key: cord-0937660-ybbutyaw
authors: Andrew, Stacy E.
title: Feline Infectious Peritonitis
date: 2000-09-30
journal: Veterinary Clinics of North America: Small Animal Practice
DOI: 10.1016/s0195-5616(00)05002-6
sha: 8f33de4bf786adf1ebd70566654a173dce97fbf5
doc_id: 937660
cord_uid: ybbutyaw

Feline infectious peritonitis (FIP) occurs most frequently in young animals from multicat households. Ocular manifestations of FIP are extremely common with the noneffusive form of the disease. All cats suspected of having FIP should undergo a thorough ophthalmic examination. Uveitis (inflarrunation of the iris, ciliary body, and choroid) is the primary clinical sign of ocular FIP. Treatment with anti-inflammatory medications is only supportive and aimed at disease palliation.

Stacy E. Andrew, DVM Feline infectious peritonitis (FIP) was first described in a 1963 article as chronic fibrinous peritonitis. 21 

The FlPV can remain stable and infective outside the host for 3 to 7 weeks under dry conditions, although it is rapidly inactivated by most household detergents. 22 The feline small intestine is the most likely reservoir for the virus. 32 All cats are susceptible to infection with FlPV, but clinical disease is seen most commonly in younger cats between 3 months and 3 years of age. 27 Young kittens are protected from feline corona viruses (FCo V) by maternal antibodies until they reach 6 weeks of age, after which time 90% of cats exposed to FCo V will seroconvert. Approximately 5% to 12% of these cats will develop classic clinical signs of FIP. 1 ' 9 The perceived increase in the prevalence of clinical cases of FIP is thought to be caused by increased fecal exposure from greater numbers of indoor cats sharing litter boxes. 4 In a recent study, pet cats had a significantly higher coronavirus antibody titer when compared with feral cats. Fifty-nine percent of pet cats and 4% of feral cats were considered coronavirus titer-positive. 25 The majority of FIP cases in the United States occur in cats from catteries, in multiplecat households, and in shelter facilities. 32 Researchers are still unsure of all transmission routes of FCoV, although ingestion and possibly inhalation of virus particles in feces are believed to be the primary routes of FIPV infection.•· 22 FIPV particles may also be transmitted via saliva, respiratory secretions, and urine in early infections.l 8 • 22 Risk factors for the development of FIP in a multicat environment include the age of the cat, its coronavirus titer, the recurrence rate of feline enteric coronavirus (FECV) fecal shedding, and the proportion of chronic shedders in the household population. 13 The mean number of cats, the mean age of cats, gender, husbandry practices, and the presence or absence of concurrent disease were shown to have no effect on the incidence of FIP. 13 The occurrence of FIP in combination with feline leukemia virus (FeLV) is no higher than the rate of FeLV in the general cat population, and the occurrence of FIP with feline immunodeficiency virus (FIV) is even less than the occurrence of FIV in the general cat population. 9 Elimination of FIP in a multicat household or breeding colony requires the total elimination of cats that are chronic shedders of FECVP The use of highly specific and highly sensitive reverse transcriptase-polymerase chain reactions (RT-PCR) has detected virus in naturally infected cats and reveals that healthy carriers can shed virus for up to 10 months. 18 This technique cannot detect the viability of FIPV organisms.• Studies have shown that 42% to 75% of cats with naturally occurring FIP shed the virus. 3 If a naive cat is placed in a multicat household and encounters FIPV-infected cats, the naive cat will become infected and will most likely shed virus for several weeks to months.• Transplacental transmission has been reported in one 4-day-old kitten that demonstrated typical FIP lesions and in stillborn kittens born to a queen with FIP in later stages of pregnancy. 31 Nevertheless, transplacental transmission is considered to be rare because most kittens removed from contact with shedding adults at 5 to 6 weeks postpartum do not seroconvert.l

The FIPV belongs to the group of FCoV, which also includes FECV. There are two theories concerning the relationship of the FCoVs. It has been debated that (1) FIPV is a separate and unique coronavirus, 30 and (2) that FIPV and FECV cannot be distinguished from each other serologically, and are in some way mutations of the same virus. Many researchers believe that there are two biotypes of FCo V s-FIPV and FECV -and that both biotypes have the potential to cause disease. 4 Current data suggest that FIPV is a mutation of FECV, and that there are actually numerous and rapidly occurring mutations of FECV resulting in multiple FIPVs. 35 The FIP-induced mutations in FECV appear frequently, which indicates the mutations are relatively modest and probably occur in a unique and highly variable region of the FECV genome. 35 Recent evidence supports the idea that FIPVs have evolved as deletion mutations of FECVs. 37 Once FECV mutates into FIPV, it gains the ability to replicate in macrophages.• FIPV-containing macrophages travel to regional lymph nodes where further viral replication occurs. The resultant viremia allows virus-laden macrophages to be deposited in the endothelium of small blood vessels. 27 The feline immune system has several mechanisms for managing this early stage of FIPV infection. Virus can be eliminated if the cat mounts a strong cell-mediated immune response. If the cat cannot exhibit a cell-mediated immune response, a profound, complement-mediated, pyogranulomatous vasculitis causing effusive FIP develops. 27 Antibody-dependent enhancement of the FIPV infection occurs and results in immune complex deposition and vasculitis. 12 Complement fixation causes the release of vasoactive amines, resulting in increased blood vessel permeability and allowing plasma protein exudation. 4 A partial cell-mediated immune response can also occur, which causes slower viral replication and the classic granuloma formation seen with noneffusive FIP. 12 Gonon and co-workers 16 demonstrated that once cats clear natural FCoV infection, they develop an antibody response against one or more of the Sglycoprotein domains, relative to the M glycoprotein, of the virus particle. The antibody response was on average 30 times higher in these cats when compared with cats that were either chronically infected or sick as a result of the infection. 16 It was not clear whether the antibody response was a mechanism or an indicator of viral clearance. 16 The anti-S antibody response does not seem to be a risk factor for developing FIP, and this finding should challenge the widely accepted belief that the S glycoprotein has a detrimental effect in FIP recombinant vaccines.16

Although cats of any age can be affected by FIP, usually one half of affected cats are less than 2 years of age. Typically, these cats have lived within a multicat facility (breeder, humane society, boarding facili~ cat show, veterinary clinic) within the previous year and may have history of stress in the previous few months (new home, elective surgery). 4 The systemic effects of FIPV infection are widespread. The specific clinical and pathologic signs observed are attributable to vasculitis-induced organ damage. 4 Classically, two forms of FIP are observed. One form is the effusive or wet type; the other is the noneffusive or dry form. With either manifestation of infection, a fatal immune-mediated vasculitis results. The time course from the onset of clinical signs to death is variable with both forms. Cats with effusive cases tend to die within 2 months of the onset of clinical signs, whereas cats with noneffusive cases have a more chronic disease course. 4 In some noneffusive cases, effusive FIP will develop before death. 32 The first clinical signs of FCo V infection are often mild upper respiratory or intestinal signs. 4 These signs are not usually severe enough to warrant veterinary attention, thus many cases go undetected in the early stages. 4 Enteritis caused by coronavirus usually manifests as transient mild diarrhea. FIPV-infected kittens may have a history of diarrhea and, occasionally, stunted growth and upper respiratory signs.' Many FCoV-infected cats do not show any clinical signs. 4 Clinical signs common in either the effusive or noneffusive forms of FIP include anorexia, weight loss, lethargy, and mild antibiotic-unresponsive fever (39-39.SOC). 27 With effusive disease, the specific clinical signs depend on the body system affected by the vasculitis. Clinical signs can include combinations of any of the following: ascites causing abdominal distention with a fluid wave; thoracic effusion resulting in dyspnea, tachypnea, and muffled heart sounds; scrotal enlargement; mucosal pallor or icterus; pericardia! effusion; abdominal masses (adhesions); and mesenteric lymphadenopathy. 4 Noneffusive disease results in clinical signs that are initially vague. In addition to the signs shared by both categories of disease, cats with noneffusive cases may have granulomatous lesions in abdominal organs (spleen, kidney, liver, omentum), the lungs, and lymph nodes. 4 Occasionally, granulomas are localized to the gastrointestinal tract, including the colon, ileocecocolic junction, or small intestine. 4 Cats with noneffusive FIP frequently have ocular signs, and as many as 25% develop multifocal progressive neurologic signs. 9 The ocular and neurologic signs are caused by granuloma formation in these tissues. Because the eye is considered part of the central nervous system, any cat with neurologic symptoms should undergo a complete ocular examination to rule out causes of systemic infectious disease. Cats with neurologic manifestations of FIP may have focal or multifocal central nervous system lesions and signs. 23 Nystagmus was the most common (12 of 24 cats) caudal fossa sign in a study of FIP cases. 23

Ocular manifestations of FIP are far more common in the noneffusive form of disease, and ocular signs may be the presenting complaint in some cats. 26 In one study, less than 5% (5 of 107) of cats with effusive FIP had ocular or neurol0gic signs, compared with 36% (34 of 94) of cats with noneffusive disease. 31 • 32 It is not unusual for cats to present with ocular signs with no sign of systemic illness. Survival after the onset of clinical signs is generally less than 1 year; however, the life span can be somewhat longer if there is only ocular involvement with the noneffusive form. 15 Cats suspected of having FIP should be examined for the following ophthalmic clinical signs: aqueous flare, ocular pain, corneal edema, keratic precipitates, fibrin, hypopyon, hyphema, miosis, ocular hypotony, iridal hyperemia I neovascularization, posterior synechiae, and posterior segment changes including chorioretinitis, perivascular cuffing, optic neuritis, and retinal detachment. The most common ocular manifestation of FIP is uveitis. Anterior uveitis (inflammation of the iris and ciliary body) is usually more noticeable to the clinician, although the anterior and posterior uvea (choroid) can be affected. An aqueous flare ( Fig. 1) is the hallmark of anterior uveitis and is the visualization of elevated protein levels in the anterior chamber. With a bright focal light source (such as the small aperture on the lens wheel of a direct ophthalmoscope), the clarity or turbidity of the anterior chamber can be assessed. If a continuous beam of light is seen going across the anterior chamber, aqueous flare is present. U there are no signs of anterior uveitis in a cat suspected of having FIP, a fundic examination should be performed.

Uveitis may also manifest as ocular pain, exhibited clinically in the cat as slight third-eyelid protrusion, squinting (blepharospasm), or tearing (epiphora). Corneal edema may be focal or diffuse and is also seen as a manifestation of uveitis. Keratic precipitates (Fig. 2) are clusters of inflammatory cells in the anterior chamber that settle ventrally on the posterior cornea or endothelium. It may be necessary to retract the third eyelid to visualize the precipitates or to tilt the cat' s nose down to encourage the eye to roll up to examine the area of interest.

Fibrin exudation from uveal blood vessels into the anterior chamber occurs with breakdown of the blood-aqueous barrier. Hypopyon (exudation of white blood cells into the anterior chamber) or hyphema (exudation of red blood cells into the anterior chamber) indicates profound blood-aqueous barrier breakdown and uveitis. Miosis refers to constriction of the pupil, which occurs owing to prostaglandin release with uveitis and subsequent stimulation of the iris sphincter muscle. Subtle or striking iris color change may be the presenting complaint/ especially in chronic cases of anterior uveitis. Ocular hypotony is lower than normal intraocular pressure owing to decreased production of aqueous humor and inflammation of the iris, with resultant increased uveoscleral (or unconventional) outflow of aqueous humor. Hyperemia of the iris refers to an increased reddening of the tissue, usually resulting from neovascularization or the ingrowth of new blood vessels. Posterior synechiae are adhesions of the iris to the lens and are caused by exudates in the anterior chamber that cause the iris to become "sticky." Chorioretinitis is inflammation or infection of the choroid and retina and is caused by FIPV-induced vasculitis (Figs. 3 and 4) . This inflamma- tion can manifest as exudate from the choroidal blood vessels and in severe cases results in retinal detachment.U Perivascular cuffing, considered suggestive of FIP infection in other organ systems, can be directly visualized in the eye (Fig. 5) . A cellular exudate can sometimes be seen outlining the retinal venules. With optic neuritis, the optic nerve will appear swollen with blurred margins.

The most common form of uveitis observed with FIPV infection is a bilateral granulomatous anterior uveitis often accompanied by chorioretinitis. 26 "Mutton fat" keratic precipitates are commonly seen with FIP and FeLV.' 5 This type of keratic precipitate is a large corneal endothelial deposit that is often yellow in color. The uveal tissues are extremely rich in blood vessels and easily exude cells and proteins when injured. 11 The blood-aqueous barrier is comprised of tight junctions between endothelial cells of iris capillaries and between nonpigmented cells of the ciliary epithelium. These junctions, as well as the bloodretinal barrier, are normally impermeable to many circulating proteins. 5 If the blood-aqueous barrier is compromised, proteins and other cells can leak into the anterior chamber and further exacerbate inflammation. FIP granulomas affect the blood-aqueous and blood-retinal barrier vessels. 15 The iris blood vessels are quite permeable in the cat when compared with other species, and the capillaries of the choriocapillaris are more permeable in kittens than in adult cats. 8 Inflammation associated with ocular FIP can gradually progress to panuveitis, which is inflammation of all parts of the eye. 15 Other sequelae or complications that can occur with ocular FIP depend on the duration of the uveitis. These complications include, but are not limited to, glaucoma owing to peripheral anterior synechiae, iridocorneal angle closure, posterior synechiae and iris bombe, or preiridal fibrovascular membrane formation; anterior or posterior lens luxation; cataract formation; blindness; and phthisis bulbi (or a fibrosed and shrunken globe). 15 The reported incidence of systemic diseases causing uveitis in cats is highly variable. A recent study 10 found that 70% of cats with uveitis had no detectable cause, whereas another study 24 found 83% of cats with uveitis were serologically positive for exposure to an infectious agent.

There is no definitive antemortem diagnostic test for FIP except histopathologic examination of tissue. Many diseases have clinical signs similar to FIP, such as lymphoma, cardiomyopathy, septic peritonitis, pyothorax, and chylothorax. Without histopathologic confirmation, the diagnosis of FIP is only presumptive. 6 The histopathologic finding required to confirm a diagnosis of FIP is a pyogranulomatous lesion. Ocular histopathology of FIP cases reveals a leukocytic infiltrate consisting of neutrophils, plasma cells, lymphocytes, and macrophages in the ciliary body (Fig. 6) and adjacent sclera. 34 Perivascular lymphocytes, plasma cells, and macrophages in the sclera, retina, optic meninges, and retrobulbar connective tissue are also observed. 34 Enucleated eyes from cats with uveitis revealed that suspected or confirmed FIP (21.5%, 34 of 158 eyes) was the second most common cause of uveitis following idiopathic uveitis (32.3%, 51 of 158 eyes). 33 Another study reported a much lower incidence of FIP lesions (0.02%, 1 of 53 cats). 10 Serology is important to diagnose and manage cases of FIP; therefore, the laboratory chosen to perform the testing must be consistent and reliable. 4 The laboratory should have established reference ranges for low-positive and highpositive titers to determine the significant level of reactivity. 4 Test results must be correlated with clinical findings. Random serologic testing is not useful owing to the low disease specificity. Serologic testing should be performed in conjunction with a compatible history, clinical signs, and globulin ratio 4 that are supportive of a diagnosis of FIP. An antibody titer only indicates that a cat is infected with, or has been infected with, a coronavirus. ELISA and an immunofluorescent antibody (IFA) test are the two most common serologic tests performed for FCoV; however, serologic tests should only be interpreted with a complete understanding of the testing mechanisms and limitations? Serologic testing for FCo V s cannot distinguish virulent from avirulent strains, ascertain the time when a cat became infected with FCoV, or indicate whether an animal is susceptible or immune to clinical disease caused by FCoV. 27 Problems inherent in FCoV serologic testing include false-positives, falsenegatives, and misinterpretations? Many laboratories perform ELISA and IFA tests. Often, an ELISA is performed first, and, if the result is negative, the testing is complete. If the ELISA is positive, an IFA is performed to determine the antibody titerP A commercial ELISA test kit is awaiting US Food and Drug Administration approval (FIP Diasystems, IDEXX Co., Portland, ME). The result is read spectrophotometrically as color development. A positive result with a previously available ELISA (Snap FIP, IDEXX Co.) was considered to be roughly equivalent to an IFA titer of 1:3200_12 The IFA test is an indirect method and is reported as the highest serum dilution conferring a positive result. 12 The test is variable owing to a lack of consistency of interpretation between experienced technicians. 12 The sensitivity of the IFA test is reported to be 95% and the specificity 98%, thus there is good predictive value for infection with coronavirus with a positive titer result. 12 The IFA is less sensitive but more specific than ELISA testingP Cats that are seronegative do not shed FCoV, whereas one third of seropositive cats do shed FCoV. 1 Evidence of viral shedding is not a good reason to euthanize a cat because most cats stop shedding within 1 year, and less than 10% develop FIP. 2 A recent study demonstrated that the probability of a cat with a high FCoV antibody titer h aving FIP was only 38.9%,3 6 thus a positive FCoV antibody titer does not rule in FIP. Some experts believe that cats with the noneffusive form of FIP generally have a high FCoV antibody titer and are rarely seronegative. 4 Reverse transcriptase-polymerase chain reaction can be performed to detect FCoV particles in tissue or fluid samples such as feces. 4 • 18 The test is highly sensitive and specific for FCoV but cannot establish a definite diagnosis of FIP. An IFA test for the FIP antigen has also been reported using smears made from nictitating membrane scrapes and was found to have 85% agreement with immunohistochemisty and serology. 19 • 20 This test detects all coronaviruses, not FIPV specifically; and further evaluation of this method of study is needed before recommending its clinical use. 12 A complete blood count and serum chemistry profile should be obtained if there is a clinical suspicion of FIP infection. Cats with FIP will usually exhibit a neutrophilia with a left shift, nonregenerative anemia caused by chronic inflammation, high serum total protein levels, and a low albumin-to-globulin ratio owing to an increase in globulin levels. Polyclonal hyperglobulinemia is reported in approximately 75% of cats with noneffusive FIP and in 50% of cats with the effusive form of disease. 9 Serum protein electrophoresis should be performed when elevated globulins are reported (Fig. 7 ). An acute phase protein, u-1-acid glycoprotein, is often elevated in plasma or effusion samples depending on organ system involvement but is not specific for FIP. 4 Aqueous humor cytology and protein concentration are not specific enough to diagnose FIP. 29 A recent study using PCR performed on aqueous humor samples of cats with neurologic and ocular lesions of FIP found that all samples were negative (16 of 16 cats) 14 ; therefore, aqueous paracentesis is of no diagnostic value in FIP-induced uveitis.

A combination of clinical signs, historical factors, and laboratory values have been used for antemortem prediction of whether a cat has FIP. Historical factors (i.e., a young cat, a multicat household, and a recent stress event), combined with clinical findings (i.e., fever, uveitis, neurologic signs, an abdominal mass, or icterus), hyperglobulinemia (>5.1 g/ dL), lymphopenia (<1.5 X 10 3 cells/ v..L), and serology revealing a high FCoV titer (> 1:160) suggest a high probability of noneffusive FIP (predictive value >85%). 27 Consistent clinical signs, lymphopenia, hyperglobulinemia, and an FCoV titer greater than 160 resulted in an 89% probability of FIP being diagnosed postmortem. 36 Clinical signs of FIP without the previous serum indicators had a 99% negative predictive value for a negative diagnosis. 27

Because ocular signs are more prevalent with the noneffusive form of disease, the focus of this article is on therapy for ocular manifestations of noneffusive FIP. FIP is generally considered to be a fatal disease, and the main treatment goal is to palliate clinical signs. Treatment of ocular disease is symptomatic, and the mainstay of therapy is topical or systemic corticosteroids or both. 26 Some cats only develop ocular FIP pyogranulomatous lesions, which manifest as uveitis in one or both eyes. These animals respond reasonably well to corticosteroids; however, if the inflammation is severe and the eye is blind and painful, enucleation is a viable treatment to increase patient comfort. 22 There are multiple therapeutic routes for uveitis. The route chosen depends on the location and severity of inflammation, as well as the characteristics of the drug chosen. The most common treatment routes for FIP-infected cats are topical and systemic. Topical medications can penetrate the cornea and reach as deep Uveitic eyes suspected of FIP infection should be stained with fluorescein dye to rule out concurrent corneal ulceration. If no ulceration is present, treatment with topical prednisolone acetate 1% ophthalmic solution four times daily is initiated, along with 1% atropine ointment as needed, once to twice daily, to induce mydriasis. Atropine solution is not recommended for use in cats because they can have a strong negative reaction to the taste of the medication after it travels down the nasolacrimal duct into the mouth. The eye should be reevaluated 24 hours after the initiation of therapy, including fluorescein stain. If improvement indicated by dilation of the pupil and reduction in aqueous flare is observed, the topical corticosteroids can be decreased slowly over a period of several weeks to the lowest dose and frequency that keeps the uveitis controlled. If no improvement is noted, administration of anti-inflammatory doses of systemic prednisone or prednisolone should be considered.

Because FIP is considered a fatal disease, prevention is important. An intranasal vaccine (Primucell FIP, Pfizer, Exton, PA) is available. The vaccine contains a temperature-sensitive mutant that provides local protection against FCoV invasion. A local secretory antibody and systemic cell-mediated immune response to FCoV occurs, resulting in a self-limiting infection that does not become systemicP Routine use of the vaccine has been questioned because of the prolonged disease incubation period, seemingly low disease prevalence, and required intranasal administration; however, it may be of benefit in naive animals before entering contaminated catteries. 17 The vaccine results in systemic mucosal (IgA), humoral (IgG), and cell-mediated response, and variable decreases in the incidence of disease have been reported after vaccine administration.28

Feline infectious peritonitis is a noncurable viral disease affecting cats worldwide. Recent evidence suggests that the FIPV has evolved as a deletion mutation of FECV. Immune complex deposition and vasculitis with pyogranulomatous lesions are the hallmark of FIP. The only definitive antemortem diagnostic test for FIP is histopathologic examination of tissue. Ocular manifestations occur commonly with noneffusive FIP. The most common clinical sign is a bilateral granulomatous anterior uveitis often accompanied by chorioretinitis. Treatment of ocular FIP is symptomatic, and the mainstay of palliative therapy is topical or systemic corticosteroids or both.

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