thickening of the intestinal tract. As mentioned above, in one study (Yin et al., 2021), 41% of cats with suspected FIP had a palpable abdominal mass, believed to be either mesenteric lymphadenomegaly or an intestinal mass. It can be particularly challenging to diagnose these cases as the lesions can be hard to initially differentiate from neoplasia (Kipar et al., 1999), toxoplasmosis (Cohen et al., 2016) or mycobacterial infection (O’Halloran and Gunn-Moore 2017). Diarrhoea is sometimes reported (Hayashi et al., 1982; Yin et al., 2021; Green et al., 2023).

FIP involving the intestinal tract can manifest as a protein-losing enteropathy, leading to low total protein and globulin values, in contrast to the usual hyperglobulinaemia in FIP. Often, these cats present with MLN enlargement due to necrogranulomatous lymphadenitis (Kipar et al., 1999; Hugo and Heading 2015), or solitary mural intestinal lesions of the colon or ileo-caecocolic junction with associated regional lymphadenopathy (Harvey et al., 1996). Cats with intestinal FIP usually have a history of weight loss, vomiting and diarrhoea or constipation.

6.2.3. Clinical Signs of FIP Associated with the Skin

Dermatological signs are occasionally reported in FIP and can manifest as single or multiple non-pruritic or pruritic nodules or papules (Cannon et al., 2005; Declercq et al., 2008; Bauer et al., 2013; Redford and Al-Dissi 2019), due to pyogranulomatous-necrotising dermal phlebitis/vasculitis. Skin fragility syndrome was reported in a cat with FIP and concurrent hepatic lipidosis (Trotman et al., 2007). Idiopathic ulcerative dermatitis (IUD) has also been reported with FIP. In one report (Avila and Rissi 2020), IUD was diagnosed in a cat with uveitis, and the small ulcer on the dorsal neck was positive for the FCoV antigen when tested by IHC. However, in another report of a cat with IUD (Bae et al., 2021), the FCoV antigen IHC of the skin was negative, although FIP was confirmed by IHC on kidney tissue. Priapism has been reported as a result of granulomatous changes in tissues surrounding the penis (Rota et al., 2008).

6.2.4. Clinical Signs of FIP Associated with the Nervous System

Neurological FIP can result in clinical signs associated with focal, multifocal, or diffuse changes in the brain, spinal cord, and meninges. Up to 30% of cats with FIP show neurological signs (Kline et al., 1994; Foley et al., 1998; Foley and Leutenegger 2001; Negrin et al., 2007; Kent 2009; Negrin et al., 2010; Ives et al., 2013; Doenges et al., 2016). Sometimes, cats with FIP present with only neurological disease (Rissi 2018). Three clinical syndromes were identified in a retrospective study of neurological FIP (Crawford et al., 2017); of 24 cats, three had a T3-L3 myelopathy, seven had central vestibular syndrome and 14 had multifocal CNS disease. Commonly reported signs include ataxia (with varying degrees of tetra- or paraparesis; Figures 6 and 7), hyperaesthesia, nystagmus, seizures (Timmann et al., 2008), behavioural and mental state changes, and cranial nerve deficits. Central vestibular clinical signs can include head tilt, vestibular ataxia, nystagmus, obtunded appearance, and postural reaction deficits; obtundation was reported in all five cats with FIP that presented with neurological signs in one case series (Green et al., 2023). Interestingly, a retrospective study (Grapes et al., 2021) that reviewed cats presenting with vestibular disease did not identify any discrete clinical characteristics that would help differentiate cats with vestibular disease due to FIP from other causes. This was a surprise given that FIP primarily affects younger cats and is often associated with concurrent non-neurological signs. The absence of clinical characteristics specifically associated with FIP may have been because the study included a number of younger cats with other diagnoses (middle ear polyps, thiamine deficiency, intracranial empyaema and otitis media/interna), and cats with intracranial empyaema can have non-neurological systemic signs. Fever was less common in cats with neurological FIP compared to those without neurological signs (Riemer et al., 2016). A retrospective study (Mella et al., 2020) of cats referred for investigation of spinal disease found FIP to be the cause in 18 of 221 cats; concurrent systemic abnormalities and abnormal findings on clinical examination were significantly associated with a diagnosis of FIP, but these features were also associated with a diagnosis of spinal lymphoma (16 cats) and empyaema (3 cats).

Figure 6. Ataxia can occur in cats with neurological FIP. Image Séverine Tasker, Bristol Veterinary School, University of Bristol, UK.

Figure 7. Ataxia (wide-based stance) and obtundation in a cat with neurological FIP. Image Allan May, University of Glasgow, UK through Diane Addie.

6.2.5. Clinical Signs of FIP Associated with the Eye

FIP was the second-most-common cause of uveitis after idiopathic uveitis in studies of 120 cats with uveitis in the USA (16% had FIP) (Jinks et al., 2016), and 92 cats with uveitis in the UK (again, 16% had FIP) (Wegg et al., 2021). A study describing the ocular lesions in 15 cats with FIP found effusions in 13 cats and no effusion in only two cats (Ziolkowska et al., 2017), although other authors have found a low prevalence of effusions in cats with FIP-associated uveitis (Wegg et al., 2021). Ocular manifestations of FIP comprise anterior and/or posterior uveitis (Foley et al., 1998; Norris et al., 2005; Doenges et al., 2016; Jinks et al., 2016; Green et al., 2023) (Figures 8–10), with anterior uveitis being more common (Carossino et al., 2022). The uveitis is unilateral or bilateral (Wegg et al., 2021). Important differential diagnoses include toxoplasmosis (Ali et al., 2021), lymphoma, feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) infection (Jinks et al., 2016; Wegg et al., 2021). Clinical signs include changes in iris colour, dyscoria or anisocoria secondary to iritis, sudden loss of vision and hyphaema (Figures 8 and 9). Keratic precipitates can appear as ‘mutton fat’ deposits on the ventral corneal endothelium (Figure 10). The iris can show swelling and a nodular surface, and aqueous flare can be detected. On ophthalmoscopic examination, chorioretinitis, fluffy perivascular cuffing (representing retinal vasculitis), dull perivascular puffy areas of pyogranulomatous chorioretinitis, linear retinal detachment, vitreous flare and fluid blistering under the retina can be seen.

Figure 8. FIP-associated anterior uveitis can manifest variably such as with the presence of hyphaema. Image Maria Bonino and Erica Carter.

Figure 9. FIP-associated anterior uveitis can manifest variably such as with the presence of hyphaema. Image Albert Lloret, Universitat Autònoma Barcelona, Spain (Addie et al., 2009).

Figure 10. FIP-associated anterior uveitis can manifest variably such as with the presence of inflammatory keratic precipitates. Image Eric Déan, Vet-Oeil Ophthalmology Clinic, France (Addie et al., 2009).

6.2.6. Miscellaneous Clinical Signs of FIP

FIP-associated rhinitis (Andre et al., 2020) was described in a young cat that presented with some upper respiratory signs as well as other more typical signs of FIP; extensive respiratory panel testing on upper respiratory tract swabs in this cat revealed only a low positive test result for Mycoplasma felis, whilst the histopathological examination of lung (and liver and intestine) and nasal samples (including FCoV antigen IHC on the nasal samples) confirmed a diagnosis of FIP. Another report described three cats with FIP that had presented with mild upper respiratory signs before showing other more typical signs of FIP (fever, icterus, lethargy, anorexia, effusions) within the following 10 days (Healey et al., 2022).

Myocarditis associated with FIP has also been described in a cat without effusion (Ernandes et al., 2019); this particular case had presented with fever, weight loss and diarrhoea before developing dyspnoea and then neurological and ocular signs of FIP. The histopathology of various organs, including cardiac tissue, was consistent with FIP, and the FCoV antigen IHC of the heart was also positive.

7. Diagnosis of FIP

This section will focus on the diagnosis of FIP in sick cats showing clinical signs that could be suggestive of FIP. A cat cannot develop FIP unless it has been previously infected with FCoV and so the demonstration of FCoV (as RNA or antigen) in affected tissues and effusions, with other findings (e.g., biochemistry, cytology) consistent with FIP, is helpful during diagnostic investigations of FIP.

The ABCD FIP Diagnostic Approach Tools found online (Tasker et al., 2023a) and in Figures 11–14 show an overview of criteria that can be used to confirm a diagnosis of FIP or make a diagnosis of FIP very likely. Now that effective antivirals for the treatment of FIP exist, the trial treatment of cases without a confirmed diagnosis of FIP, but in which the diagnosis is very likely (Figures 11–13), can be warranted, as the response to effective antivirals is usually rapid. This is discussed in Section 10 on Treatment of FIP. Further information on the diagnostic tests mentioned in Figures 11–14 is in this section.

7.1. Signalment and History for FIP

When considering FIP as a differential diagnosis, one must remember that FIP is more common in young cats (especially under two years old (Rohrbach et al., 2001; Norris et al., 2005; Pesteanu-Somogyi et al., 2006; Riemer et al., 2016; Katayama and Uemura 2021; Yin et al., 2021)) and that male cats (Rohrbach et al., 2001; Benetka et al., 2004; Norris et al., 2005; Worthing et al., 2012; Soma et al., 2013; Riemer et al., 2016) are at a slightly higher risk of disease, according to some studies. However, cats of any age or sex can be affected. In one study, the median age of a group of cats with FIP without effusions was 39 months (Cerna et al., 2022). Additionally, most cats that develop FIP come from multi-cat households or have a history of having been housed in multi-cat households. Although certain breeds have been shown to be predisposed to FIP in certain countries (Pesteanu-Somogyi et al., 2006; Worthing et al., 2012), it is believed that this is due to genetic risk factors being present in those breeds in those countries rather than the existence of worldwide generalised breed predispositions (Riemer et al., 2016), although a predilection for pedigrees has been reported (Robison et al., 1971; Rohrbach et al., 2001; Norris et al., 2005; Pesteanu-Somogyi et al., 2006; Worthing et al., 2012; Soma et al., 2013). In a study (Dunbar et al., 2024) that applied machine learning to diagnosing non-effusive FIP, the age, sex and pedigree/non-pedigree breed status of cats were found to be informative in the resulting model (although less than some of the laboratory changes; see Section 7.2. Approach to the Diagnosis of FIP), highlighting the importance of signalment when considering a diagnosis of FIP.

A recent history of stress (e.g., adoption, being in a shelter, neutering, upper respiratory tract disease, vaccination, travel, new household member) is commonly apparent (Rohrer et al., 1993; Riemer et al., 2016; Yin et al., 2021) and may contribute to the development of FIP in a FCoV-infected cat.

7.2. Approach to the Diagnosis of FIP

In cats with FIP that have an effusion, sampling the effusion is the single most useful diagnostic step (Figures 11 and 12); this is because tests on effusions often have a higher diagnostic value in comparison to tests on blood (Hartmann et al., 2003), and effusion samples are often relatively easy to obtain. If the effusion is not large in volume, imaging can be used (Pedersen 2014a) to confirm, identify and localise any small volumes present (Muller et al., 2023). Ultrasonography is generally regarded as being more sensitive than radiography for this, but it depends on where pockets of fluid reside (see Section 7.4.1 on Routine Imaging: Ultrasonographic and Radiographic Findings). Repeated ultrasonography to identify any small-volume effusion is recommended and, similarly, ultrasonography can be used to guide the sampling of small pockets of fluid (Tasker 2018). Once an effusion is sampled, the first thing to do is to take note of its appearance: if it is frank blood, or if it can be discerned as urine, FIP is very unlikely. Additionally, purulent exudates are usually not caused by FIP (Johnson et al., 2023), although occasionally bacterial translocation in cats with effusions due to FIP can complicate diagnosis and response to treatment (Séverine Tasker, personal communication). The presence of chyle will usually indicate other diseases, such as heart failure, lymphoma or a ruptured thoracic duct, but cats with FIP with pure chylous effusion have been reported (Savary et al., 2001). FIP effusions are usually clear, viscous/sticky and straw-yellow in colour (Figure 15).

Diagnosing FIP if no effusion is present, however, can be very challenging due to the high number of possible clinical signs and the non-specificity of most of them (e.g., anorexia, lethargy, weight loss, fever) and the lack of accessible fluid to sample. Peritoneal lavage can be performed by instilling 20 mL/kg of 0.9% saline into the peritoneal cavity, massaging the abdomen, and withdrawing the fluid by paracentesis (Emmler et al., 2020; Jähne et al., 2022), although the value of analysis of lavage fluid in the diagnosis of FIP of cases without effusions is not clear (Emmler et al., 2020). The definitive diagnosis of FIP in cases that do not have effusions, by collection of tissue biopsies ante-mortem, for histopathology and IHC, can be very difficult due to, for example, problems accessing affected tissues, contra-indications for general anaesthesia or invasive biopsy collection in a sick cat, and/or costs involved in collection. Cases with neurological or ocular signs can be approached via the sampling of cerebrospinal fluid (CSF) or aqueous humour, although these techniques are not commonly performed in non-referral veterinary clinics. Currently, there is no non-invasive, confirmatory test available for cats with FIP that do not have effusions, although valuable information can be gained through the analysis of FNA samples for cytology and FCoV antigen or RNA detection following collection from affected organs, if accessible, as described below. Tissue FNA samples are usually easier to obtain than tissue biopsies.

The information in this review will consider the merits and drawbacks (and sometimes sensitivity and specificity) of tests available for the diagnosis of FIP, and FCoV infection if relevant. Although each individual test will be described, it should be remembered that when a cat with suspected FIP is investigated, a veterinarian will be interpreting several test results at the same time, as well as taking into account the signalment and history of the cat. Such interpretation is important in helping to determine how likely FIP is as a diagnosis, in the absence of a definitive diagnosis. The advantage of integrating multiple test results during interpretation has been shown (Stranieri et al., 2018). Additionally, machine learning has been applied successfully to the diagnosis of FIP (Pfannschmidt et al., 2016; Dunbar et al., 2024), although a deployable machine learning model is not yet available, and specific models will need to be developed for different laboratories (Dunbar et al., 2024). The machine learning model was trained on a retrospective series of cases where non-effusive FIP status was inferred from the interpretation of history, clinical signs, signalment and laboratory data. Overall, high FCoV titres and high levels of α1-acid glycoprotein (AGP), combined with low albumin to globulin (A:G) ratio and reduced haemoglobin levels, were consistently recognised as being important but non-specific clinical markers of FIP. Signalment factors (age, sex and pedigree) were also important but to a lesser extent than the haematological and biochemical changes (Dunbar et al., 2024). Further details on these variables and their interpretation in the diagnosis of FIP are given in Section 7.3. Laboratory Changes in FIP and Section 7.6.1. FCoV Antibody Testing.

Now that effective antiviral treatments, such as GS-441524 (Krentz et al., 2021; Yin et al., 2021), are available for FIP (see Section 10 on Treatment of FIP), a rapid and sustained positive response to antiviral treatment is also a means of supporting a diagnosis of FIP.

Figure 11. European Advisory Board on Cat Diseases (ABCD) Feline Infectious Peritonitis (FIP) Diagnostic Approach Tools: diagnostic approach I, showing evidence that can contribute to being highly suspicious of a diagnosis of FIP. This tool is available online (Tasker et al., 2023a), with revisions made to the online version as required. Many features of the cat’s signalment, history and clinical examination can contribute to a suspicion of FIP. Effusion analysis is always extremely helpful, so looking for evidence of an effusion and then sampling should be prioritised whenever possible. Certain haematological features can also contribute to the suspicion of FIP as a diagnosis. Please see the ‘NOTE’ box (in brown at top of the figure) for explanation of the symbols that include ‘+’ and ‘-‘.

Figure 12. European Advisory Board on Cat Diseases (ABCD) Feline Infectious Peritonitis (FIP) Diagnostic Approach Tools: diagnostic approach IIa, showing diagnostic testing evidence that can confirm FIP as a diagnosis following being highly suspicious of FIP in cats with an effusion (1) and cats that neither have effusions nor specific clinical signs (2). This tool is available online (Tasker et al., 2023a), with revisions made to the online version as required. The symbol * after diagnostic imaging refers to the pale brown box at the bottom of the figure (that gives additional information on this scenario).

Figure 13. European Advisory Board on Cat Diseases (ABCD) Feline Infectious Peritonitis (FIP) Diagnostic Approach Tools: diagnostic approach IIb, showing diagnostic testing evidence that can confirm FIP as a diagnosis following being highly suspicious of FIP in cats with neurological signs (3) and cats with aqueous humour cytology consistent with FIP (4). This tool is available online (Tasker et al., 2023a), with revisions made to the online version as required. In this figure, the confirmation of a diagnosis of FIP requires the collection of cerebrospinal fluid (CSF) or aqueous humour. However, it is generally easier to sample effusions, if present, or accessible abnormal organs or tissues (e.g., mesenteric lymph node, identified by imaging) by fine-needle aspiration, if present, as indicated in Figure 12. The symbols * refer to the respective pale brown boxes at the bottom of the figure (that gives additional information for these scenarios). The figures 1 and 2 refer to the respective footnotes.

Figure 14. European Advisory Board on Cat Diseases (ABCD) Feline Infectious Peritonitis (FIP) Diagnostic Approach Tools: differential diagnoses. This tool is available online (Tasker et al., 2023a), with revisions made to the online version as required.

Figure 15. Abdominal effusion sample collected from a cat with FIP showing typical clear straw-yellow-coloured fluid. Image Séverine Tasker, Bristol Veterinary School, University of Bristol, UK.

7.3. Laboratory Changes in FIP

7.3.1. Routine Haematology

Routine haematological changes are not specific for FIP, but common abnormalities are lymphopenia (seen commonly and maybe more in cats with effusions than in cats without), neutrophilia, a left shift in some reports, and a mild-to-moderate normocytic, normochromic anaemia (Sparkes et al., 1991; Rohrer 1992; Sparkes et al., 1994; Norris et al., 2005; Tsai et al., 2011; Riemer et al., 2016; Yin et al., 2021; Addie et al., 2022; Cerna et al., 2022; Green et al., 2023; Taylor et al., 2023; Dunbar et al., 2024). No difference in the likelihood of anaemia was found between cats with and without effusions in one study (Addie et al., 2022). An association between FIP and microcytosis (with or without anaemia) has been reported (Riemer et al., 2016). Immune-mediated haemolytic anaemia occasionally occurs (Norris et al., 2005; Riemer et al., 2016). Interestingly, in the study (Dunbar et al., 2024) that applied machine learning to diagnosing non-effusive FIP, reduced haemoglobin was the most useful variable to evaluate on haematology. A decreasing red-blood-cell count is a poor prognostic sign (Tsai et al., 2011; Cerna et al., 2022) and, indeed, a reversal of the anaemia occurs in successfully treated cats (Addie et al., 2022; Cerna et al., 2022).

7.3.2. Serum Biochemistry

Serum biochemistry changes are also non-specific in cats with FIP, but certain abnormalities can be helpful in making one consider FIP as more likely as a diagnosis.

Hyperglobulinaemia is often reported in FIP and can be accompanied by hypoalbuminaemia or low-to-normal serum albumin (Rohrer 1992; Riemer et al., 2016; Green et al., 2023; Taylor et al., 2023). The presence of hypoalbuminaemia alongside hyperglobulinaemia means that hyperproteinaemia is not always present (Riemer et al., 2016). The A:G ratio can be low, and the value of this ratio can be used to help evaluate how likely FIP is; the A:G ratio has a higher diagnostic value than either total serum protein or globulin concentration (Hartmann et al., 2003). Various A:G ratio cut offs have been suggested, e.g., an A:G ratio of less than 0.4 makes FIP very likely, whilst an A:G ratio of greater than 0.8 makes FIP very unlikely (Sparkes et al., 1991; Norris et al., 2005; Tsai et al., 2011; Moyadee et al., 2023). One study (Jeffery et al., 2012) on a population of cats with a prevalence of FIP of 4%, reported that a serum A:G ratio of greater than 0.6 was useful in ruling out FIP, but that lower ratios were not helpful in ruling in FIP. Additionally, the frequency and magnitude of hypoalbuminaemia, hyperglobulinaemia and low A:G ratios reported in cats with FIP have decreased in more recent years (Riemer et al., 2016; Stranieri et al., 2017a), which could be due to veterinarians diagnosing FIP earlier, meaning that cases have not progressed to show these changes. In the study (Dunbar et al., 2024) that applied machine learning to diagnosing non-effusive FIP, a reduced A:G ratio was found to be useful in the deduced model. Serum protein electrophoresis (SPE) is sometimes performed to aid the diagnosis of FIP, but the changes seen are non-specific; (Rota et al., 2008; Giori et al., 2011; Stranieri et al., 2017a; Stranieri et al., 2018; Thayer et al., 2022; Farsijani et al., 2023); FIP SPE typically shows an increase in the alpha (α)2 and the gamma (γ)-globulin, with a polyclonal peak, fractions. Monoclonal elevated γ-globulins have also been reported in cats with FIP (Taylor et al., 2010), although polyclonal elevations are far more common. In one study, a low A:G ratio was found to be a negative prognostic indicator in cats with FIP given immunostimulant treatment (Cerna et al., 2022).

Increased bilirubin levels, in the absence of both marked haemolysis and moderate elevations of liver enzyme activity, should raise the suspicion of FIP, although other differential diagnoses to consider with these changes are sepsis and pancreatitis (Tasker 2018). In a retrospective study of 216 cats with hyperbilirubinaemia evaluated in referral centres in the UK (Salord Torres et al., 2024), FIP was diagnosed in 18 (8%) of the cats, with a median (range) serum bilirubin concentration of 24 (13.5-86.1) μmol/L. Hyperbilirubinaemia occurs in 22–84% of cats with FIP (Sparkes et al., 1991; Norris et al., 2005; Tsai et al., 2011; Riemer et al., 2016; Green et al., 2023; Taylor et al., 2023), and is especially seen in FIP cases with effusions (Riemer et al., 2016). Increased bilirubin values are not always correlated with elevated liver enzymes (Riemer et al., 2016), as hyperbilirubinaemia in cats with FIP is not necessarily a reflection of parenchymal liver disease. ALT, aspartate transferase (AST) and ALP were normal in 86%, 66% and 95%, respectively, of cats with FIP (Riemer et al., 2016). The hyperbilirubinaemia may be due to excessive erythrocyte fragility, leading to haemolysis, with the reduced clearing of haemoglobin breakdown products (Pedersen 2014b), or altered bilirubin metabolism due to high TNF-α levels, leading to reduced bilirubin transport into and out of liver cells and biliary system (Hartmann 2005). It has been found that the level of bilirubin can rise as FIP progresses, and that rising bilirubin levels (and falling red-blood-cell counts) are a poor prognostic sign (Tsai et al., 2011). Indeed, a study (Katayama and Uemura 2021) evaluating the response to nucleoside analogue antiviral treatment, of cats with suspected effusive FIP found that the total bilirubin levels in those that survived were significantly lower than those that did not, suggesting that circulating total bilirubin levels might be a prognostic risk factor for response to treatment in effusive FIP. A similar finding by the same group was found (Katayama and Uemura 2023) in cats with ‘mixed’ effusive and non-effusive FIP.

As described earlier, the kidneys can be affected in FIP via pyogranulomatous lesions or glomerulonephritis (Hartmann et al., 2020); these changes can result in azotaemia, although this is more common in cases without effusions (Riemer et al., 2016).

Hypoglycaemia was reported in five of 32 (15%) cats with FIP; this may reflect disease severity, the presence of severe inflammatory response syndrome, or sepsis (Green et al., 2023).

Acute phase proteins (APPs) are produced by the liver in acute infections and many inflammatory and non-inflammatory diseases in response to cytokines released from macrophages and monocytes. The major APPs in cats are AGP and serum amyloid A (SAA).

AGP has an immunomodulatory function, and assays are available for its measurement in laboratories in some countries. The reference range for AGP serum concentrations is less than 0.48 mg/mL (less than 480 µg/mL) (Duthie et al., 1997), and a moderately elevated serum AGP concentration (Katayama and Uemura 2023) and concentrations of greater than 1.5 mg/mL (Stranieri et al., 2018; Addie et al., 2022), are frequently reported in cats with FIP, although laboratories should be consulted to obtain appropriate cut-offs. The magnitude of the increase in serum AGP might be helpful in the diagnosis of FIP (Duthie et al., 1997; Paltrinieri et al., 2007a; Giori et al., 2011; Hazuchova et al., 2017). One report (Paltrinieri et al., 2007a) found that markedly elevated serum AGP concentrations of greater than 3 mg/mL could support a diagnosis of FIP in cats with a low pre-test probability of disease (i.e., with a history and clinical findings not typical of FIP), whereas less marked elevations were supportive of a diagnosis of FIP in cats with a higher pre-test probability of disease (i.e., with a history and clinical findings more typical of FIP). However another, albeit very small, study of cats with FIP actually found that even moderately elevated AGP concentrations of greater than 1.5 mg/mL were still able to discriminate between cats with and without FIP (Giori et al., 2011); interestingly, this study comprised unusual cases of FIP with atypical presentations, although a diagnosis of FIP was confirmed in all cases. In one study (Taylor et al., 2023), in which 68 cats with FIP had AGP values measured, 57% of these cats had AGP values of greater than 3 mg/mL and 15% had AGP values of 2 to 3 mg/mL. Only two (3%) of these cats had a normal AGP value of less than 0.5 mg/mL Lastly, in the study (Dunbar et al., 2024) that applied machine learning to diagnosing non-effusive FIP, an elevated AGP was found to be useful in the deduced model. However, it must be emphasised that AGP is not specific for FIP and can be increased in other diseases. It has been suggested that an AGP concentration of less than or equal to 1.5 mg/mL could be useful to rule out FIP (Stranieri et al., 2018). AGP concentrations have been found to increase moderately and transiently in all the cats in a household before the appearance of cases of FIP in an environment with endemic FCoV infection (Paltrinieri et al., 2007b). It has also been found that AGP is often hyposialylated in cats with FIP, but not usually in clinically healthy FCoV antibody-positive cats or cats with other diseases (Ceciliani et al., 2004; Rossi and Paltrinieri 2009). However, testing for the sialylation of AGP is not available routinely. A feline immunometric enzyme-linked immunosorbent assay (ELISA) has become commercially available to measure feline AGP (Thalmeier et al., 2023); a reference interval of less than 0.33 mg/mL (less than 328 µg/mL) was established, although a serum sample dilution of 32,000 was used in the study, compared to the 10,000 recommended by the manufacturer, although different laboratories might use different cut-off values. AGP measurement may be useful to differentiate likely cure of FIP from only remission after treatment (Addie et al., 2022), as described in Section 10 on Treatment of FIP.

SAA is also markedly increased in cats with FIP (Giordano et al., 2004; Krentz et al., 2021; Yin et al., 2021), especially in cats with FIP and effusions compared to those without effusions (Katayama and Uemura 2021; Katayama and Uemura 2023). Although AGP was more useful than SAA in one diagnostic study (Hazuchova et al., 2017), further work is required to evaluate its diagnostic and prognostic value. Additionally, SAA tests are more widely available than AGP tests in some parts of the world.

7.3.3. Cytology and Biochemistry on Effusions

As described in Section 7.4.1. on Routine Imaging: Ultrasonographic and Radiographic Findings, ultrasonography or radiography can be used to identify or confirm the presence of effusions and to assist in sample collection (Pedersen 2014a; Thayer et al., 2022), which can be important as the analysis of a sample of effusion is very helpful in the diagnosis of FIP.

FIP effusions are highly proteinaceous (Green et al., 2023), with a total protein concentration that is usually greater than 35 g/L, consistent with that of an exudate. An early study (Shelly et al., 1988) describing the characteristics of effusions of 12 cats with FIP reported total protein concentrations of 32–99 g/L (median 59 g/L). In contrast, the cell counts of effusions due to FIP are often relatively low, usually less than 5 × 10⁹/L cells, which would be more consistent with a modified transudate; however, sometimes, cell counts are higher, for example, up to around 20 × 10⁹/L cells. Slides for cytological examination can be prepared from effusions by making direct smears with the fluid onto microscope slides if the effusion is turbid (cloudy); if the effusion is clear with minimal turbidity, the centrifugation of a sample of effusion and preparing smears from the pellet (following resuspension in around 0.5 mL of effusion) can improve smears’ diagnostic yield (Thayer et al., 2022). Effusion cytology is typically pyogranulomatous in nature with macrophages, non-degenerate neutrophils, and few lymphocytes. Neutrophilic inflammation can predominate in some cases (Muller et al., 2023). Thick eosinophilic (pink-red) proteinaceous backgrounds are often also described on cytology (Yin et al., 2021). If cytology reveals a septic neutrophilia (typically with degenerate neutrophils containing bacteria), neoplastic cells, or a marked lymphocyte population, FIP is highly unlikely (Paltrinieri et al., 1999).

The effusions of cats with FIP typically have low A:G ratios; an A:G ratio of less than 0.4 has a high positive predictive value, whereas a value of greater than 0.8 has a high negative predictive value (Shelly et al., 1988; Riemer et al., 2016). One study found that elevated effusion AGP concentrations (of greater than 1.55 mg/mL) were more useful (sensitivity and specificity of 93%) in differentiating the effusions of cats with FIP from those of cats without FIP when compared with AGP levels in the serum or other acute phase proteins (Hazuchova et al., 2017); however, the diagnosis of FIP in the cats in this study was not always confirmed.

7.3.4. Rivalta’s Point-of-Care Test on Effusions

Rivalta’s test is a crude point-of-care assay that was originally developed to differentiate a transudate from an exudate in humans. It is important to note that a positive result is not specific for FIP, and positive results have been reported in cats without FIP, for example, in those with septic peritonitis and lymphoma (Fischer et al., 2012a). The positive predictive value was 58% in a study of cats who presented with effusion, in which the prevalence of FIP was 35% (Fischer et al., 2012a). If positive, effusion cytology can be helpful to discriminate between these causes (Paltrinieri et al., 1999). The Rivalta’s test had a high negative predictive value of 93% for the exclusion of FIP (Fischer et al., 2012a), making it useful to rule out FIP quickly and cheaply at point-of-care. A positive result needs confirmation with other tests. It may be considered in cases where rapid results are required at point-of-care or where finances are very limited such as for shelter cats, although the limitations of this test must be understood (Sweet et al., 2023).

To perform the Rivalta’s test, a commercially available point-of-care test can be used, or the test can be made up in-house. For the latter, 8 mL of distilled water at room temperature and one drop of 98% acetic acid (or alternatively white vinegar) (Fischer et al., 2013) are mixed in a test tube. One drop of effusion is then carefully placed or layered onto the surface of the solution in the test tube. A positive Rivalta’s test is indicated by the drop staying attached to the surface of the solution, retaining its shape with a connection to the surface, or floating slowly to the bottom of the tube as a drop or like a jellyfish (Figure 16). A negative test is indicated by the drop disappearing and the solution remaining clear. However, the interpretation of results can be problematic due to subjectivity and difficulties in deciding whether a result is positive or negative (Fischer et al., 2013). Using cold water can result in a false-negative reaction (Diane Addie, personal communication).

Figure 16. This image shows a positive Rivalta’s test; a drop of abdominal effusion has been placed onto the surface of a mixture of 8 mL of distilled water and one drop of 98% acetic acid (or white vinegar) in a test tube, and it has retained its shape with a connection to the solution surface. This is not very specific for FIP but can be performed in-house; a positive test increases the likelihood of FIP, while a negative test makes FIP very unlikely. Image Diane Addie, www.catvirus.com.

7.3.5. FNA Cytology

There are few data on the sensitivity and specificity of FNA cytology in the diagnosis of FIP. One study compared the usefulness of hepatic and renal FNA cytology and tru-cut biopsy (TCB) histopathology in samples collected from cats with FIP confirmed by histopathology and FCoV immunostaining (Giordano et al., 2005). In this study, the cytological and histopathological findings of the FNAs and TCBs were classified according to whether they were consistent with FIP for calculation of sensitivity. Typical FNA cytological features of FIP were: highly cellular samples containing the normal cell population of the sampled organs (e.g., hepatocytes, renal tubular epithelial cells), but also neutrophils, macrophages, plasma cells, and lymphocytes, supporting a diagnosis of pyogranulomatous inflammation. The sensitivity of FNAs and TCBs from hepatic (82% and 64%, respectively) and renal (42% and 39%, respectively) tissues was poor, although combining the analysis of TCB and FNA results for each of the tissues increased sensitivity (to 86% for hepatic and 48% for renal). However, specific lesions within the liver and kidneys were not targeted for sampling in this study, and targeted sampling under ultrasound guidance might have improved sensitivity (see Section 7.4 on Diagnostic Imaging in FIP).

One study of cats with FIP described lymph node cytology sampling in 10 cats, with all 10 showing pyogranulomatous inflammation (Green et al., 2023). Another study (Sase 2023) described pyogranulomatous changes on FNAs in two cats with FIP, although the organs sampled were not described. Interestingly, in an imaging study (Muller et al., 2023), neutrophilic inflammation was seen at a similar frequency to pyogranulomatous inflammation on FNA sampling of affected abdominal organs in cats with FIP.

7.3.6. CSF Analysis

Information on the CSF sampling technique is described in detail elsewhere (Rusbridge 1997), but referral or consultation with a neurologist for those unfamiliar with the technique is recommended. Although CSF samples are commonly collected from cats with neurological signs, care must be taken with cisternal CSF sampling as the risk of brain herniation is high (Negrin et al., 2007; Penderis 2009; Rissi 2018; Hoey et al., 2020) due to increased intracranial pressure that can arise, for example, in association with hydrocephalus due to FIP. Thus, ideally, advanced imaging, such as magnetic resonance imaging (MRI) and computed tomography (CT), should be performed before CSF sampling to assess the potential risk of herniation.

CSF samples from cats with FIP can show elevated protein concentrations (of greater than 0.30 g/L [greater than 30 mg/dl] in cisternal samples, and greater than 0.46 g/L [greater than 46 mg/dl] in lumbar samples with reference ranges of less than or equal to 0.30 g/L and less than or equal to 0.46 g/L for cisternal and lumbar CSF samples, respectively); occasionally, marked elevations of protein occur (greater than 20 g/L [200 mg/dl]). Additionally, CSF samples of cats with FIP often have an increased cell count (greater than 0.008 × 10⁹/L [greater than 8 cells/µL] in either lumbar and/or cisternal samples; reference range less than or equal to 0.008 × 10⁹/L [less than or equal to 8 cells/µL]); occasionally this pleocytosis is extremely marked in cats with FIP (cell counts of greater than 1 × 10⁹/L [greater than 1000 cells/µL]). Cytological examination of the CSF can show the pleocytosis to be predominantly neutrophilic, mononuclear, mixed, or pyogranulomatous (Singh et al., 2005; Crawford et al., 2017; Felten et al., 2021). Some cats with neurological FIP have unremarkable CSF analysis results (Foley et al., 1998; Boettcher et al., 2007).

7.3.7. Aqueous Humour Analysis

Information on the aqueous humour sampling technique is described in detail in the literature (Linn-Pearl et al., 2015), but referral or consultation with an ophthalmologist for those unfamiliar with the collection technique is recommended. Aqueous humour samples from cats with FIP show cytological features similar to what is found in CSF samples, i.e., mixed inflammation with neutrophils with or without macrophages.

7.4. Diagnostic Imaging in FIP

7.4.1. Routine Imaging: Ultrasonographic and Radiographic Findings

Ultrasonography (Figures 17 and 18) or radiography (Figure 19) can be used to locate or confirm the presence of effusions and to assist in sample collection (Pedersen 2014a).

A review of abdominal ultrasonographic findings in 16 cats with FIP (Lewis and O’Brien 2010) showed the presence of peritoneal fluid in seven cases, and retroperitoneal fluid was found in one cat. Abdominal lymphadenopathy was documented in nine cats. The liver was of normal echogenicity in 11 cats and variably hypoechoic or hyperechoic in the remainder. The spleen was of normal echogenicity in most cats and hypoechoic in two. Five cats had hypoechoic subcapsular rims in one or both kidneys. In another study of FIP cases undergoing treatment, 16 of the 18 cats showed lymphadenomegaly on abdominal ultrasonography at presentation (Zwicklbauer et al., 2023). In 22 cats with FIP that underwent ultrasonography, five cats had colonic wall thickening (Green et al., 2023). A retrospective ultrasonographic study (Ferreira et al., 2020) focused on the significance of the medullary rim sign (MRS) in the kidneys of cats; of 661 cats that had undergone abdominal ultrasonography, 23 cats were diagnosed with FIP; 15 of these had MRS (mostly the thick-marked intensity type) and eight did not, corresponding to a significant association between the presence of MRS and FIP. A diagnosis of FIP was made by the clinician without details given on diagnostic criteria for FIP. The significance of the association between MRS and FIP is not known, but it is an interesting finding.

A larger abdominal ultrasonography study on 25 cats with confirmed (12 cats; positive FCoV antigen immunostaining or FCoV RNA detected in effusion samples) or highly suspected (13 cats) FIP (Muller et al., 2023) reported abnormalities that comprised: effusion in 88% (usually anechoic but occasionally mildly echogenic), lymphadenopathy in 80% (especially lymphadomegaly and hypoechogenecity of the jejunal, ileocaecal, colic and/or hepatic LNs), hepatic changes in 80% (especially hepatomegaly in 58% and hypoechogenicity in 48%), intestinal changes in 68% of cats (asymmetric wall thickening and/or loss of wall layering, with 52% being ileocecocolic junction and/or colonic in location), splenic changes in 36% of cats (including splenomegaly, mottled parenchyma and hypoechoic nodules), renal changes in 32% (hypoechoic subcapsular rim and/or cortical nodules; interestingly MRS were not reported in this study). Most cats in this study (92%) had two or more locations of abdominal ultrasonographic abnormalities.

Pneumonia due to FIP is occasionally reported and can be associated with thoracic radiographic changes (Macdonald et al., 2003). In a retrospective study of 148 cats with pleural effusion (Hung et al., 2022), no radiographic variables were found to be predictive of a diagnosis of FIP, although only two of the 148 cats had FIP.

It is clear that no specific ultrasonographic or radiographic findings occur in FIP. However, imaging can be useful to find small volumes of effusion to sample and to direct the sampling of abnormal tissues from affected organs (Figure 20) (e.g., collecting FNAs for cytology or collecting ultrasound-guided needle cores (e.g., tru-cut) biopsies for histopathology). Illustrative details on how to find small pockets of fluid and collect FNAs under ultrasonographic guidance are available in the 2022 AAFP/EveryCat Feline Infectious Peritonitis Diagnosis Guidelines (Thayer et al., 2022).

Figure 17. Ultrasonogram of a young cat with FIP showing pericardial and pleural effusion; ultrasonography can be used to guide sampling of the effusion. Green arrow = pericardial fluid. Yellow arrow = cardiac ventricle. White arrow = pleural effusion. Image Séverine Tasker, Bristol Veterinary School, University of Bristol, UK.

Figure 18. Ultrasonogram of a young cat with FIP showing abdominal effusion; ultrasonography can be used to guide sampling of the effusion. Yellow arrow = small intestinal loop in transverse section. White arrows = peritoneal effusion—note the effusion is echogenic, suggesting cellularity. Green arrow = mesenteric fat. Image Séverine Tasker, Bristol Veterinary School, University of Bristol, UK.

Figure 19. Lateral thoracic radiograph showing the presence of a pleural effusion; Yellow arrow = area of pleural fissure lines identified. White arrow = border effacement of the cardiac silhouette. Green arrow = the pleural effusion has displaced air-filled lung dorsally and the lungs are reduced in size. Image Andrew Parry, Willows Veterinary Centre, Solihull, UK.

Figure 20. Ultrasonogram of a cat with FIP and renomegaly with a loss of normal renal architecture; ultrasonography might be useful to guide fine-needle aspirate or tissue core-biopsy sampling of organs by targeting abnormal tissue. The kidney is enlarged (50 mm, normal size range is 33–44 mm). White arrow = loss of corticomedullary distinction with heterogeneously echogenic renal parenchyma. Green arrow = pericapsular hypoechoic material is sometimes seen in cases with FIP. However, this is also encountered with other diseases (e.g., lymphoma). Image Séverine Tasker, Bristol Veterinary School, University of Bristol, UK.

7.4.2. Advanced Imaging of the CNS: MRI and CT

When a cat is showing neurological signs, imaging the brain by MRI, if available, can be useful to demonstrate neurological abnormalities due to FIP. Obstructive hydrocephalus, syringomyelia, foramen magnum herniation and the marked contrast enhancement of the meninges, third ventricle, mesencephalic aqueduct and brainstem have been reported in cats with FIP (Foley et al., 1998; Negrin et al., 2007; Penderis 2009; Crawford et al., 2017). Some cats only show abnormalities after the administration of contrast (Foley et al., 1998; Negrin et al., 2007), and some cats have normal MRI even after contrast administration, despite the presence of meningoencephalitis (Negrin et al., 2007) A description of CT findings in cats with neurological FIP has not been published, and, although hydrocephalus and/or syringohydromyelia can sometimes be detected by CT, MRI is likely to be more sensitive in the detection of subtle intraparenchymal lesions (Negrin et al., 2009) (Figures 21 and 22). Imaging of the CNS is indicated before performing CSF sampling to assess the potential risk of herniation.

Figure 21. CT of the head of a cat with neurological signs due to FIP post-contrast—reconstructed to show a sagittal midline view. White arrow = there is evidence of generalised ventriculomegaly, suggesting alteration/obstruction to CSF flow. Green arrow = homogeneous contrast enhancement of the lining of the ventricles (ependyma) is sometimes seen in patients with FIP. Yellow arrow = the increased ventricular size in this patient has led to an increase in volume of the contents of the calvarium. This patient has coning of the cerebellum—the cerebellar vermis is beginning to pass through the foramen magnum—a life threatening finding. Image Séverine Tasker, Bristol Veterinary School, University of Bristol, UK.

Figure 22. T2W transverse MRI of a cat with neurological signs due to FIP. The brain also appears swollen with a lack of visible sulci. Yellow arrow = the gyri in this patient are enlarged, with narrowing of the sulci. This will be due to parenchymal inflammation. Green arrow = the edge of the left lateral ventricle is identified and appears dilated. White arrow = the T2W isointense (to grey matter) structure is an enlarged right choroid plexus. Image Séverine Tasker, Bristol Veterinary School, University of Bristol, UK.

7.5. Direct Detection of FCoV

7.5.1. Detection of FCoV Antigen

Histopathological Examination of Tissues with FCoV antigen immunostaining

The definitive diagnosis of FIP relies on consistent histopathological changes in affected tissues, and this, with concurrent FCoV antigen immunostaining, is considered the gold standard for diagnosis (Figures 23–26).

Figure 23. (a) Histopathology: Hematoxylin and eosin stain and (b) positive FCoV antigen immunostaining in a cat with FIP: liver, fibrinous perihepatitis with embedded FCoV-infected macrophages (shorter arrows) and focal granulomatous infiltrate (longer arrows) with FCoV-positive macrophages. Image Anja Kipar, University of Zurich, Switzerland.

Figure 24. (a) Histopathology: Hematoxylin and eosin stain and (b) positive FCoV antigen immunostaining in a cat with FIP: Mesentery with focal granulomatous infiltrate with embedded small veins (arrows) and abundant FCoV-positive macrophages. Image Anja Kipar, University of Zurich, Switzerland.

Figure 25. (a) Histopathology: Hematoxylin and eosin stain and (b) positive FCoV antigen immunostaining in a cat with FIP: Mesenteric lymph node with focal granulomatous infiltrate with extensive central necrosis (N) and abundant FCoV-infected macrophages (arrows) in the surrounded infiltrate. Image Anja Kipar, University of Zurich, Switzerland.

Figure 26. Positive FCoV antigen immunostaining in a cat with FIP: Kidney, stellate vein in subcapsular cortex with granulomatous (peri)phlebitis. Focally, the granulomatous infiltration has destroyed the vascular basement membrane (left arrow), protrudes into the lumen of the vein (wall-bound thrombus; right arrow) and is present in surrounding tissue, containing abundant FCoV-infected macrophages (cells stained in brown). Shorter arrows outline the remnants of the basement membrane. Image Anja Kipar, University of Zurich, Switzerland.

Immunostaining exploits the binding of antibodies to host-cell-associated FCoV antigens, which are subsequently visualised by enzymatic reactions producing a colour change in a process called IHC. However, care must be taken to ensure that adequate controls are in place for each organ examined since non-specific staining can occur, leading to false-positive results (see below and Section: Cytology with FCoV antigen immunostaining on Effusions, FNAs, CSF and Aqueous Humour).

The ‘classical’ FIP histopathological lesion is a blood vessel surrounded by an inflammatory lesion dominated by monocytes/macrophages intermingled with a few neutrophils and lymphocytes (Kipar et al., 2005), which are mainly CD4+ (Paltrinieri et al., 1998). Occasionally, monocytes can be seen attached to endothelial cells or emigrating from the vessel (Kipar et al., 2005). Periventricular encephalitis and leptomeningitis are commonly seen in neurological FIP (Mesquita et al., 2016; Rissi 2018). A useful study (Stranieri et al., 2020b) documented the following patterns as being consistent with FIP lesions:

• Pyogranulomas on one or more serosal surfaces;
• Granulomas with or without necrotic areas;
• Lymphocytic and plasmacytic infiltrates in specific sites (e.g., band-like infiltrate in serosal surfaces, perivascular infiltrate in meninges and CNS);
• Granulomatous to necrotising vasculitis and fibrinous serositis.

Histopathology alone is sometimes used to definitively diagnose FIP (Felten et al., 2017a). In one study analysing 93 tissues from 14 cats with FIP (Stranieri et al., 2020b), histopathological lesions consistent with FIP were most commonly found in the lungs (77% of samples), then kidneys (64%), MLNs (62%), liver (57%) and spleen (57%). Differential diagnoses for pyogranulomatous inflammation include other infectious diseases (e.g., infections with mycobacteria, actinomyces, nocardia, rhodococcus, pseudomonas (Milliron et al., 2021), toxoplasmosis, bartonella (Varanat et al., 2012), fungi), as well as rarer idiopathic sterile pyogranulomatous diseases that can present with mass lesions, such as in the lymph nodes (e.g., mesenteric, submandibular) (Giuliano et al., 2020) or skin.

However, in addition to histopathological changes, a definitive diagnosis of FIP should rely on the demonstration of positive immunostaining for FCoV antigens within macrophages in the histopathological lesions, such as by IHC (Kipar et al., 1998; Kipar and Meli 2014; Stranieri et al., 2020b). Positive-FCoV antigen-IHC is highly specific and reliable (Tammer et al., 1995; Rissi 2018; Stranieri et al., 2020b) as long as it is performed with appropriate controls and reagents that prevent the non-specific binding of the FCoV antibody to the tissues, as otherwise, false-positive results occur. However, the visualisation of the pattern of FCoV antigen staining by an experienced pathologist should discern non-specific staining. Additionally, a negative result does not exclude FIP as FCoV antigens can be variably, and sparsely, distributed within lesions (Giordano et al., 2005; Emmler et al., 2020; Stranieri et al., 2020b) and might not be detected in all histopathological sections prepared from FIP-associated tissues changes (Kipar and Meli 2014). This may be in part dependent on how acute the disease is (Paltrinieri et al., 2001). If unexpected negative IHC results are obtained, it is worth ensuring that affected/diseased tissues have been sampled and/or requesting additional sections of biopsies to be cut and examined by the pathologist (Tasker 2018; Stranieri et al., 2020b). The size of samples, when small, may reduce the sensitivity of IHC, especially if FCoV antigen distribution is sparse. In one study that evaluated hepatic and renal TCB samples collected from cats with FIP (mostly at post-mortem examination) (Giordano et al., 2005), the sensitivity of IHC was only 24% in hepatic samples and 39% in renal samples. However, sampling was random rather than targeted at lesions. Another factor that may affect sensitivity of IHC is the nature of the (usually monoclonal) antibody used to bind to the FCoV antigen (Poncelet et al., 2008). Most antibodies used in IHC recognise the FCoV nucleocapsid protein (e.g. the monoclonal antibody FIPV 3-70) but they can vary in the epitopes they bind to, influencing sensitivity.

Samples of affected tissues (e.g., liver, kidney, spleen, MLNs) can be collected at post-mortem examination (this used to be common before the availability of effective antiviral treatments for FIP) or in vivo by laparotomy, laparoscopy or ultrasound-guided TCB. Eyes enucleated as a result of uveitis-associated intractable glaucoma or pain can also be submitted for histopathology and IHC (Krentz et al., 2022). However, ocular tissues characterised by heavy plasmacytic inflammation in FIP are less likely to be IHC-positive for FCoV antigens (Carossino et al., 2022). The samples most likely to be useful are those that are affected by the disease process, and this can be guided by the results of diagnostic testing (e.g., imaging results, pyogranulomatous inflammation on FNA cytology) as well as clinical signs.

If cats are euthanised due to suspected FIP, and without the option to treat the cat with effective antiviral treatment, samples should ideally be collected at post-mortem examination for histopathological examination and FCoV antigen immunostaining (see above) to confirm the disease. Gross findings sometimes are suggestive of FIP (Tasker and Dowgray 2018) (Figures 27 and 28), but lesions might not be obvious. Indeed, it is known that histopathological changes consistent with FIP can be seen in tissues that have not shown macroscopic changes at post-mortem examination (Stranieri et al., 2020b). Large pyogranulomatous lesions can also be mistaken for tumours (Figure 28).

Figure 27. Gross appearance of fibrinous plaque-like inflammation present on the surface of the spleen in a case of FIP with an abdominal effusion that underwent post-mortem examination. Image Séverine Tasker and the Pathology Department, Bristol Veterinary School, University of Bristol, UK.

Figure 28. (a,b) Gross appearance of the kidneys from two cats with FIP, showing renomegaly with pyogranulomas visible on the renal surface on post-mortem examination. (b) shows how pyogranulomas can be centred on blood vessels. These lesions could be mistaken for tumours on gross post-mortem examination, which is why histopathology, and ideally, immunohistochemistry is necessary. Images Pathology Department, Bristol Veterinary School, University of Bristol, UK.

Cytology with FCoV antigen immunostaining on Effusions, FNAs, CSF and Aqueous Humour

FCoV antigen immunostaining can be performed on cytology samples such as effusions, FNAs, CSF and aqueous humour, using immunocytochemistry (ICC) or immunofluorescence (IF). Host-cell-associated FCoV antigens, in macrophages, are detected with FCoV-specific antibodies conjugated with enzymes or fluorescent markers. The presence of FCoV antigens can then be demonstrated by either enzymatic reactions producing a colour change (see Figures 29 and 30) or by the visualisation of fluorescence using a UV microscope, respectively. The varied methods that have been used for the detection of FCoV antigens within macrophages has led to variability in the reported specificities for immunostaining in cytology samples.

Figure 29. Immunocytochemistry showing the presence of FCoV antigen in macrophages in an effusion of a cat with FIP. Overview at 40x magnification, cytospin, scattered positive macrophages clearly visible at low power (e.g., black arrowheads) before cells further identifiable. Image Alex Malbon and Anja Kipar, University of Zurich, Switzerland.

Figure 30. Immunocytochemistry showing the presence of FCoV antigen in macrophages in an effusion of a cat with FIP. 400x magnification, cytospin, highly cellular—macrophages (black arrowhead), neutrophils (white arrowhead) and fibrin (white asterisk). Scattered positive macrophages (black arrows). Image Alex Malbon and Anja Kipar, University of Zurich, Switzerland.

The FCoV immunostaining of effusion samples has shown variable sensitivity from 57 to 100% (Parodi et al., 1993; Hirschberger et al., 1995; Paltrinieri et al., 1999; Hartmann et al., 2003; Worthing et al., 2012; Litster et al., 2013; Felten et al., 2017b), depending on the methodology used. Since this technique relies on staining FCoV within macrophages in the effusion, false-negative results can occur (Hellemans et al., 2020), especially if the effusion is cell-poor and/or the FCoV antigen is masked by FCoV antibodies in the effusion.

FCoV immunostaining is generally considered to be very specific on effusions. Direct techniques that have used a single antibody, conjugated to a fluorochrome, have consistently demonstrated 100% specificity in different laboratories (Parodi et al., 1993; Hirschberger et al., 1995; Paltrinieri et al., 1999; Hartmann et al., 2003; Worthing et al., 2012). In contrast, indirect methods on effusions using avidin and biotinylated horseradish peroxidase complexes and secondary antibodies (Felten et al., 2017b), or direct methods in which two antigens are targeted with the application of two antibodies (Litster et al., 2013), have reported lower specificities of 72% and 71%, respectively. In the former study, eight (three cats with heart failure and five cats with neoplasia) of twenty-nine non-FIP effusions were found to be positive by ICC (Felten et al., 2017b), whilst in the latter study, two of seven non-FIP effusions (one of the two cats had heart failure, the other cholangiocarcinoma) were found to be positive by IF (Litster et al., 2013). Whilst a multiplex fluorescent ICC assay utilising dual antibodies (vimentin and FCoV) has been developed (Howell et al., 2020), specificity and sensitivity data using this technique are yet to be determined. It is therefore important for clinicians to be aware of variations in immunostaining techniques and to be familiar with the specificity of the methodology employed by their local laboratory, as well as confirmation of the inclusion of negative controls in testing when interpreting positive results. Many researchers use a positive FCoV immunostaining result on an effusion to confirm a diagnosis of FIP (Kipar and Meli 2014; Coggins et al., 2023; Cosaro et al., 2023).

Some diagnostic laboratories prefer to use cell pellets from centrifuged effusion samples to prepare formalin-fixed, paraffin-embedded samples that can then be treated like a tissue specimen for FCoV antigen IHC (Kipar and Meli 2014) or IF (Hellemans et al., 2020). This might improve the reliability of the detection of FCoV antigen (Kipar and Meli 2014), although the processing time required for these samples would be longer than for direct cytological immunostaining (or for RT-PCR testing; see Section on FCoV RT-PCR on Effusions). The larger the effusion volume sample is, the better the sensitivity is likely to be, probably due to a larger cell harvest. This was illustrated in a single case report (Bohm 2022), although samples were collected at different time points making comparisons difficult. Further studies are required to confirm the advantage of larger volume samples.

The FCoV immunostaining of FNA samples has not yet been described in large comprehensive studies, although it has been reported in small numbers of cats (Green et al., 2023). One study that performed hepatic and renal FNA ICC in cats with FIP (samples were collected randomly from these organs mostly at post-mortem examination) (Giordano et al., 2005) reported a sensitivity of only 17% to 31% in hepatic FNAs and 11% to 20% in renal samples.

If collecting FNAs for immunostaining, the diagnostic laboratory can be contacted to find out how they would like samples prepared for submission. Some might request cytospins, if available, whilst others ask for several FNAs to be placed into a tube containing a small amount of saline (or autologous serum) until the solution is cloudy and then submitting this to the laboratory; the cloudiness crudely indicates adequate cell presence. Others might request that the cloudy solution of FNAs is centrifuged, and the resulting cell pellet fixed by adding 2 mL of buffered formalin and agitating or vortexing before submission for immunostaining. Note that different sample preservations may be required for FNA samples being submitted for FCoV RNA detection (see Section on FCoV RT-PCR on Tissue and FNA Samples).

FCoV immunostaining using ICC has been reported as being successful in detecting FCoV in the CSF of a cat with neurological FIP (Ives et al., 2013). One study evaluated ICC in the CSF of cats with and without FIP that presented with and without neurological signs, collected at post-mortem examination (Gruendl et al., 2016). This study found that 17 of 20 cats with FIP gave positive ICC results, but of 18 cats without FIP, three also had positive results (one cat each with mediastinal lymphoma, lymphocytic meningoencephalitis and hypertensive angiopathy with brain haemorrhage), limiting the test’s specificity. The reasons for the positive ICC results in these three cats without FIP are not known, but suggested possibilities include the concurrent presence of FIP alongside the other confirmed diseases present (although the IHC staining of neurological tissues was also negative), the detection of the presence of systemic FCoV antigens in the absence of FIP or non-specific staining, aberrant antibody binding, and other methodology reasons. The analyses in this study (Gruendl et al., 2016) excluded those cats that had no cells present in their CSF as ICC could not be performed on these cats. The same group (Felten et al., 2021) performed CSF ICC on two cats with neurological signs that did not have FIP, and although one of these was positive, the cytology of the CSF was lymphomonocytic, which would not have been consistent with a diagnosis of FIP. This same study also performed CSF ICC on seven cats with confirmed FIP—three with neurological signs and four without. Two of the three cats with neurological FIP were ICC-positive whilst three of the four cats with non-neurological FIP were also ICC-positive. Most of the ICC-positive results in the FIP cats in this study showed pyogranulomatous cytology in the CSF, consistent with FIP. The application of ICC to CSF samples collected ante-mortem from a larger number of cats with neurological signs due to FIP and other causes would be desirable to further evaluate the usefulness of CSF ICC.

The use of FCoV antigen immunostaining has also been described in aqueous humour samples collected directly following euthanasia from 26 cats with confirmed FIP and 13 cats with other diseases (Felten et al., 2018); most (25 with FIP and 11 with other diseases) of these cats were also included in a subsequent study describing both FCoV RT-PCR and FCoV antigen immunostaining in cats with FIP (31 cats) and cats with other diseases (27 cats) (Sangl et al., 2020). These two studies reported sensitivities of 64% (Felten et al., 2018) and 63% (Sangl et al., 2020) for aqueous humour FCoV antigen immunostaining, but most of the cats with FIP in these studies did not have ocular signs. The specificities were 82% (Felten et al., 2018) and 80% (Sangl et al., 2020), with positive results occurring in one control cat with lymphoma and one control with a pulmonary adenocarcinoma (in both cats, the aqueous humour cytology was not consistent with FIP). Accompanying cytology is important to aid interpretation, as is ensuring the laboratory performing the FCoV antigen immunostaining has robust methods and controls. Aqueous humour as a target sample to test is interesting as it can be collected non-invasively from cats with suspected FIP, although the sample collection technique used in the published studies (Felten et al., 2018; Sangl et al., 2020) might need modification for use ante-mortem (e.g., use of a smaller 27–29 gauge insulin needle) (Linn-Pearl et al., 2015). The further evaluation of ICC on aqueous humour samples collected ante-mortem from cats with uveitis due to FIP and other causes is needed to further assess the usefulness of ICC in the diagnosis of FIP.

Detection of FCoV Antigen in Faeces by Rapid Immunomigration Tests

One study has been published (Vojtkovska et al., 2022) evaluating three rapid immunomigration (also known as lateral flow) tests to detect FCoV antigens in the faeces of cats from shelters. The tests were compared to the results of faecal RT-PCR and showed poor sensitivity (21% to 66%) but reasonable specificity (73% to 100%) (Vojtkovska et al., 2022). The study concluded that the tests had too poor a sensitivity to be used to identify cats shedding FCoV in their faeces. Moreover, the detection of FCoV in faeces (either antigen, as here, or RNA detection by RT-PCR, see Section on FCoV RT-PCR on Faecal Samples) should never be used to diagnose FIP as it is known that, based on RT-PCR studies, cats with FIP do not always shed FCoV, and cats in multi-cat households without FIP commonly shed FCoV (Table 1).

7.5.2. Detection of FCoV RNA by RT-PCR

In general, PCR is a method by which DNA is exponentially amplified by a polymerase enzyme with the use of primers (and a probe in quantitative PCR assays) to target a specific sequence, enabling sensitive detection down to a very low starting DNA copy number. Post-PCR amplification processing (e.g., sequencing) can be applied if needed.

PCR only amplifies DNA; because FCoV is an RNA virus, a pre-PCR step using a viral enzyme, reverse-transcriptase (RT), is required to generate a strand of cDNA using the original FCoV RNA template, in a process known as reverse transcription. A combination of this process and PCR is known as RT-PCR (Barker and Tasker 2020b). The RT-PCR assays available to detect FCoV RNA often amplify both cell-associated subgenomic mRNA (RNA produced in feline cells when the FCoV replicates), as well as cell-associated and virus particle-associated genomic RNA (which correlates to the presence of whole FCoV). Where in the FCoV genome the PCR primers bind to determines whether subgenomic mRNA is preferentially amplified in an RT-PCR assay (Barker and Tasker 2017; Barker and Tasker 2020b). Those RT-PCR assays that favour the amplification of subgenomic mRNA might overestimate the FCoV viral loads present in the sample (Barker and Tasker 2020b). Laboratories should be able to report the analytical sensitivity and specificity of their RT-PCRs and also provide details of the positive and negative controls that they use. Usually, highly conserved areas of the FCoV genome are targeted in RT-PCR assays to maximise sensitivity. As an RNA virus, FCoV shows a high rate of error during replication, and any mutations at the site of primer and/or probe binding can result in a loss of RT-PCR assay efficiency, and ultimately sensitivity. PCR assay conditions (e.g., temperature) can be altered to tolerate such mutations, but this can reduce specificity (Barker and Tasker 2017). Additionally, RT-PCRs designed to target type I FCoV, which represents the majority of field strains found in naturally infected cats (although geographical variation exists (Hohdatsu et al., 1992; Benetka et al., 2004)), might not amplify type II FCoV if the primers and probe bind to the region of the FCoV genome that differs between the two types (i.e., around the spike (S) protein, Figure 3) (Herrewegh et al., 1998; Terada et al., 2014; Decaro et al., 2021).

FCoV RT-PCR has been used to detect FCoV RNA in blood, effusion, tissue (including FNAs), CSF, or aqueous humour samples from suspected cases of FIP, with varying results. Bronchoalveolar-lavage FCoV RT-PCR was also used to support a diagnosis of FIP in one cat with respiratory signs but no effusion (Cerna et al., 2022).

Ideally, RT-PCR assays used should be quantitative (this is the ‘q’ in RT-qPCR) and be able to report the FCoV load present in the sample, because this information is an important aid to the interpretation of results. This is because systemic FCoV infection (viraemia) can occur in healthy cats and cats without FIP, as well as in cats with FIP. However, the FCoV viral loads in healthy cats and cats without FIP are lower than those in cats with FIP (Meli et al., 2004; Kipar et al., 2006; Kipar et al., 2010; Desmarets et al., 2016). So, a positive RT-qPCR result is not specific for FIP, but positive RT-qPCR results with a high FCoV load strongly support a very likely diagnosis of FIP.

Running FCoV RNA RT-PCRs can be rapid, although, once the time taken to submit the sample to the laboratory is factored in, the reporting of results can still take a few days. This is usually quicker than FCoV antigen immunostaining on tissue biopsy samples and often also quicker than immunostaining on effusion samples. Rapid molecular techniques (e.g., RT loop-mediated isothermal amplification; LAMP) for detecting FCoV RNA in-house as point-of-care tests have been described (Stranieri et al., 2017b; Gunther et al., 2018; Rapichai et al., 2022). These show some promise but have traditionally suffered from poor sensitivity, and further work on clinical samples is required before they can be recommended.

FCoV RT-PCR on Blood Samples

Samples derived from blood (e.g., whole blood, serum, plasma, peripheral blood mononuclear cells [PBMCs] or buffy coats) can undergo RT-PCR for FCoV RNA detection following RNA extraction. When FCoV RT-PCR was performed on plasma or serum samples from cats with and without FIP in various studies (Doenges et al., 2017; Felten et al., 2017a; Felten et al., 2017c), only 0% to 15% of FIP cases were positive for FCoV RNA, and none of the cats without FIP gave positive FCoV RT-PCR results. Although whole blood or PBMCs might be better targets for RT-PCR than serum (Doenges et al., 2017), FCoV RNA was only detected in the whole blood of two of 18 (11%) cats with FIP 14 days after experimental infection (Pedersen et al., 2015). One study was more successful in detecting FCoV RNA in blood samples from cats with FIP (Stranieri et al., 2018) when RT-PCR was applied to pellets derived from whole blood; positive results were obtained in six of eight (75%) cats with FIP, but none of eight cats with diseases other than FIP. Similarly, another study (Krentz et al., 2021) documented that 15 of 18 (83%) cats with confirmed or highly suspected FIP were positive by RT-PCR for FCoV RNA in whole-blood samples. Finally, one study that tested the whole blood of 125 cats with suspected effusive FIP by RT-PCR (Katayama and Uemura 2021) found 114 (91%) to be positive, whilst a similar study on cats with non-effusive, or ‘mixed’ effusive/non-effusive FIP, found 138/156 (89%) and 124/153 (81%) of blood samples, respectively, to be positive (Katayama and Uemura 2023). However, a positive blood sample RT-PCR result was one of the criteria used to deduce a diagnosis of FIP in these studies (Katayama and Uemura 2021; Katayama and Uemura 2023), likely biasing the numbers reported.

Interestingly the study (Krentz et al., 2021) that found FCoV RNA in whole-blood samples from 83% of 18 cats with FIP used the same RT-PCR assay [based on the 7b gene of the FCoV genome (Gut et al., 1999)] as a previous study, which documented only 11% positive RT-PCR results in blood samples from 18 cats with FIP (Pedersen et al., 2015). The reason for the discrepancy between these sensitivity results is not known and needs further investigation; for example, it may be due to sample collection, processing, or storage conditions.

The specificity of FCoV RT-PCR on blood samples is also an issue, as healthy and ill cats without FIP can have detectable FCoV RNA in the blood, albeit uncommonly. One study (Fish et al., 2018) found that nine of 205 (4%) healthy USA shelter cats were FCoV RNA RT-PCR-positive in buffy coats prepared from blood; one of those had a replicating virus in the bloodstream, as demonstrated by a positive FCoV mRNA RT-PCR result, and this 8-week-old kitten was likely undergoing viraemia. Neither this kitten, nor seven of the nine FCoV RNA RT-PCR-positive cats with follow-up available, developed FIP during the subsequent six months. Another study documented FCoV RNA RT-PCR-positive results on buffy coats in 27% of 119 sick cats with suspected FIP and 10% of 31 healthy cats from multi-cat households that either lived in a household in which a cat had been diagnosed with FIP or that had parents that were FCoV-infected (diagnostic method not stipulated for parents) (Muz and Muz 2023). Another study (Simons et al., 2005) performed FCoV mRNA RT-PCR on PBMC samples to detect replicating FCoV and found that 23 of 424 (5.4%) samples from cats without clinical signs of FIP were positive, compared to 301 of 651 (46.2%) samples from cats with clinical signs suggestive of FIP. The cross-reactivity of this FCoV mRNA RT-PCR with human DNA has been suspected (Diane Addie, personal communication).

The more recent results obtained with FCoV RT-PCR on blood samples make it an interesting avenue to explore as a test to support a diagnosis of FIP.

FCoV RT-PCR on Effusions

Effusion samples in cats with FIP often contain FCoV RNA (Pedersen et al., 2015), which can be detected by RT-PCR. The centrifugation of the effusion sample to yield a cell pellet to use for RNA extraction may improve sensitivity (Hellemans et al., 2020). Published studies amplified FCoV RNA in most (72–100%) effusion samples from cats with confirmed or suspected FIP (Doenges et al., 2017; Felten et al., 2017c; Longstaff et al., 2017; Stranieri et al., 2018; Katayama and Uemura 2021; Katayama and Uemura 2023) but usually not in any effusions from cats without FIP (Doenges et al., 2017; Felten et al., 2017c; Longstaff et al., 2017). However, subsequent studies have challenged the specificity of RT-PCR on effusions. One study (Barker et al., 2017) amplified FCoV RNA, albeit at a low level, in abdominal fluid from one of 29 control cats that did not have FIP. Another study (Felten et al., 2017a) amplified FCoV RNA from three (two of the three had only low levels of FCoV RNA) of twenty-four control cats without FIP that had effusions tested. In the latter study, the control cats that generated positive FCoV RT-PCR results had neoplasia (lymphoma and a malignant round-cell tumour) or chronic kidney disease (this cat had the higher FCoV RNA levels in the effusion). Another study (Stranieri et al., 2018) amplified FCoV RNA (levels not reported) from the effusion of one cat with intestinal carcinoma (out of six control cats with effusions tested). Finally, one study (Hellemans et al., 2020) documented a specificity of 81% for RT-PCR on effusions as positive RT-PCR results were obtained in three of 16 samples from cats without FIP; however, confirmation of the absence of FIP in these three cats was only based on the negative IF immunostaining of effusions from the cats, and it might well be that these three cats did indeed have FIP.

Thus, the presence of FCoV RNA, particularly in high levels, in an effusion that also has cytological and biochemical features suggestive of FIP, makes FIP a very likely diagnosis (Figure 12) (Coggins et al., 2023), and this might be adequate information upon which to start trial treatment for FIP now that effective antiviral treatments such as GS-441524 (Krentz et al., 2021; Yin et al., 2021) are increasingly available (see Section 10 on Treatment of FIP).

FCoV RT-PCR on Tissue and FNA Samples

When tissue biopsy samples are obtained from cats with suspected FIP, the samples should be submitted for histopathology and IHC, as this allows for a definitive diagnosis of FIP. However, if a delay in analysis is expected, tissue could be submitted for RT-PCR, as finding high levels of FCoV RNA in a sample of an affected organ can allow us to make a diagnosis of FIP very likely. This is because it is known that tissue samples from cats with FIP are significantly more likely to be FCoV RT-PCR-positive (Barker et al., 2017; Stranieri et al., 2018) and have significantly higher FCoV RNA loads in RT-PCR (Porter et al., 2014) than tissue samples from cats without FIP. In cats with FIP, FCoV RNA loads correlate with histopathological findings suggestive of FIP (Pedersen et al., 2015; Barker et al., 2017). In one study that included 20 cats with FIP confirmed by IHC, 70–90% of incisional biopsies of popliteal and MLNs, liver, spleen, omentum, and kidneys were found to be positive by RT-PCR (Emmler et al., 2020).

However, it is important to remember that cats without FIP can also be found to be positive for FCoV RNA by RT-PCR in tissues. One large study evaluating FCoV RT-PCR in 260 tissue samples from 57 cats with FIP, and 258 tissue samples from 45 cats without FIP (Barker et al., 2017), found that 90% of tissue samples from the 57 cats with FIP were FCoV RT-PCR-positive, but 8% of tissue samples from 45 cats without FIP were also FCoV RT-PCR-positive. Another larger study performed FCoV RT-PCR on 1861 samples from 87 cats without FIP and found that 24% (21/87) of the cats were FCoV RT-PCR-positive on at least one tissue or fluid sample besides faeces, and 4% (78/1861) of all of the samples tested were FCoV RT-PCR-positive (Jähne et al., 2022). Interestingly, only one of the 87 cats without FIP was found to be faeces-positive by RT-PCR (Jähne et al., 2022).

It is recommended that tissue samples are not formalin-fixed before RT-PCR, as formalin can degrade RNA and decrease PCR sensitivity (Tasker 2018), although one study has described the successful use of FCoV RT-PCR in formalin-fixed paraffin-embedded tissues in cats with FIP (Sangl et al., 2019).

FNAs, such as those obtained by ultrasound guidance, are often a good alternative to tissue samples for FCoV RT-PCR analysis, as they have the advantage of less-invasive collection. One study (although in abstract form only (Freiche et al., 2016)) described the successful amplification of FCoV RNA from ultrasound-guided FNAs of abnormal tissues (tissue type not specified) in all 11 cats with FIP without effusions that were sampled, suggesting that FNAs could be a useful sampling material for RT-PCR in cats with FIP that do not have effusions. Indeed, positive RT-PCR results on MLN FNAs collected at either ante-mortem or post-mortem examination were reported in 18 of 20 (i.e., sensitivity of 90%) cats with FIP but without effusions (Dunbar et al., 2019); in this study, the two cats with FIP that were negative on MLN FNA RT-PCR were neurological FIP cases. This study controlled and evaluated cats without FIP too, detecting MLN FCoV in only one of the 26 cats without FIP (i.e., specificity of 96%) (Dunbar et al., 2019). In this study, FCoV RNA survived well in transport as some of the FNAs tested by RT-PCR were sent by regular mail without ice or RNA preservative (Dunbar et al., 2019). The successful use of FCoV RT-PCR on MLN FNAs collected ante-mortem to diagnose FIP has also been described in a descriptive study of a small cohort of cats with FIP (Addie et al., 2022). Another study (Sase 2023) described positive FCoV RT-PCR results on FNAs collected from pyogranulomatous lesions in two cats with FIP, although the organs sampled were not described.

A study of 20 cats with FIP compared the RT-PCR results on FNAs and incisional biopsies of popliteal and MLNs, liver, and spleen. Percentages of positive RT-PCR results were similar for FNA (65% to 85%) and incisional biopsy (70% to 90%) samples (Emmler et al., 2020), suggesting FNAs to be a good sample source for RT-PCR testing, especially as they can usually be collected relatively non-invasively, as mentioned earlier.

If collecting FNAs for RT-PCR, it is good practice to consult the diagnostic laboratory for information on how they would like samples prepared and/or preserved for submission, to ensure optimal sensitivity. For example, the laboratory may request that several FNA aspirates are added to a sample tube containing a small amount of saline until the solution becomes cloudy, crudely indicating an adequate presence of cells in the sample to be submitted. Others may require you to submit FNAs in an RNA transport medium.

Positive FCoV RT-PCR tests on samples from abnormal tissues, with consistent cytology, may be adequate to make FIP a very likely diagnosis (Figure 12), enabling the start of trial treatment for FIP, now that effective antiviral treatments such as GS-441524 (Krentz et al., 2021; Yin et al., 2021) are increasingly available (see Section 10 on Treatment of FIP).

FCoV RT-PCR on CSF Samples

Samples of CSF can be submitted for FCoV RT-PCR. Studies have described the use of FCoV RT-PCR on CSF samples, but sensitivity has been poor, at only 30% (Felten et al., 2021), 31% (Foley et al., 1998), 41% (Doenges et al., 2016) or 50% (Barker et al., 2017) in cats with FIP. However, not all cats included in these studies had neurological signs, as CSF was collected at post-mortem examination independent of presenting signs (Doenges et al., 2016; Barker et al., 2017; Felten et al., 2021), such that the population tested does not necessarily reflect a population of cats with neurological signs that would have had CSF samples collected for diagnostic purposes. Indeed, in one study (Doenges et al., 2016), the sensitivity of RT-PCR rose from 41% to 86% when only cats with neurological and ophthalmological signs of FIP were considered. The same group found similar findings in a larger number of cats (Felten et al., 2021), where the sensitivity of RT-PCR was only 30% when both neurological and non-neurological FIP cases were included, but this rose to 83% when only cats with neurological FIP were included in statistical analysis.

The specificity of FCoV RT-PCR on CSF samples is good, with values of 100% (i.e., no false-positives) reported in two studies of 15 (Doenges et al., 2016) and 29 (Felten et al., 2021) cats without FIP. However, FCoV RNA has occasionally been found in the CSF of cats without FIP—in one (of 87 cats) without FIP that had disseminated lymphoma (Jähne et al., 2022) and in two persistently infected FCoV carrier cats without FIP (Diane Addie, personal communication).

In one study (Soma et al., 2018), all CSF samples with a CSF FCoV antibody titre of greater than 640 that were tested for FCoV RNA were found to be positive by RT-PCR. This study was limited by the fact that FIP was not confirmed in all cats, but it does suggest an association between high CSF FCoV antibody titres (see Section on Antibody Testing on CSF Samples) and positive CSF FCoV RT-PCR.

Thus, FCoV RT-PCR on CSF appears to be a useful additional test in cats with neurological signs, as a positive result highly supports a very likely diagnosis of FIP, but a negative result does not rule out FIP.

FCoV RT-PCR on Aqueous Humour Samples

Positive FCoV RT-PCR results have been reported on aqueous humour samples in cats with FIP (Barker et al., 2017; Emmler et al., 2020), though samples were collected at post-mortem examination. One study also described positive results in two cats on samples collected ante-mortem (Linn-Pearl et al., 2015). A further study (Sangl et al., 2020) documented positive FCoV RT-PCR on aqueous humour samples from 11 of 31 (36%) cats with confirmed FIP and none of 27 control cats without FIP. Again, these samples were collected at post-mortem examination and, interestingly, only four of the 31 cats with FIP had ocular signs of uveitis, and only two of these four cats were FCoV RT-PCR aqueous humour-positive. Although FCoV RT-PCR had a specificity of 100% in this study, its sensitivity was low, at 36%. Further studies are required on aqueous humour samples collected in vivo in cats with ocular signs consistent with FIP.

FCoV RT-PCR on Faecal Samples

FCoV RT-PCR can be performed on faecal samples or rectal swabs, although faecal samples are preferred due to their higher FCoV load for RT-PCR detection compared to swabs (Meli et al., 2022). Faecal RT-PCR is sometimes used to identify cats that are shedding FCoV for the management of infection in a multi-cat household but should never be used to diagnose FIP as it is known that the faeces of cats with FIP are not always FCoV RT-PCR-positive and those of cats without FIP in multi-cat households are commonly positive (Table 1).

In studies, the percentage of cats with FIP with positive faecal FCoV RT-PCR results have varied: from 33% (on day 0 of a treatment study, although this rose to 61% when all three faecal samples from the first three days of the study were included in the analysis) (Meli et al., 2022) to 35% (Chang et al., 2010), 65% (Barker et al., 2017), 81% (Porter et al., 2014) and 87% (Addie et al., 1996). The percentages of cats without FIP with positive FCoV RT-PCR results on faecal samples have also varied: in only one of five (20%) ill UK cats (Addie et al., 1996), 56% of 50 healthy cats in USA shelters (Fish et al., 2018), 60% of 10 ill cats without FIP in the UK (Porter et al., 2014), 71% of 82 healthy cats from German catteries (Felten et al., 2020) and 77% of 179 cats from German breeding catteries (Klein-Richers et al., 2020).

Although one study (Barker et al., 2017) showed that cats with FIP were more likely to be shedding FCoV in their faeces than cats that were euthanised due to diseases other than FIP, in an individual cat, faecal RT-PCR is not useful for the diagnosis of FIP.

7.5.3. Molecular Techniques Characterising FCoV Spike (S) Gene Mutations following Positive RT-PCR for FCoV RNA

Following the detection of FCoV RNA in a sample by RT-PCR, varied molecular techniques can then be used to derive or deduce sequence data for the S gene of the FCoV detected. As described earlier in Section 2.4 on FCoV Pathotypes and Genome Mutations, the S gene codes for the spike protein, which mediates host-receptor recognition and membrane fusion. It has been a target for distinguishing FIP-associated FCoV from less-virulent FCoV (Chang et al., 2012; Decaro et al., 2021).

Methods to determine FCoV sequences include sequencing methods, such as pyrosequencing and Sanger sequencing, most often used in research, and methods designed to detect and quantify specific mutation sequences, such as the commercially available PCR that uses allelic discrimination to detect M1058L and S1060A mutations. However, it is known that it is not a single, nor just a few, mutations that define the FIP pathotype; many are likely to be involved in the development of FIP (Zehr et al., 2023). Thus, a test based on the identification of one, or just a few mutations, can never be diagnostic for FIP.

Sequence determination methods are described elsewhere (Barker and Tasker 2020a; Barker and Tasker 2020b), but, in brief, the sequencing methodologies used in FCoV mutation assays are:

• Sanger sequencing: a DNA sequencing approach that uses the dideoxy chain termination method to sequence a segment of the S gene of FCoV (Hellemans et al., 2020).
• Pyrosequencing: a DNA sequencing approach to the S gene that is based on the sequencing-by-synthesis principle (Longstaff et al., 2017).
• Allelic discrimination: an approach available commercially that uses probes in a qPCR to determine if two specific mutation SNPs (M1058L and S1060A; Figure 1) are present in the FCoV S2 fusion domain.

However, these techniques are not always successful in deriving the FCoV sequence data in FCoV RT-PCR-positive samples. One reason for this is that the FCoV levels can be too low to allow sequence analysis, particularly in cats without FIP where FCoV levels are typically low (Jähne et al., 2022). Alternatively, sequencing techniques that target the detection of particular sequences (e.g., allelic discrimination) might not be able to generate sequence data due to mismatches or sequence variability in the FCoV S-gene sequences in the sample, and some sequence analysis methods only detect S-gene mutations in type I FCoV, and not type II FCoV (Barker et al., 2017; Decaro et al., 2021). Indeed, studies using sequencing to derive S1/S2 sequence data in cases of FIP have shown novel mutations (Andre et al., 2019; Ouyang et al., 2022), different mutations within the same cat (Healey et al., 2022), or novel mutations in the S2 fusion domain (Meli et al., 2022), highlighting the variability in sequence that can be present in the S gene, which limits application of methods targeting a specific sequence.

Sequence analysis has usually focused on the S2 subunit fusion-domain region of the S gene of type I FCoV, in which specific mutations (M1058L and S1060A) were found in the FCoV in tissues from cats with FIP but not in the FCoV in the faeces of healthy cats without FIP (Chang et al., 2012; Decaro et al., 2021; Meli et al., 2022) (Figure 1). Sanger sequencing studies found evidence of S-gene mutations in the effusion and blood samples of cats with FIP but not in their faeces, nor in the faeces of companion cats that lived with the cats with FIP (Meli et al., 2022). Other studies (Porter et al., 2014; Barker et al., 2017) analysed the FCoV of both tissue and faecal samples from cats with FIP and cats without FIP (confirmed as having diseases other than FIP by histopathology) by pyrosequencing, followed by Sanger sequencing if pyrosequencing was not successful. These studies (Porter et al., 2014; Barker et al., 2017) found that these spike M1058L and S1060A gene mutations were also found in the FCoV in tissues from cats without FIP, leading the authors to conclude that these mutations are associated with systemic FCoV infection, rather than FIP, per se. However, other studies have failed to find mutations in tissue samples from FCoV-infected cats without FIP. For example, Sanger sequencing studies on a selection of samples from cats without FIP that had tested FCoV RT-PCR-positive found no evidence of S-gene mutations in any of 16 samples tested (Jähne et al., 2022). Although this might be expected in samples derived from the intestinal tract (including faeces), eight of the samples were from the mesenteric and popliteal lymph nodes and the kidneys, where one might expect to find the mutations if they were associated with systemic spread of non-FIP-associated FCoV (Jähne et al., 2022).

One study described a cat with neurological FIP (Andre et al., 2019) in which histological changes of FIP were found only in the CNS. Upon sequencing, the FCoV in the CNS had S-gene mutations (including a functionally relevant R793M mutation in the S1/S2 cleavage site), whereas the FCoV found systemically in other organs did not. Another study, sequencing the same S1/S2 area of the S gene (Healey et al., 2022), reported the presence of both mutated and non-mutated FCoV within the same tissues of cats with FIP. Additionally, a study of seven cats that remained healthy following experimental infection with FCoV (Lutz et al., 2020) was set up to document the presence or absence of S-gene mutations in samples of tissue (primarily colon, liver, thymus) and faeces obtained from these cats; however, S-gene sequences could only be obtained in five samples (four colonic, one liver) from four of the seven healthy cats, and none of these contained the targeted S-gene mutations of M1058L or S1060A.

Overall, the results from these sequencing studies have varied. Although S-gene mutations are likely to be important in the development of FIP, as they can occur in FIP-associated FCoV, the variability of the presence of S-gene mutations in samples from cats with and without FIP suggest that other viral (including other mutations) and host factors can allow effective and sustained replication in monocytes, as well as the activation of infected monocytes, in cats that develop FIP following systemic FCoV infection (Kipar and Meli 2014). One study (Zehr et al., 2023) suggested that because multiple mutations were believed to be involved in the development of FIP, future diagnostic tests may evaluate a combination of sites within the S gene and generate a ‘risk-score’ assessment to aid in the diagnostic process for FIP (e.g., the more mutations identified, the higher the likelihood of FIP development). No such tests are yet available. A further discussion of the results, including sensitivity and specificity, of mutation analysis in different feline sample types, occurs in the next two sections: Diagnostic Use of S-Gene-Mutation Analysis on Tissue Samples and on Diagnostic Use of S-Gene-Mutation Analysis on Effusion and Other Fluid (e.g., CSF, Aqueous Humour) Samples.

Diagnostic Use of S-Gene-Mutation Analysis on Tissue Samples

An extensive study (Barker et al., 2017), which included 260 tissue samples from 57 cats with FIP and 258 tissue samples from 45 cats without FIP, calculated that S-gene-mutation analysis using pyrosequencing (with or without Sanger sequencing) on tissues, as an additional step in the detection of FCoV RNA alone by RT-qPCR, only slightly increased specificity for the diagnosis of FIP—from 93% to 95% (this difference was equivalent to five tissues)—but moderately decreased sensitivity from 90% to 81% (difference equivalent to 20 tissues). The decrease in sensitivity was because of the detection of non-mutated FCoV in cats with FIP (four samples), the presence of type II FCoV in cats with FIP (which was not detected by the mutation analysis assays used that relied on finding the specific S-gene mutations seen in type I FCoV by targeted analysis) (12 samples), and an inability to sequence the FCoV S gene due to only low FCoV copy numbers being present (four samples). The increase in specificity was due to the detection of non-mutated FCoV in cats without FIP (two samples) and an inability to sequence the FCoV S gene due to low FCoV copy numbers (three samples).

Another study (Sangl et al., 2019), which performed S-gene-mutation analysis using a commercially available allelic discriminative assay on pooled tissue samples (5 per cat) from 34 cats with FIP and 30 cats without FIP, reported a much higher specificity of 100% for S-gene-mutation analysis. In this study, only three of the 30 cats without FIP were FCoV RT-PCR-positive, and in none of these was S-gene-mutation analysis successful. Thus, it is important to note that the specificity value of 100% was not based on detecting non-mutated FCoV in cats without FIP. The sensitivity of S-gene-mutation analysis (Sangl et al., 2019) was moderate at 71%, as only 24 of the 34 FIP cases had mutations successfully detected.

One further study (Emmler et al., 2020) performed S-gene-mutation analysis using the commercially available allelic discrimination assay on FNAs and incisional biopsies of popliteal and MLNs, liver, spleen, omentum, and kidneys in 20 cats with FIP confirmed by IHC. FCoV containing S-gene mutations was present in at least one sample from each cat, but there was variation in which sample was positive. FCoV with mutations in the S gene was most frequently found in effusions (64%), followed by in incisional biopsies of the spleen, omentum, and kidney (50%), then in MLN incisional biopsies and FNAs (45%), and finally in FNAs of spleen and liver and liver incisional biopsies (40%). There was a loss in sensitivity in all tissues when compared to RT-PCR for FCoV alone, without mutation analysis.

Another study by the same group (Jähne et al., 2022) performed the same commercially available S-gene-mutation analysis using allelic discrimination on FNAs and incisional biopsies from popliteal and MLNs, liver, spleen, omentum, kidneys, lung, intestines (duodenum, jejunum, ileum, colon) and fluid (e.g., CSF, aqueous humour, effusion or lavage fluid), and faecal samples from 21 of 87 cats without FIP that had generated positive FCoV RT-PCR results in at least one sample; 14 of the 21 cats showed mutated FCoV on the commercial allelic discrimination assay, whilst the remaining seven samples had FCoV RNA loads that were too low to generate results. The group went on to sequence a number of these mutated FCoV samples by Sanger sequencing and, remarkably, none of them contained the S-gene mutations (Jähne et al., 2022). The results of this study suggest that the commercial allelic discrimination assay is incorrectly identifying FCoV with mutations in samples that do not contain the mutation, markedly questioning the assay’s performance.

Another mutation-analysis study using sequencing (Stranieri et al., 2018) on tissues (MLN, spleen, small intestine and lung) in 10 cats with confirmed FIP and eight cats with diseases other than FIP, reported a sensitivity of 70% (seven of 10 cats with FIP had mutations) and specificity of 88% (one of eight cats without FIP had a mutation) compared to values of 91% and 50% respectively for RT-PCR alone.

Finally, a Canadian study (McKay et al., 2020) that also used sequencing to deduce FCoV S-gene segment sequences, documented that only nine of the 20 (45%) S-gene sequences that could be obtained from 69 tissue samples showing typical histopathological findings of FIP possessed the S-gene mutations; a further 15% contained a novel S-gene mutation and 40% had no mutations at all in the S-gene region sequenced. Sensitivity and specificity were not calculated. The lack of finding of S-gene mutations in tissues from cats with FIP in this study highlights a possible sensitivity issue with mutation detection or that the FCoV associated with FIP in this Western Canada study had additional or alternative virulence sites that were not identified in the ‘traditional’ region of the S gene targeted by sequencing in the study.

Diagnostic Use of S-Gene-Mutation Analysis on Effusion and Other Fluid (e.g., CSF, Aqueous Humour) Samples

S-gene mutation analysis has also been performed on effusions in multiple studies using different methods with variable sensitivities of 40% (mutation analysis performed by sequencing) (Stranieri et al., 2018), 60% (mutation analysis by pyrosequencing and sequencing) (Longstaff et al., 2017), 65% (mutation analysis by sequencing) (Felten et al., 2017c) and 69% (mutation analysis by allelic discrimination) (Felten et al., 2017a). One study (Lin et al., 2022) of samples from cats with suspected FIP found the M1058L S-gene mutation in 89 of the 94 (95%) samples in which mutation analysis was possible.

A study (Barker et al., 2017) that evaluated 51 fluid samples (primarily effusions but also included CSF and aqueous humour) from 57 cats with FIP and 47 fluid samples from 45 cats without FIP calculated that S-gene-mutation analysis (via pyrosequencing and sequencing), performed in addition to (i.e., following) the detection of FCoV alone by RT-qPCR, did not increase specificity (it stayed at 98% for both RT-qPCR for FCoV alone and for RT-qPCR for FCoV followed by S-gene-mutation analysis) for the diagnosis of FIP, but markedly decreased sensitivity from 78% (RT-qPCR alone) to 60% (RT-qPCR for FCoV followed by S-gene-mutation analysis). Another study (Felten et al., 2017a) that carried out the same calculations on effusion samples, described an increase in specificity from 88% to 96% for S-gene-mutation allelic discrimination analysis over FCoV RT-PCR alone, whilst sensitivity decreased from 97% to 69%. However, only effusions from three cats without FIP were FCoV RT-PCR-positive and in only one of these was S-gene-mutation analysis successful in generating a result (and a mutated virus was detected in this one effusion). Thus, the improvement in specificity was not based on the better detection of non-mutated FCoV in non-FIP samples but by the methodology not being successful in sequencing non-FIP FCoV samples and thus not being able to detect mutated FCoV in them. Another study (Hellemans et al., 2020) documented several S-gene mutations (eight including M1058L and S1060A) by Sanger sequencing in the majority of effusion samples from cats with FIP, but sensitivity and specificity calculations were not reported for mutation analysis.

Another study (Sangl et al., 2020) using commercially available allelic discrimination analysis, evaluating aqueous humour samples by FCoV RT-PCR with subsequent mutation analysis, concluded that mutation analysis was not helpful for the diagnosis of FIP; in this study, of 11 aqueous humour samples that were FCoV RT-PCR-positive in cats with FIP, only four yielded successful results for mutation analysis (3 had a mutated virus detected and one had mixed mutated and non-mutated viruses detected).

Similarly, researchers using the commercially available allelic discrimination assay to evaluate CSF samples by FCoV RT-PCR with subsequent mutation analysis also concluded that mutation analysis was not helpful for the diagnosis of FIP (Felten et al., 2021). In this study, of nine CSF samples that were FCoV RT-PCR-positive in cats with FIP, only three yielded results for mutation analysis (all three were positive for the presence of S-gene mutations) (Felten et al., 2021). In this study, the sensitivity of mutation analysis in cats with FIP was only 10% (rising to only 17% when only cats with neurological FIP were considered). The specificity of mutation analysis could not be calculated as none of the cats without FIP yielded positive FCoV RT-PCR results upon which to subsequently perform mutation analysis by allelic discrimination.

Overall, these data show the variability in results detecting S-gene mutations using the different studies and methods. This makes it very difficult to rely on S-gene-mutation analysis for the confirmation of FIP, especially when the commercially available allelic discrimination assay is used, and caution is urged in the interpretation of results. Ahead of any S-gene-mutation analysis, one should remember that, as described above in Section 7.5.2 on Detection of FCoV RNA by RT-PCRs, a positive RT-qPCR result for FCoV RNA is not specific for FIP, but high FCoV RNA viral loads do highly support a diagnosis.

7.5.4. Detection of FCoV RNA by In-Situ Hybridisation (ISH)

RNA ISH detects specific RNA sequences through the use of oligonucleotide probes, allowing for the detection and microscopic visualization of pathogen-specific RNA sequences in tissues; it may be particularly useful when there is no known conserved or available antibody epitopes with adequate sensitivity and specificity to allow for consistent detection of a pathogen via IHC methods (Sweet et al., 2023). Previously, RNA ISH techniques have lacked sensitivity and been labour intensive, limiting their use, but more recently methods have been developed which are said to allow for improved sensitivity (Sweet et al., 2023).

One study, by Carossino et al., (2022), described the use of ISH to detect FCoV sequences in fixed samples prepared from the tissues of enucleated eyes of cats with confirmed FIP with ocular signs. They used an oligonucleotide probe directed against the conserved genetic coronavirus target of the ORF 1a and 1b gene for ISH. Of the 30 cats, only 13 cats gave positive results for IHC and/or ISH in the ocular tissues (as mentioned above, they found that ocular tissues characterised by heavy plasmacytic inflammation in FIP were less likely to be IHC-positive for FCoV antigens); 10 had positive results with both techniques whereas two were only positive on ISH and one was only positive on IHC. This suggests similar diagnostic performance of IHC and ISH, although the sensitivity with ISH was slightly higher. Another study Sweet et al., (2023), using the same oligonucleotide prob as Carossino et al., (2022), compared ISH and IHC in 30 cats with FIP. This was a proof-of-concept preliminary study and comparative numbers were not presented by the authors, but they described that the ISH positivity was stronger than the IHC positivity, suggesting improved sensitivity of ISH over IHC (Sweet et al., 2023). Neither of these studies tested non-FIP affected tissues, so specificity was not described. More studies are required to evaluate the use of ISH in the diagnosis of FIP.

7.6. Indirect Detection of FCoV

7.6.1. FCoV Antibody Testing

Antibody Testing on Blood Samples

Serum FCoV antibody tests are usually ELISAs, indirect immunofluorescence antibody (IFA) tests or rapid immunomigration tests (Addie et al., 2015b). The porcine coronavirus TGEV, or FCoV, can be used in these tests as antigen substrates, both being able to detect serum FCoV antibodies; indeed, using TGEV as a substrate in one study (Kummrow et al., 2005) showed higher sensitivity in the detection of serum FCoV antibodies than when using FCoV as a substrate. However, false-positives have been found to be slightly more likely in some assays based on the TGEV antigen (Addie et al., 2015b).

A positive FCoV antibody test indicates that the cat has encountered FCoV (by natural infection or FCoV vaccination, although this vaccine is rarely used) and has developed antibodies; seroconversion typically occurs around seven to 28 days following natural infection (Stoddart et al., 1988b; Meli et al., 2004; Vogel et al., 2010). Although cats with FIP tend to have higher FCoV antibody titres than cats without FIP (Meli et al., 2022), there is much overlap, with no difference between median FCoV antibody titres in healthy and suspected FIP cases, so using the value in an individual cat to distinguish cats with FIP is very limited (Bell et al., 2006a). In the study (Dunbar et al., 2024) that applied machine learning to diagnosing non-effusive FIP, a high FCoV serum antibody test was found to be useful in the deduced model.

It has been suggested that a negative serum-FCoV antibody result in a suspected FIP case that does not have an effusion is more useful to rule out a diagnosis of FIP than in a cat with an effusion (Sparkes et al., 1994; Addie et al., 2009; Addie et al., 2015b). However, negative results have been reported in three of seven cats with neurological FIP without effusions (Negrin et al., 2007), although in that study, the method of FCoV antibody testing was not described. It is important that the FCoV antibody assay used has adequate sensitivity; otherwise, false-negative results can occur (Addie et al., 2015b). In most tests, antibody titres are determined in multiples of serum dilutions. FCoV antibody testing that begins with a dilution of the sample of 1 in 100, or 1 in 400, is commonly insensitive, missing titres lower than the starting dilution (i.e., those less than 100 or less than 400). Only tests with a starting dilution of 1 in 25 or less are recommended.

Opinions on the usefulness of antibody testing in cats suspected to have FIP vary, but there is no ‘FIP antibody test’; all that can be measured is antibody against FCoV. It is never correct to believe that a positive FCoV antibody test in an otherwise healthy cat indicates a diagnosis of FIP.

Antibody Testing on Effusion Samples

FCoV antibody tests, including in-house rapid tests (Adaszek et al., 2023), can be performed on effusion samples; 70% of 28 ascitic samples from FIP cats were positive, compared to none of 15 samples from cats without FIP (Adaszek et al., 2023). Titred testing can also be performed. In one study, some cats with FIP (although the diagnosis was not confirmed in all cases) had unexpectedly low FCoV antibody titres in their effusions (Meli et al., 2013) and an inverse correlation between FCoV RNA load, measured by RT-qPCR, and FCoV antibodies were found in some samples, suggesting that FCoV can bind antibodies, rendering them unavailable as a ligand in the antibody test (Meli et al., 2013). False-negative results for FCoV antibodies on effusions can be a problem particularly with rapid immunomigration/immunochromatography tests (Meli et al., 2013; Addie et al., 2015b). However, other studies (Lorusso et al., 2019; Hellemans et al., 2020) found no evidence of an inverse correlation between FCoV RNA loads and antibody titres in effusions from cats with suspected FIP. Both studies concluded that a combination of both FCoV RT-PCR and antibody testing would be more helpful to support a diagnosis of FIP compared to either test alone (Lorusso et al., 2019; Hellemans et al., 2020). Similarly, one study described the success of combining a newly developed FCoV N-gene IFA test with FCoV RNA RT-PCR testing on effusions for the diagnosis of FIP (Xu et al., 2023).

Antibody Testing on CSF Samples

FCoV antibody testing has been performed on CSF samples in cats with FIP with varied results. One study (Foley et al., 1998) reported it to be useful in diagnosing FIP, with the comparison of serum and CSF FCoV titres suggesting intrathecal FCoV antibody production was occurring, although no controls were included in this study. Another study (Boettcher et al., 2007) found a significant correlation between serum and CSF FCoV antibody titres, suggesting that any CSF FCoV antibodies detected were derived from blood, and thus their detection was not additionally useful for the diagnosis of FIP. Soma et al. (Soma et al., 2018) suggested that a CSF FCoV antibody titre of greater than 640 might be useful for the diagnosis of FIP, although the diagnosis of FIP was not histopathologically confirmed in the cats in this study. Thus, it may well be that a combination of both FCoV RT-PCR and antibody testing would be most helpful to support a diagnosis of FIP compared to either test alone, although the small volumes of CSF obtained from cats for diagnostic purposes may preclude antibody analysis.

8. Epidemiological Considerations in the Management of Cats Following a Diagnosis of FIP

8.1. Does a Cat with FIP Pose a Threat to Other Cats in Its Household?

Often the question arises as to whether it is dangerous to bring a cat with FIP back into a household with other cats. The short answer is no in the vast majority of cases. In-contact cats have been likely exposed to the same FCoV isolate that originally infected the cat with FIP. Still, the question remains as to whether mutated virus associated with the switch from enteric infection to systemic infection, and the development of FIP, could be transmitted from cat to cat.

According to different studies (Table 1), 33 to 100% of cats with FIP shed FCoV in their faeces (Addie et al., 1996; Chang et al., 2010; Porter et al., 2014; Barker et al., 2017; Meli et al., 2022). One study by Chang et al., (2010), on cats from the same household, which had either no clinical signs of FCoV infection or had FIP, revealed that 11 of 17 cats with FIP had no detectable intestinal FCoV and had seemingly cleared their primary FCoV infection. In those cats with FIP that did have detectable intestinal FCoV, sequence analysis focusing on the FCoV 3c gene revealed that in all but one cat, the intestinal virus was different to the FCoV associated with FIP lesions, and thus seemed to have been acquired by FCoV superinfection from other cats in the household, resulting in renewed FCoV shedding. The authors concluded that if a cat with FIP restarts shedding, this is likely due to a new FCoV superinfection and not the original FCoV that resulted in FIP (Chang et al., 2010). Suggestion of a similar FCoV intestinal superinfection and repeat shedding has been reported in cats successfully treated with oral GS-441524 (Meli et al., 2022; Zwicklbauer et al., 2023), with one study sequencing the faecal FCoV in the treated cats to support the superinfection (Meli et al., 2022). This study (Meli et al., 2022) also sequenced faecal samples from companion cats that lived with the cats with FIP and found that all of the sequencing results on faecal samples showed an absence of the S-gene mutations, in contrast to the FCoV that were successfully sequenced from the effusion and blood samples of the cats with FIP. In the original study by Chang et al., (2010), the one cat with FIP that was shedding a FCoV strain in its faeces similar to the FCoV strain found in its ascitic fluid was believed to have been doing so due to leakage of systemic virus into the intestines due to, for example, an intestinal granuloma.

In contrast, another study reported that faecal FCoV in cats with FIP can carry the same S-gene mutations as the FCoV found systemically in the cats (Barker et al., 2017), and one study found that the full genomic RNA sequences of field FCoV strains isolated at post-mortem examination from the jejunum (enteric) and the liver (non-enteric) samples of a cat with FIP had 100% nucleotide identity, suggesting that FIP-associated FCoV can be shed under some circumstances (Dye and Siddell 2007). However, even if FIP-associated FCoV is shed in the faeces of cats with FIP, it likely cannot cause FIP following transmission to another cat as one study demonstrated that the faeces of cats with FIP did not cause FIP in another cat (Pedersen et al., 2012).

The current understanding is that the horizontal transmission of FIP, via an FIP-associated FCoV strain, is very unlikely, although FIP outbreaks are occasionally reported (see Section 4 on Pathogenesis). As mentioned earlier (Section 3.1 on Transmission of FCoV), cat to cat transmission of a highly virulent novel strain of FCoV-23 has been suggested to occur in a large outbreak of FIP in Cyprus in 2023 (Attipa et al., 2023a; Attipa et al., 2023b; Warr et al., 2023). This situation is, thankfully, very uncommon, but in this particular type of outbreak, isolation of cats to avoid spread to other cats, is indicated.

Therefore, as previously stated, in the absence of a rare FIP outbreak, it is likely safe to take a cat with FIP back into a household with cats that have already been in-contact with it, as these cats are likely to have been already FCoV-infected. It is, however, not recommended that the cat with FIP has contact with any ‘naïve’ FCoV-uninfected cat, because if the cat with FIP is shedding FCoV, it could infect any naïve cats with FCoV. However, of course, such FCoV infection in the naïve cat will not usually result in the development of FIP as it is a sporadic disease following FCoV infection.

In households where a cat with FIP has been euthanised, with no remaining cats in the household, it is recommended that the owner waits for two months before obtaining new cats, because FCoV might preserve its infectivity for days to a few weeks, depending on environmental conditions and the presence of organic matter (Scott 1988; Reissner et al., 2023). Thorough vacuuming and steam cleaning can also diminish environmental FCoV load considerably; this will reduce the chance of any new cats, if they are not already FCoV-infected, becoming infected with FCoV when introduced into the household. However, as highlighted in Table 1, the prevalence of FCoV-infection is high amongst many groups of cats, so many cats are already FCoV-infected before rehoming.

8.2. Management of Cats with FIP in the Veterinary Practice

Cats with FIP in a veterinary practice or hospital should be handled and housed like other cats, with routine infection-control measures, as any hospitalised cat is a potential source of FCoV infection (Addie 2019). There is no benefit in isolating the cat with FIP and it is not necessary to keep cats with FIP in isolation wards. Routine infection-control measures also help protect these cats from secondary infections, as their immunity is likely to be suppressed and many are lymphopenic (Riemer et al., 2016; Addie et al., 2022).

9. General Prognosis for FIP

Before effective antiviral treatments became available (Section 10 on Treatment of FIP), occasionally, cats with FIP did survive for several months or years after a diagnosis was made (Ishida et al., 2004; Ritz et al., 2007; Pedersen 2014a; Hugo and Heading 2015; Legendre et al., 2017a; Addie et al., 2022). These reports described that cats had received variable treatments (e.g., non-steroidal anti-inflammatory drugs [NSAIDs], polyprenyl immunostimulant, recombinant feline IFN-omega (rfIFN-ω) and/or glucocorticoids), although the influence of these treatments on survival was not proven. Historically, cats with FIP usually died or were euthanised within a few weeks of presentation (Tsai et al., 2011).

In a prospective study of 43 cats with FIP with effusions given systemic (2 mg/kg/day) or intracavitatory glucocorticoids, the median survival time after definitive diagnosis was only eight days (Ritz et al., 2007). Another study of cats with FIP reported a median survival time of 21 days after presentation in cats with effusions and 38 days in cats without effusions (Tsai et al., 2011). The disease progression between the onset of clinical signs and death is variable, but it appears to be shorter in younger cats and cats with effusions than in older cats and cats without effusion (Pedersen 2014b). In two studies (Ritz et al., 2007; Tsai et al., 2011), high bilirubin concentration, poor general condition, low platelet count, low lymphocyte count, low haematocrit, low sodium concentration, low potassium concentration, high AST activity, and a large volume of effusion indicated a poor prognosis. Seizures can also be considered a poor prognostic sign, since they occur significantly more frequently in animals with a marked extension of inflammatory lesions in the forebrain (Timmann et al., 2008). More recently, the use of prednisolone (as well as other glucocorticoid treatments) has been suggested by some to be associated with a poorer outcome of FIP when used with other treatments (Addie et al., 2022); in this study, prednisolone had been given to only 44% (11/25) of cats that recovered from FIP (varied other treatments were given such as rfIFN-ω and nucleoside analogues [see later]), whereas prednisolone had been given to 92% (11/12) of cats that ultimately did not recover. In a study based on owner-reported survey data describing 393 cats treated with unlicensed, mainly injectable GS-441524, high success rates were reported (88% of owners reported an improvement in clinical signs within a week of treatment and 97% of cats were still alive at the time of the survey) despite steroids being used in 38% of cats (Jones et al., 2021). However, the reliability of these data is less compared to those derived from veterinary records, and there may have been a bias to participation by owners whose cats had undergone successful treatment. Further studies on the effect of glucocorticoids on the recovery of FIP in the presence of antivirals are required.

10. Treatment of FIP

The recent availability of predictably effective antiviral treatments (Table 2), notably the nucleoside analogue GS-441524 (Murphy et al., 2018; Pedersen et al., 2019; Addie et al., 2020b; Dickinson et al., 2020; Jones et al., 2021; Katayama and Uemura 2021; Krentz et al., 2021; Addie et al., 2022; Krentz et al., 2022; Katayama and Uemura 2023; Zwicklbauer et al., 2023), for FIP has totally changed the landscape of this disease for both owners and veterinary teams. There is now an alternative to euthanasia, and FIP is frequently curable. The new antiviral treatments, which act quickly, also allow for the trial treatment of cats—for example, those in which FIP is very likely (Figures 11–13)—without absolute confirmation of diagnosis, due to the clinical improvement seen within a few days of treatment. A rapid and sustained positive response to antiviral treatment is a means of supporting a diagnosis of FIP. However, treatment is often expensive, not licensed and not available legally in many countries, which complicates access to care. Despite this, much published evidence exists for the efficacy of antivirals for FIP, as described in the Section 10.1 on Antiviral Treatments for FIP.

As antivirals are often expensive, care should be taken in discussions with owners regarding the costs of treatment and monitoring, as well as diagnostics, so that the cat’s care plan can be adapted to preserve funding for treatment and monitoring if needed. However, costs will still preclude treatment in some cats, so veterinary teams and owners must understand that sometimes euthanasia is the only, and appropriate, option for an ill cat in that situation. No other treatments are as effective as the antivirals for FIP, although mefloquine, IFN and/or the NSAID meloxicam have been used palliatively.

10.1. Antiviral Treatments for FIP

Table 2 outlines antiviral agents that have been used for the treatment of FIP.

10.1.1. GS-441524, a Nucleoside Analogue

The introduction of the adenosine nucleoside analogue, GS-441524, the active component of remdesivir, has revolutionised FIP treatment (Murphy et al., 2018; Pedersen et al., 2019). Nucleoside analogues act as an alternative substrate for viral RNA synthesis, resulting in RNA chain termination during viral RNA transcription via the inhibition of the viral RNA-dependent RNA polymerase.

Although licensed preparations of GS-441524 do not currently exist for animals nor humans, veterinarians in some countries (including the UK (Sorrell et al., 2022; Green et al., 2023; Taylor et al., 2023) and Australia (Coggins et al., 2023), and some other countries legally allowing their importation) have access to veterinary compounded ‘special’ formulations of GS-441524, which can be used legally, as no other licensed products for the treatment of FIP exist. In the UK and Australia, where these formulations are manufactured, they are closely regulated, quality-assured (physical and chemical properties are tested in each batch) and of known stability (Taylor et al., 2023). Evolving protocols have emerged for the use of these compounded products in the treatment of FIP (Coggins et al., 2023; Green et al., 2023; Taylor et al., 2023). In other countries, only illegal preparations are available, which many owners obtain themselves to treat their cats (Jones et al., 2021). Veterinarians whose clients are using illegal preparations might need to contact their professional regulatory bodies for guidance on their legal position in dealing with such cases, as prescribing or administering such treatments may be forbidden (Cooper 2021; Riley 2021; Pons-Hernandez et al., 2022). However, the provision of veterinary-led supportive care to such cats undergoing treatment (see Section 10.3 on Supportive Treatments for FIP, including Anti-Inflammatories and Drainage) and their owners in these circumstances is highly recommended (Addie et al., 2022), and this was believed to be an important component of the excellent responses to therapy with oral GS-441524 in a prospective study (Krentz et al., 2021).

Initial Studies on GS-441524

The first published studies on the efficacy of GS-441524 for the treatment of FIP used an injectable preparation of GS-441524 and tended to administer it for shorter periods, and at lower dosages, than are used now. These studies initially excluded cats with neurological or ocular signs (Murphy et al., 2018; Pedersen et al., 2019).

GS-441524 was shown to be non-toxic in vitro and effectively inhibited the replication of FIP-associated FCoV strains and field FCoV isolates in two different cell culture systems (Murphy et al., 2018). In an in vitro study (Barua et al., 2023), of six tested antiviral drugs, GS441524 showed the highest effectiveness against FIP-associated FCoV, whilst maintaining safety.

In 10 young cats with experimentally induced FIP, GS-441524 (applied subcutaneously [SC] q 24 h at either 2 mg/kg or 5 mg/kg) caused a rapid reversal of clinical signs and return to a clinically healthy status within two weeks of treatment in all 10 cats (Murphy et al., 2018). Two of the 10 treated cats had recurrences of clinical signs (the nature of which was not described) at four weeks and six weeks post-treatment – one from each dosage group. These two cats responded to a second treatment of two weeks of GS-441524. All 10 cats remained clinically healthy until the time of publication more than eight months post-infection (Murphy et al., 2018). No adverse effects were noted other than a transient ‘stinging’ injection reaction in some cats (e.g., unusual posturing, licking at the injection site, vocalisations) directly after SCn GS-441524 administration (Murphy et al., 2018).

GS-441524 treatment was then evaluated in a field clinical trial of 31 cats with naturally occurring FIP (Pedersen et al., 2019). Cats were diagnosed with FIP based on signalment, history, clinical examination, prior test results, repeat testing and/or effusion analysis, with FCoV RT-PCR performed on effusions in eight of the 31 cats. A more definitive diagnosis of FIP was desirable but not essential, and tissue IHC for FCoV antigens was performed in only five cats that died or were euthanised and underwent post-mortem examination. Cats with neurological or ocular signs were discouraged from the trial due to concerns of poor penetration of GS-441524 into the brain and/or eye from previous studies (Murphy et al., 2018) (although subsequent studies (Addie et al., 2020b; Dickinson et al., 2020; Krentz et al., 2021; Green et al., 2023; Taylor et al., 2023) have described the effective treatment of neurological or ocular FIP with higher dosages of GS-441524, see below).

Of the 31 cats with FIP recruited into the field clinical trial (Pedersen et al., 2019), five had no evidence of effusion. Cats had a mean age of 14 months (range 3–73 months). The cats were started with a first treatment course of GS-441524 at a dosage of 2 mg/kg SC q 24 h, usually for at least 84 days (i.e., 12 weeks, with longer treatment given if serum protein levels remained elevated). The dosage was increased to 4 mg/kg SC q 24 h for subsequent treatments in the trial when cats relapsed or when a treatment course of longer than 84 days was deemed necessary.

The study (Pedersen et al., 2019) did not include an untreated control group due to ethical concerns. Five of the 31 cats died, or were euthanised, within 26 days of the first treatment. The remaining 26 cats completed 84 days or more of GS-441524 treatment and showed rapid clinical improvement within 14 days. Of these 26 cats, 18 remained healthy, while eight had FIP relapses (these were non-neurological in nature in six cats and neurological in two cats) at a mean (range) of 23 (3–84) days after treatment stopped. Four of the eight cats with relapses were treated again with GS-441524 at 2 mg/kg SC q 24 h; one of these four cats relapsed with neurological FIP two weeks into the second treatment and was euthanised, whilst two cats responded but then relapsed and were treated with GS-441524 at a higher dosage of 4 mg/kg SC q 24 h. The remaining cat was changed from 2 mg/kg to 4 mg/kg SC q 24 h of GS-441524 as treatment was extended due to a lack of complete response. The remaining four of the eight cats with relapses were given the higher dosage of 4 mg/kg SC q 24 h immediately, and all responded. Of the original 31 cats in the field clinical trial (Pedersen et al., 2019), 25 (81%) were classified as long-term survivors after successful treatment; one of these cats was subsequently euthanised due to presumed unrelated heart disease, while the other 24 remained healthy at the time of publication (Pedersen et al., 2019), confirming the efficacy of SC GS-441524. Only one cat in this study was thought to have shown evidence of drug resistance following SC GS-441524 treatment, although this was not confirmed (Pedersen et al., 2019).

Subsequently, a small case series describing GS-441524 treatment at higher dosages of 5–10 mg/kg SC q 24 h for at least 84 days in four cats with neurological and ocular signs of FIP was published (Dickinson et al., 2020). Three of the four cats were alive and off treatment at the time of publication, 354–528 days after treatment had started; two cats had received 5 mg/kg SC q 24 h and one cat an escalating dosage of 10 mg/kg SC q 24 h. This provided evidence that FIP associated with neurological and ocular signs could also be successfully treated, albeit at higher dosages of GS-441524. The remaining cat was euthanised 216 days after starting treatment; this cat had not shown complete remission (at 5 mg/kg SC q 24 h), and rapid clinical deterioration occurred when treatment was stopped. Additionally, local skin reactions and discomfort around SC injections were cited as a reason for euthanasia.

Subsequent Studies on GS-441524

The problems encountered when injecting GS-441524 SC meant that antiviral formulations that could be administered per os (PO) would be attractive. The bioavailability of oral GS-441524 has been shown to be similar to that of subcutaneous GS-441524 in cats (Yan et al., 2023). The first study documenting the PO treatment of a cat with FIP was a case report published in 2020 (Addie et al., 2020b). The cat had ocular signs of FIP in the absence of effusions and was successfully treated with an unregulated PO preparation of a nucleoside analogue; the preparation used was a brand for which the manufacturers did not stipulate the identity of the active agent in the preparation, although it was subsequently confirmed to be GS-441524 by independent analysis of the same unregulated preparation in another study (Krentz et al., 2021).

In this case report (Addie et al., 2020b), the GS-441524 preparation was administered PO for 50 days at a higher dosage (believed to be 8 mg/kg/day), based on the manufacturer’s recommendation that a higher dosage was required to penetrate the eye and brain. However, the actual dosage and dose given to the cat was probably a lot more than believed, as subsequent independent analysis of the amount of GS-441524 present in the unregulated preparation used showed it to contain twice to three times more GS-441524 than stated by the manufacturer (Krentz et al., 2022; Addie et al., 2023). This discrepancy makes it very difficult to confirm the amount of GS-441524 given in studies using unregulated preparations, as further corroborated by other studies (Kent et al., 2024; Mulligan and Browning 2024) (see later in this Section). Nevertheless, within two weeks of starting treatment, the cat showed a marked increase in weight and improvement in ocular signs (return of vision) and multiple haematological (e.g., normalisation of haematocrit) and biochemical (e.g., marked reductions in AGP and globulin measurements and an increase in the A:G ratio) measurements. The cat was also given systemic anti-inflammatory prednisolone (at around 2 mg/kg PO) for six days (before starting the GS-441524 preparation) followed by topical ocular steroids for uveitis treatment. Recombinant fIFN-ω PO was also started after finishing the 50 days of GS-441524 treatment (Addie et al., 2022). This cat is still alive and well three years later, having received rfIFN-ω treatment for seven months in total (Diane Addie, personal communication). No adverse effects of GS-441524 treatment were noted, although the cat did have increased symmetric dimethylarginine concentrations during treatment (but baseline pre-treatment levels were not measured), which decreased following the discontinuation of the GS-441524 preparation. The cat was also given the hepatoprotectant S-adenosyl L-methionine (SAMe) supplementation, alongside the GS-441524, as a precaution.

Since this case report was published (Addie et al., 2020b), evidence has accumulated that oral GS-441524 is very effective for FIP (Katayama and Uemura 2021; Krentz et al., 2021; Addie et al., 2022; Katayama and Uemura 2023). Administration PO is usually less traumatic for the cat and owner, due to the often-painful nature of SC GS-441524 injections, which means compliance for the long, usually 84-day, treatment course is improved. The average pH of unregulated injectable formulations of GS-441524 has been found to be very low (1.3), well below the physiological pH conditions recommended for SC injections, and often below the pH advertised for these compounds, if stated by the producer (Kent et al., 2024). It is not known if the route of administration of the GS-441524 influences the outcome of treatment. In a recent study of 26 cats that experienced FIP treatment relapses, 23 had been treated SC rather than PO with GS-441524 (Roy et al., 2022), but, unfortunately, no control group of treated cats without relapses was presented, so it is unknown if the reason for the relapses was related to the route of administration. Additionally, the earlier studies that used GS-441524 SC did show excellent efficacy (Pedersen et al., 2019; Dickinson et al., 2020), as was reported in a study using owner-reported data (Jones et al., 2021).

A prospective field study in 2021 described the successful treatment of 18 of 18 cats with confirmed, or highly suspected, FIP, with an oral unregulated preparation of GS-441524 (Krentz et al., 2021). It was known that GS-441524 was the main component of the unregulated preparation used, as this was confirmed by mass spectrometry. Sixteen of the 18 cats had effusions and two did not; both these cases had ocular signs and one had concurrent neurological signs.

This study used dosages of either 5 mg/kg/day or 10 mg/kg/day, depending on the absence, or presence, of neurological and/or ocular signs respectively, with a treatment course lasting 84 days; these dosages were those recommended by the manufacturers. It was assumed that the dose of the active component in the tablets was as described on the package inserts. However, as described earlier, subsequent analysis of the tablets used to treat the 18 cats showed them to contain more than twice the dose of GS-441524 stated by the manufacturer (Krentz et al., 2022), meaning that the positive responses seen in the original study (Krentz et al., 2021) were associated with dosages of GS-441524 far higher than the reported 5 mg/kg/day or 10 mg/kg/day used in the published study. Indeed, it is reported that manufacturers of these unregulated products report the amount of GS-441524 that is orally bioavailable to the cat (or the approximate subcutaneous dose equivalent) instead of the amount of drug actually contained in the pill (Kent et al., 2024). This is presumably to make the conversion from injectable to oral treatments easier for lay owners. Additional independent analyses of the GS-441524 content of unregulated preparations have similarly shown some to contain more GS-441524 than stated by the manufacturers (Addie et al., 2023); Mulligan and Browning (2024) measured the content and quality of unregulated injectable GS-441524 drugs for FIP and found that some contained 10% to 25% more GS-441524 than advertised. Another study Kent et al., (2024) found an increased content of GS-441524 to be more common in the injectable, than oral, formulations, although the variability in the amount of GS-441524 present in replicates of the injectable formulations in this study was minimal, compared to the wide variability in the oral formulations. Of the 87 injectable formulations tested in the study Kent et al., (2024), 95% contained more (on average 39% more) GS-441524 than expected based on the producer’s marketed concentrations whilst 43% of the 40 oral formulations tested contained more GS-441524 (on average 75% more) than expected and 58% containing less (on average 39% less) than the expected content.

Other compounds can be present in these unregulated products. Three of the GS-441524 formulations (one injectable and two oral) tested in one study (Kent et al., 2024) contained remdesivir in addition to GS-441524. More information on the antiviral remdesivir can be found below in Section 10.1.2. Remdesivir, a Nucleoside Analogue). Other unregulated preparations contain additional ingredients to the GS-441524, but which are declared by the manufacturers, such as silymarin as a hepatoprotectant, and other herbal compounds, but their effect in the treatment of FIP is not proven, especially as treatment with GS-441524 alone is known to be effective (Murphy et al., 2018; Pedersen et al., 2019; Dickinson et al., 2020; Coggins et al., 2023; Green et al., 2023; Taylor et al., 2023).

In two studies that documented treatment with oral GS-441524 (Krentz et al., 2021; Coggins et al., 2023), the GS-441524 was given on an empty stomach, with food 30 min later, as recommended by the manufacturers. In one of the studies, GS-441524 tablets were followed by 3–5 mL of water or a tablespoon of wet food before food 30 min later (Coggins et al., 2023). However, no studies exist confirming the need for administration without food, although this protocol has been effective. If owners are struggling to tablet cats without feeding, the liquid/suspension form of GS-441524 can be tried, if available, or the tablet given whole or crushed with a small amount of a treat or paste; although this method of administration has not been published, it has been used successfully in some cases (Séverine Tasker, personal communication). Should the cat vomit GS-441524 tablets, then adding food with the GS-441524 can prevent vomiting (Diane Addie, personal communication).

The curative response seen in all 18 cats treated with oral GS-441524 was remarkable, with the shortest follow-up being 99 days after the completion of the 84-day treatment course (Krentz et al., 2021). All cats were hospitalised during the first eight days of treatment, and the intensive veterinary supportive care provided (e.g., intravenous [IV] fluid therapy, appetite stimulants, anti-emetics, analgesia [Section 10.3 on Supportive Treatments for FIP, including Anti-Inflammatories and Drainage]) might have contributed to the high success rate, highlighting the importance of veterinary involvement in the care of sick cats with FIP. Additionally, no serious adverse effects were seen with GS-441524 treatment; an increase in liver enzymes (11/18 cats; but only two were given hepatoprotectants), lymphocytosis (14/18 cats) or eosinophilia (11/18 cats) were documented, in the absence of clinical signs. Although a raised ALT may be an adverse effect of GS-441524, one group found that it could resolve during treatment, or persist after treatment had stopped, making an adverse effect less likely in their opinion (Coggins et al., 2023). Additionally, eosinophilia might be a marker of successful treatment (Coggins et al., 2023), rather than an adverse effect, as has been reported in human patients recovering from COVID-19 (Mateos Gonzalez et al., 2021). No renal adverse effects were reported (Krentz et al., 2021).

Table 2. Antiviral drugs that have been suggested for use in cats with FIP. PO indicates orally, SC indicates subcutaneously, IV indicates intravenously, ALT indicates alanine aminotransferase. Note: For all antiviral treatments, it is important to ensure the dose given to the cat preserves appropriate dosage if/when weight gain occurs as a result of recovery, e.g., in growing kittens and adults that have had weight loss. If the dose is not adjusted, underdosage occurs, which may be associated with disease relapse (Coggins et al., 2023). Accurate weight recording is also important to monitor response to treatment (Pedersen et al., 2019).

Drug	Comments	ABCD recommendation in FIP
GS-441524	Nucleoside analogue. Given PO or by SC injection; latter often stings. Often expensive. Promising results in vitro and in one in vivo experimental study (Murphy et al., 2018), and in several subsequent in vivo field studies, although FIP was not confirmed in all cases (Pedersen et al., 2019; Dickinson et al., 2020; Yin et al., 2021; Addie et al., 2022). Survival rates of 81% mainly in cats with effusions (Pedersen et al., 2019), 82% in cats with effusions (Katayama and Uemura 2021), 85% in cats with ‘mixed’ effusive/non-effusive FIP (Katayama and Uemura 2023) and 94% in cats with FIP without effusions (Katayama and Uemura 2023) have been reported. An improvement rate of 88% (many cats were still on treatment at time of writing) (Jones et al., 2021) has also been reported. More recent reports are using GS-441524 PO, which facilitates compliance. A prospective study showed 100% efficacy in 18 cats with FIP treated with PO GS-441524 (Krentz et al., 2021). Most studies use 84-day treatment courses (Katayama and Uemura 2021; Sorrell et al., 2022; Cosaro et al., 2023; Katayama and Uemura 2023) but shorter courses may be effective (Addie et al., 2020b; Yin et al., 2021; Addie et al., 2022). A shorter, 28-day, course of combined GS-441524 and GC376 (see below) treatment was effective in 98% of 46 cats with effusive or non-effusive FIP (Lv et al., 2022). Non-clinically significant transient adverse effects include elevations in ALT (although this may not be an adverse effect of GS-441524 (Coggins et al., 2023) but due to the FIP), lymphocytosis and eosinophilia. Rare reports of GS-441524 urolithiasis are emerging (Allinder et al., 2023).	No licensed product available. Available as an oral (tablet or liquid/suspension) compounded ‘special’ formulation for veterinary use in UK, Australia and some other countries allowing importation. In countries where legal sources are not available, owners often obtain illegal preparations themselves but these are of variable quality and content (Kent et al., 2024; Mulligan and Browning 2024), although excellent curative results usually occur. Oral dosages of 10–15 mg/kg q 24 h are often used for cats with effusions, with higher dosages for cats with ocular (15 mg/kg q 24 h) or neurological (10 mg/kg q 12 h; i.e. 20 mg/kg divided into 2 doses) signs, although controlled studies are lacking. Whether PO daily doses are best given q 24 h or divided q 12 h (as is routinely done for the higher dosages needed for neurological FIP) has not been confirmed but absorption varies cat to cat and it may be that administration q 12 h (or even q 8 h) is more effective in some cats (Danièlle Gunn-Moore, personal communication, based on therapeutic drug monitoring research). Many have given 84-days of treatment (Katayama and Uemura 2021; Sorrell et al., 2022; Cosaro et al., 2023; Katayama and Uemura 2023), and treatment length can be extended and/or dosage increased (by 5 mg/kg/day) if clinical signs and serum biochemistry do not normalise (Coggins et al., 2023; Taylor et al., 2023). Some have suggested treating for 14 days beyond clinical and biochemical normalisation (Coggins et al., 2023). However, courses shorter than 84-days may be effective (Addie et al., 2020b; Yin et al., 2021; Addie et al., 2022). For the shorter 28-day course of combined GS-441524 and GC376, dosages of either 2.5 or 5 mg/kg SC q 24 h of GS-441524 and either 10 or 20 mg/kg SC q 12 h of GC376 were used (Lv et al., 2022). Additionally, a randomised study of 40 cats with FIP (including some neurological cases) treated with oral GS-441524 at 15 mg/kg q 24 h showed that a 6-week course (20 cats) was as effective as a 12-week course (20 cats); all clinical and clinicopathological changes normalised by 6-weeks, and the cats remained healthy for at least a year (Katrin Hartmann, personal communication). These studies further support the possibility of shorter treatment courses being effective. PO route is usually favoured due to pain of SQ injections. PO tablets or liquid/suspension usually given on an empty stomach, at least 30 min before food, if possible. However, should the cat vomit tablets, then giving food with the GS-441524 can prevent vomiting (Diane Addie, personal communication) and administration of the GS-441524 in a small amount of a treat can also work (Séverine Tasker, personal communication).
Molnupiravir (EIDD-2801)	Nucleoside analogue given PO; promising results of 78% survival as a first-line agent (Sase 2023), and 92% survival as a rescue treatment following GS-441524 treatment in cases that relapse (Roy et al., 2022). Affordable. Rare adverse effects reported but include folded ears (which may be due to the disease rather than an adverse effect), broken whiskers and severe leucopenia at very high dosages (Roy et al., 2022) or a non-clinically relevant increase in ALT (Sase 2023). Many cats successfully treated as out patients (Sase 2023).	Licensed preparation available for use in humans in some countries. Designated as an antimicrobial reserved for human use only in European Union in 2023 (European Union 2023b) which may limit its use in cats, although licensing for molnupiravir in humans may change in the future. Use in cats shows excellent promise. Suggested dosage range is 10–20 mg/kg q 12 h for 84-days; lower dosages for FIP with effusions and higher dosages if ocular and/or neurological signs are present. The metabolite of molnupiravir, EIDD-1931, became available as a compounded ‘special’ formulation for veterinary use in UK in 2024 as a tablet for oral use (15 mg/kg q 12 h), but studies are required to evaluate its effectiveness and neutropenia is reported as a side effect (Séverine Tasker, personal communication).
Remdesivir (GC-5734)	Nucleoside analogue and prodrug of GS-441524. Usually given SC or IV. Expensive. Current descriptive studies (Hughes et al., 2021; Bohm 2022; Sorrell et al., 2022; Coggins et al., 2023; Green et al., 2023; Taylor et al., 2023) suggest favourable results. Induction remdesivir treatment (SC or IV) followed by maintenance SC remdesivir, or PO GS-441524, was associated with 86% survival at six months in 28 cats with effusive or non-effusive FIP (Coggins et al., 2023). A combination of remdesivir (IV and/or SC) subsequently treated with oral GS-441524 (24 cats), or without GS-441524 (six cats), was associated with survival of 96%, and 33%, respectively of the 30 treated cats with effusive or non-effusive FIP (Green et al., 2023); 84-day treatment protocols were used. Non-clinically significant transient adverse effects may include elevations in ALT (Green et al., 2023) but SC injections are often painful, although possibly less painful than SC GS-441524 (Kent et al., 2024). A compounded remdesivir preparation given PO for 84 days was as effective as PO GS-441524 with a 77% survival in effusive FIP (Cosaro et al., 2023).	Licensed preparation available for use in humans in some countries. Available as a compounded ‘special’ formulation for veterinary use in UK and Australia (and some other countries allowing importation). Compliance often problematic due to painful SC injections. Dosages of 6–20 mg/kg q 24 h SC or IV, with induction at 10–15 mg/kg, maintenance at 8–15 mg/kg and the higher dosages of 20 mg/kg q 24 h of remdesivir administered as 10 mg/kg q 12 h indicated for ocular or neurological FIP (Coggins et al., 2023; Green et al., 2023); see Table 3. PO GS-441524 usually favoured over injectable remdesivir unless injectable remdesivir is the only antiviral available and/or the cat is unable to tolerate oral medication. Dosage of 25-30 mg/kg q 24 h for 84-days was used when remdesivir was given PO for effusive FIP (Cosaro et al., 2023).
GC376	Inhibits 3C-like protease. Given SC. Promising results in vitro and in one in vivo experimental study, especially in cats with effusions (Kim et al., 2016). Six of 20 cats (Pedersen et al., 2018) and 1/1 cat (Addie et al., 2022) survived in field studies, although FIP was not confirmed in all cases. Resistance reported (Jiao et al., 2022) in one experimental in vivo study. A 28-day, course of combined GS-441524 and GC376 treatment was effective in 98% of 46 cats with effusive or non-effusive FIP (Lv et al., 2022).	Not commercially available yet but hopefully will be available as a licensed product for treatment of FIP in the future as one pharmaceutical company has advised it is pursuing licensing. For the 28-day course of combined GS-441524 and GC376, dosages of either 2.5 or 5 mg/kg SC q 24 h of GS-441524 and either 10 or 20 mg/kg SC q 12 h of GC376 were used (Lv et al., 2022). . Further controlled field studies required in cats.
Nirmatrelvir	Inhibits 3C-like protease. Promising results for FIP treatment in vitro (Jiao et al., 2022; Barua et al., 2023) although resistance also reported in one in vitro study (Jiao et al., 2022).	Available in combination with ritonavir (to slow down nirmatrelvir metabolism) as a treatment for COVID-19 in humans. In vivo and controlled field studies are required in cats before recommendations can be made although reports are emerging of the successful use of nirmatrelvir combined with ritonavir (Paxlovid™) in a few cats when other antiviral treatments have failed (75 mg nirmatrelvir and 25 mg ritonavir q 12 h PO, given together in a gelatin capsule before a meal, for ~20 days for a 4-5 kg cat; Richard Malik, personal communication).
Recombinant feline IFN-omega (rfIFN-ω)	Inhibits FCoV replication in vitro and reduces FCoV shedding in 9/11 cats without FIP in a shelter (Gil et al., 2013). In one uncontrolled study, 4/12 treated cats survived over two years and another 4/12 experienced remission, but FIP was not confirmed in all cases (Ishida et al., 2004). However, rfIFN-ω was not effective in one placebo-controlled study; here the cats with FIP with effusion were concurrently given high dose glucocorticoids (Ritz et al., 2007), which may have impacted results. In an uncontrolled study, rfIFN-ω was associated with a positive response in seven cats in which glucocorticoids were either not used (two cats), or tapered within a few weeks of starting rfIFN-ω (five cats) (Addie et al., 2022). Has been used following antiviral therapy for FIP to maintain remission (Addie et al., 2020b; Addie et al., 2022) but controlled studies are needed to confirm efficacy of, and need for, rfIFN-ω as many studies have shown excellent survival following nucleoside analogue (including GS-441524) treatment without follow-up rfIFN-ω to prevent FIP relapse (Pedersen et al., 2019; Dickinson et al., 2020; Katayama and Uemura 2021; Krentz et al., 2021; Coggins et al., 2023; Green et al., ; Katayama and Uemura 2023; Taylor et al., 2023).	Licensed for cats in some countries for other feline viral diseases. Further studies without concurrent glucocorticoid treatment needed. Studies are required to evaluate if rfIFN-ω useful to maintain remission of FIP after other antiviral treatment. Two dosing regimes can be used: One million (106) units/kg SC or PO q 48 h for up to five doses, and then twice a week until rfIFN-ω treatment is stopped (Addie et al., 2022). 100,000 (105) units per cat SC or PO q 24 h until rfIFN-ω treatment is stopped (Addie et al., 2020b; Addie et al., 2022); 0.1 mL of previously diluted stock solution containing 1 million units of rfIFN-ω a is diluted again with 4.9 mL of saline diluent. Hence, 0.5 mL of the total 5 mL of the new stock solution now yields 100,000 units.
Mefloquine	Effectively inhibits FCoV replication in vitro as a small molecule inhibitor (McDonagh et al., 2014) and acts as a nucleoside analogue (Delaplace et al., 2021), but full mechanism of antiviral effects not known. Affordable. Hepatic metabolism studied in vitro (Izes et al., 2020a) and pharmacokinetics studied in healthy cats (Yu et al., 2020). Its plasma protein binding properties have been studied in the blood of cats with and without FIP, and a simple high performance liquid chromatography assay developed to measure mefloquine (Izes et al., 2020b). Causes vomiting if not given with food but generally appears safe in healthy cats. Used in Australia as adjunct treatment for FIP and/or to maintain remission after other antiviral treatment (Richard Malik, Sally Coggins and Jacqueline Norris, personal communication) but no published studies yet.	Licensed preparation available for use in humans. Field studies required both alone and in combination with other drugs/antivirals for FIP treatment and to evaluate if useful to maintain remission. Has been used where other more effective antivirals cannot be used due to cost or availability although efficacy alone likely limited (Richard Malik, Sally Coggins and Jacqueline Norris, personal communication). Suggested dosage is 62.5 mg/cat PO 2–3 times a week (three times for large cat) or 20–25 mg/cat PO q 24 h, given with food.
Cyclosporine A and non-immunosuppressive derivatives (e.g., alosporivir)	Inhibits cyclophilins and thereby blocks replication of FCoV in vitro (Tanaka et al., 2012; Tanaka et al., 2013). Associated with a reduction in blood FCoV viral load in three cats with suspected FIP, and reduced pleural effusion FCoV viral load and volume in one cat that survived 264 days after presentation before dying (see supplementary data in Tanaka et al., (2015)). Can lead to immunosuppression, depending on the cyclosporine A derivative.	Further field studies needed.
Curcumin	Curcumin-encapsulated chitosan nanoparticles decreased expression of pro-inflammatory cytokines during infection of cell cultures with FIP-associated FCoV and inhibited viral replication in vitro (Ng et al., 2020). Enhanced bioavailability as curcumin-encapsulated chitosan nanoparticles over curcumin in pharmacokinetic analysis in healthy cats (Ng et al., 2020). Not effective as a small molecule inhibitor of FCoV replication in vitro (McDonagh et al., 2014). Anti-inflammatory properties.	Further studies needed.
Chloroquine	Inhibits endocytosis following attachment of FCoV to host-cell membrane (Delaplace et al., 2021). Has anti-inflammatory effects in vivo (Takano et al., 2013). Can increase liver enzyme activities. Effective as a small molecule inhibitor of FCoV replication in vitro (McDonagh et al., 2014) but reported as being too toxic for cats (Takano et al., 2013; McDonagh et al., 2014)	Not recommended.
Hydroxychloroquine	Inhibits endocytosis following attachment of FCoV to host-cell membrane (Delaplace et al., 2021). Inhibits type I and II FCoV replication in vitro, with less evidence of cytotoxicity than chloroquine (Takano et al., 2020); addition of rfIFN-ω increased its antiviral action against type I FCoV replication in vitro.	Not recommended until further studies available.
Itraconazole	Inhibits cholesterol transport in type I FCoV in vitro (Takano et al., 2019) and thus, inhibits FCoV replication. Also said to inhibit endocytosis following attachment of FCoV to host-cell membrane (Delaplace et al., 2021). Synergism of itraconazole with GS-441524 shown with type I FCoV in vitro (Doki et al., 2022). Used in a very small uncontrolled study of cats with experimentally induced FIP alongside anti-human-TNF-α antibody treatment (Doki et al., 2020b), in which two of three cats with FIP improved, and in one field case alongside prednisolone where the cat initially improved but relapsed and was euthanised at 38 days (Kameshima et al., 2020). Reduced faecal virus load but failed to eliminate FCoV infection (Addie et al., 2023). Associated with anorexia and vomiting in cats without FIP (Mancianti et al., 1998).	Not recommended. More effective treatments now available.
Nelfinavir	Acts as protease inhibitor that showed synergistic effects against FCoV in vitro with Galanthus nivalis agglutinin (Hsieh et al., 2010). No in vivo data available.	Not recommended until further studies available.
Ribavirin	Acts as a nucleoside analogue (Delaplace et al., 2021). Inhibits FCoV replication in vitro, but very toxic in cats (Weiss et al., 1990; Weiss et al., 1993a; Weiss et al., 1993b).	Not recommended.
Vidarabine	Inhibits polymerases and reduces FCoV replication in vitro, but in vivo efficacy unknown (Barlough and Scott 1990). Toxic to cats if given systemically.	Not recommended.
Galanthus nivalis agglutinin	Binds to FCoV-glycosylated envelope glycoproteins, thereby inhibiting viral attachment to the host cell and showed synergistic effects against FCoV with nelfinavir in vitro (Hsieh et al., 2010). No in vivo data available.	Not recommended until further studies available.
Indomethacin	Acts as cyclopentenone cyclooxygenase metabolite with activity against several RNA viruses, including canine coronavirus (Amici et al., 2006). No data on efficacy against FCoV in vitro or in cats with FIP available. Safety in cats is unknown.	Not recommended until further studies available.

Another study (Meli et al., 2022) by the same group who documented the successful treatment in 18 cats (Krentz et al., 2021) used samples from the 18 treated cats to show decreasing FCoV loads in their faeces, blood and effusions during treatment with oral GS-441524. The viral RNA loads in the blood and effusions were correlated, but those in the faeces were not (Meli et al., 2022). Levels of blood FcoV RNA fell quickly, with all cats yielding negative blood RT-PCR results by day 14 of treatment (Meli et al., 2022).

These 18 cats were subsequently monitored extensively, every 12 weeks, for up to one year after their GS-441524 treatment had been started (Zwicklbauer et al., 2023). Follow-up data were available for all 18 cats at 24 weeks (i.e., 12 weeks after completion of the 84-day treatment course of GS-441524 treatment), for 15/18 cats at 36 weeks, and for 14/18 at 48 weeks. No confirmed relapses of FIP were found in any of the 18 cats, suggesting effective treatment of FIP with 84 days of oral GS-441524.

Laboratory parameters remained stable after the end of the GS-441524 treatment, as did undetectable blood FCoV loads (in all but one cat on one occasion). The recurrence of faecal FCoV shedding was detected in five cats (Zwicklbauer et al., 2023).

Two cats developed mild neurological signs (neither had neurological signs at initial presentation with FIP), compatible with feline hyperaesthesia syndrome (attacks of excessive licking and twitching of the skin in the lumbar region) in weeks 36 and 48, respectively; however, FCoV-RNA remained undetectable in the blood and faeces and no increase of FCoV antibody titres was observed, suggesting that the signs were not due to FIP, although one cat did receive GS-441524 treatment sourced by the owner. The neurological signs resolved in one cat and improved markedly in the other. Delayed neurological signs could be a long-term adverse effect of the treatment or associated with a ‘long FIP syndrome,’ but further evaluation is required (Zwicklbauer et al., 2023).

Interestingly, 12 of the 18 cats showed abdominal lymphadenomegaly during the follow-up period, and in four cats this was present constantly during treatment and the follow-up period (Zwicklbauer et al., 2023). The reason for this lymphadenomegaly is not known but could be due to an exaggerated, genetically determined, immune response associated with recovery or the presence of residual virus in the abdomen. However, one of cats with lymphadenomegaly died as a result of a road traffic accident at week 35, i.e., 161 days after finishing the 84-day course of GS-441524 (Krentz et al., 2022). This cat underwent post-mortem examination and no evidence of FIP was found on histopathology, nor was FCoV antigen nor FCoV RNA found in any tissues, demonstrating the elimination of FCoV following the successful treatment of FIP with oral GS-441524 (Krentz et al., 2022), despite the lymphadenomegaly. Severe generalised follicular lymphoid hyperplasia was found on the histopathology of the abdominal lymph nodes of this cat. It is possible that the lymphadenomegaly is an adverse effect of the GS-441524. This was seen in one other FIP case treated with oral GS-441524 (Diane Addie, personal communication). A drug reaction with generalised lymphadenomegaly to phenobarbitone has been reported (Walton-Clark et al., 2022).

A large retrospective case series documented the successful treatment of 116 of 141 (82%) pet cats with suspected FIP and effusions using an unregulated GS-441524 preparation (Katayama and Uemura 2021) at a dosage believed to be 5 mg/kg/day (see earlier discussion regarding the disparity in the GS-441524 dose in this preparation compared to that stated by the manufacturers), but the frequency of administration was not stipulated; the remaining 25 cats died despite treatment. An 84-day treatment course was given, and most cats received PO rather than SC therapy; only a few cats received SC therapy, and this was said to be feasible for only a short period during early treatment and used when PO administration was not possible due to ‘disease progression’. Statistical comparison between PO and SC GS-441524 was not possible due to the small numbers treated SC (Katayama and Uemura 2021). Of the 116 survivors, three cats relapsed in the four weeks after stopping of the oral GS-441524 treatment but were said to be responding to a higher dosage of GS-441524 at the time of publication. Although the method of confirmation of diagnosis was not stated (most cats [139/141] were FCoV RT-PCR-positive on effusion samples), the study gave valuable information on which parameters might be useful to monitor to predict response to oral GS-441524 treatment. At assessment, before the start of treatment, the cats that were still alive at follow-up had had significantly better appetite and activity scores, and interestingly higher mean temperatures (39.0 °C compared to 37.9 °C), than those that had died. Additionally, survivors had had significantly lower mean bilirubin concentrations (16.1 µmol/L compared to 53.2 µmol/L); indeed, the likelihood of survival was correlated with bilirubin concentrations (Table 3).

Table 3. Likelihood of surviving suspected effusive FIP following antiviral treatment with GS-441524 was associated with the serum bilirubin concentration; from Katayama and Uemura (2021).

Total Serum Bilirubin (µmol/L)	Number of Surviving Cats over Total Number in Category	Survival %
≤8.6	28/29	97
>8.6–17.1	24/27	89
>17.1–34.2	15/20	75
>34.2–68.4	9/18	50
>68.4	1/7	14

Another large case series by the same authors (Katayama and Uemura 2023), again evaluating 84 days of a GS-441524 preparation for suspected FIP, reported the outcome of 161 cats that were described as having ‘mixed’ FIP (i.e., with signs of both effusive and non-effusive disease), and 163 cats with only non-effusive FIP (i.e., only signs of non-effusive disease). The dosages used varied depending on the ‘stage’ of FIP that the cat was allocated to, which appeared to correspond to the clinical signs of FIP present. They ranged from 7.5 mg/kg to 10 mg/kg q 24 h (although, as described earlier, there is disparity in the GS-441524 dose in these preparations). The study reported successful treatment of 137 of the 161 (85%) ‘mixed’ signs cats and 153 of the 163 (94%) cats with only non-effusive FIP (Katayama and Uemura 2023). Most (262/324; 81%) cats received their GS-441524 PO, with a small number of cats given GS-441524 SC at the start of treatment; only one cat was treated exclusively with SC GS-441524. GS-441524 was only administered SC when PO administration was ‘difficult owing to gastrointestinal dysfunction or FIP onset, such as an inability to absorb nutrients’ (Katayama and Uemura 2023). Many of the cats given SC GS-441524 died, which was said to be due to clinical deterioration, but further details were not given. Statistical comparison between PO and SC GS-441524 outcomes was not possible due to the small numbers treated SC (Katayama and Uemura 2023), as in their previous study (Katayama and Uemura 2021).

Similar to the last study (Katayama and Uemura 2021), the cats in this study (Katayama and Uemura 2023) that were alive at the completion of the 84-day treatment (termed survivors) had significantly better appetite and activity scores, and higher mean temperatures (38.9 °C in both the cats with ‘mixed’ FIP and those with non-effusive FIP) before the start of treatment than those that did not survive (37.5 °C in the cats with ‘mixed’ FIP and 37.0 °C in those with non-effusive FIP). Additionally, as before, survivors had lower bilirubin concentrations (significantly in the ‘mixed’ effusive/non-effusive FIP group and non-significantly in the non-effusive FIP group) than non-survivors (Katayama and Uemura 2023). Neurological signs carried a significantly poorer prognosis in this study amongst both the cats with ‘mixed’ FIP and those with non-effusive FIP (Katayama and Uemura 2023); combining the data in these groups revealed that 61.8% (21/34) of cats that did not survive had neurological signs, compared to only 23.4% (68/290) of cats that survived. Seizures have previously been considered a poor prognostic sign (Timmann et al., 2008). In contrast, ocular signs were not associated with survival for both the cats with ‘mixed’ FIP and those with only non-effusive FIP (Katayama and Uemura 2023); combining the data in these groups revealed that 11.8% (4/34) of cats that did not survive had ocular signs, compared to 12.8% (37/290) of cats that survived.

In both of the studies (Katayama and Uemura 2021; Katayama and Uemura 2023), body weight, haematocrit, A:G ratio and SAA levels all normalised after 84 days of GS-441524 treatment. Following the completion of the treatment, 11 cats relapsed with FIP (with mixed clinical signs such as anorexia, hypoactivity, fever, neurological signs, ascites, and pleural effusion). These cats were treated with an additional 42-day course of GS-441524 at a dosage of 10 mg/kg, but no further details of the response of these cats were given.

Another smaller retrospective study of the varied treatment of 42 cats with confirmed or suspected FIP documented the successful use of serum AGP measurements in differentiating cats that fully recovered from FIP (26 cats, at least 13 of which received GS-441524 preparations) from those did not (16 cats, none of which were given GS-441524) (Addie et al., 2022). In this study, other varied treatments were given, but an AGP concentration of less than 0.5 mg/mL was associated with (full) recovery from FIP and was more reliable to track than the resolution of lymphopenia or hyperglobulinaemia (the hyperglobulinaemia was slower to resolve), suggesting that serum AGP concentration could be used as an indicator to stop antiviral treatment with nucleoside analogues. Further prospective studies are required to confirm this, but it is likely that AGP measurement, if available, is useful to document response to treatment. Additionally, in that study (Addie et al., 2022), some cats recovered with as few as seven to eight weeks of oral GS-441524 treatment, suggesting that shorter courses of GS-441524 may be effective and that the length of treatment could be determined by the time taken to obtain a normal AGP measurement. The study recommended that two consecutively normal AGP measurements at least a week apart were required to confirm recovery from FIP (Addie et al., 2022).

Unsurprisingly, FCoV antibody concentrations are not useful to track response to treatment. Antibody titres were found to remain elevated, even years later, in almost all cats that had recovered from FIP (Addie et al., 2022; Addie et al., 2023). In the prospective study evaluating GS-441524 treatment (Krentz et al., 2021), it was found that FCoV antibody titres did decline in 14/18 treated cats, in some cats as early as 28 days after starting treatment, whilst in others it was 56 or 84 days after starting treatment that a decline was detected. However, in the follow-up study of these cats, serum FCoV antibodies were still present in all 18 cats at the first recheck at week 24; in 14/15 at week 36; and in 13/14 at week 48. In four cats (all were free roaming or had companion cats at home), an intermediate short-term rise in FCoV antibody titres was detected, despite all cats remaining in remission for FIP (Zwicklbauer et al., 2023).

A large owner-derived data retrospective study documented 393 owner (mostly in the USA) questionnaire responses on the use of unlicensed GS-441524-like treatment (mostly SC but a few with PO, or initial SC and then PO, treatment) for at least 84 days on their own cats for the treatment of FIP (Jones et al., 2021). Of 393 owners, 88% saw an improvement in clinical signs in their cats within a week of starting the SC ‘GS-441524′ treatment. Furthermore, 54% said that their cats had been cured of FIP, whilst 43% said their cats were alive and well but still in a post-treatment monitoring period. Overall, only 13% of cats showed a relapse of FIP-associated clinical signs, whilst 3% had died despite treatment. These figures may represent an underreport of failures since owners whose cats died might have been less likely to have completed the questionnaire (Jones et al., 2021). Varied unlicensed unstandardised preparations believed to contain GS-441524 compounds were used in the study.

The diagnosis of FIP was based on the owners’ individual veterinarian’s opinion and was not confirmed in the study, but the signalment and clinical signs reported were very suggestive of FIP, with most cats (57%) having effusions; around 43% had neurological and/or ocular signs too. Reported complications of treatment were similar to those reported previously (Murphy et al., 2018; Dickinson et al., 2020) such as vocalisation and pain on injection (Jones et al., 2021).

Remarkably, in this study, only 9% of owners received help from their veterinarian for treatment of their cat, and most learnt about FIP treatment online (Jones et al., 2021). It may be that the response rates could have been even higher with the aid of supportive care from veterinarians. Treatment was expensive with the average cost per cat being USD 4920 (2021 publication). Although the authors were not advocating the unauthorised use of the GS-441524-like compounds, the study is valuable for describing the experiences of owners and efficacy of such formulations. The dosages used varied greatly and were significantly higher at the end of treatment courses compared to the beginning. It is difficult to be sure of the true dosages used due to the lack of any documented quality control of GS-441524 or other compounds, nor their concentration/stability, in the preparations used.

Another retrospective study of cats with suspected FIP (Yin et al., 2021) reported that 23 of 24 (96%) cats treated with GS-441524 at 2-4 mg/kg/day for at least 28 days were cured. Unfortunately, the route of administration was not documented. Again, the true composition of the preparations administered in this study was not confirmed, but it does again suggest that shorter treatment courses may be effective.

Overall, a good appetite and/or activity level, a higher temperature, a lower bilirubin concentration (Katayama and Uemura 2021; Katayama and Uemura 2023) and the normalisation of AGP (Addie et al., 2022) appear to be prognostically useful to predict survival with GS-441524 treatment of FIP. Weight gain has been cited as a simple long-term measure of treatment efficacy with GS-441524 (Pedersen et al., 2019; Katayama and Uemura 2021; Katayama and Uemura 2023) and is easy to measure using paediatric weighing scales (which can be purchased by owners for use at home), allowing for the appropriate increased dose to be calculated to maintain the appropriate dosage. Weighing every one to two weeks is recommended.

One study used GS-441524, compounded for the study, at a dosage of 12.5-15 mg/kg q 24 h PO for 84 days for the treatment of effusive FIP in nine cats, in a comparative trial that also evaluated the efficacy of oral remdesivir (Cosaro et al., 2023). Five of nine (55%) cats treated with the PO GS-441524 survived, rising to 5/6 (83%) if those that died within 48 hours of starting treatment were excluded. In this study, FCoV antibody titres were positive at diagnosis and remained positive when tested 28 days after completion of an 84-day treatment course, showing the lack of use of antibody titres in tracking response to treatment (Cosaro et al., 2023).

GS-441524 has been used to successfully treat cats affected by FIP in the Cyprus outbreak due to FCoV-23 (see Section 4. Pathogenesis) (Attipa et al., 2023b; Warr et al., 2023).

Therapeutic drug monitoring (TDM) methods are emerging for the measurement of GS-441524 (Kimble et al., 2023), which may enable tailoring of the GS-441524 (or remdesivir, which is rapidly metabolised to GS-441524 in cats (Coggins et al., 2024)) dosage and frequency of administration to the cat being treated, although further studies are required. Some researchers using TDM suggest that GS-441524 absorption varies greatly cat to cat and it may be that more frequent administration (e.g. q 8 or 12 h) is more effective in these cats (Danièlle Gunn-Moore, personal communication) (Table 2) but published studies are required.

A report of multifocal uroliths composed of GS-441524 in two cats treated with GS-441524 has been published (Allinder et al., 2023). Clinical signs associated with urinary obstruction occurred in the cats eight or 16 weeks after GS-441524 treatment had been started for FIP and azotaemia occurred in both cats. The uroliths were radiolucent and urinary tract infections were present in both cats. Although surgical removal and/or placement of subcutaneous ureteral bypass devices was performed, neither cat survived beyond several days post-operatively due to complications. Although urolithiasis is very rare in cats treated with GS-441524, it is worth being aware of the its possibility in cats undergoing treatment. The best method for monitoring for this complication is not known but could include urine analysis for crystals (both of the cases in the report actually had struvite crystalluria, although one of the cats had many needle-like crystals which could reflect GS-441524 crystalluria although this was not confirmed), monitoring for azotaemia and urinary tract infections and observation for lower urinary tract signs. However the costs of monitoring should be balanced with the rarity of this complication. Both of the cats in the report had been treated with illegal GS-441524 and thus the doses of GS-441524 actually given to the cats was not know; it could be that the preparations used contained higher doses of the antiviral, which may have contributed to the urolith development.

Oral GS-441524 has also been used to eliminate FCoV shedding in cats (Addie et al., 2020b), and further details on this can be found below in Section 12.3 on Elimination of FCoV Shedding.

10.1.2. Remdesivir, a Nucleoside Analogue

Remdesivir, GS-5734, has been suggested as a treatment in humans for COVID-19, although clear evidence for its beneficial effect is lacking (COVID-19 Treatment Guidelines Panel 2019; Ansems et al., 2021; Pham et al., 2023) and there have been concerns over toxicity (Brandsma et al., 2022; Wu et al., 2022). In some countries where remdesivir is licensed for use in humans, it may be available to prescribe for use in cats. At least in the European Union (EU) (European Union 2023a) and the UK, veterinarians are allowed to legally prescribe remdesivir for cats with FIP if no other drugs are licensed for the treatment of FIP in cats and no other effective drugs are available to treat FIP that are licensed for treating other diseases in cats or in other animal species. However, national prescribing rules can then influence access to remdesivir.

Remdesivir is a prodrug of GS-441524 (Izes et al., 2020c), yielding active GS-441524 after intracellular conversion (Eastman et al., 2020; Li et al., 2022). It has been shown the remdesivir is very likely to be rapidly converted to GS-441524 in cats, and that liver dysfunction is unlikely to affect remdesivir metabolism (Coggins et al., 2024). Remdesivir is injected intravenously [IV] or SC as it has been said to be inactive PO (Xie and Wang 2021). However, one study (Cook et al., 2022a), evaluating the pharmacokinetics of remdesivir in cats, reported that oral remdesivir administration might be feasible, and, indeed, a study using oral remdesivir for the effective treatment of FIP has been published (Cosaro et al., 2023).

Remdesivir has been used to treat FIP in cats (Hughes et al., 2021; Bohm 2022; Sorrell et al., 2022; Coggins et al., 2023; Green et al., 2023; Taylor et al., 2023). Descriptive case series exist of its use in Australia and the UK (Coggins et al., 2023; Green et al., 2023; Taylor et al., 2023), where a veterinary compounded ‘special’ formulation of injectable remdesivir is available (this preparation is of a higher concentration than the human-licensed remdesivir, allowing for smaller volumes of injection, and an opened vial can be used for up to 30 days after broaching). These studies often used treatment protocols that transitioned from using injectable remdesivir to oral GS-441524 for ease when oral GS-441524 became available as an alternative to injectable remdesivir. They used injectable (IV or SC) remdesivir initially (e.g., for one to 14 days, sometimes with a higher induction dosage of remdesivir, see Tables 2 and 4), usually followed by oral GS-441524 (Sorrell et al., 2022; Coggins et al., 2023; Green et al., 2023; Taylor et al., 2023), or sometimes continued remdesivir (Taylor et al., 2023) (when a drop to a maintenance dosage of remdesivir was instigated as recommended by Coggins et al., (2023)) to complete the 84-day treatment course.

In one case series describing the treatment outcome of 32 cats with effusive (25 cats) or non-effusive (7 cats) FIP in the UK, 30 cats received remdesivir (Green et al., 2023). This comprised remdesivir alone (6 cats) or remdesivir transitioned to PO GS-441524 (24 cats). Four of the six cats given remdesivir alone died, whereas only one of the twenty-four cats given combination treatment died. However, three of the four cats that died on remdesivir alone did so within two days of starting treatment; the fourth died after 13 days of treatment. Overall, 26/32 cats (81.3%) in the study were alive and in clinical and biochemical remission at the end of the 84-day treatment period. In this study, a poor prognosis appeared to be associated with hypoglycaemia and the Ragdoll breed (Green et al., 2023). Non-clinically significant transient adverse effects can include elevations in ALT (Green et al., 2023) A comparison between treatment protocols was not possible due to the retrospective nature of the study and because drug availability dictated the protocol used (Green et al., 2023).

A retrospective case series in Australia (Coggins et al., 2023) described 28 FIP cats (23 with effusions) that were treated with either remdesivir alone (15 cats) or remdesivir transitioned to PO GS-441524 (13 cats; possible once oral GS-441524 became available) for at least 84 days. Of the 28 cats, 24 (86%) survived to six months. Three cats died within two days, and, of the 25 cats that survived at least two days, 96% (24) survived to six months. Interestingly, 10 of these 25 cats needed an extension of the 84-day treatment and five cats also needed a dosage increase (5 mg/kg of remdesivir or GS-441524) when relapse of FIP was suspected (based on clinical signs and/or diagnostic testing). In three cats, a second 84-day treatment course was given (Coggins et al., 2023). The authors recorded a 30% relapse rate in the first cats treated; these had received remdesivir alone (as it was the only legally available antiviral at that time) at an induction dosage of 10 mg/kg q 24 h (as a slow IV infusion on days 0, 1, 2 and 3) followed by a maintenance dosage of 6 mg/kg (or 10 mg/kg if ocular or neurological signs present) SC q 24 h for a minimum of 84 days. Thereafter, subsequently treated cats were given higher dosages of remdesivir according to Table 4 below. Cats treated with this higher remdesivir dosage protocol, or cats given remdesivir before being transitioned to PO GS441524, did not relapse. This suggests the need for a higher dosage of remdesivir to effect a ‘cure’ and/or that a more favourable response is seen when PO GS-441524 is used in the FIP treatment protocol.

Table 4. Remdesivir higher dosage treatment protocol used in the study by Coggins et al. 2023 (Coggins et al., 2023).

FIP Presentation	Induction Dosage of Remdesivir	Maintenance Dosage of Remdesivir
Effusive	10 mg/kg q 24 h IV or SC for 4 days	8–10 mg/kg q 24 h SC to 84 days
Non-effusive	15 mg/kg q 24 h IV or SC for 4 days	10–12 mg/kg q 24 h SC to 84 days
Neurological and/or ocular signs present	15 mg/kg q 24 h IV or SC for 4 days	12–15 mg/kg q 24 h SC to 84 days

This case series from Australia (Coggins et al., 2023) also provided information on what might be useful markers to monitor for treatment response. The resolution of fever and inappetence was achieved within one week, and the resolution of icterus, effusions, and ophthalmic changes within two to four weeks of starting treatment. Monitoring body weight (every two weeks in this study) was important to assess response to treatment and ensure the appropriate dosage is still given, despite weight gain. Thus, regular weighing is recommended. Hyperbilirubinaemia, hyperproteinaemia and leucocyte abnormalities normalised within two to three weeks, but hyperglobulinaemia took around five weeks to normalise; the authors suggested that if hyperglobulinaemia persists beyond 42 days of treatment, a dosage increase in antiviral should be considered. Plasma albumin concentration and packed cell volume (PCV) took longer to improve and remained slightly below their reference intervals at treatment completion in some cats. The authors also noted that in some effusive FIP cases, a pattern of a drop in body weight, a serum globulin concentration spike and PCV drop occurred when an effusion was resorbed a couple of weeks into treatment; this is an important observation for veterinarians to be aware of, as it is not indicative of treatment failure, and cats usually respond well to ongoing treatment. The pattern is believed to be due to systemic protein resorption from the effusion and transient haemodilution due to body cavity fluid shifts (Coggins et al., 2023).

A large retrospective case series describing the treatment of 307 cats with FIP in the UK (Taylor et al., 2023) also used the veterinary compounded ‘special’ formulations of injectable remdesivir and oral tablets of GS-441524. Only 10% of the cats had a diagnosis of FIP ‘confirmed’ with positive FCoV immunostaining, with the remaining cats having a diagnosis of FIP that was either very likely (33%) or highly suspicious (58%) based on the European ABCD FIP Diagnostic Approach Tools (Tasker et al., 2023a). The predominant type of FIP in the cats was abdominal effusive (in 50%) and then neurological (14%) followed by abdominal lesions (11%). Three treatment protocols were used, depending on availability of the antivirals at the time of treatment of the cats:

• remdesivir alone (in 34%); at a median (range) starting dosage of 10 (5–20) mg/kg
• remdesivir followed by GS-441524 (56%); the GS-441524 was started after a median (range) of 15 (2–150) days of remdesivir with a median (range) starting dosage of 10 (5–27) mg/kg for remdesivir and 12 (5–27) mg/kg for GS-441524
• GS-441524 alone (10%); at a median (range) starting dosage of 12.9 (8.3–20) mg/kg.

Of the 275 cats that received remdesivir, the initial administration route was IV in 56% and SC in the remaining 44%. For the 153 cats that initially received remdesivir IV, the administration route was changed to SC in 75% of cats after a median (range) of 3 (1–17) days of IV administration. All remdesivir doses were given q 24 h whereas GS-441524 was dosed q 24 h in most (81%) of cats and q 12 h in the remainder (19%). The median (range) initial treatment period duration of continuous antiviral treatment was 84 (1-330) days with 17% of cats receiving treatment for more than 84 days. And the longest follow-up time point after starting treatment was 248 (1-814) days. Around one-quarter (27%) of cats had their antiviral dose increased during treatment. At ‘completion’ of their initial treatment period, most cats (259/307; 84%) had a ‘complete’ response to treatment, some a ‘partial’ response (18/307; 6%), and 10% (30/307) showed ‘no’ response to treatment and were euthanased or died during this period. When relapses occurred after an initial response to treatment, they usually (91%) occurred during the initial treatment period or within 60 days of stopping treatment, and were mostly with clinical signs different from their initial presentation, with a tendency for neurological signs at relapse. Overall, 89% of cats were alive at the end of the initial treatment period and 84% were alive at the longest follow-up time point after completion of the initial treatment. The cats achieving a complete response within 30 days of starting treatment were significantly more likely to be alive at the end of the initial treatment period than those cats that did not. These successful treatment metrics were achieved without the addition of any additional immunostimulant treatments (no cats received polyprenyl immunostimulant and only one cat received rfIFN-ω). The most common adverse effect was injection pain (in 48% of cats given SC remdesivir). Increased ALT activity occurred in 28% of cats (especially those receiving GS-441524), eosinophilia in 15.0% (especially in those receiving remdesivir) and lymphocytosis in 11% of cats.

It was not possible to compare the efficacy of the different treatment protocols because cases were not randomised to treatment groups; the protocols varied as they evolved over time as the GS-441524 became available and as experience grew with antivirals, resulting in, for example, increases in recommended dosages for different types of FIP and/or prolongation of treatment if responses were suboptimal (Taylor et al., 2023). Affordability also influenced choice of antiviral as remdesivir was more expensive.

With respect to monitoring, the serum globulin concentration took the longest time (two to three months) to normalise in this study (Taylor et al., 2023), as reported by others (Addie et al., 2022), compared to temperature (often within a month) and resolution of clinical signs (within one to two months). It should be noted that the hyperglobulinaemia can initially worsen before subsequent normalisation, as reported above and elsewhere (Pedersen et al., 2019; Hughes et al., 2021)

Overall, remdesivir IV (administered slowly over 30–60 min with a syringe driver) has been mostly used at the start of 84-day treatment courses for very sick cats that are unable to tolerate oral medication, such as those with severe FIP disease that are obtunded (Coggins et al., 2023; Green et al., 2023; Taylor et al., 2023) or those that have severe malabsorption, when there are concerns over hydration status or SC injections are not tolerated (Taylor et al., 2023), and when oral GS-441524 formulations are not available.

Remdesivir SC injections caused local skin reactions and pain in 48% of cats in one study (Taylor et al., 2023), as is also the case for injectable GS-441524, although SC remdesivir is possibly less painful than SC GS-441524 (Kent et al., 2024). One published case report described successful treatment of confirmed FIP with IV remdesivir for three days, followed by SC remdesivir for another 77 days, without problems (Bohm 2022). This cat remained in remission at the 7-month follow-up timepoint (Bohm 2022). However, in another study (Coggins et al., 2023), transition from parenteral remdesivir to PO GS-441524 occurred as a result of injection site discomfort; the discomfort was described as severe in two, and mild in 13, of the 25 cats in the study that survived 84 days of treatment. A similar need to transition from injectable remdesivir to PO GS-441524 due to painful injections was reported in another case series (Green et al., 2023). If SC remdesivir injections are problematic and a switch to oral GS-441524 is not possible, pre-injection oral gabapentin, rotating injection sites, room-temperature remdesivir, the use of topical local anaesthesia, oral transmucosal buprenorphine and positive behavioural engagement at the time of injection, can help tolerance (Sorrell et al., 2022; Coggins et al., 2023; Green et al., 2023).

Problems with injecting and cost (of injecting as well as the drug itself, as remdesivir is often more expensive than oral GS-441524) were the main reasons for switching from injectable remdesivir to oral GS-441524 (Green et al., 2023; Taylor et al., 2023). Indeed, many cats are treated successfully with only oral GS-441524 and this is now the preferred treatment when available.

However PO remdesivir has also been investigated. A randomised, double-blinded 84-day treatment trial for cats showed that PO remdesivir (25-30 mg/kg q 24 h) was as effective as PO GS-441524 (12.5-15 mg/kg q 24 h), for the treatment of effusive FIP in 18 cats (Cosaro et al., 2023). Seven of nine (77%) cats treated with remdesivir, and five of nine (55%) cats treated with GS-441524, survived; these percentages were not significantly different. Three of the 18 cats died within 48 hours of enrolment into the study, and if these three cats were excluded, 7/9 (77%) of the cats treated with remdesivir and 5/6 (83%) of the cats treated with GS-441524 survived, showing that the prognosis for remission was good once the cat had survived 48 hours of antiviral treatment. These findings suggest that PO administered remdesivir is effective for effusive FIP. In this study one of the cats that died in the remdesivir group had developed hyperaesthesia after treatment stopped, followed by seizures 139 days after treatment completion, which resulted in euthanasia. In this case, it is possible that the hyperaesthesia syndrome represented neurological FIP, but this could not be confirmed as post-mortem examination was declined. More research is required to determine whether hyperaesthesia post-treatment represents neurological FIP in a relapse or a long-term adverse effect of treatment or a ‘long FIP syndrome,’ as suggested by others (Zwicklbauer et al., 2023).

10.1.3. Molnupiravir, a Nucleoside Analogue

Molnupiravir, also known as EIDD-2801, has been used in humans for the treatment of COVID-19 (Painter et al., 2021; Tian et al., 2022). Its active metabolite is EIDD-1931 (Roy et al., 2022) and its action is through the inhibition of RNA synthesis (Barua et al., 2023). In vitro studies with serotype II FCoV showed it to have promising antiviral action (Cook et al., 2022b; Barua et al., 2023), although the mutagenic nature of its metabolite (Zhou et al., 2021b) is of potential concern and warrants further investigation.

The use of unlicensed formulations of molnupiravir was first described using data from questionnaires completed by owners whose cats with FIP had received molnupiravir treatment (Roy et al., 2022). The molnupiravir was given either as first-line treatment in four cats or as rescue treatment in 26 cats that had received an initial treatment for suspected FIP with unlicensed GS-441524, or a drug combination including unlicensed GS-441524 as the main drug. Thirteen of the cats had been treated with injectable GS-441524 only, three cats with oral GS-441524 only, and an additional seven cats with a combination of injectable and oral GS-441524 throughout the duration of therapy. Two were treated with a combination of unlicensed GS-441524 and unlicensed protease inhibitor antiviral GC376 (see Section 10.1.4 on GC376, a protease inhibitor), whilst one cat was treated with injectable and oral GS-441524, injectable GC376 and molnupiravir. Sixteen cats had received one initial treatment course based on GS-441524 before receiving molnupiravir, seven had received two courses, and three cats had received three courses (Roy et al., 2022). The reported apparent (as the dose content of the preparations is not known) starting dosages for the unlicensed GS-441524 used in the cats ranged from 2 mg/kg to 10 mg/kg; with the most common dosages being 5–6 mg/kg (eight cats) and 10 mg/kg (seven cats). Most (21) cats were dosed q 24 h, four were dosed q 12 h, and one cat was initially dosed q 12 h for one week before switching to q 24 h. The median duration of GS-441524-based therapy was 84 days before starting molnupiravir. Thus, the initial treatment course dosages were very varied.

The reason for the apparent failure of GS-441524 treatment was unknown but could have been due to inappropriate dosages, as unlicensed preparations of GS-441524 were also used, or due to the emergence of resistance to GS-441524. A dosage range of 12–15 mg/kg PO q 12 h of molnupiravir for 12–13 weeks was reported as being successful, with the higher end of the dosage range used to treat cats with neurological signs, although higher dosages have been subsequently recommended (Sase 2023). Of the 30 cats in the original report (Roy et al., 2022), 28 (including 24 of the 26 cats that received molnupiravir as rescue treatment) were living FIP disease-free at the time of publication. Very few adverse effects were reported, but included, rarely, and at very high dosages of 23 mg/kg PO q 12 h, broken whiskers and severe leucopenia (Roy et al., 2022).

In the subsequent report (Sase 2023), describing a case series of 18 cats with FIP (13 with effusions, three with neurological or ocular signs) treated with an in-house compounded formulation of oral molnupiravir at dosages of 10 mg/kg q 12 h (effusion present), 15 mg/kg q 12 h (non-effusive lesions present) or 20 mg/kg q 12 h (if any neurological or ocular signs present) for 84-days. Four cats (all had effusions) died within seven days of starting treatment but the remaining 14 cats remain alive and healthy 139-206 days after starting treatment. Although the diagnosis of FIP in all cats was described as presumptive, 17 of the 18 cats were RT-PCR positive for FCoV in samples of effusion (12 cats), blood (three cats) or pyogranulomatous lesion FNAs (two cats). In this series the molnupiravir was given as the initial treatment for FIP and was found to be safe and effective. Signs resolved quickly, within a few days, and pyogranulomatous lesions visible on ultrasonography in five cats reduced in size or became undetectable after starting treatment. Adverse effects were uncommon and mostly related to mild to moderate increases in ALT activity, which were largely not clinically relevant. Interestingly, only two of the 18 cats in this study needed hospitalisation, which could be advantageous in terms of limiting the costs of treatment to increase access to care.

A previous pharmacokinetic study of 10 mg/kg of oral molnupiravir in cats had reported nausea post-administration (Cook et al., 2022a), but this was not reported in the published studies (Roy et al., 2022; Sase 2023).

No licensed products of molnupiravir are available for use in cats, but a human-licensed product exists for the treatment of COVID-19, with low rates of resistance to SARS-CoV-2 reported in in vitro studies (Tian et al., 2022). Although the human-licensed products cannot be used in cats legally in all countries (e.g., molnupiravir is currently listed as being restricted to human use only in the EU (European Union 2023b), although this may change as the application for licensing of molnupiravir in humans in the EU has been withdrawn), this antiviral shows much promise for the treatment of FIP. Molnupiravir has been used to successfully treat cats affected by FIP in the Cyprus outbreak due to FCoV-23 (see Section 4. Pathogenesis) (Attipa et al., 2023b), in which a special licence was granted by the Cypriot government to allow the stocks that had been sourced for human treatment, and which were going out of date, to be used to treat affected cats. The molnupiravir sources that owners have obtained for treatment have been a lot cheaper than GS-441524 (Roy et al., 2022), making this treatment more affordable.

10.1.4. GC376, a Protease Inhibitor

Protease inhibitors prevent viral replication by selectively binding to viral proteases and blocking the proteolytic cleavage of protein precursors needed for the production of infectious viral particles. Inhibitors that target the 3C-like protease with broad spectrum activity against human and animal coronaviruses have been created (Kim et al., 2013). Examples of protease inhibitors include the 3C-like protease inhibitors GC376, discussed below, and nirmatrelvir (Barua et al., 2023).

The 3C-like protease inhibitor GC376 showed strong activity against FCoV in vitro (Kim et al., 2016) and was effective in treating FIP in an experimental setting; of eight cats with experimentally induced FIP, six remained healthy for an eight month follow-up period (Kim et al., 2016), although one of these six cats subsequently succumbed to neurological FIP (Pedersen et al., 2018).

In a subsequent field trial of natural FIP (Pedersen et al., 2018), a cohort of 20 client-owned cats were treated with GC376 at 15 mg/kg SC q 12 h; this was a higher dosage than that used in the original experimental study (Kim et al., 2016) due to treatment failure in the first cat enrolled in the field trial. Some adverse effects occurred, including injection site reactions and retarded development or the abnormal eruption of permanent teeth (Pedersen et al., 2018). There were no untreated controls in this study and FIP was not confirmed in all cats.

Nineteen of 20 treated cats in the field trail given GC376 at 15 mg/kg SC q 12 h regained health within two weeks of treatment (Pedersen et al., 2018). However, clinical signs recurred one to seven weeks after initial treatment. Relapses no longer responsive to treatment occurred in 12/19 cats within one to seven weeks of initial or repeat treatments. Most of these relapsed cats developed neurological FIP. At the time of study publication, seven of the 20 treated cats were in remission (Pedersen et al., 2018), although this had decreased to six at the time of another publication by the same group (Pedersen et al., 2019). Most of the cats that were in remission had presented with effusive FIP at a young age. Cats presenting with neurological signs were excluded from the study due to GC376 not penetrating the CNS (Pedersen et al., 2018).

Published retrospective data of cats with suspected FIP (Yin et al., 2021) mentioned that some cats had been treated successfully with GC376, at 6–8 mg/kg/day for at least four weeks, with or without a nucleoside analogue, but full data on the route of administration, composition of the preparations used, and response to treatment were not provided. Successful treatment with GC376 was also mentioned in one cat in another retrospective study (Addie et al., 2022), in combination with other agents including rfIFN-ω. Additionally, five of the 26 cats that were given molnupiravir as rescue treatment for FIP relapse had received GC376 previously, in combination with GS-441524 (Roy et al., 2022). These retrospective studies are with unregulated preparations of GC376. It is of interest that a study that independently tested five vials of one unregulated brand of GC376, found that none of the vials actually contained GC376; one contained GS-441524 and the remaining four contained molnupiravir (Mulligan and Browning 2024), again making interpretation of retrospective studies documenting GC376 useage problematic.

Resistance to GC376 (and nirmatrelvir) in type II FIP-associated FCoV has been reported (Jiao et al., 2022); in this in vitro study, resistance was mediated by mutations in the FCoV RNA-dependent RNA polymerase hydrolysis site. Mutated and non-mutated type II FCoV were then used to induce FIP in an experimental in vivo model; the cats infected with the mutated FCoV were resistant to GC376 treatment with two of the three cats dying, where all three cats infected with non-mutated FCoV were successfully treated with GC376 (Jiao et al., 2022). The two cats that died were positive for FCoV-RNA in all organs sampled, with the highest viral loads in the kidney, followed by the liver and then the cerebellum/pons, i.e., the cats that died following infection with GC376-resistant mutated FCoV did not have a predominant neurological FIP.

In the field GC376 treatment study (Pedersen et al., 2018), the 3C-like protease gene sequences of the FCoV infecting a number of cats were compared pre- and post-treatment (samples obtained at post-mortem examination after euthanasia for persistent or relapse of FIP); only one cat showed a change in its 3C-like protease gene sequence. This cat had shown a relapse in FIP with an effusion 30 weeks after starting treatment that comprised two courses totalling 16 weeks. The three gene changes/mutations found in the FCoV infecting that cat were then studied for resistance to GC376 in vitro (Perera et al., 2019); one of the mutations conferred a small reduction in susceptibility to GC376, suggesting resistance.

Efficacy in field studies of cats with naturally occurring FIP appears greater with GS-441524 (Pedersen et al., 2019; Dickinson et al., 2020) than with GC376 (Pedersen et al., 2018), as only six of 20 cats treated with GC376 remain in remission (quoted in (Pedersen et al., 2019)) compared to 25 of 31 cats treated with GS-441524 (Pedersen et al., 2019), and three of the four cats with neurological and ocular signs treated with the higher dose of GS-441524 also went into remission (Dickinson et al., 2020). Both GC376 and GS-441524 treatments cause similar injection site reactions and appear to be relatively safe, although GC376 interfered with the development of permanent teeth in younger kittens. However, GS-441524 can be given orally, in contrast to GC376, and thus, injection reactions can be avoided. The efficacy of GC376 might have been better if all original 20 cats had been treated initially for 84 days (Pedersen et al., 2018), rather than with progressively longer treatment courses given following the poor response to two weeks of treatment at the start of the trial.

Despite these reports of resistance and efficacy comparisons, protease inhibitors such as GC376 could still offer promise for the treatment of FIP if used in antiviral drug combinations to help avoid the development of resistance (Jiao et al., 2022). Indeed, a shorter, 28-day, course of combined GS-441524 (either 2.5 or 5 mg/kg SC q 24 h) and GC376 (either 10 or 20 mg/kg SC q 12 h) treatment was effective in 98% of 46 cats with effusive (36 cats) or non-effusive (10 cats) FIP (Lv et al., 2022), showing promise for future studies. The different dosages used did not appear to influence survival. None of the cats in the latter study showed any obvious skin reaction to the SC injections during treatment, although a small number of cats showed slight pain during the injection; the authors had adjusted the pH value of the drug to 3–4, and its reduced acidity was thought to result in the better tolerance of injections.

It is hoped that GC376 will be licensed for the treatment of cats with FIP by a USA company within the next few years.

10.1.5. General Considerations for Use of Nucleoside Analogues and Protease Inhibitors

Antiviral Drug Resistance

Drug resistance can occur to antiviral agents, especially with prolonged use and high viral mutation rates (Delaplace et al., 2021). As mentioned above for GC376 treatment, it would be useful to evaluate different types of antiviral drugs, such as protease inhibitors and nucleoside analogues, in combination, to further improve efficacy and/or reduce the possibility of the development of resistance (White et al., 2021). This is performed for HIV infection and hepatitis C in humans (Pedersen et al., 2019). However, synergistic effects of FCoV antivirals in vitro have not always been demonstrated. In one large study, certain combinations of antiviral drugs showed additive activities against type II FCoV in vitro, but none of the combinations showed more efficacy than GS-41524 or GC376 used as in vitro monotherapies (Cook et al., 2022b). However, other in vitro studies have suggested synergy between certain antivirals against type II FCoV in vitro, e.g., GC376 and remdesivir (Cook et al., 2022a). Another in vitro study showed evidence of antiviral synergy between GS-441524 and itraconazole, especially against a type I FCoV (Doki et al., 2022). More work is needed in this field and it is likely that a ‘one size fits all’ monotherapy approach for the treatment of FIP is oversimplistic (Cook et al., 2022a), similar to the suggested need for drug combinations in the treatment of human coronavirus infections (White et al., 2021).

It has been suggested that the PO, rather than injectable, administration of a nucleoside analogue is more efficacious because it allows the antiviral to go straight to the site of major FCoV replication, and that the inadequate penetration of the gut could lead to drug-resistant FCoV mutants (Addie et al., 2022; Addie et al., 2023), although studies confirming the distribution of antivirals based on route of administration have not been published. One study, based on owner-reported survey data, described a high success rate (97% of cats were still alive at the time of publication) in 393 cats treated with unlicensed GS-441524, despite 72% of these cats receiving injectable GS-441524 (Jones et al., 2021).

Concerns regarding antiviral resistance are behind the reluctance of some to use antivirals in healthy FCoV-infected cats (Meli et al., 2022), as described below in Section 12.3 on Elimination of FCoV Shedding.

Monitoring of Cats Undergoing Antiviral Treatment

In the first week, one should see an improvement in clinical signs including a reduction in an effusion if present (Lv et al., 2022). If an effusion is still present at two weeks, consider increasing dosage of the antiviral (e.g., GS-441524 by 5 mg/mg if possible) being given. Haematological and serum biochemistry abnormalities can take longer to normalise, between four and 12 weeks, with the hyperglobulinaemia usually taking the longest to normalise (Taylor et al., 2023). As mentioned above, in some effusive FIP cases, a pattern of a drop in body weight, a serum globulin concentration spike and PCV drop occurred when an effusion was resorbed two weeks into treatment and this does not indicate treatment failure (Coggins et al., 2023).

Ideally, serum biochemistry and haematology are repeated after two weeks and then monthly; this should include AGP if possible as this may be useful to predict remission, by returning to normal if elevated before treatment as described by Addie et al., (2022). Regular accurate weighing every one to two weeks is useful and important to ensure improvement is occurring and allow for the dose to be increased accordingly to ensure the correct dosage is maintained (Pedersen et al., 2019; Katayama and Uemura 2021; Katayama and Uemura 2023). Repeat ultrasonography (Muller et al., 2023; Sase 2023) may be useful to document appropriate resolution of the effusion after two weeks too; point-of-care ultrasonography (POCUS) to monitor for effusion resolution and/or lymph node size is useful if available and affordable. Some abnormalities, such as lymphadenopathy, can remain (Krentz et al., 2022; Taylor et al., 2023; Zwicklbauer et al., 2023). It may be wise to monitor cats on GS-441524 for urinary tract signs in view of the, albeit very rare, reports of GS-441524 urolithiasis (Allinder et al., 2023). ALT may temporarily rise during treatment.

However, sometimes preservation of funds for the treatment is required, and thus, for cost limited clients, monitoring weight via paediatric weighing scales (available online to be used at home) is cheaper. Abdominal girth measurements can be used as a crude alternative for monitoring of abdominal effusion volume. Laboratory testing can also be done at less cost by measuring only key variables in-house e.g. globulin, bilirubin and/or spinning microhaematocrit tube for packed cell volume/total proteins/colour of plasma.

Consideration can be given to stopping treatment once previous abnormalities (clinical signs, POCUS results, serum biochemistry [including albumin to globulin ratio of greater than 0.6 and normal AGP if possible], and haematology) are resolved for at least two weeks. This is usually following 84 days of treatment, although in the future it may be that shorter courses (maybe with combination antivirals) of treatment are found to be adequate. As mentioned above under Section 10.1.1. GS-441524, a Nucleoside Analogue, good appetite and/or activity level, a higher temperature, a lower bilirubin concentration (Katayama and Uemura 2021; Katayama and Uemura 2023) and the normalisation of AGP (Addie et al., 2022) were prognostically useful to predict survival with GS-441524 treatment.

The cat should be monitored in the post-treatment phase too, for around 12 weeks, and stress minimised throughout this period in order to try and help prevent any chance of relapse.

Vaccination and Neutering

There has been concern regarding inducing a relapse of FIP in successfully treated cats with stress that may be associated with neutering or vaccination. In previously treated and recovered cats, successful vaccination in 23 cats and successful neutering in 21 cats, occurred without ill effect (Taylor et al., 2023). In a further two cases, these procedures were performed during GS-441524 treatment, again without ill effect. Similarly, a recent study (Coggins et al., 2023) documented that two cats underwent successful surgery (neutering and enucleation) during remdesivir or GS-441524 treatment. A cost–benefit assessment needs to be performed to decide whether vaccination, including which vaccines (Day et al., 2016; Stone et al., 2020; European Advisory Board of Cat Diseases 2022), and neutering are required in an individual cat according to risk, but these procedures do appear to be safe. Feline-friendly handling and methods (including appropriate analgesia for neutering for example, gabapentin to reduce stress associated with a vet visit if needed) are recommended (Taylor et al., 2022b).

10.1.6. Interferons

Interferons (IFN) have been used in cats with FIP.

Type I IFN is an important cytokine for host defence against viruses, and FCoV has been shown to inhibit its production (Dedeurwaerder et al., 2014; Chen et al., 2019), with type II FCoV inhibiting IFN production more strongly than type I FCoV (Doki et al., 2018). Recombinant fIFN-ω, which is licensed in many European countries, is a commercially available monomeric glycoprotein distantly related in structure to IFN-alpha (IFN-α) and IFN-beta (IFN-β) but unrelated to IFN-γ. It has antiviral properties, stimulates natural killer cell activity, and enhances the expression of major histocompatibility complex class I (but not class II) antigens (Addie 2008). rfIFN-ω inhibits FCoV replication in vitro (Mochizuki et al., 1994), but did not abrogate the FCoV shedding in nine of 11 cats (without FIP) in a shelter (Gil et al., 2013).

Preliminary results on IFN treatment of cats with FIP were obtained in one uncontrolled trial (Ishida et al., 2004). Four of twelve cats with FIP treated with rfIFN-ω survived for over two years and another four experienced remission, but FIP was not confirmed in any of the cases that survived, although it was confirmed in the cats that died (Ishida et al., 2004). In a randomised placebo-controlled double-blind treatment trial in 36 cats with confirmed effusive FIP and one cat without effusion, rfIFN-ω was used along with systemic (2 mg/kg/day) or intracavitatory glucocorticoids (Ritz et al., 2007). This study concluded that rfIFN-ω was not effective. However, in a later non-controlled observational study in which glucocorticoids were either not used, or where glucocorticoid dosages were more rapidly tapered, with meloxicam used as an alternative to glucocorticoids to mitigate inflammation, seven cats recovered and other cats experienced prolonged remission following rfIFN-ω treatment (Addie et al., 2022). This suggested that rfIFN-ω might have some beneficial effects when used without glucocorticoids, but further controlled studies are required.

As mentioned earlier, in a successfully treated single FIP uveitis case (Addie et al., 2020b), GS-441524 was discontinued after 50 days, when serum AGP had returned to normal, and at this point daily oral administration of 100,000 units of rfIFN-ω was started as follow-up treatment. This cat continued in remission and remains healthy after three years having received rfIFN-ω treatment for seven months (Diane Addie, personal communication). The use of both oral and SC rfIFN-ω, usually in combination with, or after, other treatments for FIP, including nucleoside analogues, has been described in a retrospective series of cats with confirmed or suspected FIP in an attempt to avert relapses after stopping the nucleoside analogue treatment (Addie et al., 2022). However, many studies have shown excellent survival following nucleoside analogue (including GS-441524) treatment without follow-up rfIFN-ω (Pedersen et al., 2019; Dickinson et al., 2020; Katayama and Uemura 2021; Krentz et al., 2021; Coggins et al., 2023; Green et al., ; Katayama and Uemura 2023), so the need for rfIFN-ω treatment is still in question.

When used, dosages of rfIFN-ω have varied (Addie et al., 2020b; Addie et al., 2022; Sorrell et al., 2022). It is sold in vials of 10 million (10⁷) units, and one vial is reconstituted with 1 mL of saline diluent; 0.1 mL of the diluted stock solution then contains 1 million units of rfIFN-ω. Once diluted, rfIFN-ω maintains its potency in the fridge for up to three weeks, so the rest of stock solution should be frozen if not in use, where it can be kept frozen for up to six months. Two dosage regimes for rfIFN-ω have been reported and are given in Table 2.

An in vitro study evaluating the effect of rfIFN-ω with hydroxychloroquine found increased antiviral activity of hydroxychloroquine against type I, but not type II, FCoV infection of cell cultures with rfIFN-ω (Takano et al., 2020), suggesting that combination treatment could be considered, although in vivo studies are needed.

Feline fibroblastic IFN-β also inhibits FCoV replication in cell culture (Weiss and Toivio-Kinnucan 1988), but no in vivo studies exist.

Human IFN-α was effective against an FIP-associated FCoV strain in vitro (Weiss and Oostrom-Ram 1989) but in a placebo-controlled treatment study of 74 specific pathogen-free cats in which FIP was induced experimentally, neither the prophylactic, nor therapeutic, administration of high doses (10⁴ or 10⁶ IU/kg) of IFN-α, feline IFN-β (10³ IU/kg), the immunomodulator Propionibacterium acnes (0.4 mg/cat or 4 mg/cat), or a combination, significantly reduced mortality in treated versus untreated cats (Weiss et al., 1990). However, in the cats treated with 10⁶ IU/kg IFN-α in combination with P. acnes, the mean survival time was prolonged, but only by a short amount (Weiss et al., 1990). As an explanation for the limited efficacy of IFN-α, it has been suggested that ORF-7-encoded accessory protein 7a of FIP-associated FCoV strains can act as a type I IFN antagonist and counteract the IFN-α-induced antiviral response (Dedeurwaerder et al., 2014). When human IFNs are injected (i.e., SC as per dosage regimes above) into cats, antibodies are raised against them, limiting their longer-term usefulness, although when administered PO, no antibody formation occurs (but systemic efficacy is likely limited). A cat with panuveitis and skin lesions due to FIP treated with human IFN-α and prednisolone survived 10 weeks before euthanasia (Bauer et al., 2013).

10.1.7. Anti-Malarial Compounds

Several anti-malarial drugs have been investigated for their antiviral effects. An anti-malarial Chinese herbal extract of unknown identity was found to inhibit the in vitro growth of FIP-associated FCoV (Nishijima et al., 2023). Chloroquine is too toxic for cats (Takano et al., 2013; McDonagh et al., 2014), and hydroxychloroquine, although used in in vitro studies only, has been suggested as a less-toxic alternative to chloroquine (Takano et al., 2020).

Another agent that shows promise in cats is mefloquine, and although the full mechanism of its antiviral action is not known (McDonagh et al., 2014; Yu et al., 2020), it is believed to act as a nucleoside analogue (Delaplace et al., 2021). Studies have been published on mefloquine’s hepatic metabolism using an in vitro model (Izes et al., 2020a), its pharmacokinetics in healthy cats (Yu et al., 2020), and its plasma protein-binding properties in the plasma of healthy cats and cats with FIP (Izes et al., 2020b). Although studies are needed on its efficacy in cats with FIP, veterinarians in Australia (Richard Malik, Sally Coggins and Jacqueline Norris, personal communication) are using oral mefloquine to treat cats with FIP when finances prohibit the use of a full course of, or increased dosage of, more effective antivirals, such as GS-441524, as mefloquine is more affordable (Sorrell et al., 2022). Used dosages are shown in Table 2. However, mefloquine is probably only effective as adjunct treatment and it can cause vomiting if not given with food, but it generally appears safe in healthy cats.

10.1.8. Cyclosporine A

Cyclosporine A can act as an antiviral drug as it binds to cellular cyclophilins thereby inhibiting calcineurin, which is required by many viruses for replication (Tanaka et al., 2012; Tanaka et al., 2013). Cyclosporine A inhibits FCoV replication in vitro (Tanaka et al., 2012) and was also associated with a reduction in pleural fluid volume and a decrease in viral load in a cat with FIP (Tanaka et al., 2015) (Table 2), but the cat succumbed to FIP 264 days after treatment initiation. Thus, cyclosporine A might be an option in combination with other therapeutic agents, but more studies are needed.

10.1.9. Curcumin

Curcumin, a derivative of turmeric, has antiviral and anti-inflammatory properties. Curcumin-encapsulated chitosan nanoparticles (Cur-CS), created to increase the bioavailability of curcumin, were evaluated in vitro and found to decrease the expression of pro-inflammatory cytokines TNF-α, interleukin- (IL-) 6, and IL-1β produced during infection of cell cultures with an FIP-associated FCoV as well as to inhibit viral replication (Ng et al., 2020). The same study confirmed the enhanced bioavailability of Cur-CS over curcumin in pharmacokinetic analysis in healthy cats. However, another in vitro study failed to find any inhibitory effect of curcumin on FCoV proliferation (McDonagh et al., 2014). Thus, further studies on this agent are required.

10.1.10. Miscellaneous Antiviral Treatments

Some other drugs have only been investigated in vitro, and their in vivo efficacy is currently unknown. These include vidarabine, which inhibits polymerase activity (Barlough and Scott 1990); nelfinavir, a commercially available protease inhibitor of human immunodeficiency virus (Hsieh et al., 2010); Galanthus nivalis agglutinin, a carbohydrate-binding agent that binds to FCoV-glycosylated envelope glycoproteins, thereby inhibiting viral attachment to the host cell (van der Meer et al., 2007; Hsieh et al., 2010); K31, a novel compound that binds and alters the conformation of the FCoV nucleocapsid protein (Mohseni et al., 2023); plant-derived flavonoids (including isoginkgetin) (Triratapiban et al., 2023); ERDRP-0516, a non-nucleoside inhibitor of the RNA-dependent RNA polymerase (Camero et al., 2022); and rottlerin (with enhanced delivery via liposomes), a natural polyphenol ketone compound derived from the fruit powder of the Kamala tree which inhibits early and late stage FCoV replication (Choi et al., 2023). One study has shown evidence of antiviral synergy between GS-441524 and itraconazole in vitro, especially against a type I FCoV (Doki et al., 2022). Some drugs are effective in vitro, but are too toxic for cats, such as ribavirin (Weiss and Oostrom-Ram 1989; Weiss et al., 1993a; Weiss et al., 1993b).

Promising experimental approaches include inhibition of the binding of FCoV spike protein to receptors on the host-cell membrane that mediates fusion of the viral envelope with host-cell membranes (Kim et al., 2013; Liu et al., 2013), circular triple helix-forming oligonucleotide RNA targeting viral RNA (Choong et al., 2014), cholesterol synthesis and transport inhibitors inducing cholesterol accumulation in cells and thereby inhibiting FCoV replication (Takano et al., 2017a; Takano et al., 2019; Doki et al., 2020a; Doki et al., 2022) and small interfering RNAs (siRNA) leading to RNA interference and thus, inhibition of virus replication (McDonagh et al., 2011; McDonagh et al., 2015; Delaplace et al., 2021).

10.2. Immunomodulatory Drugs for FIP

Immunomodulators are often used in cats with FIP. The idea behind these treatments is generally stimulation of the immune response towards a CMI response to FCoV in FIP. An early effective T cell response has been suggested as protecting from the development of FIP (de Groot-Mijnes et al., 2005). However, this is a complex area and, whilst there is a lack of documented efficacy in well-controlled studies (Hartmann and Ritz 2008a; Hartmann 2016), general recommendations cannot be made. Some old case reports suggest some effect through immunomodulator treatment (e.g., tylosine, promodulin, acemannan) but FIP was not always confirmed (Colgrove and Parker 1971; Robison et al., 1971; Ford 1986; Bolcskei and Bilkei 1995a; Bolcskei and Bilkei 1995b; Hartmann and Ritz 2008a).

Table 5 shows immunomodulatory treatments that have been used for FIP.

Table 5. Immunomodulatory and supportive treatments that have been used in cats with FIP. SC; subcutaneously, PO; orally, IM; intramuscularly, CRI; constant rate infusion, NSAID; non-steroidal anti-inflammatory drug, rfIFN-ω; recombinant feline IFN-omega.

Drug	Comments	ABCD recommendation in FIP
Meloxicam	Meloxicam, a NSAID licensed for use in cats, was associated with long-term survival in one cat (Hugo and Heading 2015), and in three cats in which it was used alongside rfIFN-ω (Addie et al., 2022).	Worthy of further studies. In some countries metamizole used in place of NSAIDs. Do not use in dehydration or hypotension and care in renal disease or anorexic cats. Was associated with worsening acute kidney injury in one cat with FIP (Green et al., 2023).
Gabapentin	Anxiolytic/analgesic/sedative which can help if SC injections (e.g., remdesivir) are needed (when oral GS-441524 cannot be given) that cause pain. Not licensed.	No prospective studies in cats with FIP but has been used successfully (Sorrell et al., 2022; Coggins et al., 2023; Taylor et al., 2023). Adverse effects can include sedation and ataxia. Typically give 50 or 100 mgs (can be up to 200 mg if required but start at low dose initially) per cat PO (Rodan et al., 2022) around two hours before SC injection.
Mirtazapine	Appetite stimulant/anti-nausea. For prevention and treatment of vomiting and nausea and as appetite stimulant; can be given as a trial if nausea suspected.	No published studies in cats with FIP. Has been used in anorexic cats before and during treatment (Addie et al., 2022; Cosaro et al., 2023; Green et al., 2023; Taylor et al., 2023). Please note that efficacious antiviral treatment e.g., GS-441524 usually causes a rapid return of appetite. Given at 2 mg/cat PO or as transdermal q 24 h (q 48 h if renal/hepatic involvement of FIP) (Taylor et al., 2022a).
Maropitant	For prevention and treatment of vomiting and nausea. SC injection can be painful.	No published evaluation studies in cats with FIP, although used as supportive treatment (Krentz et al., 2021; Green et al., 2023; Taylor et al., 2023); use if indicated. Dosage is 1 mg/kg SC, IV or PO q 24 h (Taylor et al., 2022a).
Metoclopramide	Prevention and treatment of nausea and vomiting, and management of ileus and delayed gastric emptying.	No published evaluation studies in cats with FIP but use if indicated. Dosage 0.25–0.5 mg/kg IV, IM, SC or PO q 8h or 1–2 mg/kg IV over 24 h as a CRI; CRI can be more effective than bolus dosing (Taylor et al., 2022a).
Ondansetron	For prevention and treatment of vomiting and nausea refractory to other agents such as maropitant, mirtazapine and metoclopramide. Expensive. Injectable or oral formulations available.	No published evaluation studies in cats with FIP, although used as supportive treatment (Green et al., 2023; Taylor et al., 2023); use if indicated. Dosage is 0.1–1 mg/kg IV (slowly), IM, SC, or PO q 6–12 h (Taylor et al., 2022a).
Hepatoprotectants such as S-Adenosylmethionine (SAMe)	Various preparations exist. Sometimes used during antiviral (especially GS-441524) treatment of FIP if hepatocellular enzymes (ALT) become elevated, or when these are normal by some (Addie et al., 2022), as protection against hepatic damage; however, ALT normalisation usually occurs rapidly during, or following cessation, of antiviral treatment without the use of hepatoprotectants, so their need is not proven.	No published evaluation studies in FIP but has been used during treatment (Krentz et al., 2021; Addie et al., 2022) without problems. This is an option if clinical concerns exist regarding hepatotoxicity. Might not be needed
Prednisolone/ dexamethasone	Acts as anti-inflammatory or immunosuppressant depending on dosage used. No controlled studies available. Median survival time of FIP cats treated with prednisolone was only eight days (Ritz et al., 2007). Does not cure FIP. Cats treated with systemic glucocorticoids along with polyprenyl immunostimulant (PI) had a shorter survival than those treated with PI alone (Legendre et al., 2017a).	Not recommended although can be used as palliative treatment and topical glucocorticoid treatment can be used for the treatment of ocular FIP with uveitis if needed. Suggested that glucocorticoid treatment is associated with a poorer FIP outcome when used concurrently with other treatments (e.g., such as rfIFN-ω (Addie et al., 2022), PI (Legendre et al., 2017a)).
Polyprenyl immunostimulant (PI)	Shows promise in the treatment of FIP without effusions, especially in cats with haematocrit and/or A:G ratios that are normal or that increase with treatment (Cerna et al., 2022). Takes a long time for response; reported normalisation times are ~182 days for haematocrit and ~375 days for the A:G ratio (Cerna et al., 2022). Reversal of lymphopenia with treatment (Cerna et al., 2022).	Do not use with systemic glucocorticoids (Legendre et al., 2017a) but topical glucocorticoid treatment can be used with PI in ocular FIP uveitis (Legendre et al., 2017a). Dosage 3 mg/kg PO three times a week or q 48 h (Legendre and Bartges 2009; Legendre et al., 2017a; Addie et al., 2022; Cerna et al., 2022). Some cats are changed to a maintenance dosage of 3 mg/kg PO once or twice a week after one year of treatment (Cerna et al., 2022).
Pentoxyfylline/ propentofylline	Aim at treating vasculitis. One placebo-controlled double-blind study on propentofylline showed no efficacy (but all cats were also given glucocorticoids) (Fischer et al., 2011)	Controlled field studies without glucocorticoids required.
Anti-TNF-α antibody	Blocks TNF-α that is involved in exacerbating clinical signs of FIP (Takano et al., 2007a; Takano et al., 2007b; Takano et al., 2009). Some efficacy in a placebo-controlled study including a few cats (three treated, three placebo) with experimentally induced FIP (Doki et al., 2016). Used in an uncontrolled very small study of cats with experimentally induced FIP alongside itraconazole treatment (Doki et al., 2020b) in which two of three cats with FIP improved.	Controlled field studies required.
Azathioprine	Aims to immunosuppress (and to lower the prednisolone/dexamethasone dose). No published studies available.	Not recommended due to toxicity in cats.
Chlorambucil	Aims to immunosuppress (and to lower the prednisolone/dexamethasone dose). No published studies.	Not recommended.
Cyclophosphamide	Aims to immunosuppress (and to lower the prednisolone/ dexamethasone dose). No published studies.	Not recommended.
Ozagrel hydrochloride	Inhibits thromboxane synthesis leading to reduced platelet aggregation and cytokine release. Used in two cats with some improvement of clinical signs (Watari et al., 1998) but unsuccessful in other cases (Addie 2008).	Not recommended.

Polyprenyl Immunostimulant

Polyprenyl immunostimulant (PI) is a drug that has shown promise for the immunomodulation treatment of FIP. PI is a commercially available oral agent that is given three times a week and is thought to act by upregulating Th-1 cytokines and CMI by upregulating innate immunity via toll-like receptors (Kuritz 2008; Legendre and Bartges 2009; Legendre et al., 2017a).

Although licensed for the treatment of feline herpesvirus (FHV) (Legendre et al., 2017b), it has been used off-label to treat FIP at higher dosages. In a case series of three non-effusive FIP cats (confirmed by histopathology in only one of the three cats), PI was associated with prolonged survival (Legendre and Bartges 2009). In a field study, treatment with PI was evaluated in 60 cats that were suspected to have FIP without effusion by primary care and specialist veterinarians, but confirmation of FIP was not established in all cats and no untreated controls were included (Legendre et al., 2017a). Of the 60 treated cats, 16 survived over 100 days; of these, eight survived over 200 days, including four who survived over 300 days. Veterinarians of treated cats that survived over 30 days reported improvements in clinical signs and behaviour. The survival times were significantly longer in cats that were not treated with systemic glucocorticoids concurrently, although topical ophthalmic glucocorticoids did not appear to affect survival like systemic glucocorticoids (Legendre et al., 2017a).

PI was used (amongst other treatments) in three cats that recovered from FIP and one who succumbed in a descriptive study (Addie et al., 2022). Another study (Cerna et al., 2022), which evaluated 29 cats with FIP (86% did not have effusions) that had received PI for at least 365 days, reported a mean survival time of around eight years. Here, diagnosis of FIP was based on a positive FCoV IHC or RT-PCR result, i.e., a diagnosis of FIP was confirmed or very likely (Tasker et al., 2023a). A low haematocrit and/or low A:G ratio (or which stayed low with treatment) was a negative prognostic indicator for response to PI (Cerna et al., 2022). Prednisolone was only given to two cats in the study, but both of these cats survived for less than the mean survival time. Some surviving cats stayed on PI treatment throughout the study (some moved onto a maintenance dosage after a year of treatment) whilst others had their PI treatment stopped once their haematocrit and A:G ratio had normalised (Cerna et al., 2022).

The dosages of PI used in different studies (Legendre and Bartges 2009; Legendre et al., 2017a; Addie et al., 2022; Cerna et al., 2022) have generally comprised 3 mg/kg PO three times a week or q 48 h. In one study (Cerna et al., 2022), the dosage was reduced to 3 mg/kg once or twice a week only as a maintenance dosage at about a year after diagnosis.

Thus, treatment with PI might hold some promise for cats with FIP but controlled studies to compare PI and antivirals, and/or PI given as adjunct treatment to antivirals, are required. PI enhances CMI and therefore is more likely to be effective in cats without effusions which have better CMI than cats with effusions that have more impaired T cell immunity (Cerna et al., 2022).

10.3. Supportive Treatments for FIP, Including Anti-Inflammatories and Drainage

Table 5 outlines agents that have been used in the supportive treatment of FIP. It is important to realise that supportive treatment should be tailored to the needs of the individual cat. The remarkable response seen in the cats with FIP treated with oral GS-441524 in one study (Krentz et al., 2021) was partly attributed to the intensive supportive care provided during hospitalisation of the cats over the first eight days of treatment, comprising IV fluid therapy, appetite stimulants, anti-emetics and analgesia. Good reviews on supporting the inappetant hospitalised cat (Taylor et al., 2022a), as well as minimising stress in hospitalised cats (Rodan et al., 2022; Taylor et al., 2022b), are available. Rehydration and the maintenance of fluid balance are important in dehydrated inappetant cats, necessitating fluid therapy. Vitamin supplementation (particularly B12) can be given (Jones et al., 2021; Addie et al., 2022; Sorrell et al., 2022), although the value of supplementation in the absence of hypocobalaminaemia is not known (Taylor et al., 2022a). In cats that are hypoglycaemic, dextrose supplementation may be indicated (Green et al., 2023).

The importance of supportive care also highlights the need for veterinarians to be involved in the treatment of cats with FIP. As described earlier, the use of illegally obtained antivirals by owners often means that veterinarians are not involved in the care of cats undergoing treatment for FIP (Jones et al., 2021) due to legislative and legal fear in veterinarians if they deal with these cats. This creates a disconnect between owners and veterinarians. However, it is possible for vets to give supportive care to cats in this situation for welfare reasons, as long as documentation is created to confirm there has been no veterinary involvement in the advising, obtaining or prescribing of the illegal drugs.

Although glucocorticoids, for inflammation and/or immune-mediated pathology, have commonly been used to treat FIP palliatively in the past, a positive effect has not been substantiated. Two separate double-blind controlled studies that evaluated rfIFN-ω (Ritz et al., 2007) and propentofylline (Fischer et al., 2011) as treatments for FIP gave all of the cats (both those in the treatment and the control groups) glucocorticoid treatment. The cats given the additional drugs did not survive any longer than those given glucocorticoids only but of importance is that those on glucocorticoids only survived for a median of eight days, confirming a poor outcome with glucocorticoid treatment alone in these cats (Izes et al., 2020c). In another study, cats without effusion treated with both systemic glucocorticoids and the immunomodulator PI had poorer survival than those treated with PI alone (Legendre et al., 2017a), again suggesting a negative effect of glucocorticoids, although a definitive diagnosis of FIP was not established in all cats. In the study based on owner-reported survey data, describing 393 cats treated with unlicensed, mainly injectable, GS-441524, high success rates were reported despite steroids (presumed glucocorticoid; but not specified in the owner survey) being used in 38% of cats (Jones et al., 2021). However, concern over the use of systemic glucocorticoids to treat FIP has been raised, and discontinuation of glucocorticoids within one to two weeks of starting remdesivir, with or without transition to GS-441524, has been reported (Coggins et al., 2023) and a preference stated for NSAIDs, over glucocorticoids, if an anti-inflammatory treatment is required (Addie et al., 2022). The latter recommendation was made due to a better success rate (92%; 11/12) in cats that were not given prednisolone compared to those that were (44%; 11/25); various other treatments were also given to these cats. Despite this, adverse effects of NSAIDs have to be considered, i.e., blood pressure and kidney function have to adequate, and the cat should be eating before receiving NSAIDs. In some countries, such as Germany, metamizole is used in place of NSAIDs as an analgesic with anti-fever and anti-inflammatory properties (Krentz et al., 2021). In the study (Green et al., 2023) describing 32 cats with effusive or non-effusive FIP treated with a combination of remdesivir and GS-441524, only three cats in total received systemic steroids (two hydrocortisone, one prednisolone), with two of these surviving; the surviving cat given prednisolone had received a decreasing dosage from 0.8 mg/kg/day over 16 days.

If uveitis is present, it is important to regularly monitor intraocular pressure (feline reference range 15–25 mmHg) as although low in uveitis, an increase could signify the development of secondary glaucoma, necessitating specific treatment (Tasker and Dietrich 2022). If anisocoria is present, this can be due to potential posterior synechiae, raising the risk of secondary glaucoma in the face of prolonged (and low-grade) uveitis (Ursula Dietrich, personal communication). FIP antiviral treatment will help control intraocular inflammation by the treatment of the underlying disease (Legendre et al., 2017a; Addie et al., 2020b), but there is believed to be an immune-mediated component to the uveitis that may require topical anti-inflammatory treatment (e.g., prednisolone acetate drops) (Tasker and Dietrich 2022; Taylor et al., 2023). One case report has described the use of topical ocular prednisolone acetate in a cat with uveitis receiving antiviral GS-441524 (Addie et al., 2020b). When needed, this can be used alongside antivirals, and it can be tapered to a maintenance dosage over time. Miosis may require atropine treatment. The cause of uveitis in FIP is thought to be a result from granuloma formation, pyogranulomatous vasculitis and possibly immune complex deposition, so only immunosuppressive topical corticosteroids usually work in those severe fibrinous uveitis cases seen in FIP, rather than topical NSAIDs (Ursula Dietrich, personal communication). Residual scarring can occur following chronic uveitis and if the eye is non-painful with a normal intraocular pressure, enucleation is not required. However enucleation might be required due to pain and glaucoma (Tasker and Dietrich 2022).

If a pleural effusion results in dyspnoea, drainage is indicated to provide some relief to the cat. Drainage does not tend to produce long-term relief for ascitic patients but is indicated if the degree of abdominal effusion is compromising respiration.

If seizures occur in neurological cases of FIP, anti-seizure medication may be required (Taylor et al., 2023), such as levetiracetam.

If indicated, cats can also be treated with broad-spectrum antibiotics (e.g., if bacterial translocation is suspected) and supportive therapy (e.g., fluids if dehydrated) (Hartmann and Ritz 2008b; Taylor et al., 2023). Very occasionally blood transfusions are given (Taylor et al., 2023) if there is a severe anaemia, most commonly due to severe haemolysis (Norris et al., 2005; Riemer et al., 2016).

Pentoxyfylline or propentofylline has been given to cats with FIP because they can down-regulate pro-inflammatory cytokines which are thought to increase vasculitis. However, in a placebo-controlled double-blind study in cats with confirmed FIP, there was no significant difference in survival time, quality of life, or any clinical or laboratory parameter in cats treated with propentofylline versus cats receiving placebo. However, all cats received glucocorticoids in this study (Fischer et al., 2011), and further studies without glucocorticoids would be valuable.

A thromboxane synthetase inhibitor (ozagrel hydrochloride) that inhibits platelet aggregation and cytokine release was used in two cats in an uncontrolled study, with some improvement of clinical signs (Watari et al., 1998), but a follow-up study was unsuccessful (Addie 2008).

A placebo-controlled study in a small number of cats (three treated, three placebo) in an experimental model of FIP found a possible beneficial effect of treatment with antibodies acting against feline TNF-α (Doki et al., 2016). In that study, progression to FIP was prevented in two of the three cats treated with these antibodies, whereas all three cats developed FIP in the placebo group. TNF-α is thought to be involved in FCoV replication in macrophages (Takano et al., 2007b) and contributes to development of clinical signs in cats with FIP. An uncontrolled very small study used anti-human-TNF-α antibody treatment alongside itraconazole (Doki et al., 2020b); only three of the 10 cats inoculated in this experimental study developed FIP, and two of these three treated cats improved with anti-human-TNF-α antibody and itraconazole treatment. No field studies have been conducted so far.

11. Vaccination

11.1. Efficacy of FIP Vaccines

At present, there is one intranasal FIP vaccine commercially available in the USA and in some European countries. It contains a temperature-sensitive mutant of the type II FCoV strain DF2. Type I coronaviruses are, however, more prevalent in the field in most countries (Addie and Jarrett 2001; Addie et al., 2003; Kummrow et al., 2005). The vaccine aims to induce local mucosal immune responses through the induction of IgA and CMI. However, it also induces the development of systemic antibodies against FCoV, although usually with low titres.

The efficacy of this vaccine is in question and its use is not recommended by ABCD. Results from experimental studies have been inconsistent, with preventable fractions between 0 and 75% reported (Gerber et al., 1990; Gerber 1995; Hoskins 1995a; Hoskins 1995b; McArdle et al., 1995; Scott et al., 1995a; Scott et al., 1995b). Results from field studies have been equally inconsistent (Fehr D et al., 1995; Postorino Reeves 1995; Fehr et al., 1997). No difference in the development of FIP between the vaccinated and placebo groups was found during the first 150 days after vaccination when the vaccine was used in Persian breeding colonies (Fehr D et al., 1995). However, after 150 days, significantly fewer cases of FIP occurred in the vaccinated cats compared to the placebo group (Fehr D et al., 1995). In another trial, a preventable fraction of 75% was found when the vaccine was tested in a large cat shelter in the USA (Postorino Reeves 1995), although the published study description was very short, making it difficult to interpret the study fully. In this study, all kittens were antibody-negative prior to vaccination. The conclusion is that the vaccine is likely not effective in antibody-positive cats that have already been exposed to FCoV. The ADE of infection that was a feature of some experimental vaccine trials (McArdle et al., 1995; Scott et al., 1995a; Scott et al., 1995b), where more vaccinated than control cats developed FIP, has not been observed in field studies, suggesting that the vaccine can be considered safe (Fehr D et al., 1995; Postorino Reeves 1995; Fehr et al., 1997). However, ADE is still of concern in the development of vaccines (Hohdatsu et al., 2003; Balint et al., 2014; Takano et al., 2017b). Different approaches to vaccination, such as the use of adenovirus-vectored vaccines based on the nucleocapsid protein of feline coronavirus which induce strong CMI (Wang et al., 2024), show promise for the future.

11.2. Use of the FIP Vaccine Available in some Countries

The ABCD considers the presently available FIP vaccine to be non-core, with questionable efficacy (Horzinek and Lutz 2000). There is no benefit in the use of this vaccine in FCoV antibody-positive cats, which severely limits its use, as many cats are already FCoV antibody-positive at the age (at least 16 weeks) that the vaccine can be administered (Table 1). FCoV antibody-negative kittens could potentially benefit from vaccination, particularly if they subsequently enter a FCoV-endemic environment and thus would be at risk of developing FIP. The fact that in multi-cat environments most kittens are already infected at the age of 16 weeks is a major limiting factor (Addie and Jarrett 1992; Lutz et al., 2002; Pedersen et al., 2008).

11.2.1. Primary Course

If vaccination is to be given, the first dose should not be given before 16 weeks of age, with a second dose being given three weeks after the first dose.

11.2.2. Booster Vaccinations

If primary vaccination has been performed, annual boosters can be considered, and, although studies on duration of immunity are lacking, it is thought to be short-lived (Addie et al., 2003).

12. Control of FCoV Infection and FIP

12.1. Reducing FCoV Transmission

Since FCoV is transmitted predominantly via the faecal-oral route, hygiene is the mainstay of FCoV (and therefore FIP) control in any multi-cat environment. FCoV infection is maintained in a household by continual cycles of infection and re-infection (Foley et al., 1997b; Addie et al., 2003), with the source of infection usually being faeces in the litter tray. Rarely is FIP a problem amongst cats leading an indoor–outdoor lifestyle or in stray cats that bury their faeces outside, unless these cats originate from multi-cat environments (Riemer et al., 2016). Indeed, in multivariable analysis, Italian stray colony cats were found to be less likely to be FCoV antibody-positive compared to owned cats (Spada et al., 2022).

The goal in every cat household must be to reduce the FCoV infection pressure and risk of transmission. This can be achieved by keeping cats in small well-adapted groups (not more than three per room has been suggested), observing strict hygiene, and providing outdoor access if possible (Horzinek and Lutz 2000; Addie et al., 2009). If outside access is not possible, enough litter trays should be provided, i.e., one more than the number of cats present, in the areas that the cats have access to. Litter trays should be positioned in different rooms away from food and water bowls. Litter trays should have faeces removed at least twice a day and be completely emptied at least weekly and cleaned using detergent. Utensils should be cleaned daily. One study (Addie et al., 2020a) suggested that a clumping bentonite-based Fuller’s earth cat litter, which tracked minimally, was associated with a reduced FCoV load in a multi-cat household compared to another type of Fuller’s earth litter. This effect was believed to be due to a binding effect of the clay in the litter as well as its non-tracking property, helping reduce spread. Further studies are required.

Although FCoV is only rarely shed in the saliva, food and water bowls should still be cleaned daily using detergent or in a dishwasher at a cycle of at least 60 °C, because of the risk of indirect transmission from cat litter-contaminated fomites.

12.2. Managing FCoV Shedders

FIP is especially a problem of cats kept in larger groups, particularly in breeding catteries and rescue situations (Pedersen 2019), due to the high prevalence of FCoV infection in multi-cat environments (Table 1).

Type I coronavirus faecal shedding in cats occurs over several months or is sometimes lifelong, especially in multi-cat households (Addie and Jarrett 2001; Addie et al., 2003; Pedersen et al., 2008). Cats can be identified as shedders by the submission and analysis of faeces (preferable) or a rectal swab by FCoV RT-qPCR. The laboratory performing the testing should provide the FCoV load present (or a RT-PCR cycle threshold value) and an interpretation of the results. However, a universally accepted protocol for the identification of shedders does not exist. Testing faecal samples collected weekly on four occasions (Rohner 1999; Horzinek and Lutz 2000) has been recommended for the detection of shedders, although other reports have described testing at least three faecal samples collected at between 5- and 28-day (Klein-Richers et al., 2020; Felten et al., 2023), or 30-day, intervals (Felten et al., 2020).

The identification of cats that are shedding, or are inferred to be shedding, FCoV, and their separation from cats believed to be non-shedders, has been suggested as a method for reducing transmission rates (Hickman et al., 1995; Horzinek and Lutz 2000). However, one must remember that the results of screening for FCoV shedders gives only a temporary picture and results can change over time, necessitating retesting. Additionally, the recommendations on how to reduce the FCoV infection pressure, described above under Section 12.1 on Reducing FCoV Transmission, should be strictly enforced. Additionally, FCoV-infected cats should not be exposed to stressful situations to try and help reduce viral load; it is known that FCoV shedding increases in cats after entering a shelter, which is believed to be due to stress (Pedersen et al., 2004).

The use of FCoV antibody testing on blood samples at a single time point, instead of repeated faecal sampling for RT-qPCR, is less useful for identifying FCoV shedders (Felten et al., 2020), despite the finding of a positive correlation between antibody titres and both the likelihood and frequency of faecal FCoV shedding and faecal viral load (Addie and Jarrett 2001; Felten et al., 2020). The following data help illustrate this: 15 of 64 antibody-positive cats did not have FCoV RNA in any of their four sequentially (at intervals of 5–30 days) collected faecal samples, whilst two of the 18 antibody-negative cats had FCoV RNA in all of their four sequentially collected faecal samples (Felten et al., 2020). Similarly, another study identified FCoV RNA in 10 of 81 faecal or rectal swab samples collected from antibody-negative cats (Addie and Jarrett 2001). Thus, serum antibody status cannot reliably predict faecal shedding. In some circumstances, this lack of antibodies in shedding cats might be explainable by early FCoV infection, as antibody development can take seven to 28 days post-infection (Stoddart et al., 1988b; Meli et al., 2004).

12.3. Elimination of FCoV Shedding

Using antivirals, such as GS-441524, to clear FCoV infection in cats without FIP (Addie et al., 2020c; Addie et al., 2023) is very controversial for two reasons: one is the potential risk that doing so will cause drug-resistant escape mutant viruses to develop, and the second is the concern that clearing a household of FCoV is difficult to achieve and maintain.

Regarding the appearance of drug-resistant escape mutant viruses: such mutant viruses have been demonstrated in vitro with the protease inhibitor GC376 (Jiao et al., 2022) but have yet to be demonstrated in vivo in cats treated with oral GS-441524. Possible indirect evidence for resistance to GS-441524 occurred in one of 26 cats with FIP that was treated with a very low dosage (2 mg/kg) of injectable GS-441524 SC; in this cat, FCoV RNA levels did not decrease over 26 days (in ascitic fluid over nine days, sample type thereafter not stipulated), which the authors attributed to a ‘failure to halt virus replication’ (Pedersen et al., 2019). Drug resistance can develop in situations where drugs are used for a long duration (Strasfeld and Chou 2010). Another explanation for the failure of this cat to respond to the GS-441524 treatment was that the dosage could have been too low to cross the blood–brain barrier; indeed, the cat developed ocular and neurological signs before dying, which supports this hypothesis.

The second objection to using antivirals in cats without FIP is the concern that eradication of FCoV from multi-cat households is difficult and complex and cannot be maintained because the virus is ubiquitous and so infection can be easily re-introduced. Indeed, in an FCoV eradication study, one household (which failed to meet the inclusion criteria for the study, but in which FCoV eradication was performed) had FCoV re-introduced with the introduction of many FCoV-infected kittens. Therefore, this is a real risk, even though other households did successfully introduce previously FCoV-infected cats through quarantine, isolation and GS-441524 treatment, thus preventing re-infection of their other cats (Addie et al., 2023).

For people wishing to eradicate FCoV from their household, the authors would urge them to bear in mind that FCoV infection is often self-limiting in households of fewer than 10 cats (Addie et al., 1995a). In some situations, FCoV eradication from a household for FIP prevention can be achieved by excellent hygiene, quarantine and testing prior to introducing cats or kittens into households. The FCoV load can also be reduced in multi-cat households using clumping bentonite-based Fuller’s earth cat litter (Addie et al., 2020a) and avoiding stress (Pedersen et al., 2004), as described earlier. Itraconazole (Addie et al., 2023) and rfIFN-ω (Gil et al., 2013) reduced, but unfortunately did not abrogate, coronavirus shedding. Whether mefloquine can halt faecal FCoV shedding is currently unknown.

12.4. Further Considerations in Breeding Catteries

Breeding catteries are those households in which the reduction of FCoV infection pressure is of particular importance. A study of 37 breeding catteries in Germany, which performed RT-PCR on faecal samples collected from cats in the catteries, did not find any FCoV-free catteries (Klein-Richers et al., 2020), showing how highly prevalent FCoV is in such environments. In this study, in which all of the breeding households had at least five cats, using multivariable analysis, they found that only having cats of less than one year of age was associated with an increased risk of FCoV shedding; management and husbandry measures (e.g., thoroughness of cleaning, number of litter trays, cleaning and disinfection frequency), surprisingly, were not associated with prevalence of faecal shedding (Klein-Richers et al., 2020). A subsequent study (Felten et al., 2023) that evaluated some of the same cats from the original 37 breeding catteries in Germany (Klein-Richers et al., 2020) reported that 125/222 (56%) cats were RT-PCR-positive on faeces for FCoV RNA in at least three of the four faecal samples taken, i.e., these cats were believed to be persistent shedders, albeit with the understanding of the limitation of testing the cats for up to four months only. The same study (Felten et al., 2023) reported that 55/222 (24%) cats had all four faecal samples testing negative for FCoV RNA, i.e., these cats were deemed to be non-shedders. Multivariable analysis found that persistent FCoV shedding was significantly associated with breed (Persians were at increased risk) and increased frequency of cleaning of litter trays per day. Conversely, non-shedding status was also significantly associated with breed (Birman and Norwegian Forest more likely to be non-shedders), as well as having fewer cats in the household and with a lower frequency of disinfection of litter trays per month. These results are difficult to explain as one would expect that more frequent cleaning, and increased disinfection, of litter trays would be associated with a reduction in FCoV shedding. It may be that FCoV shedders are more likely to have diarrhoea, as has been reported (Felten et al., 2022), stimulating more frequent cleaning or disinfection of litter trays, but faecal scoring was not performed in this study and so this cannot be confirmed or refuted (Felten et al., 2023).

Keeping no more than three well-adapted cats per room (and keeping such cat groups stable) and providing outdoor access if possible (Addie et al., 2009) is also helpful.

Special measures in kittens can be considered. FIP usually occurs after the kittens have left the breeder and are in a new household (Cave et al., 2002). It has been suggested that most kittens are considered protected from FCoV infection by maternally-derived antibodies until they are five to six weeks (Addie and Jarrett 1990) or even up to 10 weeks of age (Foley et al., 1997b). In some studies, FCoV transmission has been prevented by isolating pregnant queens two weeks before birth and then moving their kittens away to a clean environment away from other cats when they are five to six weeks old and maintaining them there until they go to a new home (Addie and Jarrett 1992; Addie and Jarrett 1995). For this method to succeed, the breeder is required to follow strict quarantine hygiene methods. However, the procedure failed in another study in which kittens were found to shed FCoV already as early as at the age of two weeks (Lutz et al., 2002). Veterinary behaviourists also advise against early weaning due to socialisation problems arising in these kittens (Philip and Seitz 1959; Guyot et al., 1980; Bateson 1981), and this, together with the laborious nature of early weaning, makes it unpopular amongst most veterinarians (Horzinek and Lutz 2000).

Although commercial PCR tests are available which purport to detect cats that are resistant to FIP (e.g., feline IFN-γ gene SNPs discussed briefly in Section 5 on Immunity), they are not recommended as a basis for breeding decisions. Positive selective breeding for ‘resistance to FIP’ in a colony of laboratory cats was shown to decrease the survival of the offspring after intraperitoneal inoculation with FIP-associated FCoV (Pedersen et al., 2016). The diminished resistance to FIP in these cats was associated with decreased genomic heterozygosity.

12.5. Further Considerations in Rescue Facilities, Shelters and Boarding Catteries

Preventing FCoV infection in rescue facilities, shelters, and boarding catteries is extremely difficult. In catteries and shelters with multiple cats, FCoV infection is virtually always present (Cave et al., 2004) (Table 1). Incoming cats should be quarantined for a minimum of three weeks to allow for the emergence of any incubating infections. As mentioned previously, after entry into a shelter, the shedding of FCoV increases dramatically within one week amongst cats that were already infected at entry; this was believed to be due to stress because more than one-half of initially FHV-negative cats began shedding FHV a week later, and latent FHV recrudescence occurs due to stress (Pedersen et al., 2004). Stress reduction is of particular importance, as stress can lead to increased virus production and a risk of the development of FIP. Cats who develop FIP frequently have a history of stress prior to presenting with FIP (Rohrer et al., 1993; Riemer et al., 2016; Thayer et al., 2022), probably due to the immunosuppressive effects of stress, allowing increased virus production.

Strict hygiene protocols for care workers, cleaning and disinfection must be enforced to reduce FCoV contamination and viral spread. Special care should be given to cleaning litter trays with boiling water or steam between use in different cats, having litter trays and scoops dedicated to each cat pen, and avoiding fomite transmission on cleaning utensils, such as brushes.

Ideally, cats should be kept in small groups of three or fewer cats per room (Addie et al., 2009) and with limited exchange of animals between groups. New catteries should be designed with infectious disease control and stress reduction as priorities (Möstl et al., 2013; Wagner et al., 2018a; Wagner et al., 2018b). More information on control of infectious diseases in shelters can be found in the ABCD guidelines on prevention and management of feline infectious diseases (Möstl et al., 2015) and infectious diseases in shelter situations and their management (Möstl et al., 2021).

12.6. Management of FCoV-Infected Cats without Clinical Signs

Stress (e.g., surgery, boarding, adoption) (Rohrer et al., 1993; Riemer et al., 2016; Thayer et al., 2022) or immunosuppression caused by co-infection with immunosuppressive viruses (e.g., FIV or FeLV) (Cotter et al., 1973; Poland et al., 1996) or any treatment inducing immunosuppression (Addie et al., 2015b) might increase the risk of FIP development in FCoV-infected cats. However, cats might have diseases that require immunosuppressive treatment despite the presence of FCoV infection. The minimisation of stress and avoidance of secondary infections are therefore important to prevent the development of FIP in FCoV-infected cats.

As mentioned in Section 11.1 on Efficacy of FIP Vaccines, FIP vaccination is not useful in FCoV-infected cats.

The question has been raised whether FCoV-infected cats should receive other vaccinations, since vaccination was identified as a stressor preceding onset of FIP in one study (Riemer et al., 2016). However, no evidence exists to support that FCoV-infected cats should be vaccinated less often than uninfected cats. Therefore, until the contrary has been demonstrated, FCoV-positive cats not showing any signs of illness should receive vaccination similarly to uninfected cats, with a cost–benefit assessment performed to decide whether vaccination (including which vaccines) (Day et al., 2016; Stone et al., 2020; 2022) are required.

12.7. Maintaining a FCoV-Negative Status

If a household has achieved a FCoV-negative status, efforts should be made to keep it FCoV-free (Addie et al., 2023) by testing new cats and kittens for FCoV infection preferably before bringing them into the household or, if that is not possible, by keeping them in quarantine until they are FCoV-free (see Section 12.2 on Managing FCoV Shedders and Section 12.6 on Management of FCoV-Infected Cats Without Clinical Signs). Certain geographical areas, such as the Falkland Islands (Addie et al., 2012), have been maintained as FCoV-free using these principles.

13. Conclusions

While FIP can present at any age, it presents typically in young cats, and effusions, fever, anorexia, and weight loss are common presenting signs. The sampling of effusions or abnormal tissues (by FNA) for cytology and FCoV analysis (either RT-qPCR for FCoV RNA load and/or immunostaining for FCoV antigen) can aid diagnosis. Definitive diagnosis depends on histopathological changes in affected tissues containing FCoV antigen within macrophages detected by immunostaining. Antiviral compounds, especially nucleoside analogues such as oral GS-441524, although not yet licensed for FIP treatment, are now available and are very effective curative treatments. However, treatment is often costly. Trial treatments of cases without a definitive diagnosis of FIP, but in which a diagnosis is very likely, might be warranted, as the response to effective antivirals is usually rapid; this can provide a diagnostic treatment trial. Without effective antiviral treatment, FIP has a very poor prognosis.

These guidelines will continue to be updated regularly on the ABCD website FIP section (www.abcdcatsvets.org) as new data become available. A previous version of the ABCD guidelines was published in 2009 (Addie et al., 2009); the current guidelines are a major update of the previous version, reviewing the large body of research published in the field to give a comprehensive review with summary information.

Acknowledgments: Thank you to Karin de Lange for her help with the production of the ABCD FIP diagnostic approach tools. Thank you to Andrew Parry for his help in describing the diagnostic imaging figures and Emi Barker for sourcing images. Thanks are due to Alex Malbon and Anja Kipar for providing excellent cytology and histopathology images with and without immunostaining.

ABCD Europe gratefully acknowledges the support of Boehringer Ingelheim (the founding sponsor of the ABCD), Virbac and MSD Animal Health.

References

Adaszek Ł, Kalinowski M, Rutkowska-Szulczyk M, Mazurek Ł, Szulc D, Staniec M, Pietras-Ożga D, Michalak K, Buczek K, Winiarczyk S (2023): Comparison of the sensitivity of rapid tests FCoV Ab (Vet Expert) and PCR in the diagnosis of feline infectious peritonitis (FIP) in cats with the effusive form of the disease. Medycyna Weterynaryjna 79 130-133.

Addie D, Belak S, Boucraut-Baralon C, Egberink H, Frymus T, Gruffydd-Jones T, Hartmann K, Hosie MJ, Lloret A, Lutz H, Marsilio F, Pennisi MG, Radford AD, Thiry E, Truyen U, Horzinek MC (2009): Feline infectious peritonitis. ABCD guidelines on prevention and management. Journal of Feline Medicine and Surgery 11 (7) 594-604.

Addie D, Houe L, Maitland K, Passantino G, Decaro N (2020a): Effect of cat litters on feline coronavirus infection of cell culture and cats. Journal of Feline Medicine and Surgery 22 (4) 350-357.

Addie DD, Jarrett O (1990): Control of feline coronavirus infection in kittens. Veterinary Record 126 (7) 164.

Addie DD, Jarrett O (1992): A study of naturally occurring feline coronavirus infections in kittens. Veterinary Record 130 (7) 133-137.

Addie DD, Jarrett O (1995): Control of feline coronavirus infections in breeding catteries by serotesting, isolation, and early weaning. Feline Practice 23 (3) 92-95.

Addie DD, Toth S, Murray GD, Jarrett O (1995a): Risk of feline infectious peritonitis in cats naturally infected with feline coronavirus. American Journal of Veterinary Research 56 (4) 429-434.

Addie DD, Toth S, Murray GD, Jarrett O (1995b): The risk of typical and antibody-enhanced feline infectious peritonitis among cats from feline coronavirus endemic households. Feline Practice 23 (3) 24-26.

Addie DD, Toth S, Herrewegh AA, Jarrett O (1996): Feline coronavirus in the intestinal contents of cats with feline infectious peritonitis. Veterinary Record 139 (21) 522-523.

Addie DD (2000): Clustering of feline coronaviruses in multicat households. Veterinary Journal 159 (1) 8-9.

Addie DD, Dennis JM, Toth S, Callanan JJ, Reid S, Jarrett O (2000): Long-term impact on a closed household of pet cats of natural infection with feline coronavirus, feline leukaemia virus and feline immunodeficiency virus. Veterinary Record 146 (15) 419-424.

Addie DD, Jarrett O (2001): Use of a reverse-transcriptase polymerase chain reaction for monitoring the shedding of feline coronavirus by healthy cats. Veterinary Record 148 (21) 649-653.

Addie DD, Schaap IAT, Nicolson L, Jarrett O (2003): Persistence and transmission of natural type I feline coronavirus infection. Journal of General Virology 84 (Pt 10) 2735-2744.

Addie DD, McDonald M, Audhuy S, Burr P, Hollins J, Kovacic R, Lutz H, Luxton Z, Mazar S, Meli ML (2012): Quarantine protects Falkland Islands (Malvinas) cats from feline coronavirus infection. Journal of Feline Medicine and Surgery 14 (2) 171-176.

Addie DD, Boucraut-Baralon C, Egberink H, Frymus T, Gruffydd-Jones T, Hartmann K, Horzinek MC, Hosie MJ, Lloret A, Lutz H, Marsilio F, Pennisi MG, Radford AD, Thiry E, Truyen U, Mostl K, European Advisory Board on Cat D (2015a): Disinfectant choices in veterinary practices, shelters and households: ABCD guidelines on safe and effective disinfection for feline environments. Journal of Feline Medicine and Surgery 17 (7) 594-605.

Addie DD, le Poder S, Burr P, Decaro N, Graham E, Hofmann-Lehmann R, Jarrett O, McDonald M, Meli ML (2015b): Utility of feline coronavirus antibody tests. Journal of Feline Medicine and Surgery 17 (2) 152-162.

Addie DD (2019): Feline infectious peritonitis : answers to frequently asked questions concerning FIP and coronavirus. Veterinary Nursing 34 (8) 201-206.

Addie DD, Covell-Ritchie J, Jarrett O, Fosbery M (2020b): Rapid Resolution of Non-Effusive Feline Infectious Peritonitis Uveitis with an Oral Adenosine Nucleoside Analogue and Feline Interferon Omega. Viruses 12 (11).

Addie DD, Curran S, Bellini F, Crowe B, Sheehan E, Ukrainchuk L, Decaro N (2020c): Oral Mutian(R)X stopped faecal feline coronavirus shedding by naturally infected cats. Research in Veterinary Science 130 222-229.

Addie DD, Silveira C, Aston C, Brauckmann P, Covell-Ritchie J, Felstead C, Fosbery M, Gibbins C, Macaulay K, McMurrough J, Pattison E, Robertson E (2022): Alpha-1 Acid Glycoprotein Reduction Differentiated Recovery from Remission in a Small Cohort of Cats Treated for Feline Infectious Peritonitis. Viruses 14 (4) 744.

Addie DD, Bellini F, Covell-Ritchie J, Crowe B, Curran S, Fosbery M, Hills S, Johnson E, Johnson C, Lloyd S, Jarrett O (2023): Stopping Feline Coronavirus Shedding Prevented Feline Infectious Peritonitis. Viruses 15 (4) 818.

Addie DDI, T. (2008): Feline Infectious Peritonitis: Therapy and Prevention. in Bonagura J.D. and T D.C. (eds.), Kirk’s Current Veterinary Therapy XIV (Saunders, Elsevier).

Ali KM, Abu-Seida AM, Abuowarda M (2021): Feline ocular toxoplasmosis: seroprevalence, diagnosis and treatment outcome of 60 clinical cases. Polish Journal of Veterinary Sciences 24 (1) 51-61.

Allinder M, Tynan B, Martin C, Furbish A, Austin G, Bartges J, Lourenco BN (2023): Uroliths composed of antiviral compound GS-441524 in 2 cats undergoing treatment for feline infectious peritonitis. Journal of Veterinary Internal Medicine.

Amer A, Siti Suri A, Abdul Rahman O, Mohd HB, Faruku B, Saeed S, Tengku Azmi TI (2012): Isolation and molecular characterization of type I and type II feline coronavirus in Malaysia. Virology Journal 9 278.

Amici C, Di Caro A, Ciucci A, Chiappa L, Castilletti C, Martella V, Decaro N, Buonavoglia C, Capobianchi MR, Santoro MG (2006): Indomethacin has a potent antiviral activity against SARS coronavirus. Antiviral Therapy 11 (8) 1021-1030.

An DJ, Jeoung HY, Jeong W, Park JY, Lee MH, Park BK (2011): Prevalence of Korean cats with natural feline coronavirus infections. Virology Journal 8 455.

Andersen LA, Levy JK, McManus CM, McGorray SP, Leutenegger CM, Piccione J, Blackwelder LK, Tucker SJ (2018): Prevalence of enteropathogens in cats with and without diarrhea in four different management models for unowned cats in the southeast United States. Veterinary Journal 236 49-55.

Andre NM, Cossic B, Davies E, Miller AD, Whittaker GR (2019): Distinct mutation in the feline coronavirus spike protein cleavage activation site in a cat with feline infectious peritonitis-associated meningoencephalomyelitis. Journal of Feline Medicine and Surgery Open Reports 5 (1) 2055116919856103.

Andre NM, Miller AD, Whittaker GR (2020): Feline infectious peritonitis virus-associated rhinitis in a cat. Journal of Feline Medicine and Surgery Open Reports 6 (1) 2055116920930582.

Ansems K, Grundeis F, Dahms K, Mikolajewska A, Thieme V, Piechotta V, Metzendorf MI, Stegemann M, Benstoem C, Fichtner F (2021): Remdesivir for the treatment of COVID-19. Cochrane Database of Systematic Reviews 8 CD014962.

Aplasca AC, Martinez MP, Evans SJM, Martinez ME, Cianciolo RE, Bundschuh M, Puchulu-Campanella E, Chen X, Yan P, Bundschuh R, Seeley KE, Bapodra-Villaverde P, Garner MM, Junge RE (2023): An Outbreak of Feline Infectious Peritonitis in Three Related Sand Cats (Felis Margarita) in Human Care. Journal of Zoo and Wildlife Medicine 54 (3) 628-638.

Arshad SS, Lee WW, Hassan L, Kamarudin AIM, Sitl-Farawahida AW, Cheng NABY (2004): Serological survey of catteries for cats infected with feline coronavirus. Journal of Veterinary Malaysia 17 (1) 19-22.

Aslam MW, Lau SF, Radzi R, Omar S, Kaka U, Ahmed I (2023): Clinicopathological and Radiological Features of Cats Presented with Infectious Respiratory Disease Signs: A Focus on Rhodococcus equi and Klebsiella pneumoniae. Microorganisms 11 (3).

Attipa C, Gunn-Moore D, Mazeri S, Epaminondas D, Lyraki M, Hardas A, Loukaidou S, Gentil M (2023a): Concerning feline infectious peritonitis outbreak in Cyprus. Veterinary Record 192 (11) 449-450.

Attipa C, Warr A, O’Shea M, Fletcher S, Malbon A, Lyraki M, Hammond R, Hardas A, Zanti A, Loukaidou S, Gentil M, Gunn-Moore D, Mazeri S, Tait-Burkard C (2023b): Emergence and spread of feline infection peritonitis due to a highly pathogenic canine/feline recombinant coronavirus. bioRxiv.

Avila VA, Rissi DR (2020): Ulcerative dermatitis due to feline infectious peritonitis virus infection in a cat. Brazilian Journal of Veterinary Pathology 13 48-50.

Avizeh R, Mosallanejad B, Seyfiabad Shapouri MR (2012): Antibody detection of feline infectious peritonitis virus (FIPV) in sera of companion cats in Ahvaz, south west of Iran. Archives of Razi Institute 67 (1) 69-74.

Bae H, Kim J, Chun D, Jung DI, Park J, Young Kim D, Yu D (2021): Idiopathic ulcerative dermatitis in a cat with feline infectious peritonitis. Veterinary Medicine Science 7 (2) 572-576.

Baek S, Jo J, Song K, Seo K (2017): Recurrent pericardial effusion with feline infectious peritonitis in a cat. J. Vet. Clinics 34 (6) 437-440.

Balint A, Farsang A, Szeredi L, Zadori Z, Belak S (2014): Recombinant feline coronaviruses as vaccine candidates confer protection in SPF but not in conventional cats. Veterinary Microbiology 169 (3-4) 154-162.

Baneth G, Kass PH, Steinfeld D, Besser M (1999): A seroepidemiological study of feline coronavirus, feline immunodeficiency virus and feline leukemia virus among cats in Israel. Israel Journal of Veterinary Medicine 54 (2) 39-43.

Bank-Wolf BR, Stallkamp I, Wiese S, Moritz A, Tekes G, Thiel HJ (2014): Mutations of 3c and spike protein genes correlate with the occurrence of feline infectious peritonitis. Veterinary Microbiology 173 (3-4) 177-188.

Barker E, Tasker S (2020a): Update on feline infectious peritonitis. In Practice 42 (7) 372-383.

Barker EN, Tasker S, Gruffydd-Jones TJ, Tuplin CK, Burton K, Porter E, Day MJ, Harley R, Fews D, Helps CR, Siddell SG (2013): Phylogenetic analysis of feline coronavirus strains in an epizootic outbreak of feline infectious peritonitis. Journal of Veterinary Internal Medicine 27 (3) 445-450.

Barker EN, Stranieri A, Helps CR, Porter EL, Davidson AD, Day MJ, Knowles T, Kipar A, Tasker S (2017): Limitations of using feline coronavirus spike protein gene mutations to diagnose feline infectious peritonitis. Veterinary Research 48 (1) 60.

Barker EN, Tasker S (2017): Diagnosing FIP: Has recent research made it any easier? In Amercian College of Veterinary Internal Medicine Forum, June 8-10 National Harbor, Maryland, USA.

Barker EN, Lait P, Ressel L, Blackwell EJ, Tasker S, Kedward-Dixon H, Kipar A, Helps CR (2020): Evaluation of Interferon-Gamma Polymorphisms as a Risk Factor in Feline Infectious Peritonitis Development in Non-Pedigree Cats-A Large Cohort Study. Pathogens 9 (7).

Barker EN, Tasker S (2020b): Advances in Molecular Diagnostics and Treatment of Feline Infectious Peritonitis. Advances in Small Animal Care 1 161-188.

Barlough JE, Scott FW (1990): Effectiveness of three antiviral agents against FIP virus in vitro. Veterinary Record 126 (22) 556-558.

Barua S, Kaltenboeck B, Juan YC, Bird RC, Wang C (2023): Comparative Evaluation of GS-441524, Teriflunomide, Ruxolitinib, Molnupiravir, Ritonavir, and Nirmatrelvir for In Vitro Antiviral Activity against Feline Infectious Peritonitis Virus. Vet Sci 10 (8).

Bateson P (1981): Discontinuities in development and changes in the organisation of play in cats. in K Immelmann, G Barlow, M Main and L Petrinovich (eds.), Behavioural Development (Cambridge University Press: New York).

Bauer BS, Kerr ME, Sandmeyer LS, Grahn BH (2013): Positive immunostaining for feline infectious peritonitis (FIP) in a Sphinx cat with cutaneous lesions and bilateral panuveitis. Veterinary Ophthalmology 16 Suppl 1 (Suppl 1) 160-163.

Beatty J, Barrs V (2010): Pleural effusion in the cat: a practical approach to determining aetiology. Journal of Feline Medicine and Surgery 12 (9) 693-707.

Bell ET, Malik R, Norris JM (2006a): The relationship between the feline coronavirus antibody titre and the age, breed, gender and health status of Australian cats. Australian Veterinary Journal 84 (1-2) 2-7.

Bell ET, Toribio JA, White JD, Malik R, Norris JM (2006b): Seroprevalence study of feline coronavirus in owned and feral cats in Sydney, Australia. Australian Veterinary Journal 84 (3) 74-81.

Belouzard S, Millet JK, Licitra BN, Whittaker GR (2012): Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses 4 (6) 1011-1033.

Benetka V, Kubber-Heiss A, Kolodziejek J, Nowotny N, Hofmann-Parisot M, Mostl K (2004): Prevalence of feline coronavirus types I and II in cats with histopathologically verified feline infectious peritonitis. Veterinary Microbiology 99 (1) 31-42.

Benetka V, Kolodziejek J, Walk K, Rennhofer M, Mostl K (2006): M gene analysis of atypical strains of feline and canine coronavirus circulating in an Austrian animal shelter. Veterinary Record 159 (6) 170-174.

Berg AL, Ekman K, Belak S, Berg M (2005): Cellular composition and interferon-gamma expression of the local inflammatory response in feline infectious peritonitis (FIP). Veterinary Microbiology 111 (1-2) 15-23.

Boettcher IC, Steinberg T, Matiasek K, Greene CE, Hartmann K, Fischer A (2007): Use of anti-coronavirus antibody testing of cerebrospinal fluid for diagnosis of feline infectious peritonitis involving the central nervous system in cats. Journal of the American Veterinary Medical Association 230 (2) 199-205.

Bohm M (2022): Successful treatment of a South African cat with effusive feline infectious peritonitis with remdesivir. Journal of the South African Veterinary Association 93 (2) 112-115.

Bolcskei A, Bilkei G (1995a): Langzeitstudie über behandelte FIP-verdächtige Katzen. Die Auswirkung verschiedener Therapieversuche auf das Überleben FIP-verdächtiger Katzen. Tierarztliche Umschau 50 21.

Bolcskei A, Bilkei G (1995b): Langzeitstudie über behandelte FIP-verdächtige Katzen. Überlebensrate der FIP-verdächtigen Katzen nach Behandlung mit Ampicillin, Prednisolon und Cyclophosphamid. Tierarztliche Umschau 50 592.

Borschensky CM, Reinacher M (2014): Mutations in the 3c and 7b genes of feline coronavirus in spontaneously affected FIP cats. Research in Veterinary Science 97 (2) 333-340.

Bosch BJ, van der Zee R, de Haan CA, Rottier PJ (2003): The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. Journal of Virology 77 (16) 8801-8811.

Brandsma I, Derr R, Zhang G, Moelijker N, Hendriks G, Osterlund T (2022): Genotoxicity assessment of potentially mutagenic nucleoside analogues using ToxTracker(R). Toxicology Letters 362 50-58.

Brown MA, Troyer JL, Pecon-Slattery J, Roelke ME, O’Brien SJ (2009): Genetics and pathogenesis of feline infectious peritonitis virus. Emerging Infectious Diseases 15 (9) 1445-1452.

Bubenikova J, Vrabelova J, Stejskalova K, Futas J, Plasil M, Cerna P, Oppelt J, Lobova D, Molinkova D, Horin P (2020): Candidate Gene Markers Associated with Fecal Shedding of the Feline Enteric Coronavirus (FECV). Pathogens 9 (11).

Camero M, Lanave G, Catella C, Lucente MS, Sposato A, Mari V, Tempesta M, Martella V, Buonavoglia A (2022): ERDRP-0519 inhibits feline coronavirus in vitro. BMC Veterinary Research 18 (1) 55.

Cannon MJ, Silkstone MA, Kipar AM (2005): Cutaneous lesions associated with coronavirus-induced vasculitis in a cat with feline infectious peritonitis and concurrent feline immunodeficiency virus infection. Journal of Feline Medicine and Surgery 7 (4) 233-236.

Carossino M, Del Piero F, Lee J, Needle DB, Levine JM, Riis RR, Maes R, Wise AG, Mullaney K, Ferracone J, Langohr IM (2022): Relationship between Uveal Inflammation and Viral Detection in 30 Cats with Feline Infectious Peritonitis. Pathogens 11 (8).

Cave TA, Thompson H, Reid SW, Hodgson DR, Addie DD (2002): Kitten mortality in the United Kingdom: a retrospective analysis of 274 histopathological examinations (1986 to 2000). Veterinary Record 151 (17) 497-501.

Cave TA, Golder MC, Simpson J, Addie DD (2004): Risk factors for feline coronavirus seropositivity in cats relinquished to a UK rescue charity. Journal of Feline Medicine and Surgery 6 (2) 53-58.

Ceciliani F, Grossi C, Giordano A, Pocacqua V, Paltrinieri S (2004): Decreased sialylation of the acute phase protein alpha1-acid glycoprotein in feline infectious peritonitis (FIP). Veterinary Immunology and Immunopathology 99 (3-4) 229-236.

Cerna P, Ayoob A, Baylor C, Champagne E, Hazanow S, Heidel RE, Wirth K, Legendre AM, Gunn-Moore DA (2022): Retrospective Survival Analysis of Cats with Feline Infectious Peritonitis Treated with Polyprenyl Immunostimulant That Survived over 365 Days. Pathogens 11 (8).

Chang HW, de Groot RJ, Egberink HF, Rottier PJ (2010): Feline infectious peritonitis: insights into feline coronavirus pathobiogenesis and epidemiology based on genetic analysis of the viral 3c gene. Journal of General Virology 91 (Pt 2) 415-420.

Chang HW, Egberink HF, Rottier PJ (2011): Sequence analysis of feline coronaviruses and the circulating virulent/avirulent theory. Emerging Infectious Diseases 17 (4) 744-746.

Chang HW, Egberink HF, Halpin R, Spiro DJ, Rottier PJ (2012): Spike protein fusion Peptide and feline coronavirus virulence. Emerging Infectious Diseases 18 (7) 1089-1095.

Chen D, Lopez-Perez AM, Vernau KM, Maggs DJ, Kim S, Foley J (2023): Prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and feline enteric coronavirus (FECV) in shelter-housed cats in the Central Valley of California, USA. Vet Rec Open 10 (2) e73.

Chen S, Tian J, Li Z, Kang H, Zhang J, Huang J, Yin H, Hu X, Qu L (2019): Feline Infectious Peritonitis Virus Nsp5 Inhibits Type I Interferon Production by Cleaving NEMO at Multiple Sites. Viruses 12 (1).

Choi JC, Jung SW, Choi IY, Kang YL, Lee DH, Lee SW, Park SY, Song CS, Choi IS, Lee JB, Oh C (2023): Rottlerin-Liposome Inhibits the Endocytosis of Feline Coronavirus Infection. Vet Sci 10 (6).

Choong OK, Mehrbod P, Tejo BA, Omar AR (2014): In vitro antiviral activity of circular triple helix forming oligonucleotide RNA towards Feline Infectious Peritonitis virus replication. BioMed Research International 2014 654712.

Coggins SJ, Norris JM, Malik R, Govendir M, Hall EJ, Kimble B, Thompson MF (2023): Outcomes of treatment of cats with feline infectious peritonitis using parenteral remdesivir, with or without transition to oral GS-441524. Journal of Veterinary Internal Medicine 10.1111/JVIM.16803.

Coggins SJ, Kimble B, Malik R, Thompson MF, Norris JM, Govendir M (2024): Assessing in vitro stability of remdesivir (GS-5734) and conversion to GS-441524 in feline plasma and whole blood. Veterinary Quarterly 44 (1) 1-9.

Cohen TM, Blois S, Vince AR (2016): Fatal extraintestinal toxoplasmosis in a young male cat with enlarged mesenteric lymph nodes. Canadian Veterinary Journal 57 (5) 483-486.

Colgrove DJ, Parker AJ (1971): Feline infectious peritonitis. Journal of Small Animal Practice 12 (4) 225-232.

Cook S, Wittenburg L, Yan VC, Theil JH, Castillo D, Reagan KL, Williams S, Pham C-D, Li C, Muller FL, Murphy BG (2022a): An Optimized Bioassay for Screening Combined Anticoronaviral Compounds for Efficacy against Feline Infectious Peritonitis Virus with Pharmacokinetic Analyses of GS-441524, Remdesivir, and Molnupiravir in Cats. Viruses 14 (11) 2429.

Cook SE, Vogel H, Castillo D, Olsen M, Pedersen N, Murphy BG (2022b): Investigation of monotherapy and combined anticoronaviral therapies against feline coronavirus serotype II in vitro. Journal of Feline Medicine and Surgery 24 (10) 943-953.

Cooper G (2021): Comments on: Dealing with black market medications. In Practice 43 (6) 343-343.

Cornelissen E, Dewerchin HL, Van Hamme E, Nauwynck HJ (2007): Absence of surface expression of feline infectious peritonitis virus (FIPV) antigens on infected cells isolated from cats with FIP. Veterinary Microbiology 121 (1-2) 131-137.

Cosaro E, Pires J, Castillo D, Murphy BG, Reagan KL (2023): Efficacy of Oral Remdesivir Compared to GS-441524 for Treatment of Cats with Naturally Occurring Effusive Feline Infectious Peritonitis: A Blinded, Non-Inferiority Study. Viruses 15 (8) 1680.

Cotter SM, Gilmore CE, Rollins C (1973): Multiple cases of feline leukemia and feline infectious peritonitis in a household. Journal of the American Veterinary Medical Association 162 (12) 1054-1058.

COVID-19 Treatment Guidelines Panel (2019): Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Accessed 18th July 2023. https://www.covid19treatmentguidelines.nih.gov/.

Crawford AH, Stoll AL, Sanchez-Masian D, Shea A, Michaels J, Fraser AR, Beltran E (2017): Clinicopathologic Features and Magnetic Resonance Imaging Findings in 24 Cats With Histopathologically Confirmed Neurologic Feline Infectious Peritonitis. Journal of Veterinary Internal Medicine 31 (5) 1477-1486.

Curtis BE, Abdo Z, Graham B, LaVoy A, Evans SJM, Santangelo K, Dean GA (2024): An Aptamer-Based Proteomic Analysis of Plasma from Cats (Felis catus) with Clinical Feline Infectious Peritonitis. Viruses 16 (1).

Day MJ, Horzinek MC, Schultz RD, Squires RA (2016): WSAVA Guidelines for the vaccination of dogs and cats. Journal of Small Animal Practice 57 (1) E1-E45.

de Groot-Mijnes JD, van Dun JM, van der Most RG, de Groot RJ (2005): Natural history of a recurrent feline coronavirus infection and the role of cellular immunity in survival and disease. Journal of Virology 79 (2) 1036-1044.

De Groot RJ, Horzinek MC (1995): Feline infectious peritonitis. in SG Siddell (ed.), The Coronaviridae (Plenum Press: New York).

De Groot RJ, Baker SC, Baric RS, Enjuanes L, Gorbalenya AE, Holmes KV, Perlman S, Poon L, Rottier PJM, Talbot PJ, Woo PCY, Ziebuhr J (2012): Family Coronaviridae in AMQ King, MJ Adams, EB Carstens and EJ Lefkowitz (eds.), Ninth Report International Committee on Taxonomy of Viruses (Elsevier: Amsterdam).

Dean GA, Olivry T, Stanton C, Pedersen NC (2003): In vivo cytokine response to experimental feline infectious peritonitis virus infection. Veterinary Microbiology 97 (1-2) 1-12.

Decaro N, Mari V, Lanave G, Lorusso E, Lucente MS, Desario C, Colaianni ML, Elia G, Ferringo F, Alfano F, Buonavoglia C (2021): Mutation analysis of the spike protein in Italian feline infectious peritonitis virus and feline enteric coronavirus sequences. Research in Veterinary Science 135 15-19.

Declercq J, De Bosschere H, Schwarzkopf I, Declercq L (2008): Papular cutaneous lesions in a cat associated with feline infectious peritonitis. Veterinary Dermatology 19 (5) 255-258.

Dedeurwaerder A, Olyslaegers DAJ, Desmarets LMB, Roukaerts IDM, Theuns S, Nauwynck HJ (2014): ORF7-encoded accessory protein 7a of feline infectious peritonitis virus as a counteragent against IFN-alpha-induced antiviral response. Journal of General Virology 95 393-402.

Delaplace M, Huet H, Gambino A, Le Poder S (2021): Feline Coronavirus Antivirals: A Review. Pathogens 10 (9) 1150.

Desmarets LM, Theuns S, Olyslaegers DA, Dedeurwaerder A, Vermeulen BL, Roukaerts ID, Nauwynck HJ (2013): Establishment of feline intestinal epithelial cell cultures for the propagation and study of feline enteric coronaviruses. Veterinary Research 44 71.

Desmarets LM, Vermeulen BL, Theuns S, Conceicao-Neto N, Zeller M, Roukaerts ID, Acar DD, Olyslaegers DA, Van Ranst M, Matthijnssens J, Nauwynck HJ (2016): Experimental feline enteric coronavirus infection reveals an aberrant infection pattern and shedding of mutants with impaired infectivity in enterocyte cultures. Scientific Reports 6 20022.

Dewerchin HL, Cornelissen E, Nauwynck HJ (2005): Replication of feline coronaviruses in peripheral blood monocytes. Archives of Virology 150 (12) 2483-2500.

Dickinson PJ, Bannasch M, Thomasy SM, Murthy VD, Vernau KM, Liepnieks M, Montgomery E, Knickelbein KE, Murphy B, Pedersen NC (2020): Antiviral treatment using the adenosine nucleoside analogue GS-441524 in cats with clinically diagnosed neurological feline infectious peritonitis. Journal of Veterinary Internal Medicine 34 (4) 1587-1593.

Doenges SJ, Weber K, Dorsch R, Fux R, Fischer A, Matiasek LA, Matiasek K, Hartmann K (2016): Detection of feline coronavirus in cerebrospinal fluid for diagnosis of feline infectious peritonitis in cats with and without neurological signs. Journal of Feline Medicine and Surgery 18 (2) 104-109.

Doenges SJ, Weber K, Dorsch R, Fux R, Hartmann K (2017): Comparison of real-time reverse transcriptase polymerase chain reaction of peripheral blood mononuclear cells, serum and cell-free body cavity effusion for the diagnosis of feline infectious peritonitis. Journal of Feline Medicine and Surgery 19 (4) 344-350.

Doki T, Takano T, Nishiyama Y, Nakamura M, Hohdatsu T (2013): Generation, characterization and therapeutic potential of anti-feline TNF-alpha MAbs for feline infectious peritonitis. Research in Veterinary Science 95 (3) 1248-1254.

Doki T, Takano T, Kawagoe K, Kito A, Hohdatsu T (2016): Therapeutic effect of anti-feline TNF-alpha monoclonal antibody for feline infectious peritonitis. Research in Veterinary Science 104 17-23.

Doki T, Yabe M, Takano T, Hohdatsu T (2018): Differential induction of type I interferon by type I and type II feline coronaviruses in vitro. Research in Veterinary Science 120 57-62.

Doki T, Tarusawa T, Hohdatsu T, Takano T (2020a): In Vivo Antiviral Effects of U18666A Against Type I Feline Infectious Peritonitis Virus. Pathogens 9 (1).

Doki T, Toda M, Hasegawa N, Hohdatsu T, Takano T (2020b): Therapeutic effect of an anti-human-TNF-alpha antibody and itraconazole on feline infectious peritonitis. Archives of Virology 165 (5) 1197-1206.

Doki T, Takahashi K, Hasegawa N, Takano T (2022): In vitro antiviral effects of GS-441524 and itraconazole combination against feline infectious peritonitis virus. Research in Veterinary Science 144 27-33.

Dong B, Zhang X, Zhong X, Hu W, Lin Z, Zhang S, Deng H, Lin W (2024): Prevalence of natural feline coronavirus infection in domestic cats in Fujian, China. Virology Journal 21 (1) 2.

Duarte A, Veiga I, Tavares L (2009): Genetic diversity and phylogenetic analysis of Feline Coronavirus sequences from Portugal. Veterinary Microbiology 138 (1-2) 163-168.

Duijvestijn MBHM, Schuurman NNMP, Vernooij JCM, van Leeuwen MAJM, Bosch B-J, van den Brand JMA, Wagenaar JA, van Kuppeveld FJM, Egberink HF, Verhagen JH (2023): Serological Survey of Retrovirus and Coronavirus Infections, including SARS-CoV-2, in Rural Stray Cats in The Netherlands, 2020-2022. Viruses 15 (7) 1531.

Dunbar D, Kwok W, Graham E, Armitage A, Irvine R, Johnston P, McDonald M, Montgomery D, Nicolson L, Robertson E, Weir W, Addie DD (2019): Diagnosis of non-effusive feline infectious peritonitis by reverse transcriptase quantitative PCR from mesenteric lymph node fine-needle aspirates. Journal of Feline Medicine and Surgery 21 (10) 910-921.

Dunbar D, Babayan SA, Krumrie S, Haining H, Hosie MJ, Weir W (2024): Assessing the feasibility of applying machine learning to diagnosing non-effusive feline infectious peritonitis. Scientific Reports 14 (1) 2517.

Duthie S, Eckersall PD, Addie DD, Lawrence CE, Jarrett O (1997): Value of alpha 1-acid glycoprotein in the diagnosis of feline infectious peritonitis. Veterinary Record 141 (12) 299-303.

Dye C, Siddell SG (2007): Genomic RNA sequence of feline coronavirus strain FCoV C1Je. Journal of Feline Medicine and Surgery 9 (3) 202-213.

Dye C, Temperton N, Siddell SG (2007): Type I feline coronavirus spike glycoprotein fails to recognize aminopeptidase N as a functional receptor on feline cell lines. Journal of General Virology 88 (Pt 6) 1753-1760.

Eastman RT, Roth JS, Brimacombe KR, Simeonov A, Shen M, Patnaik S, Hall MD (2020): Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Central Science 6 (5) 672-683.

Emmler L, Felten S, Matiasek K, Balzer HJ, Pantchev N, Leutenegger C, Hartmann K (2020): Feline coronavirus with and without spike gene mutations detected by real-time RT-PCRs in cats with feline infectious peritonitis. Journal of Feline Medicine and Surgery 22 (8) 791-799.

Ernandes MA, Cantoni AM, Armando F, Corradi A, Ressel L, Tamborini A (2019): Feline coronavirus-associated myocarditis in a domestic longhair cat. Journal of Feline Medicine and Surgery Open Reports 5 (2) 2055116919879256.

European Advisory Board of Cat Diseases (2022): European Advisory Board for Cat Diseases Matrix vaccination guidelines. Accessed 10th February 2024. https://www.abcdcatsvets.org/wp-content/uploads/2022/11/TOOL_Vaccine-recommendations_Feb_2020_EN.pdf.

European Union (2023a): Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on veterinary medicinal products and repealing Directive 2001/82/EC. Official Journal of the European Union. https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32019R0006 Accessed 17th August 2023.

European Union (2023b): Commission Implementing Regulation (EU) 2022/1255 of 19 July 2022 designating antimicrobials or groups of antimicrobials reserved for treatment of certain infections in humans, in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council Official Journal of the European Union. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32022R1255 Accessed 7th May 2023.

Evermann JF, Heeney JL, Roelke ME, McKeirnan AJ, O’Brien SJ (1988): Biological and pathological consequences of feline infectious peritonitis virus infection in the cheetah. Archives of Virology 102 (3-4) 155-171.

Farsijani F, Safi S, Shirazi Beheshtiha SH (2023): Comparison of the Performance of Bioresonance, Electrophoresis and RT-PCR in the Diagnosis of Feline Infectious Peritonitis. Arch Razi Inst 78 (3) 1077-1085.

Fehr D, Holznagel E, Bolla S, Hauser B, Herrewegh AA, Horzinek MC, Lutz H (1997): Placebo-controlled evaluation of a modified life virus vaccine against feline infectious peritonitis: safety and efficacy under field conditions. Vaccine 15 (10) 1101-1109.

Fehr D, Holznagel E, Bolla S, Hauser B, Herrewegh AAPM, Horzinek MC, H L (1995): Evaluation of the Safety and Efficacy of a Modified-Live FIPV Vaccine under Field Conditions. Feline Practice 23 83-88.

Felten S, Leutenegger CM, Balzer HJ, Pantchev N, Matiasek K, Wess G, Egberink H, Hartmann K (2017a): Sensitivity and specificity of a real-time reverse transcriptase polymerase chain reaction detecting feline coronavirus mutations in effusion and serum/plasma of cats to diagnose feline infectious peritonitis. BMC Veterinary Research 13 (1) 228.

Felten S, Matiasek K, Gruendl S, Sangl L, Wess G, Hartmann K (2017b): Investigation into the utility of an immunocytochemical assay in body cavity effusions for diagnosis of feline infectious peritonitis. Journal of Feline Medicine and Surgery 19 (4) 410-418.

Felten S, Weider K, Doenges S, Gruendl S, Matiasek K, Hermanns W, Mueller E, Matiasek L, Fischer A, Weber K, Hirschberger J, Wess G, Hartmann K (2017c): Detection of feline coronavirus spike gene mutations as a tool to diagnose feline infectious peritonitis. Journal of Feline Medicine and Surgery 19 (4) 321-335.

Felten S, Matiasek K, Gruendl S, Sangl L, Hartmann K (2018): Utility of an immunocytochemical assay using aqueous humor in the diagnosis of feline infectious peritonitis. Veterinary Ophthalmology 21 (1) 27-34.

Felten S, Hartmann K (2019): Diagnosis of Feline Infectious Peritonitis: A Review of the Current Literature. Viruses 11 (11).

Felten S, Klein-Richers U, Hofmann-Lehmann R, Bergmann M, Unterer S, Leutenegger CM, Hartmann K (2020): Correlation of Feline Coronavirus Shedding in Feces with Coronavirus Antibody Titer. Pathogens 9 (8) 598.

Felten S, Matiasek K, Leutenegger CM, Sangl L, Herre S, Dorfelt S, Fischer A, Hartmann K (2021): Diagnostic Value of Detecting Feline Coronavirus RNA and Spike Gene Mutations in Cerebrospinal Fluid to Confirm Feline Infectious Peritonitis. Viruses 13 (2) 186.

Felten S, Klein-Richers U, Unterer S, Bergmann M, Leutenegger CM, Pantchev N, Balzer J, Zablotski Y, Hofmann-Lehmann R, Hartmann K (2022): Role of Feline Coronavirus as Contributor to Diarrhea in Cats from Breeding Catteries. Viruses 14 (5).

Felten S, Klein-Richers U, Unterer S, Bergmann M, Zablotski Y, Hofmann-Lehmann R, Hartmann K (2023): Patterns of Feline Coronavirus Shedding and Associated Factors in Cats from Breeding Catteries. Viruses 15 (6) 1279.

Ferreira A, Marwood R, Batchelor D, Maddox T, Mortier JR (2020): Prevalence and clinical significance of the medullary rim sign identified on ultrasound of feline kidneys. Veterinary Record 186 (16) 533.

Fischer Y, Ritz S, Weber K, Sauter-Louis C, Hartmann K (2011): Randomized, Placebo Controlled Study of the Effect of Propentofylline on Survival Time and Quality of Life of Cats with Feline Infectious Peritonitis. Journal of Veterinary Internal Medicine 25 (6) 1270-1276.

Fischer Y, Sauter-Louis C, Hartmann K (2012a): Diagnostic accuracy of the Rivalta test for feline infectious peritonitis. Veterinary Clinical Pathology 41 (4) 558-567.

Fischer Y, Wess G, Hartmann K (2012b): [Pericardial effusion in a cat with feline infectious peritonitis]. Schweizer Archiv fur Tierheilkunde 154 (1) 27-31.

Fischer Y, Weber K, Sauter-Louis C, Hartmann K (2013): The Rivalta’s test as a diagnostic variable in feline effusions – evaluation of optimum reaction and storage conditions. Tierärztliche Praxis 41 (5) 297-303.

Fish EJ, Diniz PPV, Juan YC, Bossong F, Collisson EW, Drechsler Y, Kaltenboeck B (2018): Cross-sectional quantitative RT-PCR study of feline coronavirus viremia and replication in peripheral blood of healthy shelter cats in Southern California. Journal of Feline Medicine and Surgery 20 (4) 295-301.

Foley J, Pedersen N (1996): The inheritence of susceptibility to feline infectious peritonitis in purebred catteries. Feline Practice 24 14-22.

Foley JE, Poland A, Carlson J, Pedersen NC (1997a): Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus. Journal of the American Veterinary Medical Association 210 (9) 1313-1318.

Foley JE, Poland A, Carlson J, Pedersen NC (1997b): Patterns of feline coronavirus infection and fecal shedding from cats in multiple-cat environments. Journal of the American Veterinary Medical Association 210 (9) 1307-1312.

Foley JE, Lapointe JM, Koblik P, Poland A, Pedersen NC (1998): Diagnostic features of clinical neurologic feline infectious peritonitis. Journal of Veterinary Internal Medicine 12 (6) 415-423.

Foley JE, Leutenegger C (2001): A review of coronavirus infection in the central nervous system of cats and mice. Journal of Veterinary Internal Medicine 15 (5) 438-444.

Ford RB (1986): Biological response modifiers in the management of viral infection. Veterinary Clinics of North America: Small Animal Practice 16 (6) 1191-1204.

Freiche GM, Guidez CL, Duarte M, Le poder YB (2016): Sequencing of 3c and spike genes in feline infectious peritonitis: which samples are the most relevant for analysis? A retrospective study of 33 cases from 2008 to 2014. J. Vet. Intern. Med. (abstract) 30 411.

Gao YY, Wang Q, Liang XY, Zhang S, Bao D, Zhao H, Li SB, Wang K, Hu GX, Gao FS (2023): An updated review of feline coronavirus: mind the two biotypes. Virus Research 326 199059.

Gelain ME, Meli M, Paltrinieri S (2006): Whole blood cytokine profiles in cats infected by feline coronavirus and healthy non-FCoV infected specific pathogen-free cats. Journal of Feline Medicine and Surgery 8 (6) 389-399.

Gerber JD, Ingersoll JD, Gast AM, Christianson KK, Selzer NL, Landon RM, Pfeiffer NE, Sharpee RL, Beckenhauer WH (1990): Protection against feline infectious peritonitis by intranasal inoculation of a temperature-sensitive FIPV vaccine. Vaccine 8 (6) 536-542.

Gerber JD (1995): Overview of the Development of a Modified Live Temperature-Sensitive FIP Virus Vaccine. Feline Practice 23 62-66.

Gil S, Leal RO, Duarte A, McGahie D, Sepulveda N, Siborro I, Cravo J, Cartaxeiro C, Tavares LM (2013): Relevance of feline interferon omega for clinical improvement and reduction of concurrent viral excretion in retrovirus infected cats from a rescue shelter. Research in Veterinary Science 94 (3) 753-763.

Giordano A, Spagnolo V, Colombo A, Paltrinieri S (2004): Changes in some acute phase protein and immunoglobulin concentrations in cats affected by feline infectious peritonitis or exposed to feline coronavirus infection. Veterinary Journal 167 (1) 38-44.

Giordano A, Paltrinieri S, Bertazzolo W, Milesi E, Parodi M (2005): Sensitivity of Tru-cut and fine needle aspiration biopsies of liver and kidney for diagnosis of feline infectious peritonitis. Veterinary Clinical Pathology 34 (4) 368-374.

Giordano A, Paltrinieri S (2009): Interferon-gamma in the serum and effusions of cats with feline coronavirus infection. Veterinary Journal 180 (3) 396-368.

Giori L, Giordano A, Giudice C, Grieco V, Paltrinieri S (2011): Performances of different diagnostic tests for feline infectious peritonitis in challenging clinical cases. Journal of Small Animal Practice 52 (3) 152-157.

Giuliano A, Watson P, Owen L, Skelly B, Davison L, Dobson J, Costantino-Casas F (2020): Idiopathic sterile pyogranuloma in three domestic cats. Journal of Small Animal Practice 61 (3) 202-205.

Gonon V, Duquesne V, Klonjkowski B, Monteil M, Aubert A, Eloit M (1999): Clearance of infection in cats naturally infected with feline coronaviruses is associated with an anti-S glycoprotein antibody response. Journal of General Virology 80 2315-2317.

Graham EM, Went K, Serra F, Dunbar D, Fuentes M, Mcdonald M, Jackson MW (2012): Early molecular diagnosis of an effusive FIP outbreak in antibody-negative kittens. Journal of Feline Medicine and Surgery 14 652.

Grapes NJ, Taylor-Brown FE, Volk HA, De Decker S (2021): Clinical reasoning in feline vestibular syndrome: which presenting features are the most important? Journal of Feline Medicine and Surgery 23 (8) 669-678.

Green J, Syme H, Tayler S (2023): Thirty-two cats with effusive or non-effusive feline infectious peritonitis treated with a combination of remdesivir and GS-441524. Journal of Veterinary Internal Medicine 37 (5) 1784-1793.

Gruendl S, Matiasek K, Matiasek L, Fischer A, Felten S, Jurina K, Hartmann K (2016): Diagnostic utility of cerebrospinal fluid immunocytochemistry for diagnosis of feline infectious peritonitis manifesting in the central nervous system. Journal of Feline Medicine and Surgery 19 (6) 576-585.

Gulersoy E, Ok M, Uney K, Durgut MK, Parlak TM, Ekici YE (2023): Intestinal injury and vasculitis biomarkers in cats with feline enteric coronavirus and effusive feline infectious peritonitis. Veterinary Medicine Science 9 (6) 2420-2429.

Gunn-Moore DA, Caney SM, Gruffydd-Jones TJ, Helps CR, Harbour DA (1998): Antibody and cytokine responses in kittens during the development of feline infectious peritonitis (FIP). Veterinary Immunology and Immunopathology 65 (2-4) 221-242.

Gunther S, Felten S, Wess G, Hartmann K, Weber K (2018): Detection of feline Coronavirus in effusions of cats with and without feline infectious peritonitis using loop-mediated isothermal amplification. Journal of Virological Methods 256 32-36.

Gut M, M. Leutenegger C, B. Huder J, C. Pedersen N, Lutz H (1999): One-tube fluorogenic reverse transcription-polymerase chain reaction for the quantitation of feline coronaviruses. Journal of Virological Methods 77 (1) 37-46.

Guyot GW, Cross HA, Bennett TL (1980): Early social isolation of the domestic cat: responses to separation from social and nonsocial rearing stimuli. Developmental Psychobiology 13 (3) 309-315.

Haake C, Cook S, Pusterla N, Murphy B (2020): Coronavirus Infections in Companion Animals: Virology, Epidemiology, Clinical and Pathologic Features. Viruses 12 (9) 1023.

Hartmann K, Binder C, Hirschberger J, Cole D, Reinacher M, Schroo S, Frost J, Egberink H, Lutz H, Hermanns W (2003): Comparison of different tests to diagnose feline infectious peritonitis. Journal of Veterinary Internal Medicine 17 (6) 781-790.

Hartmann K (2005): Feline infectious peritonitis. Veterinary Clinics of North America Small Animal Practice 35 (1) 39-79.

Hartmann K, Ritz S (2008a): Treatment of cats with feline infectious peritonitis. Veterinary Immunology and Immunopathology 123 (1-2) 172-175.

Hartmann K, Ritz S (2008b): Feline Infectious Peritonitis. in dM K (ed.), Clinical Case Veterinary Interferon Handbook (Virbac SA, BP 27, O6510 CARROS, France.).

Hartmann K (2016): Coronavirus Infections (Canine and Feline), including Feline Infectious Peritonitis. in SJ Ettinger, EC Feldman and E Côté (eds.), Textbook of Veterinary Internal Medicine (Elsevier: St. Louis).

Hartmann K, Pennisi MG, Dorsch R (2020): Infectious Agents in Feline Chronic Kidney Disease. Advances in Small Animal Care 1 189-206.

Harvey CJ, Lopez JW, Hendrick MJ (1996): An uncommon intestinal manifestation of feline infectious peritonitis: 26 cases (1986-1993). Journal of the American Veterinary Medical Association 209 (6) 1117-1120.

Hayashi T, Watabe Y, Nakayama H, Fujiwara K (1982): Enteritis due to feline infectious peritonitis virus. Japanese Journal of Veterinary Research 44 (1) 97-106.

Hazuchova K, Held S, Neiger R (2017): Usefulness of acute phase proteins in differentiating between feline infectious peritonitis and other diseases in cats with body cavity effusions. Journal of Feline Medicine and Surgery 19 (8) 809-816.

Healey EA, Andre NM, Miller AD, Whitaker GR, Berliner EA (2022): Outbreak of feline infectious peritonitis (FIP) in shelter-housed cats: molecular analysis of the feline coronavirus S1/S2 cleavage site consistent with a ‘circulating virulent–avirulent theory’ of FIP pathogenesis. Journal of Feline Medicine and Surgery Open Reports 8 (1) 20551169221074226.

Hellemans A, Acar DD, Stroobants VJE, Theuns S, Desmarets LMB, Nauwynck HJ (2020): A comparative study of techniques used for the diagnosis of effusive feline infectious peritonitis. Vlaams Diergeneeskundig Tijdschrift 89 100-110.

Herrewegh AA, de Groot RJ, Cepica A, Egberink HF, Horzinek MC, Rottier PJ (1995a): Detection of feline coronavirus RNA in feces, tissues, and body fluids of naturally infected cats by reverse transcriptase PCR. Journal of Clinical Microbiology 33 (3) 684-689.

Herrewegh AA, Vennema H, Horzinek MC, Rottier PJ, de Groot RJ (1995b): The molecular genetics of feline coronaviruses: comparative sequence analysis of the ORF7a/7b transcription unit of different biotypes. Virology 212 (2) 622-631.

Herrewegh AA, Mahler M, Hedrich HJ, Haagmans BL, Egberink HF, Horzinek MC, Rottier PJ, de Groot RJ (1997): Persistence and evolution of feline coronavirus in a closed cat-breeding colony. Virology 234 (2) 349-363.

Herrewegh AA, Smeenk I, Horzinek MC, Rottier PJ, de Groot RJ (1998): Feline coronavirus type II strains 79-1683 and 79-1146 originate from a double recombination between feline coronavirus type I and canine coronavirus. Journal of Virology 72 (5) 4508-4514.

Hickman MA, Morris JG, Rogers QR (1995): Elimination of Feline Coronavirus Infection from a Large Experimental Specific Pathogen-Free Cat Breeding Colony by Serologic Testing and Isolation Feline Practice 23 (3) 96-102.

Hirschberger J, Hartmann K, Wilhelm N, Frost J, Lutz H, Kraft W (1995): [Clinical symptoms and diagnosis of feline infectious peritonitis]. Tierarztliche Praxis 23 (1) 92-99.

Hoey C, Nye G, Fadda A, Bradshaw J, Barker EN (2020): Subarachnoid diverticulum associated with feline infectious peritonitis in a Siberian cat. Journal of Feline Medicine and Surgery Open Reports 6 (2) 2055116920941477.

Hohdatsu T, Okada S, Ishizuka Y, Yamada H, Koyama H (1992): The prevalence of types I and II feline coronavirus infections in cats. Journal of Veterinary Medical Science 54 (3) 557-562.

Hohdatsu T, Yamato H, Ohkawa T, Kaneko M, Motokawa K, Kusuhara H, Kaneshima T, Arai S, Koyama H (2003): Vaccine efficacy of a cell lysate with recombinant baculovirus-expressed feline infectious peritonitis (FIP) virus nucleocapsid protein against progression of FIP. Veterinary Microbiology 97 (1-2) 31-44.

Horzinek MC, Osterhaus AD (1979): Feline infectious peritonitis: a worldwide serosurvey. American Journal of Veterinary Research 40 (10) 1487-1492.

Horzinek MC, Lutz H (2000): An Update on Feline Infectious Peritonitis. Veterinary Sciences Tomorrow Nr.0 1-10.

Hosie MJ, Hofmann-Lehmann R, Hartmann K, Egberink H, Truyen U, Addie DD, Belak S, Boucraut-Baralon C, Frymus T, Lloret A, Lutz H, Marsilio F, Pennisi MG, Tasker S, Thiry E, Mostl K (2021): Anthropogenic Infection of Cats during the 2020 COVID-19 Pandemic. Viruses 13 (2) 185.

Hoskins JD (1995a): The Potential Use of a Modified Live FIPV Vaccine to Prevent Experimental FECV Infection. Feline Practice 23 (3) 89-90.

Hoskins JD (1995b): Independent Evaluation of a Modified Live Feline Infectious Peritonitis Virus Vaccine Under Experimental Conditions (Louisiana Experience). Feline Practice 23 (3) 72-73.

Howell M, Evans SJM, Cornwall M, Santangelo KS (2020): Multiplex fluorescent immunocytochemistry for the diagnosis of feline infectious peritonitis: Determining optimal storage conditions. Veterinary Clinical Pathology 49 (4) 640-645.

Hsieh LE, Lin CN, Su BL, Jan TR, Chen CM, Wang CH, Lin DS, Lin CT, Chueh LL (2010): Synergistic antiviral effect of Galanthus nivalis agglutinin and nelfinavir against feline coronavirus. Antiviral Research 88 (1) 25-30.

Hsieh LE, Huang WP, Tang DJ, Wang YT, Chen CT, Chueh LL (2013): 3C protein of feline coronavirus inhibits viral replication independently of the autophagy pathway. Research in Veterinary Science 95 (3) 1241-1247.

Hsieh LE, Chueh LL (2014): Identification and genotyping of feline infectious peritonitis-associated single nucleotide polymorphisms in the feline interferon-gamma gene. Veterinary Research 45 57.

Hughes D, Howard G, Malik R (2021): Treatment of FIP in cats with remdesivir. The Veterinarian May 19-27.

Hugo TB, Heading KL (2015): Prolonged survival of a cat diagnosed with feline infectious peritonitis by immunohistochemistry. Canadian Veterinary Journal 56 (1) 53-58.

Hung L, Hopper BJ, Lenard Z (2022): Retrospective analysis of radiographic signs in feline pleural effusions to predict disease aetiology. BMC Veterinary Research 18 (1) 118.

Ishida T, Shibanai A, Tanaka S, Uchida K, Mochizuki M (2004): Use of recombinant feline interferon and glucocorticoid in the treatment of feline infectious peritonitis. Journal of Feline Medicine and Surgery 6 (2) 107-109.

Ives EJ, Vanhaesebrouck AE, Cian F (2013): Immunocytochemical demonstration of feline infectious peritonitis virus within cerebrospinal fluid macrophages. Journal of Feline Medicine and Surgery 15 (12) 1149-1153.

Izes AM, Kimble B, Norris JM, Govendir M (2020a): In vitro hepatic metabolism of mefloquine using microsomes from cats, dogs and the common brush-tailed possum (Trichosurus vulpecula). PloS One 15 (4) e0230975.

Izes AM, Kimble B, Norris JM, Govendir M (2020b): Assay validation and determination of in vitro binding of mefloquine to plasma proteins from clinically normal and FIP-affected cats. PloS One 15 (8) e0236754.

Izes AM, Yu J, Norris JM, Govendir M (2020c): Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats. Veterinary Quarterly 40 (1) 322-330.

Jähne S, Felten S, Bergmann M, Erber K, Matiasek K, Meli ML, Hofmann-Lehmann R, Hartmann K (2022): Detection of Feline Coronavirus Variants in Cats without Feline Infectious Peritonitis. Viruses 14 (8) 1671.

Jaimes JA, Whittaker GR (2018): Feline coronavirus: Insights into viral pathogenesis based on the spike protein structure and function. Virology 517 108-121.

Jaimes JA, Millet JK, Stout AE, Andre NM, Whittaker GR (2020): A Tale of Two Viruses: The Distinct Spike Glycoproteins of Feline Coronaviruses. Viruses 12 (1).

Jeffery U, Deitz K, Hostetter S (2012): Positive predictive value of albumin: globulin ratio for feline infectious peritonitis in a mid-western referral hospital population. Journal of Feline Medicine and Surgery 14 (12) 903-905.

Jiao Z, Yan Y, Chen Y, Wang G, Wang X, Li L, Yang M, Hu X, Guo Y, Shi Y, Peng G (2022): Adaptive Mutation in the Main Protease Cleavage Site of Feline Coronavirus Renders the Virus More Resistant to Main Protease Inhibitors. Journal of Virology 96 (17) e0090722.

Jinks MR, English RV, Gilger BC (2016): Causes of endogenous uveitis in cats presented to referral clinics in North Carolina. Veterinary Ophthalmology 19 30-37.

Johnson LR, Epstein SE, Reagan KL (2023): Etiology and effusion characteristics in 29 cats and 60 dogs with pyothorax (2010-2020). Journal of Veterinary Internal Medicine 37 (3) 1155-1165.

Jones S, Novicoff W, Nadeau J, Evans S (2021): Unlicensed GS-441524-Like Antiviral Therapy Can Be Effective for at-Home Treatment of Feline Infectious Peritonitis. Animals 11 (8) 2257.

Kameshima S, Kimura Y, Doki T, Takano T, Park CH, Itoh N (2020): Clinical efficacy of combination therapy of itraconazole and prednisolone for treating effusive feline infectious peritonitis. Journal of Veterinary Medical Science 82 (10) 1492-1496.

Kass PH, Dent TH (1995): The epidemiology of feline infectious peritonitis in catteries. Feline Practice 23 27-32.

Katayama M, Uemura Y (2021): Therapeutic Effects of Mutian(®) Xraphconn on 141 Client-Owned Cats with Feline Infectious Peritonitis Predicted by Total Bilirubin Levels. Veterinary Sciences 8 (12) 328.

Katayama M, Uemura Y (2023): Prognostic Prediction for Therapeutic Effects of Mutian on 324 Client-Owned Cats with Feline Infectious Peritonitis Based on Clinical Laboratory Indicators and Physical Signs. Veterinary Sciences 10 (2) 136.

Kedward-Dixon H, Barker EN, Tasker S, Kipar A, Helps CR (2020): Evaluation of polymorphisms in inflammatory mediator and cellular adhesion genes as risk factors for feline infectious peritonitis. Journal of Feline Medicine and Surgery 22 (6) 564-570.

Kennedy M, Citino S, McNabb AH, Moffatt AS, Gertz K, Kania S (2002): Detection of feline coronavirus in captive Felidae in the USA. J Vet Diagn Invest 14 (6) 520-522.

Kent AM, Guan S, Jacque N, Novicoff W, Evans SJM (2024): Unlicensed antiviral products used for the at-home treatment of feline infectious peritonitis contain GS-441524 at significantly different amounts than advertised. Journal of the American Veterinary Medical Association 1-9.

Kent M (2009): The cat with neurological manifestations of systemic disease. Key conditions impacting on the CNS. Journal of Feline Medicine and Surgery 11 (5) 395-407.

Kim Y, Mandadapu SR, Groutas WC, Chang KO (2013): Potent inhibition of feline coronaviruses with peptidyl compounds targeting coronavirus 3C-like protease. Antiviral Research 97 (2) 161-168.

Kim Y, Liu H, Galasiti Kankanamalage AC, Weerasekara S, Hua DH, Groutas WC, Chang KO, Pedersen NC (2016): Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor. PLoS Pathog 12 (3) e1005531.

Kimble B, Coggins SJ, Norris JM, Thompson MF, Govendir M (2023): Quantification of GS-441524 concentration in feline plasma using high performance liquid chromatography with fluorescence detection. Veterinary Quarterly 43 (1) 1-9.

Kipar A, Kremendahl J, Addie DD, Leukert W, Grant CK, Reinacher M (1998): Fatal enteritis associated with coronavirus infection in cats. Journal of Comparative Pathology 119 (1) 1-14.

Kipar A, Koehler K, Bellmann S, Reinacher M (1999): Feline infectious peritonitis presenting as a tumour in the abdominal cavity. Veterinary Record 144 (5) 118-122.

Kipar A, May H, Menger S, Weber M, Leukert W, Reinacher M (2005): Morphologic features and development of granulomatous vasculitis in feline infectious peritonitis. Veterinary Pathology 42 (3) 321-330.

Kipar A, Baptiste K, Barth A, Reinacher M (2006): Natural FCoV infection: cats with FIP exhibit significantly higher viral loads than healthy infected cats. Journal of Feline Medicine and Surgery 8 (1) 69-72.

Kipar A, Meli ML, Baptiste KE, Bowker LJ, Lutz H (2010): Sites of feline coronavirus persistence in healthy cats. Journal of General Virology 91 (Pt 7) 1698-1707.

Kipar A, Meli ML (2014): Feline Infectious Peritonitis: Still an Enigma? Veterinary Pathology 51 (2) 505-526.

Kiss I, Poland AM, Pedersen NC (2004): Disease outcome and cytokine responses in cats immunized with an avirulent feline infectious peritonitis virus (FIPV)-UCD1 and challenge-exposed with virulent FIPV-UCD8. Journal of Feline Medicine and Surgery 6 (2) 89-97.

Klein-Richers U, Hartmann K, Hofmann-Lehmann R, Unterer S, Bergmann M, Rieger A, Leutenegger C, Pantchev N, Balzer J, Felten S (2020): Prevalence of Feline Coronavirus Shedding in German Catteries and Associated Risk Factors. Viruses 12 (9).

Kline KL, Joseph RJ, Averdill DR (1994): Feline infectious peritonitis with neurologic involvement: clinical and pathological findings in 24 cats. Journal of the American Animal Hospital Association 30 111-118.

Kokkinaki KCG, Saridomichelakis MN, Mylonakis ME, Leontides L, Xenoulis PG (2023): Seroprevalence of and risk factors for feline coronavirus infection in cats from Greece. Comparative Immunology, Microbiology and Infectious Diseases 94 101962.

Konig A, Hartmann K, Mueller RS, Wess G, Schulz BS (2019): Retrospective analysis of pleural effusion in cats. Journal of Feline Medicine and Surgery 21 (12) 1102-1110.

Krentz D, Zenger K, Alberer M, Felten S, Bergmann M, Dorsch R, Matiasek K, Kolberg L, Hofmann-Lehmann R, Meli ML, Spiri AM, Horak J, Weber S, Holicki CM, Groschup MH, Zablotski Y, Lescrinier E, Koletzko B, von Both U, Hartmann K (2021): Curing Cats with Feline Infectious Peritonitis with an Oral Multi-Component Drug Containing GS-441524. Viruses 13 (11).

Krentz D, Zwicklbauer K, Felten S, Bergmann M, Dorsch R, Hofmann-Lehmann R, Meli ML, Spiri AM, von Both U, Alberer M, Hönl A, Matiasek K, Hartmann K (2022): Clinical Follow-Up and Postmortem Findings in a Cat That Was Cured of Feline Infectious Peritonitis with an Oral Antiviral Drug Containing GS-441524. Viruses 14 (9) 2040.

Kummrow M, Meli ML, Haessig M, Goenczi E, Poland A, Pedersen NC, Hofmann-Lehmann R, Lutz H (2005): Feline coronavirus serotypes 1 and 2: seroprevalence and association with disease in Switzerland. Clin Diagn Lab Immunol 12 (10) 1209-1215.

Kuritz T (2008): Patent: Methods and compositions for modulation of innate immunity. In. USA.

Lai MM, Cavanagh D (1997): The molecular biology of coronaviruses. Advances in Virus Research 48 1-100.

Le Poder S, Pham-Hung d’Alexandry d’Orangiani AL, Duarte L, Fournier A, Horhogea C, Pinhas C, Vabret A, Eloit M (2013): Infection of cats with atypical feline coronaviruses harbouring a truncated form of the canine type I non-structural ORF3 gene. Infection, Genetics and Evolution 20 488-494.

Legendre AM, Bartges JW (2009): Effect of Polyprenyl Immunostimulant on the survival times of three cats with the dry form of feline infectious peritonitis. Journal of Feline Medicine and Surgery 11 (8) 624-626.

Legendre AM, Kuritz T, Galyon G, Baylor VM, Heidel RE (2017a): Polyprenyl Immunostimulant Treatment of Cats with Presumptive Non-Effusive Feline Infectious Peritonitis In a Field Study. Frontiers in Veterinary Science 4 7.

Legendre AM, Kuritz T, Heidel RE, Baylor VM (2017b): Polyprenyl Immunostimulant in Feline Rhinotracheitis: Randomized Placebo-Controlled Experimental and Field Safety Studies. Frontiers in Veterinary Science 4 24.

Levy JK, Crawford PC, Lappin MR, Dubovi EJ, Levy MG, Alleman R, Tucker SJ, Clifford EL (2008): Infectious diseases of dogs and cats on Isabela Island, Galapagos. Journal of Veterinary Internal Medicine 22 (1) 60-65.

Lewis CS, Porter E, Matthews D, Kipar A, Tasker S, Helps CR, SiddelL SG (2015): Genotyping coronaviruses associated with feline infectious peritonitis. Journal of General Virology 96 1358-1368.

Lewis KM, O’Brien RT (2010): Abdominal Ultrasonographic Findings Associated With Feline Infectious Peritonitis: A Retrospective Review of 16 Cases. Journal of the American Animal Hospital Association 46 (3) 152-160.

Li F (2016): Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu Rev Virol 3 (1) 237-261.

Li Y, Cao L, Li G, Cong F, Li Y, Sun J, Luo Y, Chen G, Li G, Wang P, Xing F, Ji Y, Zhao J, Zhang Y, Guo D, Zhang X (2022): Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models. Journal of Medicinal Chemistry 65 (4) 2785-2793.

Licitra BN, Millet JK, Regan AD, Hamilton BS, Rinaldi VD, Duhamel GE, Whittaker GR (2013): Mutation in spike protein cleavage site and pathogenesis of feline coronavirus. Emerging Infectious Diseases 19 (7) 1066-1073.

Lin CN, Su BL, Wang CH, Hsieh MW, Chueh TJ, Chueh LL (2009): Genetic diversity and correlation with feline infectious peritonitis of feline coronavirus type I and II: a 5-year study in Taiwan. Veterinary Microbiology 136 (3-4) 233-239.

Lin L, Yao D, Wu L, Fan R, Liu Y, Zhou Z (2022): Molecular epidemiology of type I and II feline coronavirus from cats with suspected feline infectious peritonitis in China between 2019 and 2021. Archives of Virology 167 (1) 189-194.

Linn-Pearl RN, Powell RM, Newman HA, Gould DJ (2015): Validity of aqueocentesis as a component of anterior uveitis investigation in dogs and cats. Veterinary Ophthalmology 18 (4) 326-334.

Litster AL, Pogranichniy R, Lin TL (2013): Diagnostic utility of a direct immunofluorescence test to detect feline coronavirus antigen in macrophages in effusive feline infectious peritonitis. Veterinary Journal 198 (2) 362-366.

Liu IJ, Tsai WT, Hsieh LE, Chueh LL (2013): Peptides corresponding to the predicted heptad repeat 2 domain of the feline coronavirus spike protein are potent inhibitors of viral infection. PloS One 8 (12) e82081.

Longstaff L, Porter E, Crossley VJ, Hayhow SE, Helps CR, Tasker S (2017): Feline coronavirus quantitative reverse transcriptase polymerase chain reaction on effusion samples in cats with and without feline infectious peritonitis. Journal of Feline Medicine and Surgery 19 (2) 240-245.

Lorusso E, Mari V, Losurdo M, Lanave G, Trotta A, Dowgier G, Colaianni ML, Zatelli A, Elia G, Buonavoglia D, Decaro N (2019): Discrepancies between feline coronavirus antibody and nucleic acid detection in effusions of cats with suspected feline infectious peritonitis. Research in Veterinary Science 125 421-424.

Lutz H, Hofmann-Lehmann R, Winkler G, Kottwitz B, Dittmer A, Wolfensberger C, Arnold P (1990): Feline immunodeficiency virus in Switzerland: clinical aspects and epidemiology in comparison with feline leukemia virus and coronaviruses. Schweizer Archiv fur Tierheilkunde 132 (5) 217-225.

Lutz H, Gut M, Leutenegger CM, Schiller I, Wiseman A, Meli M (2002): Kinetics of FCoV infection in kittens born in catteries of high risk for FIP under different rearing conditions. In Second International Feline Coronavirus/Feline Infectious Peritonitis Symposium. Glasgow, Scotland, UK.

Lutz M, Steiner AR, Cattori V, Hofmann-Lehmann R, Lutz H, Kipar A, Meli ML (2020): FCoV Viral Sequences of Systemically Infected Healthy Cats Lack Gene Mutations Previously Linked to the Development of FIP. Pathogens 9 (8) 603.

Lv J, Bai Y, Wang Y, Yang L, Jin Y, Dong J (2022): Effect of GS-441524 in combination with the 3C-like protease inhibitor GC376 on the treatment of naturally transmitted feline infectious peritonitis. Frontiers in Veterinary Science 9 1002488.

Macdonald ES, Norris CR, Berghaus RB, Griffey SM (2003): Clinicopathologic and radiographic features and etiologic agents in cats with histologically confirmed infectious pneumonia: 39 cases (1991-2000). Journal of the American Veterinary Medical Association 223 (8) 1142-1150.

Malbon AJ, Fonfara S, Meli ML, Hahn S, Egberink H, Kipar A (2019): Feline Infectious Peritonitis as a Systemic Inflammatory Disease: Contribution of Liver and Heart to the Pathogenesis. Viruses 11 (12).

Malbon AJ, Michalopoulou E, Meli ML, Barker EN, Tasker S, Baptiste K, Kipar A (2020a): Colony Stimulating Factors in Early Feline Infectious Peritonitis Virus Infection of Monocytes and in End Stage Feline Infectious Peritonitis; A Combined In Vivo And In Vitro Approach. Pathogens 9 (11) 893.

Malbon AJ, Russo G, Burgener C, Barker EN, Meli ML, Tasker S, Kipar A (2020b): The Effect of Natural Feline Coronavirus Infection on the Host Immune Response: A Whole-Transcriptome Analysis of the Mesenteric Lymph Nodes in Cats with and without Feline Infectious Peritonitis. Pathogens 9 (7).

Mancianti F, Pedonese F, Zullino C (1998): Efficacy of oral administration of itraconazole to cats with dermatophytosis caused by Microsporum canis. Journal of the American Veterinary Medical Association 213 (7) 993-995.

Marzok M, Kandeel M, Al-Mubarak A, Farag A, Elgohary A, El-khodery S (2023): Global prevalence of feline coronavirus infection (FCoV) in domestic cats; systematic meta-analysis. Journal of Animal and Plant Sciences 33 (6) 1269-1285.

Mateos Gonzalez M, Sierra Gonzalo E, Casado Lopez I, Arnalich Fernandez F, Beato Perez JL, Monge Monge D, Vargas Nunez JA, Garcia Fenoll R, Suarez Fernandez C, Freire Castro SJ, Mendez Bailon M, Perales Fraile I, Madrazo M, Pesqueira Fontan PM, Magallanes Gamboa JO, Gonzalez Garcia A, Crestelo Vieitez A, Fonseca Aizpuru EM, Aranguren Arostegui A, Coduras Erdozain A, Martinez Cilleros C, Loureiro Amigo J, Epelde F, Lumbreras Bermejo C, Anton Santos JM, For The S-C-N (2021): The Prognostic Value of Eosinophil Recovery in COVID-19: A Multicentre, Retrospective Cohort Study on Patients Hospitalised in Spanish Hospitals. Journal of Clinical Medicine 10 (2).

McArdle F, Tennant B, Bennett M, Kelly DF, Gaskell CJ, Gaskell RM (1995): Independent Evaluation of a Modified Live FIPV Vaccine Under Experimental Conditions (University of Liverpool Experience}. Feline Practice 23 (3) 67-71.

McDonagh P, Sheehy PA, Norris JM (2011): In vitro inhibition of feline coronavirus replication by small interfering RNAs. Veterinary Microbiology 150 (3-4) 220-229.

McDonagh P, Sheehy PA, Norris JM (2014): Identification and characterisation of small molecule inhibitors of feline coronavirus replication. Veterinary Microbiology 174 (3-4) 438-447.

McDonagh P, Sheehy PA, Norris JM (2015): Combination siRNA therapy against feline coronavirus can delay the emergence of antiviral resistance in vitro. Veterinary Microbiology 176 (1-2) 10-18.

McKay LA, Meachem M, Snead E, Brannen T, Mutlow N, Ruelle L, Davies JL, van der Meer F (2020): Prevalence and mutation analysis of the spike protein in feline enteric coronavirus and feline infectious peritonitis detected in household and shelter cats in western Canada. Canadian Journal of Veterinary Research 84 (1) 18-23.

Meli M, Kipar A, Muller C, Jenal K, Gonczi E, Borel N, Gunn-Moore D, Chalmers S, Lin F, Reinacher M, Lutz H (2004): High viral loads despite absence of clinical and pathological findings in cats experimentally infected with feline coronavirus (FCoV) type I and in naturally infected FCoV-infected cats. Journal of Feline Medicine and Surgery 6 (2) 69-81.

Meli ML, Burr P, Decaro N, Graham E, Jarrett O, Lutz H, McDonald M, Addie DD (2013): Samples with high virus load cause a trend toward lower signal in feline coronavirus antibody tests. Journal of Feline Medicine and Surgery 15 (4) 295-299.

Meli ML, Spiri AM, Zwicklbauer K, Krentz D, Felten S, Bergmann M, Dorsch R, Matiasek K, Alberer M, Kolberg L, von Both U, Hartmann K, Hofmann-Lehmann R (2022): Fecal Feline Coronavirus RNA Shedding and Spike Gene Mutations in Cats with Feline Infectious Peritonitis Treated with GS-441524. Viruses 14 (5) 1069.

Mella SL, Cardy TJ, Volk HA, De Decker S (2020): Clinical reasoning in feline spinal disease: which combination of clinical information is useful? Journal of Feline Medicine and Surgery 22 (6) 521-530.

Mesquita LP, Hora AS, de Siqueira A, Salvagni FA, Brandao PE, Maiorka PC (2016): Glial response in the central nervous system of cats with feline infectious peritonitis. Journal of Feline Medicine and Surgery 18 (12) 1023-1030.

Millet JK, Whittaker GR (2015): Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. Virus Research 202 120-134.

Milliron SM, Seyler ZG, Myers AN, Rodrigues Hoffmann A, Hnot M, Wiener DJ (2021): Pyogranulomatous panniculitis in a domestic cat associated with Pseudomonas luteola infection. Veterinary Dermatology 32 (1) 83-e15.

Mochizuki M, Nakatani H, Yoshida M (1994): Inhibitory effects of recombinant feline interferon on the replication of feline enteropathogenic viruses in vitro. Veterinary Microbiology 39 (1-2) 145-152.

Mohseni N, Royster A, Ren S, Ma Y, Pintado M, Mir M, Mir S (2023): A novel compound targets the feline infectious peritonitis virus nucleocapsid protein and inhibits viral replication in cell culture. Journal of Biological Chemistry 299 (3) 102976.

Möstl K, Egberink H, Addie D, Frymus T, Boucraut-Baralon C, Truyen U, Hartmann K, Lutz H, Gruffydd-Jones T, Radford AD, Lloret A, Pennisi MG, Hosie MJ, Marsilio F, Thiry E, Belak S, MC H (2013): Prevention of infectious diseases in cat shelters: ABCD guidelines. J Feline Med Surg 15 546-554.

Möstl K, Addie DD, Boucraut-Baralon C, Egberink H, Frymus T, Gruffydd-Jones T, Hartmann K, Hosie MJ, Lloret A, Lutz H, Marsilio F, Pennisi MG, Radford AD, Thiry E, Truyen U, Horzinek MC (2015): Something old, something new: Update of the 2009 and 2013 ABCD guidelines on prevention and management of feline infectious diseases. Journal of Feline Medicine and Surgery 17 (7) 570-582.

Möstl K, Addie DD, Belak S, Boucraut-Baralon C, Egberink H, Frymus T, Hartmann K, Hofmann-Lehmann R, Frymus T, Lloret A, Marsilio F, Pennisi MG, Tasker S, Thiry E, Truyen U, Hosie MJ (2021): Infectious diseases in shelter situations and their management. http://www.abcdcatsvets.org/infectious-diseases-in-shelter-situations-and-their-management/ Accessed 22nd May 2022.

Moyadee W, Chiteafea N, Tuanthap S, Choowongkomon K, Roytrakul S, Rungsuriyawiboon O, Boonkaewwan C, Tansakul N, Rattanasrisomporn A, Rattanasrisomporn J (2023): The first study on clinicopathological changes in cats with feline infectious peritonitis with and without retrovirus coinfection. Veterinary World 16 (4) 820-827.

Muirden A (2002): Prevalence of feline leukaemia virus and antibodies to feline immunodeficiency virus and feline coronavirus in stray cats sent to an RSPCA hospital. Veterinary Record 150 (20) 621-625.

Muller TR, Penninck DG, Webster CR, Conrado FO (2023): Abdominal ultrasonographic findings of cats with feline infectious peritonitis: an update. Journal of Feline Medicine and Surgery 25 (12) 1098612X231216000.

Mulligan AJ, Browning ME (2024): Quality assessment and characterization of unregulated antiviral drugs for feline infectious peritonitis: implications for treatment, safety, and efficacy. American Journal of Veterinary Research 10.2460/ajvr.23.10.0221.

Murphy BG, Perron M, Murakami E, Bauer K, Park Y, Eckstrand C, Liepnieks M, Pedersen NC (2018): The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Veterinary Microbiology 219 226-233.

Mustaffa-Kamal F, Liu H, Pedersen NC, Sparger EE (2019): Characterization of antiviral T cell responses during primary and secondary challenge of laboratory cats with feline infectious peritonitis virus (FIPV). BMC Veterinary Research 15 (1) 165.

Muz D, Muz MN (2023): Detection of Feline Coronavirus, Feline Immunodeficiency Virus, Feline Leukemia Virus and Other Pathogen Genetic Material in Whole Blood from Domestic Cats in Türkiye. Acta Vet Eurasia 49 141-148.

Myrrha LW, Silva FMF, Vidigal PMP, Resende M, Bressan GC, Fietto JLR, Santos MR, Silva LMN, Assao VS, Silva-Ju Nior A, de Almeida MR (2019): Feline coronavirus isolates from a part of Brazil: insights into molecular epidemiology and phylogeny inferred from the 7b gene. Journal of Veterinary Medical Science 81 (10) 1455-1460.

Negrin A, Lamb CR, Cappello R, Cherubini GB (2007): Results of magnetic resonance imaging in 14 cats with meningoencephalitis. Journal of Feline Medicine and Surgery 9 (2) 109-116.

Negrin A, Schatzberg S, Platt SR (2009): The paralyzed cat. Neuroanatomic diagnosis and specific spinal cord diseases. Journal of Feline Medicine and Surgery 11 (5) 361-372.

Negrin A, Cherubini GB, Lamb C, Benigni L, Adams V, Platt S (2010): Clinical signs, magnetic resonance imaging findings and outcome in 77 cats with vestibular disease: a retrospective study. Journal of Feline Medicine and Surgery 12 (4) 291-299.

Nekouei O, St-Hilaire S, Hui PC, Chan K, Chan IS, Ngan SYL, Chan Y, Chung KP, Hong S, Chan HM, Or HLI, Chan FY, Yim HT, Barrs VR (2022): Potential therapeutic effects of GS-441524 and GC376 in cats with feline infectious peritonitis. Vet Evid 7 (1).

Ng SW, Selvarajah GT, Hussein MZ, Yeap SK, Omar AR (2020): In Vitro Evaluation of Curcumin-Encapsulated Chitosan Nanoparticles against Feline Infectious Peritonitis Virus and Pharmacokinetics Study in Cats. BioMed Research International 2020 3012198.

Nishijima R, Endo T, Gankhuyag E, Khin S, Jafar SM, Shinohara Y, Tanaka Y, Sawakami K, Yohda M, Furuya T (2023): Detection of anti-feline infectious peritonitis virus activity of a Chinese herb extract using geneLEAD VIII, a fully automated nucleic acid extraction/quantitative PCR testing system. Journal of Veterinary Medical Science 85 (4) 443-446.

Norris JM, Bosward KL, White JD, Baral RM, Catt MJ, Malik R (2005): Clinicopathological findings associated with feline infectious peritonitis in Sydney, Australia: 42 cases (1990-2002). Australian Veterinary Journal 83 (11) 666-673.

O’Halloran C, Gunn-Moore D (2017): Mycobacteria in cats: an update. In Practice 39 (October) 399-406.

Oguzoglu TÇ, Sahna KC, Ataseven VS, Muz D (2010): Prevalence of feline coronavirus (FCoV) and feline leukemia virus (FeLV) in Turkish cats. Ankara Universitesi Veteriner Fakultesi Dergisi 57 (4) 271-274.

Osterhaus AD, Horzinek MC, Reynolds DJ (1977): Seroepidemiology of feline infectious peritonitis virus infections using transmissible gastroenteritis virus as antigen. Journal of Veterinary Medicine. Series B 24 (10) 835-841.

Ouyang H, Liu J, Yin Y, Cao S, Yan R, Ren Y, Zhou D, Li Q, Li J, Liao X, Ji W, Du B, Si Y, Hu C (2022): Epidemiology and Comparative Analyses of the S Gene on Feline Coronavirus in Central China. Pathogens 11 (4).

Owens RA, Flores R, Di Serio F, Li SF, Pallás V, Randles JW, Sano T, Vidalakis G (2012): Viroids. in AMQ King, MJ Adams, EB Carstens and EJ Lefkowitz (eds.), Ninth Report of the International Committee on Taxonomy of Viruses.

Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut N, Morin MJ, Szewczyk LJ, Painter GR (2021): Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2. Antimicrobial Agents and Chemotherapy 65 (5).

Paltrinieri S, Cammarata MP, Cammarata G, Comazzi S (1998): Some aspects of humoral and cellular immunity in naturally occuring feline infectious peritonitis. Veterinary Immunology and Immunopathology 65 (2-4) 205-220.

Paltrinieri S, Cammarata MP, Cammarata G (1999): In vivo diagnosis of feline infectious peritonitis by comparison of protein content, cytology, and direct immunofluorescence test on peritoneal and pleural effusions. Journal of Veterinary Diagnostic Investigation 11 (4) 358-361.

Paltrinieri S, Grieco V, Comazzi S, Cammarata Parodi M (2001): Laboratory profiles in cats with different pathological and immunohistochemical findings due to feline infectious peritonitis (FIP). Journal of Feline Medicine and Surgery 3 (3) 149-159.

Paltrinieri S, Giordano A, Tranquillo V, Guazzetti S (2007a): Critical assessment of the diagnostic value of feline alpha1-acid glycoprotein for feline infectious peritonitis using the likelihood ratios approach. Journal of Veterinary Diagnostic Investigation 19 (3) 266-272.

Paltrinieri S, Metzger C, Battilani M, Pocacqua V, Gelain ME, Giordano A (2007b): Serum alpha1-acid glycoprotein (AGP) concentration in non-symptomatic cats with feline coronavirus (FCoV) infection. Journal of Feline Medicine and Surgery 9 (4) 271-277.

Paltrinieri S, Giordano A, Stranieri A, Lauzi S (2021): Feline infectious peritonitis (FIP) and coronavirus disease 19 (COVID-19): Are they similar? Transboundary and Emerging Diseases 68 (4) 1786-1799.

Paris JK, Wills S, Balzer HJ, Shaw DJ, Gunn-Moore DA (2014): Enteropathogen co-infection in UK cats with diarrhoea. BMC Veterinary Research 10 13.

Parodi MC, Cammarata G, Paltrinieri S, Lavazza A, Ape F (1993): Using Direct Immunofluorescence to Detect Coronaviruses in Peritoneal and Pleural Effusions. Journal of Small Animal Practice 34 (12) 609-613.

Pastoret PP, Henroteaux M (1978): Epigenetic transmission of feline infectious peritonitis. Comparative Immunology, Microbiology and Infectious Diseases 1 (1-2) 67-70.

Paul A, Stayt J (2019): The intestinal microbiome in dogs and cats with diarrhoea as detected by a faecal polymerase chain reaction-based panel in Perth, Western Australia. Australian Veterinary Journal 97 (10) 418-421.

Pearson M, LaVoy A, Evans S, Vilander A, Webb C, Graham B, Musselman E, LeCureux J, VandeWoude S, Dean GA (2019): Mucosal Immune Response to Feline Enteric Coronavirus Infection. Viruses 11 (10).

Pedersen NC (1976): Serologic studies of naturally occurring feline infectious peritonitis. American Journal of Veterinary Research 37 (12) 1449-1453.

Pedersen NC, Boyle JF, Floyd K, Fudge A, Barker J (1981): An enteric coronavirus infection of cats and its relationship to feline infectious peritonitis. American Journal of Veterinary Research 42 (3) 368-377.

Pedersen NC, Evermann JF, McKeirnan AJ, Ott RL (1984): Pathogenicity studies of feline coronavirus isolates 79-1146 and 79-1683. American Journal of Veterinary Research 45 (12) 2580-2585.

Pedersen NC (1987): Virologic and immunologic aspects of feline infectious peritonitis virus infection. Advances in Experimental Medicine and Biology 218 529-550.

Pedersen NC, Sato R, Foley JE, Poland AM (2004): Common virus infections in cats, before and after being placed in shelters, with emphasis on feline enteric coronavirus. Journal of Feline Medicine and Surgery 6 (2) 83-88.

Pedersen NC, Allen CE, Lyons LA (2008): Pathogenesis of feline enteric coronavirus infection. Journal of Feline Medicine and Surgery 10 (6) 529-541.

Pedersen NC (2009): A review of feline infectious peritonitis virus infection: 1963-2008. Journal of Feline Medicine and Surgery 11 (4) 225-258.

Pedersen NC, Liu H, Dodd KA, Pesavento PA (2009): Significance of Coronavirus Mutants in Feces and Diseased Tissues of Cats Suffering from Feline Infectious Peritonitis. Viruses 1 (2) 166-184.

Pedersen NC, Liu H, Scarlett J, Leutenegger CM, Golovko L, Kennedy H, Kamal FM (2012): Feline infectious peritonitis: role of the feline coronavirus 3c gene in intestinal tropism and pathogenicity based upon isolates from resident and adopted shelter cats. Virus Research 165 (1) 17-28.

Pedersen NC (2014a): An update on feline infectious peritonitis: diagnostics and therapeutics. Veterinary Journal 201 (2) 133-141.

Pedersen NC (2014b): An update on feline infectious peritonitis: virology and immunopathogenesis. Veterinary Journal 201 (2) 123-132.

Pedersen NC, Liu H, Gandolfi B, Lyons LA (2014): The influence of age and genetics on natural resistance to experimentally induced feline infectious peritonitis. Veterinary Immunology and Immunopathology 162 (1-2) 33-40.

Pedersen NC, Eckstrand C, Liu H, Leutenegger C, Murphy B (2015): Levels of feline infectious peritonitis virus in blood, effusions, and various tissues and the role of lymphopenia in disease outcome following experimental infection. Veterinary Microbiology 175 (2-4) 157-166.

Pedersen NC, Liu H, Durden M, Lyons LA (2016): Natural resistance to experimental feline infectious peritonitis virus infection is decreased rather than increased by positive genetic selection. Veterinary Immunology and Immunopathology 171 17-20.

Pedersen NC, Kim Y, Liu H, Galasiti Kankanamalage AC, Eckstrand C, Groutas WC, Bannasch M, Meadows JM, Chang KO (2018): Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. Journal of Feline Medicine and Surgery 20 (4) 378-392.

Pedersen NC (2019): Fifty years’ fascination with FIP culminates in a promising new antiviral. Journal of Feline Medicine and Surgery 21 (4) 269-270.

Pedersen NC, Perron M, Bannasch M, Montgomery E, Murakami E, Liepnieks M, Liu H (2019): Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. Journal of Feline Medicine and Surgery 21 (4) 271-281.

Penderis J (2009): The Wobbly Cat. Diagnostic and therapeutic approach to generalised ataxia. Journal of Feline Medicine and Surgery 11 (5) 349-359.

Perera KD, Rathnayake AD, Liu H, Pedersen NC, Groutas WC, Chang KO, Kim Y (2019): Characterization of amino acid substitutions in feline coronavirus 3C-like protease from a cat with feline infectious peritonitis treated with a protease inhibitor. Veterinary Microbiology 237 108398.

Pesteanu-Somogyi LD, Radzai C, Pressler BM (2006): Prevalence of feline infectious peritonitis in specific cat breeds. Journal of Feline Medicine and Surgery 8 (1) 1-5.

Pfannschmidt K, Hüllermeier E, Held S, Neiger R (2016): Evaluating Tests in Medical Diagnosis: Combining Machine Learning with Game-Theoretical Concepts. In Information Processing and Management of Uncertainty in Knowledge-Based Systems, edited by JP Carvalho, M-J Lesot, U Kaymak, S Vieira, B Bouchon-Meunier and RR Yager, 450-461. Cham: Springer International Publishing.

Pham HT, Mai-Phan TA, Vu AK, Truong TH, Tran MH (2023): Clinical use of remdesivir in COVID-19 treatment: a retrospective cohort study. BMJ Open 13 (6) e070489.

Philip F, Seitz D (1959): Infantile Experience and Adult Behavior in Animal Subjects. Psychosomatic Medicine 11 435.

Poland AM, Vennema H, Foley JE, Pedersen NC (1996): Two related strains of feline infectious peritonitis virus isolated from immunocompromised cats infected with a feline enteric coronavirus. Journal of Clinical Microbiology 34 (12) 3180-3184.

Poncelet L, Coppens A, Peeters D, Bianchi E, Grant CK, Kadhim H (2008): Detection of antigenic heterogeneity in feline coronavirus nucleocapsid in feline pyogranulomatous meningoencephalitis. Veterinary Pathology 45 (2) 140-153.

Pons-Hernandez M, Wyatt T, Hall A (2022): Investigating the illicit market in veterinary medicines: An exploratory online study with pet owners in the United Kingdom. Trends Organ Crime 1-21.

Porter E, Tasker S, Day MJ, Harley R, Kipar A, Siddell SG, Helps CR (2014): Amino acid changes in the spike protein of feline coronavirus correlate with systemic spread of virus from the intestine and not with feline infectious peritonitis. Veterinary Research 45 (1) 49.

Posch A, Posch U, Kubber-Heiss A, Stur I, Seiser M, Mostl K (2001): Feline Coronaviren: Differenzierung der Typen I und II mittels RT-PCR und deren Vorkommen in österreichischen Katzenpopulationen. Veterinary Medicine Austria 88 235-243.

Postorino Reeves N (1995): Vaccination against naturally occurring FIP in a single large cat shelter. Feline Practice 23 (3) 81-82.

Pratelli A (2008): Comparison of serologic techniques for the detection of antibodies against feline coronaviruses. Journal of Veterinary Diagnostic Investigation 20 (1) 45-50.

Pratelli A, Yesilbag K, Siniscalchi M, Yalcm E, Yilmaz Z (2009): Prevalence of feline coronavirus antibodies in cats in Bursa province, Turkey, by an enzyme-linked immunosorbent assay. Journal of Feline Medicine and Surgery 11 (10) 881-884.

Rapichai W, Saejung W, Khumtong K, Boonkaewwan C, Tuanthap S, Lieberzeit PA, Choowongkomon K, Rattanasrisomporn J (2022): Development of Colorimetric Reverse Transcription Loop-Mediated Isothermal Amplification Assay for Detecting Feline Coronavirus. Animals 12 (16).

Raukar J (2021): Prevalence of feline coronavirus, feline leukemia virus, and feline immunodeficiency virus in client-owned cats in Croatia. Journal of Advances in Natural Sciences 8 24-38.

Redford T, Al-Dissi AN (2019): Feline infectious peritonitis in a cat presented because of papular skin lesions. Canadian Veterinary Journal 60 (2) 183-185.

Reissner J, Siller P, Bartel A, Roesler U, Friese A (2023): Stability of Feline Coronavirus in aerosols and dried in organic matrices on surfaces at various environmental conditions. Sci Rep 13 (1) 22012.

Riemer F, Kuehner KA, Ritz S, Sauter-Louis C, Hartmann K (2016): Clinical and laboratory features of cats with feline infectious peritonitis – a retrospective study of 231 confirmed cases (2000-2010). Journal of Feline Medicine and Surgery 18 348-356.

Riley N (2021): Dealing with black market medications. In Practice 43 (5) 293-294.

Rissi DR (2018): A retrospective study of the neuropathology and diagnosis of naturally occurring feline infectious peritonitis. Journal of Veterinary Diagnostic Investigation 30 (3) 392-399.

Ritz S, Egberink H, Hartmann K (2007): Effect of feline interferon-omega on the survival time and quality of life of cats with feline infectious peritonitis. Journal of Veterinary Internal Medicine 21 (6) 1193-1197.

Robison RL, Holzworth J, Gilmore CE (1971): Naturally occurring feline infectious peritonitis: signs and clinical diagnosis. Journal of the American Veterinary Medical Association 158 (6) Suppl 2:981-986.

Rodan I, Dowgray N, Carney HC, Carozza E, Ellis SL, Heath S, Niel L, St Denis K, Taylor S (2022): 2022 AAFP/ISFM Cat Friendly Veterinary Interaction Guidelines: Approach and Handling Techniques. Journal of Feline Medicine and Surgery 24 (11) 1093-1132.

Rohner M (1999): Determination of the excretion kinetics of feline coronaviruses under field conditions. University of Zürich.

Rohrbach BW, Legendre AM, Baldwin CA, Lein DH, Reed WM, Wilson RB (2001): Epidemiology of feline infectious peritonitis among cats examined at veterinary medical teaching hospitals. Journal of the American Veterinary Medical Association 218 (7) 1111-1115.

Rohrer C (1992): Die Diagnostik der Felinen Infektiösen Peritonitis (FIP): eine restrospektive Studie. University of Zürich.

Rohrer C, Suter PF, Lutz H (1993): The diagnosis of feline infectious peritonitis (FIP): a retrospective and prospective study. Kleintierpraxis 38 379-389.

Rossi G, Paltrinieri S (2009): Total sialic acid: an acute phase reactant in cats with a possible role in feline coronavirus infection. Canadian Journal of Veterinary Research 73 (2) 144-150.

Rota A, Paltrinieri S, Jussich S, Ubertalli G, Appino S (2008): Priapism in a castrated cat associated with feline infectious peritonitis. Journal of Feline Medicine and Surgery 10 (2) 181-184.

Rottier PJ, Nakamura K, Schellen P, Volders H, Haijema BJ (2005): Acquisition of macrophage tropism during the pathogenesis of feline infectious peritonitis is determined by mutations in the feline coronavirus spike protein. Journal of Virology 79 (22) 14122-14130.

Roy M, Jacque N, Novicoff W, Li E, Negash R, Evans SJM (2022): Unlicensed Molnupiravir is an Effective Rescue Treatment Following Failure of Unlicensed GS-441524-like Therapy for Cats with Suspected Feline Infectious Peritonitis. Pathogens 11 (10) 1209.

Rusbridge C (1997): Collection and interpretation of cerebrospinal fluid in cats and dogs. In Practice 19 (6) 322-331.

Sabshin SJ, Levy JK, Tupler T, Tucker SJ, Greiner EC, Leutenegger CM (2012): Enteropathogens identified in cats entering a Florida animal shelter with normal feces or diarrhea. Journal of the American Veterinary Medical Association 241 (3) 331-337.

Salord Torres X, Jeevaratnam K, Schofield I, Taylor S, Stallwood J, Heyes M, Hughes D, Defauw P (2024): Diagnostic and predictive ability of hyperbilirubinemia severity in cats: A multicenter retrospective study. Journal of Veterinary Internal Medicine.

Sangl L, Matiasek K, Felten S, Grundl S, Bergmann M, Balzer HJ, Pantchev N, Leutenegger CM, Hartmann K (2019): Detection of feline coronavirus mutations in paraffin-embedded tissues in cats with feline infectious peritonitis and controls. Journal of Feline Medicine and Surgery 21 (2) 133-142.

Sangl L, Felten S, Matiasek K, Dorfelt S, Bergmann M, Balzer HJ, Pantchev N, Leutenegger C, Hartmann K (2020): Detection of feline coronavirus RNA, spike gene mutations, and feline coronavirus antigen in macrophages in aqueous humor of cats in the diagnosis of feline infectious peritonitis. Journal of Veterinary Diagnostic Investigation 32 (4) 527-534.

Sase O (2023): Molnupiravir treatment of 18 cats with feline infectious peritonitis: A case series. Journal of Veterinary Internal Medicine 37 (5) 1876-1880.

Savary KC, Sellon RK, Law JM (2001): Chylous abdominal effusion in a cat with feline infectious peritonitis. Journal of the American Animal Hospital Association 37 (1) 35-40.

Scott FW (1988): Update on FIP. In Proceedings of the 12th annual Kal Kan Symposium for the Treatment of Small Animal Diseases 43-47. Johnson, OH, USA

Scott FW, Corapi WV, Olsen CW (1995a): Independent Evaluation of a Modified Live FIPV Vaccine Under Experimental Conditions (Cornell Experience). Feline Practice 23 (3) 74-76.

Scott FW, Olsen CW, Corapi WV (1995b): Antibody-Dependent Enhancement of Feline Infectious Peritonitis Virus Infection. Feline Practice 23 (3) 77-80.

Sharif S, Arshad SS, Hair-Bejo M, Omar AR, Zeenathul NA, Hafidz MA (2009): Prevalence of feline coronavirus in two cat populations in Malaysia. Journal of Feline Medicine and Surgery 11 (12) 1031-1034.

Shelly SM, Scarlettkranz J, Blue JT (1988): Protein Electrophoresis on Effusions from Cats as a Diagnostic-Test for Feline Infectious Peritonitis. Journal of the American Animal Hospital Association 24 (5) 495-500.

Shi W, Cai Y, Zhu H, Peng H, Voyer J, Rits-Volloch S, Cao H, Mayer ML, Song K, Xu C, Lu J, Zhang J, Chen B (2023): Cryo-EM structure of SARS-CoV-2 postfusion spike in membrane. Nature 619 (7969) 403-409.

Shiba N, Maeda K, Kato H, Mochizuki M, Iwata H (2007): Differentiation of feline coronavirus type I and II infections by virus neutralization test. Veterinary Microbiology 124 (3-4) 348-352.

Simons FA, Vennema H, Rofina JE, Pol JM, Horzinek MC, Rottier PJ, Egberink HF (2005): A mRNA PCR for the diagnosis of feline infectious peritonitis. Journal of Virological Methods 124 (1-2) 111-116.

Singh M, Foster DJ, Child G, Lamb WA (2005): Inflammatory cerebrospinal fluid analysis in cats: clinical diagnosis and outcome. Journal of Feline Medicine and Surgery 7 (2) 77-93.

Soma T, Wada M, Taharaguchi S, Tajima T (2013): Detection of ascitic feline coronavirus RNA from cats with clinically suspected feline infectious peritonitis. Journal of Veterinary Medical Science 75 (10) 1389-1392.

Soma T, Saito N, Kawaguchi M, Sasai K (2018): Feline coronavirus antibody titer in cerebrospinal fluid from cats with neurological signs. Journal of Veterinary Medical Science 80 (1) 59-62.

Sorrell S, Pugalendhi SJ, Gunn-Moore D (2022): Current treatment options for feline infectious peritonitis in the UK. Companion Animal 27 79-90.

Spada E, Canzi I, Baggiani L, Perego R, Vitale F, Migliazzo A, Proverbio D (2016): Prevalence of Leishmania infantum and co-infections in stray cats in northern Italy. Comparative Immunology, Microbiology and Infectious Diseases 45 53-58.

Spada E, Carrera Nulla A, Perego R, Baggiani L, Proverbio D (2022): Evaluation of Association between Blood Phenotypes A, B and AB and Feline Coronavirus Infection in Cats. Pathogens 11 (8).

Sparkes AH, Gruffydd-Jones TJ, Harbour DA (1991): Feline infectious peritonitis: a review of clinicopathological changes in 65 cases, and a critical assessment of their diagnostic value. Veterinary Record 129 (10) 209-212.

Sparkes AH, Gruffydd-Jones TJ, Harbour DA (1992): Feline coronavirus antibodies in UK cats. Veterinary Record 131 (10) 223-224.

Sparkes AH, Gruffydd-Jones TJ, Harbour DA (1994): An appraisal of the value of laboratory tests in the diagnosis of feline infectious peritonitis. Journal of the American Animal Hospital Association 30 345-350.

Spencer SE, Knowles T, Ramsey IK, Tasker S (2017): Pyrexia in cats: Retrospective analysis of signalment, clinical investigations, diagnosis and influence of prior treatment in 106 referred cases. Journal of Feline Medicine and Surgery 19 (11) 1123-1130.

Stoddart ME, Gaskell RM, Harbour DA, Gaskell CJ (1988a): Virus shedding and immune responses in cats inoculated with cell culture-adapted feline infectious peritonitis virus. Veterinary Microbiology 16 (2) 145-158.

Stoddart ME, Gaskell RM, Harbour DA, Pearson GR (1988b): The sites of early viral replication in feline infectious peritonitis. Veterinary Microbiology 18 (3-4) 259-271.

Stone AE, Brummet GO, Carozza EM, Kass PH, Petersen EP, Sykes J, Westman ME (2020): 2020 AAHA/AAFP Feline Vaccination Guidelines. Journal of Feline Medicine and Surgery 22 (9) 813-830.

Stout AE, Andre NM, Whittaker GR (2021): Feline Coronavirus and Feline Infectious Peritonitis in Nondomestic Felid Species. Journal of Zoo and Wildlife Medicine 52 (1) 14-27.

Stranieri A, Giordano A, Bo S, Braghiroli C, Paltrinieri S (2017a): Frequency of electrophoretic changes consistent with feline infectious peritonitis in two different time periods (2004-2009 vs 2013-2014). Journal of Feline Medicine and Surgery 19 880-887.

Stranieri A, Lauzi S, Giordano A, Paltrinieri S (2017b): Reverse transcriptase loop-mediated isothermal amplification for the detection of feline coronavirus. Journal of Virological Methods 243 105-108.

Stranieri A, Giordano A, Paltrinieri S, Giudice C, Cannito V, Lauzi S (2018): Comparison of the performance of laboratory tests in the diagnosis of feline infectious peritonitis. Journal of Veterinary Diagnostic Investigation 30 (3) 459-463.

Stranieri A, Probo M, Pisu MC, Fioletti A, Meazzi S, Gelain ME, Bonsembiante F, Lauzi S, Paltrinieri S (2020a): Preliminary investigation on feline coronavirus presence in the reproductive tract of the tom cat as a potential route of viral transmission. Journal of Feline Medicine and Surgery 22 (2) 178-185.

Stranieri A, Scavone D, Paltrinieri S, Giordano A, Bonsembiante F, Ferro S, Gelain ME, Meazzi S, Lauzi S (2020b): Concordance between Histology, Immunohistochemistry, and RT-PCR in the Diagnosis of Feline Infectious Peritonitis. Pathogens 9 (10).

Strasfeld L, Chou S (2010): Antiviral drug resistance: mechanisms and clinical implications. Infectious Disease Clinics of North America 24 (3) 809-833.

Ström Holst B, Englund L, Palacios S, Renstrom L, Berndtsson LT (2006): Prevalence of antibodies against feline coronavirus and Chlamydophila felis in Swedish cats. Journal of Feline Medicine and Surgery 8 (3) 207-211.

Sweet A, Andre N, Licitra BN, Whittaker G (2023): RNA in-situ hybridization for pathology-based diagnosis of feline infectious peritonitis (FIP): current diagnostics for FIP and comparison to the current gold standard. Qeios NUN8KB.3.

Sweet AN, Andre NM, Stout AE, Licitra BN, Whittaker GR (2022): Clinical and Molecular Relationships between COVID-19 and Feline Infectious Peritonitis (FIP). Viruses 14 (3).

Taharaguchi S, Soma T, Hara M (2012): Prevalence of feline coronavirus antibodies in Japanese domestic cats during the past decade. Journal of Veterinary Medical Science 74 (10) 1355-1358.

Takano T, Hohdatsu T, Hashida Y, Kaneko Y, Tanabe M, Koyama H (2007a): A “possible” involvement of TNF-alpha in apoptosis induction in peripheral blood lymphocytes of cats with feline infectious peritonitis. Veterinary Microbiology 119 (2-4) 121-131.

Takano T, Hohdatsu T, Toda A, Tanabe M, Koyama H (2007b): TNF-alpha, produced by feline infectious peritonitis virus (FIPV)-infected macrophages, upregulates expression of type II FIPV receptor feline aminopeptidase N in feline macrophages. Virology 364 (1) 64-72.

Takano T, Azuma N, Satoh M, Toda A, Hashida Y, Satoh R, Hohdatsu T (2009): Neutrophil survival factors (TNF-alpha, GM-CSF, and G-CSF) produced by macrophages in cats infected with feline infectious peritonitis virus contribute to the pathogenesis of granulomatous lesions. Archives of Virology 154 (5) 775-781.

Takano T, Katoh Y, Doki T, Hohdatsu T (2013): Effect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo. Antiviral Research 99 (2) 100-107.

Takano T, Endoh M, Fukatsu H, Sakurada H, Doki T, Hohdatsu T (2017a): The cholesterol transport inhibitor U18666A inhibits type I feline coronavirus infection. Antiviral Research 145 96-102.

Takano T, Nakaguchi M, Doki T, Hohdatsu T (2017b): Antibody-dependent enhancement of serotype II feline enteric coronavirus infection in primary feline monocytes. Archives of Virology 162 (11) 3339-3345.

Takano T, Akiyama M, Doki T, Hohdatsu T (2019): Antiviral activity of itraconazole against type I feline coronavirus infection. Veterinary Research 50 (1) 5.

Takano T, Satoh K, Doki T, Tanabe T, Hohdatsu T (2020): Antiviral Effects of Hydroxychloroquine and Type I Interferon on In Vitro Fatal Feline Coronavirus Infection. Viruses 12 (5).

Tammer R, Evensen O, Lutz H, Reinacher M (1995): Immunohistological demonstration of feline infectious peritonitis virus antigen in paraffin-embedded tissues using feline ascites or murine monoclonal antibodies. Veterinary Immunology and Immunopathology 49 (1-2) 177-182.

Tanaka Y, Sato Y, Osawa S, Inoue M, Tanaka S, Sasaki T (2012): Suppression of feline coronavirus replication in vitro by cyclosporin A. Veterinary Research 43 (1) 41.

Tanaka Y, Sato Y, Sasaki T (2013): Suppression of coronavirus replication by cyclophilin inhibitors. Viruses 5 (5) 1250-1260.

Tanaka Y, Sato Y, Takahashi D, Matsumoto H, Sasaki T (2015): Treatment of a case of feline infectious peritonitis with cyclosporin A. Veterinary Record Case Reports 3 (e000134).

Tasker S (2018): Diagnosis of feline infectious peritonitis: Update on evidence supporting available tests. Journal of Feline Medicine and Surgery 20 (3) 228-243.

Tasker S, Dowgray N (2018): Managing feline coronavirus and feline infectious peritonitis in the multi-cat/shelter environment. in R Dean, M Roberts and J Stavisky (eds.), BSAVA Manual of Canine and Feline Shelter Medicine: Principles of Health and Welfare in a Multi-animal Environment. (BSAVA Publications: Gloucester).

Tasker S, Dietrich U (2022): Feline uveitis. In British Small Animal Association (BSAVA) Congress Proceedings 2022. Manchester, United Kingdom.

Tasker S, Addie DD, Egberink H, Hartmann K, Hofmann-Lehmann R, Hosie MJ, Truyen U, Belak S, Boucraut-Baralon C, Frymus T, Lloret A, Marsilio F, Pennisi MG, Thiry E, Mostl K (2023a): ABCD FIP Diagnostic Tools. https://www.abcdcatsvets.org/portfolio-item/factsheets-tools-for-feline-infectious-peritonitis-fip/ Accessed 23rd December 2023.

Tasker S, Addie DD, Egberink H, Hofmann-Lehmann R, Hosie MJ, Truyen U, Belák S, Boucraut-Baralon C, Frymus T, Lloret A, Marsilio F, Pennisi MG, Thiry E, Möstl K, Hartmann K (2023b): Feline Infectious Peritonitis: European Advisory Board on Cat Diseases Guidelines. Viruses 15 (9) 1847.

Taylor S, Chan DL, Villaverde C, Ryan L, Peron F, Quimby J, O’Brien C, Chalhoub S (2022a): 2022 ISFM Consensus Guidelines on Management of the Inappetent Hospitalised Cat. Journal of Feline Medicine and Surgery 24 (7) 614-640.

Taylor S, St Denis K, Collins S, Dowgray N, Ellis SL, Heath S, Rodan I, Ryan L (2022b): 2022 ISFM/AAFP Cat Friendly Veterinary Environment Guidelines. Journal of Feline Medicine and Surgery 24 (11) 1133-1163.

Taylor SS, Tappin SW, Dodkin SJ, Papasouliotis K, Casamian-Sorrosal D, Tasker S (2010): Serum protein electrophoresis in 155 cats. Journal of Feline Medicine and Surgery 12 (8) 643-653.

Taylor SS, Coggins S, Barker EN, Gunn-Moore D, Jeevaratnam K, Norris JM, Hughes D, Stacey E, MacFarlane L, O’Brien C, Korman R, McLauchlan G, Salord Torres X, Taylor A, Bongers J, Espada Castro L, Foreman M, McMurrough J, Thomas B, Royaux E, Calvo Saiz I, Bertoldi G, Harlos C, Work M, Prior C, Sorrell S, Malik R, Tasker S (2023): Retrospective study and outcome of 307 cats with feline infectious peritonitis treated with legally sourced veterinary compounded preparations of remdesivir and GS-441524 (2020-2022). Journal of Feline Medicine and Surgery 25 (9) 1098612X231194460.

Tekelioglu BK, Berriatua E, Turan N, Helps CR, Kocak M, Yilmaz H (2015): A retrospective clinical and epidemiological study on feline coronavirus (FCoV) in cats in Istanbul, Turkey. Preventive Veterinary Medicine 119 (1-2) 41-47.

Tekes G, Hofmann-Lehmann R, Bank-Wolf B, Maier R, Thiel HJ, Thiel V (2010): Chimeric feline coronaviruses that encode type II spike protein on type I genetic background display accelerated viral growth and altered receptor usage. Journal of Virology 84 (3) 1326-1333.

Tekes G, Ehmann R, Boulant S, Stanifer ML (2020): Development of Feline Ileum- and Colon-Derived Organoids and Their Potential Use to Support Feline Coronavirus Infection. Cells 9 (9) 2085.

Terada Y, Matsui N, Noguchi K, Kuwata R, Shimoda H, Soma T, Mochizuki M, Maeda K (2014): Emergence of pathogenic coronaviruses in cats by homologous recombination between feline and canine coronaviruses. PloS One 9 (9) e106534.

Thalmeier S, Güssow A, Häuser MK, Bauer N, Hazuchova K (2023): Cat alpha-1-acid glycoprotein enzyme-linked immunosorbent assay: performance characteristics and reference intervals. Journal of Feline Medicine and Surgery 25 (5) 1098612X231162836.

Thayer V, Gogolski S, Felten S, Hartmann K, Kennedy M, Olah GA (2022): 2022 AAFP/EveryCat Feline Infectious Peritonitis Diagnosis Guidelines. Journal of Feline Medicine and Surgery 24 (9) 905-933.

Tian L, Pang Z, Li M, Lou F, An X, Zhu S, Song L, Tong Y, Fan H, Fan J (2022): Molnupiravir and Its Antiviral Activity Against COVID-19. Frontiers in Immunology 13 855496.

Timmann D, Cizinauskas S, Tomek A, Doherr M, Vandevelde M, Jaggy A (2008): Retrospective analysis of seizures associated with feline infectious peritonitis in cats. Journal of Feline Medicine and Surgery 10 (1) 9-15.

Triratapiban C, Lueangaramkul V, Phecharat N, Pantanam A, Lekcharoensuk P, Theerawatanasirikul S (2023): First study on in vitro antiviral and virucidal effects of flavonoids against feline infectious peritonitis virus at the early stage of infection. Veterinary World 16 (3) 618-630.

Trotman TK, Mauldin E, Hoffmann V, Del Piero F, Hess RS (2007): Skin fragility syndrome in a cat with feline infectious peritonitis and hepatic lipidosis. Veterinary Dermatology 18 (5) 365-369.

Trulove SG, Mccahon HA, Nichols R, Fooshee SK (1992): Pyogranulomatous Pneumonia Associated with Generalized Noneffusive Feline Infectious Peritonitis. Feline Practice 20 (3) 25-29.

Tsai HY, Chueh LL, Lin CN, Su BL (2011): Clinicopathological findings and disease staging of feline infectious peritonitis: 51 cases from 2003 to 2009 in Taiwan. Journal of Feline Medicine and Surgery 13 (2) 74-80.

Tusell SM, Schittone SA, Holmes KV (2007): Mutational analysis of aminopeptidase N, a receptor for several group 1 coronaviruses, identifies key determinants of viral host range. Journal of Virology 81 (3) 1261-1273.

van der Meer FJ, de Haan CA, Schuurman NM, Haijema BJ, Verheije MH, Bosch BJ, Balzarini J, Egberink HF (2007): The carbohydrate-binding plant lectins and the non-peptidic antibiotic pradimicin A target the glycans of the coronavirus envelope glycoproteins. Journal of Antimicrobial Chemotherapy 60 (4) 741-749.

Varanat M, Broadhurst J, Linder KE, Maggi RG, Breitschwerdt EB (2012): Identification of Bartonella henselae in 2 cats with pyogranulomatous myocarditis and diaphragmatic myositis. Veterinary Pathology 49 (4) 608-611.

Vennema H, de Groot RJ, Harbour DA, Dalderup M, Gruffydd-Jones T, Horzinek MC, Spaan WJ (1990): Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization. Journal of Virology 64 (3) 1407-1409.

Vennema H, Rossen JW, Wesseling J, Horzinek MC, Rottier PJ (1992): Genomic organization and expression of the 3′ end of the canine and feline enteric coronaviruses. Virology 191 (1) 134-140.

Vermeulen BL, Devriendt B, Olyslaegers DA, Dedeurwaerder A, Desmarets LM, Favoreel HW, Dewerchin HL, Nauwynck HJ (2013): Suppression of NK cells and regulatory T lymphocytes in cats naturally infected with feline infectious peritonitis virus. Veterinary Microbiology 164 (1-2) 46-59.

Villar M, Fernandez de Mera IG, Artigas-Jeronimo S, Contreras M, Gortazar C, de la Fuente J (2020): Coronavirus in cat flea: findings and questions regarding COVID-19. Parasit Vectors 13 (1) 409.

Vogel L, Van der Lubben M, te Lintelo EG, Bekker CP, Geerts T, Schuijff LS, Grinwis GC, Egberink HF, Rottier PJ (2010): Pathogenic characteristics of persistent feline enteric coronavirus infection in cats. Veterinary Research 41 (5) 71.

Vojtkovska V, Lukesova G, Voslarova E, Konvalinova J, Vecerek V, Lobova D (2022): Direct Detection of Feline Coronavirus by Three Rapid Antigen Immunochromatographic Tests and by Real-Time PCR in Cat Shelters. Vet Sci 9 (2).

Wagner D, Hurley K, Stavisky J (2018a): Shelter housing for cats: Practical aspects of design and construction, and adaptation of existing accommodation. Journal of Feline Medicine and Surgery 20 (7) 643-652.

Wagner D, Hurley K, Stavisky J (2018b): Shelter housing for cats: Principles of design for health, welfare and rehoming. Journal of Feline Medicine and Surgery 20 (7) 635-642.

Walton-Clark M, Travail V, Best M (2022): Phenobarbital-induced autoimmune haemolytic anaemia, thrombocytopenia and peripheral lymphadenomegaly due to reactive lymphoid hyperplasia in a cat. Journal of Feline Medicine and Surgery Open Reports 8 (1) 20551169221079238.

Wang Y, Liu Y, Wang J, Zhang M, Deng X, Song J, Zhu J, Yu L, Li G, Liu G (2024): An adenovirus-vectored vaccine based on the N protein of feline coronavirus elicit robust protective immune responses. Antiviral Research 223 105825.

Wang YT, Su BL, Hsieh LE, Chueh LL (2013): An outbreak of feline infectious peritonitis in a Taiwanese shelter: epidemiologic and molecular evidence for horizontal transmission of a novel type II feline coronavirus. Veterinary Research 44 (1) 57.

Wang YT, Chueh LL, Wan CH (2014a): An eight-year epidemiologic study based on baculovirus-expressed type-specific spike proteins for the differentiation of type I and II feline coronavirus infections. BMC Veterinary Research 10 186.

Wang YT, Hsieh LE, Dai YR, Chueh LL (2014b): Polymorphisms in the feline TNFA and CD209 genes are associated with the outcome of feline coronavirus infection. Veterinary Research 45 123.

Warr A, Attipa C, Gunn-Moore D, Tait-Burkard C (2023): FCoV-23 causing FIP in a cat imported to the UK from Cyprus. Veterinary Record 193 (10) 414-415.

Watanabe R, Eckstrand C, Liu H, Pedersen NC (2018): Characterization of peritoneal cells from cats with experimentally-induced feline infectious peritonitis (FIP) using RNA-seq. Veterinary Research 49 (1) 81.

Watari T, Kaneshima T, Tsujimoto H, Ono K, Hasegawa A (1998): Effect of thromboxane synthetase inhibitor on feline infectious peritonitis in cats. Journal of Veterinary Medical Science 60 (5) 657-659.

Wegg ML, Jeanes EC, Pollard D, Fleming L, Dawson C (2021): A multicenter retrospective study into endogenous causes of uveitis in cats in the United Kingdom: Ninety two cases. Veterinary Ophthalmology 24 (6) 591-598.

Weiss RC, Scott FW (1981): Pathogenesis of feline infetious peritonitis: pathologic changes and immunofluorescence. American Journal of Veterinary Research 42 (12) 2036-2048.

Weiss RC, Toivio-Kinnucan M (1988): Inhibition of feline infectious peritonitis virus replication by recombinant human leukocyte (alpha) interferon and feline fibroblastic (beta) interferon. American Journal of Veterinary Research 49 (8) 1329-1335.

Weiss RC, Oostrom-Ram T (1989): Inhibitory effects of ribavirin alone or combined with human alpha interferon on feline infectious peritonitis virus replication in vitro. Veterinary Microbiology 20 (3) 255-265.

Weiss RC, Cox NR, Oostrom-Ram T (1990): Effect of interferon or Propionibacterium acnes on the course of experimentally induced feline infectious peritonitis in specific-pathogen-free and random-source cats. American Journal of Veterinary Research 51 (5) 726-733.

Weiss RC, Cox NR, Boudreaux MK (1993a): Toxicologic effects of ribavirin in cats. Journal of Veterinary Pharmacology and Therapeutics 16 (3) 301-316.

Weiss RC, Cox NR, Martinez ML (1993b): Evaluation of free or liposome-encapsulated ribavirin for antiviral therapy of experimentally induced feline infectious peritonitis. Research in Veterinary Science 55 (2) 162-172.

White JM, Schiffer JT, Bender Ignacio RA, Xu S, Kainov D, Ianevski A, Aittokallio T, Frieman M, Olinger GG, Polyak SJ (2021): Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses. MBio 12 (6) e0334721.

Worthing KA, Wigney DI, Dhand NK, Fawcett A, McDonagh P, Malik R, Norris JM (2012): Risk factors for feline infectious peritonitis in Australian cats. Journal of Feline Medicine and Surgery 14 (6) 405-412.

Wu B, Luo M, Wu F, He Z, Li Y, Xu T (2022): Acute Kidney Injury Associated With Remdesivir: A Comprehensive Pharmacovigilance Analysis of COVID-19 Reports in FAERS. Frontiers in Pharmacology 13 692828.

Xia H, Li X, Zhao W, Jia S, Zhang X, Irwin DM, Zhang S (2020): Adaptive Evolution of Feline Coronavirus Genes Based on Selection Analysis. BioMed Research International 2020 9089768.

Xie J, Wang Z (2021): Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment. Acta Pharmaceutica Sinica B 11 (6) 1607-1616.

Xu L, Ye S, Ding Y, Xiao Y, Yao C, Wang Z, Cai S, Ou J, Mao J, Hu X, Cheng S, Wang J, Lu G, Li S (2023): A Combined Method Based on the FIPV N Monoclonal Antibody Immunofluorescence Assay and RT-nPCR Method for the Rapid Diagnosis of FIP-Suspected Ascites. Transboundary and Emerging Diseases 2023 8429106.

Yan Y, Li J, Jiao Z, Yang M, Li L, Wang G, Chen Y, Li M, Shen Z, Shi Y, Peng G (2023): Better therapeutic effect of oral administration of GS441524 compared with GC376. Veterinary Microbiology 283 109781.

Yin Y, Li T, Wang C, Liu X, Ouyang H, Ji W, Liu J, Liao X, Li J, Hu C (2021): A retrospective study of clinical and laboratory features and treatment on cats highly suspected of feline infectious peritonitis in Wuhan, China. Scientific Reports 11 (1) 5208.

Yu J, Kimble B, Norris JM, Govendir M (2020): Pharmacokinetic Profile of Oral Administration of Mefloquine to Clinically Normal Cats: A Preliminary In-Vivo Study of a Potential Treatment for Feline Infectious Peritonitis (FIP). Animals 10 (6).

Zehr JD, Kosakovsky Pond SL, Millet JK, Olarte-Castillo XA, Lucaci AG, Shank SD, Ceres KM, Choi A, Whittaker GR, Goodman LB, Stanhope MJ (2023): Natural selection differences detected in key protein domains between non-pathogenic and pathogenic feline coronavirus phenotypes. Virus Evolution 9 (1).

Zhao S, Li W, Schuurman N, van Kuppeveld F, Bosch BJ, Egberink H (2019): Serological Screening for Coronavirus Infections in Cats. Viruses 11 (8).

Zhou Q, Li Y, Huang J, Fu N, Song X, Sha X, Zhang B (2021a): Prevalence and molecular characteristics of feline coronavirus in southwest China from 2017 to 2020. Journal of General Virology 102 (9).

Zhou S, Hill CS, Sarkar S, Tse LV, Woodburn BMD, Schinazi RF, Sheahan TP, Baric RS, Heise MT, Swanstrom R (2021b): beta-d-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells. Journal of Infectious Diseases 224 (3) 415-419.

Ziolkowska N, Pazdzior-Czapula K, Lewczuk B, Mikulska-Skupien E, Przybylska-Gornowicz B, Kwiecinska K, Ziolkowski H (2017): Feline Infectious Peritonitis: Immunohistochemical Features of Ocular Inflammation and the Distribution of Viral Antigens in Structures of the Eye. Veterinary Pathology 54 (6) 933-944.

Zwicklbauer K, Krentz D, Bergmann M, Felten S, Dorsch R, Fischer A, Hofmann-Lehmann R, Meli ML, Spiri AM, Alberer M, Kolberg L, Matiasek K, Zablotski Y, von Both U, Hartmann K (2023): Long-term follow-up of cats in complete remission after treatment of feline infectious peritonitis with oral GS-441524. Journal of Feline Medicine and Surgery 25 (8) 1098612X231183250.