FIP= Feline Coronavirus (FCoV)

Feline coronavirus (FCoV) belongs to the genus Alpha-coronavirus 1 of the subfamily Coronavirinae, family Coronaviridae within the order Nidovirales (de Groot et al., 2011). Coronaviruses are divided into five antigenic groups. Group I includes FCoV, transmissible gastroenteritis virus (TGEV), porcine respiratory coronavirus (PRCV) and canine coronavirus (CCV). (Wege et al., 1982).

Feline infectious peritonitis was first described in 1963 (Holzworth, 1963), hoverer there are reports of clinical cases that were likely FIP going back to 1914 (Pedersen, 2009b). The disease was thought to be viral when first described, but no specific etiologic agent was identified until 1968 (Zook et al., 1968). In 1970 FIPV was identified to be a coronavirus due to its close similarity to other members of the family Coronaviridae (Ward, 1970). Since its recognition in the 1960s, FIP has seen a steady increase in disease incidence, and it is currently one of the leading infectious causes of death among young cats from shelters and catteries (Pedersen, 2009b; Pedersen, 2014).

Feline coronavirus (FCoV) is one of the most poorly understood feline viruses. Two primary forms (biotypes) of FCoV are recognized, the avirulent enteric form (FECV) and the virulent form (FIPV) causing the fatal feline infectious peritonitis (FIP). The most popular etiological hypothesis is that FIP arises in some cats infected with the FECV form when the relatively avirulent (FCoV) form mutates into a pathogenic (FIPV) form. The peplomer proteins of the virus are used for virus attachment to cellular surface proteins, they are shaped so that they can bind specifically to topical enterocytes. Replication of non-mutated FCoV is thus primarily restricted to enterocytes. The mutated FIP-causing FCoV has a broader cell tropism, including macrophages (Hartmann, 2005). FCoV replicates in enterocytes, however, in some cases a mutation occurs in a certain region of the FCoV genome (Pedersen, 1995; Vennema et al., 1995), leading to the ability of the virus to replicate within macrophages, which seems to be a key pathogenic event in the development of FIP.

There is no evidence that certain strains of FECV are more likely to mutate to FIPVs, but this needs to be more thoroughly studied. The mutation responsible for the FIPV biotype is consistently found in the 3c gene, which encodes a small protein of unknown function (Vennema et al., 1998). The mutations are usually SNPs causing premature stop codons or deletion mutations that negate or significantly truncate the 3c gene product. The specific deleterious mutation in ORF 3c can differ even between affected kittens in the same litter (Pedersen, 2009), again supporting internal mutation and auto-infection rather than cat-to-cat transmission as the primary route of exposure. Loss of 3c gene function does not prevent replication in vivo or in vitro but is thought to drastically alter cell tropism by enhancing internalization and replication of FIPVs in macrophages (Dewerchin et al.,2005; Rottier et al., 2005).

Prevalence of FCoV

FCoV and FIP are major problems in multiple-cat households and, to a much lesser extent, in free-roaming cats. FCoV is distributed worldwide in household and wild cats (Horzinek et al.,1979; Barlough et al., 1982). The virus is endemic especially in environments in which many cats are kept together in a small space (eg, catteries, shelters, pet stores). There is virtually no multiple-cat household without endemic FCoV. At least 50% of cats in the United States and Europe have antibodies against coronaviruses. In Switzerland, 80% of breeding cats and 50% of free-roaming cats tested positive for antibodies. In Great Britain, 82% of show cats, 53% of cats in breeding institutions, and 15% of cats in single-cat households had antibodies (Sparks et al., 1992). Feline coronavirus (FCoV) infection is very common in domestic cats, with up to 90% of cats within multi-cat households being infected (Pedersen et al., 2004; Pedersen, 1976). The majority of FCoV infections are asymptomatic or are associated with mild intestinal disease. However, an estimated 1% to 5% of infected cats develop feline infectious peritonitis (FIP) (Addie et al., 1992; Addie et al., 1995), characterised by the development of a variable combination of pyogranulomatous polyserositis, vasculitis and granulomatous lesions in organs, and an extremely high mortality rate (Kipar et al., 2014; Pedersen, 2014). The effusive or also called “wet” form is characterised by protein-rich effusions in the body cavities of affected cats and the non-effusive or also called “dry” form is characterised by granulomatous-necrotizing lesions, periphlebitis and granulomatous inflammatory lesions in several organs, especially, liver, kidney, spleen, meninges, and eyes (Kipar et al., 2005).


The infection is spread by the oro-fecal route and viral shedding in faeces occurs within a week of exposure (Pedersen et al.,2008). This shedding occurs from the ileum, the colon and the rectum. (Herrewegh et al.,1995). Shedding of FECV can be persistent for up to 18 months or more, be persistent for 4 to 6 months and intermittent for months thereafter or cleared within 6 to 8 months (Pedersen et al.,2008). As the most common mode of infection is through virus-containing faeces, the major source of FCoV for uninfected cats is litter boxes shared with infected cats (Pedersen et al., 1993). If multiple cats are using the same litter box, they readily infect each other. Continuous reinfection through the contaminated litter box of a cat already infected also seems to play an important role in the endemic survival of the virus. Rarely, virus can be transmitted through saliva, by mutual grooming, by sharing the same food bowl, or through close contact. Sneezed droplet transmission is also possible. Transplacental transmission can occur, because FIP was found in a 4-dayold kitten and in stillborn and weak newborn kittens born to a queen that had FIP during the later stages of pregnancy (Addie et al., 1990). This mode of transmission is uncommon under natural circumstances, however. Most kittens that are removed from contact with adult virus-shedding cats at 5 to 6 weeks of age do not become infected. Most commonly, kittens are infected at the age of 6 to 8 weeks, at a time when their maternal antibodies wane, mostly through contact with faeces from their mothers or other FCoV-excreting cats (Addie et al., 1992). Cats are usually infected with non-pathogenic FCoV through FCoV containing faeces shed by a cat with a harmless FCoV enteric infection or by a cat with FIP. Mutated FIP-causing FCoV has not been found in secretions or excretions of cats with FIP. Thus, transmission of the mutated FIP causing FCoV is considered unlikely under natural circumstances. FIP causing FCoV can, however, be transmitted iatrogenically or under experimental conditions if, for example, effusion from a cat with FIP containing infected macrophages is injected into a naive cat (Weiss, 1994). FCoV is a relatively fragile virus (inactivated at room temperature within 24 to 48 hours), but in dry conditions (eg, in carpet), it has been shown to survive for up to 7 weeks outside the cat. Indirect fomite transmission is thus possible, and the virus can be transmitted through clothes, toys, and grooming tools. In organ homogenates, it is even resistant to repeated freezing at -70°C for many months. The virus is destroyed by most household disinfectants and detergents (Hartmann, 2005).


Several hypotheses have been suggested concerning the cause of FIP pathogenesis. The internal mutation theory, is that a mutant FCoV strain is able to infect monocytes and macrophages, leading to FIP (Poland et al., 1996). This mutant virus strain has been named feline infectious peritonitis virus (FIPV), whereas the strain that causes enteric infection was named feline enteric coronavirus (FECV) (Pedersen et al., 1981). Because FIPV and FECV cannot be distinguished by their antigenicity, or even by genome sequence analysis, they are considered to be two, distinctly different pathotypes, which differ only in their pathogenicity (Vennema, 1999). There is a general consensus that FIPVs arise by internal mutation from FECVs in the same environment (Pedersen et al., 2009; Pedersen et al., 2012; Harley et al., 2013). Except in unusual circumstances (Wang et al., 2013), the causative mutations occur independently within each cat and each FIPV strain has unique genetic features (Pedersen et al., 2009; Pedersen et al., 2012; Chang et al., 2012; Barker et al., 2013; Licitra et al., 2013). Currently, three different genes have been associated with the FECV-to-FIPV mutation or biotype conversion. Each mutation is a result of positive selection pressures, initially for a switch from enterocyte to monocyte/macrophage tropism, then ultimately for infection, replication and survival in peritoneal macrophages in the face of host immunity.

Mutations in the ORF 3c accessory gene and S gene

The ORF 3c accessory gene was the first gene to be implicated in FECV-to- FIPV conversion (Vennema et al., 1998), and these findings have been corroborated in subsequent studies (Poland et al., 1996; Chang et al., 2010; Pedersen et al., 2012). Two thirds or more of FIPVs have ORF 3c mutations that lead to a truncated protein product, i.e. nucleotide deletions and insertions leading to frame shifting, and single nucleotide polymorphisms causing premature stop codons (Pedersen et al., 2009; Chang et al., 2012; Hsieh et al., 2013). The first mutation in the S gene that was associated with the FIPV biotype was not reported until few years ago (Chang et al., 2012), who sequenced and compared the complete genomes of 11 FIPV-FECV pairs.

Factors affecting the development of FIP infection

The resistance to FCoV infection seems to occur also in natural infections. A study in vivo showed that a small percentage of cats in FCoV endemic households had no shedding and remained seronegative or had a low antibody titer over a time period of 5 years (Addie et al., 2001). An ineffective immune response against FCoV infection seems to be an important factor in FIP pathogenesis (Kiss et al., 2000). It has been hypothesized that animals with a weak cell-mediated immunity (CMI) in combination with a strong humoral immune response are likely to develop FIP and cats with a strong CMI may not develop the disease (Pedersen, 2005).

FECVs mutate in a manner that causes them to lose tropism for enterocytes, while gaining tropism for macrophages. The exact site where these mutations occur is unknown, but it is apparently at some point between the intestine (enterocyte) and FIP lesions (macrophage). A possible intermediate site for this transformation would be blood monocytes/macrophages, which are known to be infected during FECV infection (Kipar et al., 2010). FECV-to- FIPV transition appears to involve positive selection for mutants that are increasingly fit for replication in macrophages and unfit for replication in enterocytes. The ultimate target cell is not just any macrophage, but rather a distinct population of precursor monocytes/ macrophages that have a specific affinity for the endothelium of venules in the serosa, omentum, pleura, meninges and uveal tract.

Immune system

It is assumed that immunity is largely cell-mediated and that the production of antibodies is counterproductive. Antibodies enhance the uptake and replication of FIPVs in macrophages and also contribute to a type III hypersensitivity (antibody-mediated or Arthus-type) vasculitis (Pedersen, 2009). It is also assumed that much of the pathology occurring in FIP is associated with how macrophages respond to viral infection and how the immune system of the host responds to the infected cells. In this scenario, the effusive form of FIP results from a failure to mount T cell immunity in the face of a vigorous B cell response. At the opposite extreme, cats that resist disease presumably mount a vigorous cell-mediated immune response that is able to overcome any negative effects of antibodies. Cats with the dry form of FIP represent an intermediate state involving a cellular response that is partially effective in containing the virus to a relatively small number of macrophages in a few focal sites within specific target organs. The two forms of FIP are somewhat interchangeable, when it has been observed in experimental infection, the dry form always follows a brief bout of effusive disease. In the terminal stages of naturally occurring dry FIP, immunity can completely collapse and the disease reverts to a more effusive form (Pedersen, 2014a.)

Genetic predisposition

Host genetic factors are also important for the susceptibility of monocytes to FCoV infection. Studies in vitro showed that monocytes from different cats do not have the same susceptibility to FCoV infection (by the same strain of FCoV) suggesting that cellular factors, influenced by genetic background and/or differentiation/activation status, are very important in determining the occurrence of FIP (Dewerchin et al.,2005; Pedersen, 2009). A genome- wide association study of a relatively large number of Birman cats identified five regions on four different chromosomes that could harbor genes involved in susceptibility (Golovko et al., 2013). Five candidate genes (ELMO1, RRAGA, TNSF10, ERAP1 and ERAP2) were identified in these four regions; all are associated with processes relevant to FIP, such as cellular migration, phagocytosis, apoptosis and virus–host interactions.

Clinical signs

The clinical signs differ between the different forms of FIP, however, in all cases, the earliest signs FIP, besides a failure to thrive in young cats, include a progressively worsening malaise, fluctuating fever, inappetence and weight loss (Pedersen, 2008).

Effusive ( ́wet ́) form

Abdominal distension is the most common physical finding in wet FIP and ranks higher than cardiovascular disease, neoplasia, hepatic or renal disease as causes of ascites in cats (Wright et al., 1999). The abdomen, besides being greatly enlarged, is often doughy feeling and painless on palpation, and a fluid wave is easily induced on percussion. Dyspnea can be a feature of cats with pleural involvement and thoracic effusions Intact males frequently develop scrotal enlargement due to extension of the peritonitis to the tunics surrounding the testes and edema (Pedersen, 2008). A syndrome of hepatic lipidosis and extreme skin fragility has been described in one cat with wet FIP (Trotman et al., 2007). In-utero FIPV infections have been observed in kittens born to queens that developed effusive FIP during pregnancy; pneumonia, pleuritis and hepatitis were the principal lesions in affected kittens (Mc Kiernan et al., 1981).

Non-effusive ( ́dry ́) form

Granulomatous FIP is called ‘dry’, parenchymatous, or non-effusive because there is no inflammatory exudation into body cavities. Involvement of the eyes and/or CNS predominates in 60% of the cats with dry FIP (Pedersen, 2008). The abdominal lesions of dry FIP are much larger, fewer in number and less widespread than the lesions of wet FIP. Lesions of dry FIP tend to extend downward from the serosal or pleural surfaces into underlying parenchyma (Pedersen, 2008). Abdominal lesions are frequently found in the kidneys and mesenteric lymph nodes and somewhat less frequently in the liver and hepatic lymph nodes (Pedersen, 2008). Involvement of the wall of the caecum and colon with associated ceco-colic lymphadenopathy is a specific form of dry FIP associated with signs typical of an ulcerative colitis (Harvey et al., 1996; Van Kruiningen et al., 1983). Involvement of the pericardium has been described and can lead to fluid distention of the pericardial sac, cardiac tamponade and heart failure (deMadron et al., 1986). Over one-half of cats with inflammatory disease of the CNS have FIP, as well as one sixth of the total number of cats showing CNS signs from any cause (Bradshaw et al., 2004). Most cats with CNS FIP are less than 2 years of age and often originate from large multiple cat households (Foley et al., 1998). Uveitis and chorioretinitis are the predominant ocular manifestations of dry FIP (Foley et al., 1998; Campbell et al., 1975, 1978; Doherty et al., 1971; Gelatt et al., 1973; Gillespie et al., 1973). Ocular disease in dry FIP occurs solely or in association with lesions in the CNS or peritoneal cavity. A change in the coloration of the iris is a frequent early sign of ocular FIP. Keratic precipitates on the caudal aspect of the cornea are characteristic of FIP and are due to accumulations of fibrin, macrophages, and other inflammatory cells. Focal lesions akin to the granulomas of parenchymatous organs may be apparent in the iris and distort the shape of the pupil (Pedersen, 2008).