Feline infectious peritonitis: Strategies for diagnosing and treating this deadly disease in young cats

Feline infectious peritonitis (FIP) is one of the leading infectious causes of mortality in young cats.1 In this article, we review the clinical signs, diagnostic options, and treatments for this complex disorder.

FIP OVERVIEW

How it all begins

Feline coronavirus is a single-stranded RNA virus that is endemic in many multicat households, shelters, and catteries.2 In the common enteric form, feline coronavirus replicates in enterocytes and causes mild, self-limiting diarrhea. The virus may be shed in feces for several months after infection and is spread to other cats through oral ingestion. It survives in the environment for several weeks, and transmission may occur through shared litter pans, mutual grooming, or fomites. Young cats are more vulnerable to infection than adults are.2

THINKSTOCK/JANIE AIREY

Mutations routinely occur within the feline coronavirus genome through nucleotide substitution, deletion, and recombination.3 Certain mutations transform the virus into a virulent biotype, which is able to replicate in monocytes and macrophages. This mutated form is called FIP virus and causes a fatal systemic inflammatory disease. Estimates vary, but fewer than 10% of cats infected with feline coronavirus will develop FIP.2 Why the disease arises in some cats but not in others is not completely understood.2 Purebreed cats appear to be predisposed, although the incidence within specific breeds varies among countries.2

The cat's immune system appears to play a crucial role. Those with a prompt and robust cell-mediated immune response are able to destroy the FIP virus and are unlikely to develop clinical disease.2

GETTY IMAGES/ISTOCKPHOTO

Effusive vs. noneffusive

There are two main forms of FIP: effusive (wet) and noneffusive or granulomatous (dry). Some patients will switch between the two forms over the course of their illness. The development of one type vs. the other depends on the balance between the host's humoral (antibody-related) and cell-mediated immune responses. Cats with strong humoral responses develop effusive FIP, while those with mixed responses manifest the dry form.2

How FIP takes hold

The FIP virus infects mononuclear phagocytes and spreads hematogenously through infected monocytes. These may attach to the vascular endothelium or migrate into tissues. The virus replicates within macrophages, which die as the virus is released. This death of the cell and viral release triggers a marked inflammatory reaction, with the recruitment of more inflammatory cells and the release of cytokines and the activation of complement.

Vasoactive agents result in vasculitis and effusion in the chest, abdomen, or pericardial sac.4 Perivascular pyogranulomatous lesions develop on serosal surfaces and within solid organs and are characterized by an infiltrate of macrophages and neutrophils.

Because the FIP virus is strongly cell-bound and tissue-bound, shedding is unlikely unless there is effacement of the renal tubules or intestinal mucosa. Consequently, FIP is not regarded as a contagious disease, and the risk of horizontal transmission to other cats is minimal.2

DIAGNOSIS

In some cases, the diagnosis can be elusive and may depend on the logical exclusion of other possibilities. Clinicians often have to piece together supportive evidence and weigh the likelihood of FIP in a particular patient. Since feline coronavirus is endemic in many cat populations, FIP cannot be definitively diagnosed based solely on evidence of exposure to the virus. Instead, evidence is needed that the virus has moved beyond the gastrointestinal tract and is replicating in the internal organs, as this behavior differentiates the virulent virus from the nonvirulent forms. Unfortunately, proving this key piece of evidence can be difficult.

Clinical presentation

FIP is commonly reported in cats < 2 years of age, although it may arise in older cats from shelter environments. Generally, affected cats have an insidious onset of clinical signs with episodes of fever, malaise, and hyporexia. Kittens may fail to thrive and appear stunted.

Cats with effusive disease may present with abdominal distention, dyspnea, or both. Abdominal palpation may indicate mesenteric lymphadenopathy, renomegaly, or areas of thickened intestine.

Uveitis or chorioretinitis may be noted in cats with the dry form, and a careful ophthalmologic examination should be performed in any cat with an unexplained fever. Neurologic problems, including seizures, changes in mentation, and spinal compromise, are routinely reported in cats with dry FIP.2

Routine laboratory findings

A mature neutrophilia is expected in cats with FIP, along with lymphopenia. Many cats have concurrent nonregenerative anemia, attributed to chronic inflammatory disease and secondary suppression of erythropoiesis.5 Hyperglobulinemia is routinely reported in cats with FIP, particularly the dry form. The albumin:globulin ratio is often < 0.8 (a ratio < 0.6 is highly suggestive of FIP).2 Hyperbilirubinemia is also commonly noted, although overt icterus is unusual.

Fluid analysis

FIP is the most common cause of abdominal effusion in cats < 2 years of age.2 An examination of abdominal or pleural effusion often provides strong supportive evidence of FIP. The fluid is usually light to dark yellow and may be cloudy or mucinous.5 The total protein content is predictably > 3.5 g/dl, with an albumin:globulin ratio < 0.6. The nucleated cell count is generally < 5,000/μl and consists primarily of macrophages and nontoxic neutrophils.

The Rivalta test is a simple in-house test you can perform to exclude FIP as a cause of effusion; however, it lacks specificity, as any protein-rich fluid is likely to produce a positive result.6 Mix one drop of 98% acetic acid with 5 ml of distilled water in a test tube. Place a drop of the effusion on top of this solution and observe its motion. If the effusion dissipates, the fluid is transudate and is not consistent with FIP. If the effusion is still clearly visible, it is consistent with an exudate but not diagnostic for FIP.

Imaging studies

Radiography can confirm the presence of free fluid in effusive cases but has limited value in cats with dry FIP. Abdominal ultrasonography permits the identification and collection of ascitic fluid along with an evaluation of the internal organs. Renomegaly, lymphadenopathy, and regional thickening of the small bowel or colon are commonly noted in affected cats.

Gross surgical or postmortem findings

In cats with effusive FIP, serosal surfaces are often covered in pyogranulomatous lesions of varying size.2 The omentum is often markedly thickened and contracted. Firm white or mottled granulomas may be seen on the surface of affected organs. Lymphadenopathy is expected, and affected nodes are firm and nodular. In cats with dry FIP, fewer but larger lesions are noted. These start on the serosal surface of the organs and extend into the parenchyma.

Cytologic and histologic examination

The results of a cytologic examination of affected tissues in cats with effusive FIP show a pyogranulomatous reaction with clusters of macrophages and neutrophils.2 A histologic evaluation of affected tissues reveals widespread perivascular inflammation, with a predominance of macrophages. Edema and necrosis are also evident. In cats with dry FIP, dense lymphocytic aggregates are often noted around affected vessels. Necrosis and fibrin deposition are less dramatic than in the effusive form.

Additional testing for FIP

Antibody testing. Many veterinary laboratories provide qualitative and quantitative testing for feline coronavirus antibodies in serum. An in-clinic ELISA test is also available and can be performed on serum or plasma. These tests cannot differentiate cats with exposure to the harmless enteric form from those with FIP. Negative results strongly discount FIP infection, but a positive titer has little diagnostic value unless it is more than 1:1,600.6

It is interesting to note that titers can fall dramatically in the terminal stages of the disease. Efforts have been made to improve the specificity of serologic tests for FIP, including the development of an assay for antibodies against the 7b protein of feline coronavirus. This antigen was thought to be associated with FIP viral strains but is also expressed by the enteric biotype. Thus, positive results with the FIP 7b ELISA test should not be regarded as definitive evidence of the disease.7

PCR testing. A polymerase chain reaction (PCR) test for identification of feline coronavirus messenger RNA (mRNA) is offered through several commercial laboratories. The concept behind this test is that the presence of mRNA indicates active viral replication within the body, which would be indicative of FIP rather than enteric feline coronavirus infection.8 The test can be performed on whole blood, cavity effusions, or aqueous humor.

Conflicting reports exist regarding the reliability of this test, and it seems as though results from the testing of whole blood are questionable. In one report, more than half of the healthy control group had positive results, suggesting poor specificity.9 However, real-time testing of effusions appears to be much more reliable and can accurately differentiate cats with FIP from those with other causes of ascites or pleural fluid.6

Immunocytochemistry and immunohistochemistry. Samples of effusion or affected tissues may be tested for the presence of viral antigens using anti-FIP antibodies.10 Essentially, polyclonal or monoclonal antibodies with high specificity for the feline coronavirus are mixed with the sample and allowed to attach to infected macrophages. The antibodies are subsequently detected using a marker agent, either fluorescein (effusion or fresh tissue) or horseradish peroxidase (formalin-fixed tissue).

These tests are generally regarded as the diagnostic gold standard, and a positive result is definitive confirmation of FIP. Unfortunately, false negative results may occur when low cellularity effusions are tested or if unaffected organs are biopsied.2

TREATMENT

Most experts regard FIP as an incurable disease, although some cases of apparently spontaneous remission have been reported. Numerous medical therapies are described in the literature, usually with conflicting accounts of efficacy. It seems likely that some medical interventions have a positive effect, but such responses are generally transient, and owners should always be informed of the grave prognosis associated with FIP.

Administering glucocorticoids appears to improve survival times in cats with FIP and may mitigate morbidity associated with fever and hyporexia. Giving other immunosuppressive agents, such as cyclophosphamide or chlorambucil, appears to offer little advantage and may cause myelosuppression.2

Feline interferon omega administration was reported to induce remission in one study but showed no benefit in a larger population of affected cats.11,12

Pentoxifylline therapy has been suggested because it inhibits tumor necrosis factor alpha and has an antivasculitis effect; however, a recent placebo-controlled study using a related agent failed to identify a positive effect in cats with FIP.13

The administration of various antiviral agents has demonstrated efficacy against feline coronavirus in vitro, but we are not aware of any reports describing their effects in cats with experimental or spontaneous infections.14

A report published in 2009 described the effect of Polyprenyl Immunostimulant (Sass & Sass) administration in three cats with dry FIP.15 The findings were encouraging, as two of the three cats were alive > 24 months after diagnosis. This product is thought to upregulate innate immunity and is marketed for the reduction of clinical signs in cats with rhinotracheitis.

PROGNOSIS

Most cats with effusive disease die or are euthanized within a few weeks of the onset of clinical signs.2 The dry form tends to move more slowly, and cats may survive for several months from when signs are first noted. Cats with neurologic involvement often have a short survival time.

PREVENTION

An intranasal vaccine (Felocell FIP—Zoetis) is licensed for cats > 16 weeks old. This attenuated, temperature-sensitive strain of FIP virus is presumed to trigger protective IgA antibodies. Based on independent testing, the efficacy of this product is questionable, and it is not regarded as a core vaccine.16

Because the virus can survive in the environment for several weeks, a new cat should not be introduced into a single-cat household until three months after the demise of the cat with FIP. In multicat households, fecal PCR testing has been proposed as a way to identify those cats that are shedding feline coronavirus and assess the risk to a newcomer. However, fecal excretion can be sporadic, and these tests suffer from low sensitivity. If a new cat is introduced, it is prudent the owner select an adult rather than a kitten, as older cats are innately more resistant to infection with feline coronavirus.

In shelter environments, feline coronavirus is generally endemic, and efforts to eradicate it are futile. However, the incidence of FIP can be reduced through management strategies such as preventing overcrowding and diagnosing and treating common intestinal and respiratory infections. These factors are thought to stress the immune system and predispose juveniles to the development of FIP.17

Most cats in breeding facilities are also infected with feline coronavirus, and kittens are predictably exposed from contact with the queen or the contaminated environment. As infection with feline coronavirus occurs around 9 or 10 weeks of age, isolation of the litter at 6 weeks of age may be helpful.17 However, strict quarantine regulations are needed, including separate caretakers and air space. As genetic factors probably influence the development of FIP, any queen or tom with two or more infected litters should be removed from a breeding program.2

CONCLUSION

In many patients, diagnosing FIP requires a careful assessment of the entire clinical picture and systematic collection of supportive and corroborative data. Clinicians need a good understanding of the tests available and must be prepared to counsel clients about the limitations and reliability of diagnostic methods. A definitive antemortem diagnosis may be difficult, particularly in cats with the dry form of the disease, and it may be necessary to reach a conclusion based on overall likelihood rather than irrefutable test results.

Audrey K. Cook, BVM&S, MRCVS, DACVIM, DECVIM-CA, Department of Small Animal Clinical Sciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX 77843

Whitney R. Nelson, DVM, DACVIM, Pieper Memorial Veterinary Center, 730 Randolph Road, Middletown, CT 06457

REFERENCES

1. Cave TA, Thompson H, Reid SW, et al. Kitten mortality in the United Kingdom: a retrospective analysis of 274 histopathological examinations (1986-2000). Vet Rec 2002;151:497-501.

2. Pedersen NC. A review of feline infectious peritonitis virus infection:1963-2008. J Feline Med Surg 2009;11:225-258.

3. Vennema H, Poland AM, Foley JE, et al. Feline infectious peritonitis viruses arise by mutation from endemic feline enteric coronaviruses. Virology 1998;243:150-157.

4. Kipar A, May H, Menger S, et al. Morphologic features and development of granulomatous vasculitis in feline infectious peritonitis. Vet Pathol 2005;42:321-330.

5. Sparkes AH, Gruffydd-Jones TJ, Harbour DA. Feline infectious peritonitis; a review of clinicopathological changes in 65 cases, and a critical assessment of their diagnostic value. Vet Rec 1991;129:209-212.

6. Hartmann K, Binder C, Hirschberger J, et al. Comparison of different tests to diagnose feline infectious peritonitis. J Vet Intern Med 2003;17:781-790.

7. Kennedy MA, Abd-Eldaim M, Zika SE, et al. Evaluation of antibodies against feline coronavirus 7b protein for diagnosis of feline infectious peritonitis in cats. Am J Vet Res 2008;69:1179-1182.

8. Simons FA, Vennema H, Rofina JE, et al. A mRNA PCR for the diagnosis of feline infectious peritonitis. J Virol Methods 2005;124:111-116.

9. Can-Sahna K, Soydal Ataseven V, Pinar D, et al. The detection of feline coronaviruses in blood samples from cats by mRNA RT-PCR. J Feline Med Surg 2007;9:369-372.

10. Paltrinieri S, Parodi MC, Cammarata G. In vivo diagnosis of feline infectious peritonitis by comparison of protein content, cytology, and direct immunofluorescence test on peritoneal and pleural effusions. J Vet Diagn Invest 1999;11:358-361.

11. Ishida T, Shibanai A, Tanaka S, et al. Use of recombinant feline interferon and glucocorticoid in the treatment of feline infectious peritonitis. J Feline Med Surg 2004;6:107-109.

12. Ritz S, Egberink H, Hartmann K. Effect of feline interferon-omega on the survival time and quality of life of cats with feline infectious peritonitis. J Vet Intern Med 2007;21:1193-1197.

13. Fischer Y, Ritz S, Weber K, et al. Randomized, placebo controlled study on the effect of propentofylline on survival time and quality of life of cats with feline infectious peritonitis. J Vet Intern Med 2011;25:1270-1276.

14. Barlough JE, Shacklett BL. Antiviral studies of feline infectious peritonitis virus in vitro. Vet Rec 1994;135:177-179.

15. Legendre AM, Bartges JW. Effect of Polyprenyl Immunostimulant on the survival times of three cats with the dry form of feline infectious peritonitis. J Feline Med Surg 2009;11:624-626.

16. Fehr D, Holznagel E, Bolla S, et al. Placebo-controlled evaluation of a modified life virus vaccine against feline infectious peritonitis: safety and efficacy under field conditions. Vaccine 1997;15:1101-1109.

17. Addie DD, Paltrinieri S, Pedersen NC. Recommendations from workshops of the second international feline coronavirus/feline infectious peritonitis symposium. J Feline Med Surg 2004;6:125-130.