Andrew H. Sparkes, BVetMed, PhD, DECVIM-CA, MRCVS
From a clinical perspective, two biotypes of feline coronavirus (FCoV) exist, recognising the fact that certain mutations within FCoV isolates results in a dramatic shift in the pathogenicity of the virus such that certain variants develop a tropism for macrophages, and have the capacity to cause fatal FIP. In contrast, the majority of FCoV strains are of much lower virulence and are more adapted to replication in enterocytes lining the gastrointestinal tract, generally causing no more than mild diarrhoea. These two biotypes of FCoV are frequently referred to as feline infectious peritonitis virus (FIPV) and feline enteric coronavirus (FECV), but it is clear that these are not two different viruses but simply strains of a single virus with markedly different virulence resulting from small mutations in their genomes. These two biotypes are indistinguishable antigenically and serologically.
Infection with FCoV is ubiquitous in domestic cat populations throughout the world. Serological surveys have demonstrated that typically 25-40% of household pet cats are FCoV seropositive, whilst this figure generally rises to 80-100% for cats from breeding catteries and other large catteries. Despite this high level of exposure to FCoV, FIP remains a relatively uncommon disease. This, along with other observations, suggests that the majority of natural FCoV infections are likely to be with FECV biotypes, and that FIPV variants are relatively uncommon.
Clinical FIP occurs when a cat is exposed to and infected with a virulent mutant of FCoV, and where the infection is unable to be contained by the host's immune response. There are several potential sources of virulent FIP producing strains of FCoV for a susceptible cat, including asymptomatic carrier cats shedding virus, clinical cases of FIP which may be shedding virus, and also environmental contamination. There have also been occasional reports suggesting the possibility of transplacental transmission of FIP, but if this does occur it appears to be exceptionally rare. However, it is now believed that the majority of clinical cases arise through spontaneous in situ mutation of an existing FCoV infection leading to the emergence of a virulent FIP producing variant.
Feline infectious peritonitis is a disease with extremely diverse clinical manifestations. There are no clinical signs that are pathognomonic, and the diverse nature of the signs means that FIP has to be considered in the differential diagnosis of many clinical presentations. The disease takes on one of two broad forms-effusive (or 'wet') FIP and non-effusive (or 'dry') FIP. In effusive disease, lesions are focused on the serosal surfaces of body cavities and the vasculitis present results in the outpouring of a protein rich fluid into the cavity (most commonly the abdomen). In non-effusive disease lesions are still most common in the abdominal cavity but granulomas develop within organs and other structures (usually towards the serosal surfaces) leading to more diverse and often more vague clinical signs. Other sites are also commonly affected, particularly the eyes and the CNS. Effusive disease is more common than non-effusive and in general probably accounts for around 60-70% of cases. The clinical course of FIP varies from several days at one end of the extreme, to several months at the other. Generally effusive disease tends to have a somewhat shorter duration than non-effusive disease and most cases have a course of a few weeks.
Making a presumptive diagnosis of FIP
As routine laboratory tests will not confirm a suspected diagnosis of FIP it is important that the complete clinical picture is considered before assuming a cat is suffering from this disease. Cases of FIP are far more common in young cats (less than two years of age), in pedigree cats, and in other cats from multicat households. Older cats and cats from single cat households also develop FIP, but these cases are less common, and with appropriate clinical signs and supportive laboratory data, the index of suspicion will be higher in cats known to have come from a higher risk background. In cases of suspected FIP, a thorough clinical examination is mandatory to try and identify any signs that are consistent with the diagnosis. This should include both a thorough ocular and neurological examination whether effusive or non-effusive disease is suspected. If non-effusive disease is suspected, careful examination for the presence of small amounts of effusion (e.g., screening thoracic and abdominal radiographs) is prudent. If an effusion is present, laboratory analysis of the fluid is one of the most useful of the routine laboratory tests. Similarly if abdominal effusive disease is suspected, thoracic radiographs to detect a pleural effusion can be valuable, as few other diseases would produce an effusion characteristic of FIP in both the abdominal and thoracic cavities. As FIP is a progressive disease, the clinical manifestations will change over time. Reaching a diagnosis in the early stages when clinical signs are vague may be extremely challenging, but in most cases, as time goes by, more classical signs of FIP will develop. However, this does mean that repeat and thorough clinical examinations will be required in on-going cases in order to detect the development of these signs.
Routine laboratory tests
Results of routine laboratory tests are useful in either supporting a presumptive diagnosis of FIP, or suggesting that some other cause for the signs is more likely. On routine haematology, the most consistent features are a lymphopenia, a neutrophilic leucocytosis that may be accompanied by a left shift, and a mild to moderate nonregenerative anaemia. Results of routine serum biochemistry, as with haematology, are non-specific. The most commonly observed changes are hyperproteinaemia due to hyperglobulinaemia, often accompanied by low or low normal serum albumin concentrations. These changes result in a low albumin:globulin ratio. The prevalence and severity of the hyperproteinaemia seen in FIP varies. It has been reported to occur in between 50% and 80% of FIP cases, and varies from mild to very marked elevations in globulin concentrations, producing total protein concentrations sometimes in excess of 100 g/l. Results of protein electrophoresis show that the elevated globulin levels are usually due to a combination of elevated alpha2- and gamma-globulins and sometimes also beta-globulins. However, these proteins are simply markers of inflammation, and therefore elevated concentrations are not specific for cases of FIP. Other biochemical changes seen with FIP include hyperbilirubinaemia in approximately 25% of cases, elevated liver enzymes, and mild to moderate azotaemia (renal or pre-renal in origin). Although all the routine changes seen with FIP are nonspecific, and can occur with many other diseases, they are still valuable in making a presumptive diagnosis of the disease. Results of these tests can be misleading though, as occasionally cases of confirmed FIP show no abnormalities on routine haematology and biochemistry, whereas other diseases may at times lead to all of the changes classically associated with FIP.
Coronavirus serology results are no more (or less) valuable than those of routine haematology and biochemistry. No serological assays have the ability to distinguish between the different virulence strains of FCoV and thus a positive titre simply shows that a cat has been exposed to a strain of FCoV, to which it has mounted a humoral immune response. The titre cannot distinguish the type of FCoV strain, whether the infection is current or previous, or whether the cat is susceptible to the development of FIP. Interpretation of coronavirus titres thus requires great care.
The analysis of effusions remains one of the most valuable routine tests for the diagnosis of FIP. Studies have shown that in FIP effusions, the total protein content of the fluid is in excess of 35 g/l with levels of around 60 g/l being typical. In addition to total protein, the albumin:globulin ratio should always be determined as FIP cases invariably have a globulin concentration greater than or equal to 50% of the total protein content. The total cell count of FIP effusions is usually <20 x 106/ml, with a predominance of nondegenerate neutrophils and macrophages. An effusion in more than one body cavity (e.g., thorax and abdomen) provides even more compelling evidence for FIP.
Polymerase chain reaction
Rather than provide a simple diagnostic test for FIP, the advent of RT-PCR has enabled a better understanding of the complexity of infection with FCoV in the cat. Studies have shown that in cases of confirmed FIP, the RT-PCR test is typically positive in 80-90% of cases. However, when the same test is applied to healthy cats from FCoV-endemic catteries, studies have shown many of these are also RT-PCR positive-generally in the order of 30-80%! Thus the RT-PCR assays do not have the ability to distinguish between different virulence strains of FCoV, and the high rate of positive results from blood samples of healthy cats suggests that this test has little, if any value.
Towards a definitive diagnosis
The results of the investigations already outlined may, in many cases, give sufficient grounds for a presumptive diagnosis of FIP to be made. However, in many situations a definitive diagnosis is desirable prior to a decision on whether euthanasia should be performed, and where the presence of disease has implications for other in-contact animals. Definitive diagnosis of FIP is possible. RT-PCR analysis of effusions is potentially useful. Whilst not providing 100% sensitivity or 100% specificity, the results of RT-PCR on effusions appears to be a helpful diagnostic tool providing strong additional evidence to support or rule out a diagnosis of FIP. Similarly, direct immunofluorescence staining of cytological preparations of effusions to detect FCoV antigens has been used and also appears reasonably reliable for the confirmation of effusive FIP and could be used to support a diagnosis of FIP. The only way of making a definitive diagnosis of FIP is by histopathological examination of affected tissues collected either at post mortem examination, or collected ante mortem from appropriate sites. For absolute confirmation (which may be required in some cases) it is possible to detect the presence of FCoV within the lesions by immunohistochemical means thus demonstrating the presence of FCoV antigen within the typical histological lesions.
A commercial FIP vaccine has been developed based on the intranasal administration of a temperature-sensitive mutant FIPV isolate. This vaccine is now widely available in many parts of the world. Under field conditions, there is evidence of efficacy when administered to seronegative cats or cats with low FCoV antibody titres but not when used in catteries where FIP is endemic. Even when efficacy has been demonstrated, it is clear that this is considerably less than 100% protection. In addition to these limitations, the vaccine is currently only licensed for use in kittens over 16 weeks of age, and in endemic situations most kittens of this age will already be infected with FCoV.