Feline Infectious Peritonitis

Written by: Brigid L. • 2017 Scholar

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Introduction

Feline Infectious Peritonitis (FIP) is an immune-mediated, viral disease.¹ FIP is characterized by persistent, insidious fevers that are non-responsive to antibiotic treatments.¹ The disease can present in two forms, Wet, or Effusive, and Dry that exist on a continuum.² The dry FIP is a chronic form of the disease that eventually progresses to an effusive state.² It typically presents with vague clinical signs such as weight loss, dull coat, and icterus.¹ In more rare cases, cats can develop white precipitates in the eyes or experience eye bleeds.² In 10% of dry FIP cases, neurologic signs develop such as ataxia, tremors and nystagmus.³ The wet form is generally more acute, characterized by cavity effusions that can develop in the thorax, abdomen, or rarely the pericardium.² In the wet form, the effusions develop due to damage to the blood vessels that causes leaks throughout the vasculature.² FIP is a dangerous disease that is typically fatal.

Epidemiology

Feline Infectious Peritonitis is a progressive disease that develops from a common, innocuous virus, Feline coronavirus.² FIP develops in about 12% of cats that contract feline coronavirus.² The feline coronavirus is a pervasive virus primarily shed through feces.² Due to this, feline coronavirus is extremely common in areas with crowded conditions, such as catteries and shelters. In most healthy cats, the immune system quickly eliminates feline coronavirus with little to no symptoms while infected. Unfortunately, it is impossible to predict which cats will succumb to the mutation of feline coronavirus to FIP. Predisposing factors have been identified that could help guide diagnosis. Cats infected with feline coronavirus under persistent stress are more likely to develop FIP than unstressed cats.² Most importantly, however, is age. 70% of cats that develop FIP are less than a year old.⁴

Pathogenesis

FIP develops from feline coronavirus through a series of mutations that are believed to occur during periods of rapid viral replication.² Identified FIP mutations occur in the non-structural genes, through more remain to be identified. The identified mutations can experimentally demonstrate the disease; however, they are not linked to any molecular changes.² At present, there is no defined incubation period, but experimental feline coronavirus infections have developed into clinical FIP in six weeks.⁵ Experimental incubation periods have been determined: 2-14 days for effusive forms and several weeks for the dry form.⁶

Sufficient replicating virus is a prerequisite for the FIP mutation and following disease to occur.² If the cat is not infected with a high enough load of feline coronavirus, there is no real threat of FIP mutation. Sufficient load is ensured via viral persistence and resurgence. Viral persistence is maintained in the colon of infected cats.⁷ Persistence can also be maintained in other tissues through macrophage infections.⁷ The eventual progression of FIP from feline coronavirus has been demonstrated in enterocytes of the colon, though most researchers also believe it can occur in any infected tissue macrophages.⁸

The development of FIP has been definitively linked to several progressive steps. Firstly, the feline coronavirus contracted must be able to create a systemic infection via monocytes and macrophages.⁹ The ability of feline coronavirus to create a systemic disease has been linked to a mutation in the S gene.⁹ Secondly, the ability to replicate within monocytes and macrophages must be efficient and sustainable.⁸ If the virus cannot sustain the ability to replicate in these cells, it cannot maintain a long-term systemic infection necessary for FIP to develop. Lastly, and most importantly, the monocytes that infected with FIP need to be activated. This process is ultimately responsible for the FIP disease and creates the granulomatous phlebitis and periphlebitis seen in FIP.¹⁰ The activation of the FIP-infected monocytes most likely occurs during high-level monocyte-mediate viremia.¹⁰ Once the FIP-infected monocytes are infected, high levels of cytokines, TNF-alpha and IL-1beta, and other molecules occur.¹⁰ This leads to the destruction of the vasculature’s basement membrane and activation of the vasculature’s endothelial cells. This ultimately leads to a systemic increase in vascular endothelial growth factor (VEGF).¹¹ VEGF creates the development of effusions in cats with FIP as it increases the vasculature permeability.¹¹

Since the development of disease is dependent on viral infection of macrophages, the cat’s T cell response is the only effective response to FIP.² There is a strong suggestion that the type of immune response mounted by the cat’s immune system can lead to FIP disease. Cats mounting a strong cell-mediated immune response against feline coronavirus are less likely to develop FIP.² Cats that develop a strong humoral response may be more likely to develop FIP.² The antibodies created allow the virus to more easily can access to macrophages and replicate.² This can lead to a shortened disease course and earlier death.²

Presentation and Diagnosis

FIP is an extremely difficult disease to diagnose definitely. Currently, no single test can diagnose every case of FIP. To begin diagnosis, the patient’s history and clinical presentation are important to consider. FIP occurs most commonly in male cats under 3 years of age.¹² Recent history of stress, such as vaccination or recent adoption, is also important to consider.¹² There are many clinical signs that may point towards FIP such as fever of unknown origin, anorexia, weight loss, icterus, effusions, or neurological symptoms.² However, these clinical signs are vague and only add FIP to the differential diagnosis list; they are not diagnostic in themselves.²

Once FIP is a differential diagnosis for the patient, there are several laboratory tests that can be run in order to try and reach a definitive diagnosis. As a beginning step, a routine complete blood chemistry can help support a diagnosis. FIP is accompanied by lymphopenia and neutrophilia.¹² FIP patients can also have mild-moderate normocytic and normochromic anemia.¹² Rarely, FIP patients have hemolytic anemia¹². A serum blood chemistry can also be run on potential FIP patients for more information. FIP patients often have hyperproteinemia due to hyperglobulinemia, but low albumin.¹⁴ A low albumin to globulin ratio is very typical of FIP patients.¹³ A ratio lower than 0.4 is very indicative of FIP while a ratio over 0.6 can often rule out FIP.¹³ Patients with a suspected wet form of FIP often have hyperbilirubinemia that can worsen over time indicating a progression of disease.¹⁴ A simple urinalysis for FIP patients may show a hyperbilirubinuria.1 If the patient history, clinical signs, and routine lab work support FIP, several specialized tests can be performed.

The first test only requires a simple blood draw. The patient serum can be tested for the presence of feline coronavirus.¹⁵ These tests are typically an enzyme-linked immunosorbent assay (ELISA). These tests typically use coronavirus-infected feline cells as a substrate. Titers are read in a set of serum dilutions.¹⁵ These types of tests only test for an increase in feline coronavirus antibodies. While FIP cases tend to have higher feline coronavirus antibody titers compared to non-FIP cats, there is no clear-cut number that indicates FIP.¹⁵ The use of this test is very limited and can lead to misdiagnosis if used alone.

A more accurate test relies on effusion samples. An analysis of the effusions in a patient can be very helpful for diagnosis. FIP cats typically have effusions that are straw yellow, viscous, protein rich, and have low cellularity.15 The effusion of a positive cat typically has a protein concentration over 35 grams/liter and will have a albumin to globulin ration that is low.¹⁵ The level of AGP, an acute phase protein, in the effusion is the most accurate indicator of FIP. FIP- positive cats will have AGP concentrations over 1.55 mg/ml.¹⁵

Another important diagnostic indicator relies on PCR of patient samples. There are a couple of diagnostic tests that utilize PCR. The first PCR test measures the levels of feline coronavirus in the patient. A reverse transcriptase-PCR to test for feline coronavirus can be performed on blood, effusion samples, feces or tissue samples.¹⁶ FIP positive cats will have higher levels of feline coronavirus than non-FIP cats.¹⁶ This test can have false-positives as some non-FIP cats can have abnormally high levels of feline coronavirus.¹⁶ Tests performed on effusion samples were shown to have good sensitivity and high specificity.¹⁶ However, tests performed on serum and plasma samples were relatively ineffective and are not recommended.¹⁶ Secondly, a PCR test can be run to target a mutation in the S protein that has been used as a marker for feline coronavirus associated with FIP.¹⁵ The presence of the S protein mutation is not a definitive diagnosis of FIP, but shows a possible progression of disease.¹⁵

Lastly, immunostaining of samples for feline coronavirus antigen can be performed on formalin- fixed tissue or cytology samples.¹⁵ Samples have an antibody for feline coronavirus applied followed by some sort of reaction, such as a color change or fluorescence, to identify if antibody has bound. A positive immunostaining of the tissue can confirm a diagnosis of FIP as the test has been shown to be very specific.¹⁵ However, false negatives do occur and a negative test cannot rule out FIP.¹⁵ The staining of effusion samples rather than tissue samples is less sensitive and tissue samples are more highly recommended.¹⁵

Prognosis and Treatment

Prognosis for FIP-positive cats is grave.² Mortality occurs in nearly 100% of cases.² The clinical course of the disease can range from days to months depending on the clinical presentation of the cat. The effusive form is much more deadly and kills more quickly than the dry form.² The outcome for FIP-positive cats is due to the unstoppable clinical course. There is currently no effective treatments for FIP-positive cats.

Some antiviral medications have been used in experimental studies, but have not been shown to be efficacious enough for patient use.² Chloroquine, used to treat malaria, has been shown to inhibit FIP viral replication while also having some anti-inflammatory effects.¹⁷ Treated cats did have better clinical scores, but there is a possible toxic effect to the drug indicated by increased alanine aminotransferase levels.¹⁷ Cyclosporine A possess the ability to block replication of coronaviruses in cell culture, but has not been tested in vivo.¹⁷ Immunosuppressive drugs have been used in the past on FIP patients, but they have limited success.² Prednisolone and cyclophosphamide can reduce clinical signs in FIP cats, but they do little to alter the disease outcome.¹⁷

Current recommended procedures for FIP-positive cats revolve around quality of life until their eventual demise. Cats that are suffering from FIP can undergo therapeutic paracentesis to alleviate symptoms.² This may encourage the cat to eat and help with wight loss.² Euthanasia is an appropriate treatment for FIP as it can be a very difficult condition for the cat and owner to manage.²

Disease Management

Manage of the disease is important to consider in multiple cat households such as breeding catteries and shelters. No vaccination in currently available for FIP due to the enhancement of the disease through antibodies.² Disease management revolves mostly around hygiene of facilities since FIP develops from feline coronavirus, a virus transmitted predominately through the fecal-oral route. It is beneficial in multi-cat situations to keep less than three cats per room.² Sufficient litter pans should be available to the cats. Litter pans should be cleaned frequently and kept away from food bowls.² If feline coronavirus shedding cats have been identified, it is recommended that they are separated from other cats to reduce risk of transmission.² In situations in which an FIP cat occurs in a single-cat household, it is recommended to wait at least two months prior to obtaining a new cat.² This will allow environmental feline coronavirus to die off before a new cat is introduced.²

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Works Sited:

1. Tilley, LP, Smith, FWK. Blackwell’s Five-Minute Veterinary Consult: Canine and Feline (6th Ed). Ames, Iowa: Wiley Blackwell.
2. Addie D, Belak S, Boucraut-Baralon C, Egberink H, Frymus T, Gruffydd-Jones T, Hartmann K, Hosie MJ, Lioret A, Luts H, Marsilio F, Pennisi MG, Radford AD, Thiry E, Tryyen U, Horzinek MC. Feline infectious peritonitis: ABCD guidelines on prevention and management. Journal of Feline Medicine and Surgery 2009; 11: 594- 604.
3. Kline KL, Joseph RJ, Averill DR. Feline infectious peritonitis with neurologic involvement: clinical and pathological findings in 24 cats. Journal of the American Hospital Association 1994; 30: 111-118.
4. Hartmann, K. Feline infectious peritonitis. Veterinary Clinics of North America: Small Animal Practice 2005; 35: 39-79.
5. De Groot-Mijnes JDF, van Dun JM, van der Most RG, de Groot RJ. Natural history of a recurrent feline coronavirus infection and the role of cellular immunity in survival and disease. Journal of Virology. 2005; 79: 1036–1044.
6. Pedersen NC, Boyle JF, Floyd K. Infection studies in kittens, using feline infectious peritonitis virus propagated in cell culture. American Journal of Veterinary Research. 1981; 42: 363–367.
7. Kipar A, Meli ML, Baptiste KE, Bowker LJ, Lutz H. Sites of feline coronavirus persistence in healthy cats. Journal of General Virology. 2010; 91: 1698–1707.
8. Kipar, A. FIP: an update on the pathogenesis of an enigmatic disease. Fourth International Society for Companion Animal Infectious Diseases Symposium: 2016.
9. Porter E, Tasker S, Day MJ, Harley R, Kipar A, Siddell SG, Helps CR. 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. 2014; 45: 49.
10. Kipar A, May H, Menger S, Weber M, Leukert W, Reinacher M. Morphological features and development of granulomatous vasculitis in feline infectious peritonitis. Veterinary Pathology. 2005; 42: 321–330.
11. Takano T, Ohyama T, Kokumoto A, Satoh R, Hohdatsu T. Vascular endothelial growth factor, produced by feline infectious peritonitis virus-infected monocytes and macrophages, induces vascular permeability and effusion in cats with FIP. Virus Research 2011; 158: 161–168.
12. Riemer F, Kuehner KA, Ritz S, Sauter-Louis C, Hartmann K. 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. 2016; 18: 348–356.
13. Jeffery U, Deitz K, Hostetter S. Positive predictive value of albumin: globulin ratio for feline infectious peritonitis in a mid-western referral hospital population. Journal of Feline Medicine and Surgery. 2012; 14: 903–905.
14. Tsai HY, Chueh LL, Lin CN, Su BL. Clinicopathological findings and disease staging of feline infectious peritonitis: 51 cases from 2003 to 2009 in Taiwan. Journal of Feline Medicine and Surgery. 2011; 13: 74–80.
15. Tasker, S. FIP dilemmas in diagnosis. The Feline Center. 2016.
16. Pedersen NC, Eckstrand C, Liu H, Leutenegger C, Murphy B. Levels of feline
17. infectious peritonitis virus in blood, effusions, and various tissues and the role of lymphopenia in disease outcome following experimental infection. Veterinary Microbiology. 2015; 175: 157–166.
18. Pedersen, NC. An update on feline infectious peritonitis: diagnostics and therapeutics. The Veterinary Journal. 2014; 201: 133-141.

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