Feline Infectious Peritonitis: An Overview of Disease Transmission, Pathogenesis, Signs and Treatment With Emphasis on Diagnosis

Kristina Baranik, DVM; Bruce E. LeRoy, DVM, PhD; Kenneth S. Latimer, DVM, PhD; A. Wayne Roberts, MS; Melanie Johnson, DVM; Heather L.Tarpley, DVM

Class of 2004 (Baranik), Department of Pathology (LeRoy, Latimer, Johnson, Tarpley) and Diagnostic Laboratory (Roberts), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

Feline infections peritonitis (FIP) is caused by a feline coronavirus. The feline coronaviruses (FCoV) are related to canine coronavirus (CCV) and transmissible gastroenteritis virus (TGEV) of pigs. Both of these related viruses can infect cats, and experimental inoculation with CCV can cause clinical signs of FIP.⁴ Originally, it was thought that there were only two types of feline coronavirus that infected cats, and the more virulent type, FIP virus (FIPV), caused the clinical disease of FIP. It is now known that, in fact, FIPV is a mutant of FCoV. Not only can the genetic makeup of the virus impart greater disease-causing potential, but also the cat’s genome can determine the severity of disease. It has been shown that a genetic predisposition can put some cats at greater risk of FIP than others. In one study of a group of Persian cats experiencing an epidemic of FIP, many of the kittens that were affected were found to be sired by the same tom.⁶ It has also been observed that cheetahs (Fig. 1) are at increased risk for FIP infection.^4,11,13 This is most likely due to the high degree of homozygosity in its genome. This may create a weaker cell-mediated immune response when compared with other Felidae.

Fig. 1. The cheetah is at higher risk of developing FIP. Photo courtesy of the Cheetah Conservation Fund (CCF) website at http://www.cheetah.org/

Transmission and Pathogenesis

FCoV usually does not survive well outside the host, though under ideal conditions it may persist up to seven weeks in the environment.⁴ FCoV is shed in the feces and to a lesser degree in the saliva of infected cats.¹ Coronaviruses of other animals, wild and domestic, are shed to a high degree in mucosal secretions from the respiratory tract; this has not been shown to be a significant route of transmission in domesti`c cats. The most likely mode of transmission is via the orofecal route.⁴ Coronaviruses appear to be resistant to trypsin and low pH,¹³ which gives them access to the target cells in the lower small intestine and colon. The receptor for coronavirus is an enzyme called aminopeptidase-N which is located on the brush border of enterocytes.^1,4 Enteric coronaviruses replicate in the intestinal epithelium and may lead to ulceration and blunting of the villi commonly leading to diarrhea.

FIPV probably arises from a mutation in the 7b open reading frame (ORF) of FCoV, however deletion in the 7a ORF has also been reported.⁶ FIPV initially replicates in the tonsils or gut,⁵ and then in regional lymph nodes. FIPV has the ability to replicate in macrophages, which disseminate the virus to many parts of the body. At this point in the FIPV infection, the host’s immune response determines the severity of disease. A strong cell-mediated immune response may terminate the infection and FIP does not develop. In a cat with a poor CMIR, antibodies may develop, but these antibodies are not necessarily protective. In fact, some studies have shown that antibodies may actually enhance the disease process by facilitating uptake of virus into macrophages and accelerating the course of disease.⁴ This antibody-dependent enhancement does not appear to occur in naturally infected pet cats. Instead, cats which are seropositive prior to exposure to FCoV are less likely to progress to FIP than cats which are seronegative before exposure.⁴ Cats that are able to eliminate FIPV may become healthy persistent carriers of FCoV; some cats may be carriers for at least 26 months¹ and never develop FIP infection. In others, infection may recrudesce after a period of weeks to months, and sometimes coinfection with FeLV or FIV can suppress the CMIR enough to allow expression of FIP.⁵

As mentioned previously, production of antibodies may aid in neutralizing FIP infection. However, these antibodies also play a key role in the expression of disease. The mechanism by which FIP causes the characteristic granulomatous lesions and thoracic and/or abdominal effusions, as seen in the effusive form of FIP, is the formation of antigen-antibody (IgG) complexes. The antigen-antibody complexes activate complement, leading to chemotaxis and accumulation of neutrophils. When macrophages encounter the complexes, they are stimulated to secrete TNF-a, IL-1, platelet activating factor, nitric oxide, and oxygen radicals.¹² IL-1 and TNF-a act on endothelium and are major components in increasing the permeability of vessels to allow emigration of neutrophils and proteins such as fibrinogen. This increased vascular permeability is directly responsible for the proteinaceous abdominal and pleural effusion that is commonly seen in the effusive form of FIP. Products of neutrophil degranulation, free radicals and proteases, and nitric oxide from macrophages damage tissue and lead to vasculitis and organ damage with serosal fibrin deposition which creates a grossly granular appearance on affected organ and tissue surfaces.⁴

Clinical findings

Disease due to FIPV can occur in domestic cats of any age or sex, though it may be a bit more prevalent in purebred cats, and especially intact males.¹¹ It is most commonly observed in cats between 3 months and 3 years of age.² Cats that are affected are usually from catteries, multicat households, or shelters.² Clinical presentation of cats with FIP can vary considerably. Sometimes cats with FCoV infection will suffer from mild diarrhea or upper respiratory disease, or they may be asymptomatic. The effusive from of FIP is associated with a poor CMIR and more rapid onset of signs; the non-effusive form tends to be more insidious and is associated with a mild CMIR insufficient to eliminate the infection. Some cats with non-effusive FIP will develop the effusive form in the terminal stages of illness. Signs of the more acute, effusive disease may include abdominal distension, dyspnea, fever, icterus, and lethargy. Thoracic auscultation may reveal muffled heart sounds if pleural effusion is present. Cats with non-effusive FIP may experience weight loss, fever, lethargy, and icterus. In either form, all or none of these signs may be present. Some affected cats lose weight despite a normal appetite. In some cases, cats can present with a mass in the abdomen and are thought to have some kind of neoplasia.⁷ In most of these cases, the mass is a greatly enlarged mesenteric lymph node with granulomatous inflammation; further immunohistologic testing reveals FIPV at the root of the problem. Other organs that can be affected, like kidney or spleen, can be mistaken for an abdominal mass also. Affected organs may appear to have irregular surfaces on radiographs or ultrasound. Sometimes, CNS and/or ocular signs are the first indication of disease. With the neurologic presentation, signs may be include paresis, hyperesthesia, seizures, ataxia, and changes in personality.³ Ocular signs may include ocular pain, corneal edema, keratic precipitates, fibrin exudation into the anterior chamber, hypopyon, hymphema, and miosis.² Color changes can be seen in the iris. Ocular signs are more commonly seen in the non-effusive form of FIP. If a careful history is obtained, it is often discovered that the cat was housed in a shelter, cattery, or other multicat environment sometime in the past year. Often the cat has experienced some kind of stress in the past few months

Diagnosis

Although several methods of diagnosis have been proposed, there is no documented method for a simple, noninvasive definitive test for FIP. Many clues can be gathered from CBC, blood chemistries, and serology however. Many cats clinically ill with FIP will show the following abnormalities:

• normocytic, normochromic, nonregenerative anemia
• hyperproteinemia with hyperglobulinemia
• decreased A:G ratio
• leukocytosis with neutrophilia

While these changes may be useful to form a suspicion of FIP, many cats with other diseases and signs similar to FIP or without any clinical signs of FIP can have these same parameters.⁹ Blood chemistry abnormalities may occur if specific organs are affected. For example, FIP that results in antigen-antibody complexes in the kidney can cause a pyogranulomatous glomerulonephritis resulting in azotemia. Additionally, the finding of low urine specific gravity and proteinuria could be confounding since these changes can be indicative of primary renal disease or FIP. Anemia may certainly be consistent with either disease. Unfortunately, there are no specific changes in the CBC, blood chemistries, and urinalyses that are pathognomonic for FIP.

Abdominal or pleural effusion can make diagnosis a bit easier since this is a hallmark feature of disease due to FIP. The effusion from an FIP patient may be distinguished by cytology and has a very characteristic appearance. Grossly (Fig. 2), the fluid may appear yellow and contain fibrin clots and a high protein concentration (>3.5g/dl).⁸ Nucleated cell count ranges from 1000-30,000 cells/µl. Cytologic evaluation (Fig. 3) usually reveals nondegenerate neutrophils, macrophages, and lymphocytes. An eosinophilic, finely granular background material is seen on smears due to the high protein content of the fluid.⁸ This appearance, combined with clinical findings and other data allows a presumptive diagnosis of FIP.

Fig. 2. The yellow color and frothy appearance of the effusion is due to the high content of fibrin in the fluid. This is typical of effusion due to FIP.	Fig. 3. The cytology of FIP effusion usually contains neutrophils, macrophages and lymphocytes.

Serology can be useful as an aid in diagnosis of FIP, but when used alone is practically meaningless. The antibody titer (usually determined by indirect immunoflourescence on serum) only indicates whether or not the cat has been exposed to FCoV, but cannot distinguish between enteric coronavirus and FIPV.¹⁰ In fact, many healthy cats test positive on serology so extreme caution must be used when interpreting results. In mutlicat households, it is not uncommon to find 75-90% of cats seropositive for FCoV. Even in single cat households, up to 25% of cats have significant antibody titers.¹¹ Another factor to consider is that a cat which is terminally ill with FIP may have a decreasing titer.¹⁰ This is probably due to a small amount of antibody in the serum due to a high concentration of it bound in antigen-antibody complexes. Additionally, kittens born to a seropositive queen will test positive in the first few weeks of life due to maternal antibodies, but these levels decrease by six weeks of age. Kittens will often titer negative from this point until about 12-16 weeks¹⁰ when they make their own antibodies. This can lead to negative results on serology if the kittens are tested from 6-12 weeks, and the erroneous conclusion that these kittens have not been exposed to FCoV.

Another diagnostic test that has been developed for FIP is revese-transciptase polymerase chain reaction (RT-PCR). This test can be performed on saliva, feces, and rectal swabs. Rectal swabs seem to be the best sample to use since feces can be contaminated and lead to false positive results, and saliva does not shed virus in a pattern that is useful for testing.¹ RT-PCR does seem to correlate with antibody titers, so this test may be useful as an aid in diagnosis, but again it cannot distinguish between enteric corona infection and FIP.

Another method of testing for FIP is fluorescent antibody (FA) which can be performed on tissue, fluid from effusions, or feces. This method is performed at Athens Diagnostic Laboratory at the University of Georgia. This test detects FCoV antigen and is very accurate. It has become a common practice to perform FA on fluid from effusions, and this has significant diagnostic value. Though enteric coronaviruses will yield a positive result, unless fecal contamination of the effusion sample has occurred, effusion FA is a very reliable and minimally invasive diagnostic procedure.

Presently the only accepted definitive diagnosis of FIP requires biopsy of affected tissues obtained at necropsy or from a surgical biopsy. Common necropsy (Fig. 4) findings include icterus, abdominal or pleural effusion, and multifocal, pale pyogranulomatous lesions covering all affected surfaces. Histopathological examination (Fig. 5) of affected tissues often shows necrogranulomatous inflammation (large areas of necrosis with infiltration by macrophages and neutrophils). Vasculitis will be present, and appears as a vessel surrounded by an area of necrosis bordered by macrophages, lymphocytes, plasma cells, and neutrophils.^4,5 Immunohistochemistry (IHC) (Fig. 6) for FCoV can be performed and aids in the definitive diagnosis of FIP.

Fig. 4. The characteristic necropsy findings of FIP consist of a finely granular appearance to the abdominal viscera due to fibrin deposition. There is often effusion present, but it is difficult to see in this picture.

Fig. 5. Kidney, the inflammatory cells shown (neutrophils, macrophages) are typical of the response to FIP infection.	Fig. 6. Kidney, the DAB-stained cells are interpreted to be macrophages that contain coronavirus antigen. This is considered to be diagnostic for FIP virus infection.

Treatment/Prevention

There is currently no effective treatment for FIP. Paliative measures can be taken to provide comfort to affected cats, but there is no cure. One common goal of treatment is to reduce inflammation, and thus discomfort, with corticosteroids. Other drugs that have been used include cyclophosphamide, chlorambucil, and interferon.⁴ Cats with non-effusive FIP may respond well with pharmacologic intervention and live for several months before succumbing to the disease.

A vaccine, Primucell, which consists of a temperature sensitive mutant of FCoV is available as an intranasal vaccine. This vaccine produces a local IgA response and CMI systematically. There has been some debate concerning side effects of the vaccine in the past, but it does appear to be quite safe (Fig. 7). It is recommended for use when introducing new cats into endemic populations, but it probably does not reduce the risk of infections for cats that have already been exposed and are seropositive for FCoV.

Fig. 7. Contented healthy cats

In Conclusion

Although much work has been done concerning feline coronaviruses, research must continue in this area. A better diagnostic method must be found and standardized. Obviously, there is no good method of screening cats since so many are exposed to FCoV, and cats should not be culled simply based on a positive antibody titer. Until more is known regarding FIP, it will remain one of the leading causes of death among cats in catteries, shelters, and large multiple-cat households.¹¹

References

1. Addie DD, Jarrett, O: Use of a reverse-transcriptase polymerase chain reaction for monitoring the shedding of feline coronavirus by healthy cats. Vet Rec 148: 649-653, 2001.

2. Andrew SE: Feline Infectious Peritonitis. Vet Clin N Am: Small Animal Pract 30:5, 2000

3. Foley JE, Lapointe JM, Koblik P, Poland A, Pederson NC: Diagnostic features of clinical neurologic feline infectious peritonitis. J Vet Intern Med 12: 415-423, 1998.

4. Greene, CE: Infectious Doseases of the Dog and Cat. WB Saunders Company, Philadelphia, 1998, pp58-69.

5. Jubb KVF, Kennedy PC, Palmer N: Pathology of Domestic Animals vol 2. Academic Press, 1993, pp 438-441.

6. Kennedy M, Boedecker N, Gibbs P, Kania S: Deletions of the 7a ORF of feline coronavirus associated with and epidemic of feline infectious peritonitis. Vet Micro 81: 227-234, 2001.

7. Koehler K, Bellman S, Reinacher: Feline infectious peritonitis presenting as a tumour in the abdominal cavity. Vet Rec 144: 118-122, 1999

8. Latimer KS, Mahaffey EA, Prasse KW: Duncan and Prasse’s Veterinary Laboratory Medicine Clinical Pathology 4th edition, Iowa State Press, Ames, 2003, pp 315-318, 358-359.

9. Paltrinieri S, Comazzi S, Spagnolo V, Giordano A: Laboratory changes consistent with feline infectious peritonitis in cats from multicat environments. J Vet Med (A Physiology Pathology Clinical Medicine) 49: 503-510, 2002.

10. Pederson NC: The history and interpretation of feline coronavirus serology. Fel Pract 23: 46-51, 1995.

11. Rohrbach BW, Legendre AM, Baldwin CA, Lein DH, Reed WM, Wilson RB: Epidemiology of feline infectious peritonitis among cats examined at veterinary teaching hosptals 218: 1111-1116, 2001.

12. Tizard, IR: Veterinary Immunology An Introduction. WB Saunders Company, Philadelphia, 1996, pp 368-380.

13. Williams ES, Barker IK: Infectious Diseases of Wild Mammals. Iowa State University Press, Ames, 2001, pp 245-253.

Acknowledgements

"Cable Car and Cats" by John Landon is from his page at the Visions Art Gallery website and is used with permission.

Image of contented healthy cats is from Greg Lehey's Cats and is used with permission.

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