FELINE INFECTIOUS PERITONITIS

• 1. Define feline infectious peritonitis.

  Feline infectious peritonitis (FIP) is a disseminated disease caused by feline coronaviruses (FCoV). Field strains of FCoV vary in disease-inducing potential. Some isolates cause FIP (feline infectious peritonitis virus [FIPV]), and some isolates cause a more localized gastrointestinal disturbance that often results in diarrhea (feline enteric coronavirus [FECV]). These two strains cannot be distinguished from one another morphologically or antigenically. FECV can mutate spontaneously in the host to become a FIP-inducing stain.

• 2. How do cats become infected with FCoV?

  Cats usually become infected with FCoV by ingestion of virus, but inhalation may provide viral entrance. Because cats shed viral particles in feces, litterbox exposure and mutual grooming are probably the most important sources of infection. Cats living in multiple cat households or having exposure to multiple cats are at a greater risk of contracting FCoV and, as a result, FIP, in part because of higher levels of virus exposure and probably a higher level of stress.

• 3. Why is disease limited to enteric signs in some cats, whereas others develop FIP?

  Both viral strain factors and host factors may play a role. FECV attaches to an enzyme in the intestinal brush border and replicates in enterocytes. This process causes the villous tips to slough, and diarrhea ensues, which usually is self-limiting. If the cat is exposed to FIPV or if FECV mutates to FIPV, the organism is able to replicate in enterocytes and macrophages. Disseminated infection can then occur. Genetic predispositions also are suspected. Host-derived immunity also may play a role in resistance to development of FIP.

• 4. Describe the typical presentation for a cat with FIP.

  Cats with FIP can present for evaluation of many clinical syndromes. Anorexia is common, but some cats have a normal appetite. Ascites may be the only clinical sign. Historically, the cat is usually young, lives in a multicat household or cattery, and has been recently stressed with a new environment, surgery, or illness. The history may include diarrhea, lethargy, weight loss, or inappetence. Many cats present with a low-grade fever unresponsive to antibiotics. The clinical disease of FIP has two primary clinical forms, the effusive (wet) form and the noneffusive (dry) form. The most common historical and physical examination findings of noneffusive FIP relate to organomegaly and resultant organ failure. Hepatic, ocular, renal, alimenteric, and central nervous system dysfunction are common. Clinical manifestations of the effusive form relate to the development of body cavity effusions. A distended abdomen due to ascites and dyspnea and muffled heart and lung sounds due to pleural effusion are common. Although these distinctions are useful in diagnosing the disease and recognizing signs, they are not mutually exclusive; an individual cat can have manifestions of both forms. Some cats may initially have manifestations most consistent with the noneffusive form and later become effusive or vice versa.

  Clinical Abnormalities Suggestive of Feline Infectious Peritonitis

  Signalment and history Cats < 3 years of age or > 10 years of age Purebred cat Purchase from a crowded cat environment Previous history of gastrointestinal or upper respiratory disease Serologic evidence of infection by feline leukemia virus Nonspecific signs of anorexia, weight loss, or depression Seizures, nystagmus, or ataxia Acute, fulminant course in cats with effusive disease Chronic, intermittent course in cats with noneffusive disease Physical examination Fever Weight loss Pale mucous membranes with or without petechiae Dyspnea with a restrictive breathing pattern Muffled heart or lung sounds Abdominal distention with a fluid wave with or without scrotal swelling Icterus with or without hepatomegaly Chorioretinitis or iridocyclitis Multifocal neurologic abnormalities Irregularly marginated kidneys with or without renomegaly Mesenteric lymphadenopathy Splenomegaly Clinicopathologic abnormalities Nonregenerative anemia Neutrophilic leukocytosis with or without a left shift Lymphopenia Hyperglobulinemia characterized as a polyclonal gammopathy with increases in alpha2 and gammaglobulins; rare monoclonal gammopathies Nonseptic, pyogranulomatous exudate in pleural space, peritoneal cavity, or pericardial space Increased protein concentrations and neutrophilic pleocytosis in cerebrospinal fluid Positive coronavirus antibody titer Pyogranulomatous or granulomatous inflammation in perivascular location on histologic examination of tissues Positive results of immunofluorescence or polymerase chain reaction performed on pleural or peritoneal exudate

• 5. What are the neurologic manifestations of FIP?

  Some studies estimate that 12–35% of cats with FIP have neurologic signs. These numbers vary widely among institutions and possibly are affected by a skewed population. Some cats may show only central neurologic signs. The most common neurologic signs associated with FIP are ataxia, followed by nystagmus and seizures. Other neurologic signs depend on the location of the granuloma or whether the virus is causing meningitis.

• 6. What are the most common ocular manifestations of FIP?

  Uveitis can be detected in cats with either form of disease, but it is thought to be more common in cats with noneffusive FIP. The most common ocular sign in FIP is iritis, which manifests as a color change (see Chapter 67). Keratic precipitates also may be seen because large numbers of inflammatory cells settle on the back of the cornea. Chorioretinitis due to vasculitis is recognized in some affected cats.

• 7. Why do effusions form in some cases of FIP?

  When the organism is disseminating in infected macrophages, the body responds with antibody production, resulting in complement activation. It is hypothesized that the combination of viral particles or antigens bind to antibody, resulting in complement fixation and circulating immune complexes, which attach to blood vessels and cause severe vasculitis. It is also possible that complement is fixed to immune complexes in tissues. Vasculitis results in leakage of high protein fluids from affected organs; common sites of leakage are the peritoneum, kidney, and uvea. Exudation of fluid and plasma proteins occurs primarily in body cavities, resulting in ascites and pleural effusion. Cats developing the effusive form of disease may have poor cell-mediated immune responses.

• 8. Describe the pathophysiology of the noneffusive form of FIP.

  It is hypothesized that the noneffusive form of FIP occurs in cats that are capable of mounting a partial cell-mediated immune response that does not totally contain the infection. Effusion may be less likely because less virus is available for the formation of immune complexes, resulting in less severe vasculitis. When circulating or tissue-associated immune complexes fix complement, neutrophils and macrophages are attracted to the involved organs and pyogranulomatous inflammation develops. Pyogranulomatous inflammation may become severe enough to cause organ dysfunction or failure.

• 9. At what age are cats more likely to develop FIP?

  FIP is said to be a disease of the very young and the very old. Newborn kittens usually are protected by maternal antibodies that last for the first few weeks of life. As maternal antibody protection fades, the kittens are susceptible to infection. The most common age range for cats with FIP is 3 months to 3 years. Another peak in susceptibility occurs in cats older than 10 years, presumably because of an age-related decline in immune responses.

• 10. What is the relation between FIP and feline leukemia virus?

  Previously it was believed that feline leukemia virus (FeLV) compromised the immune system and facilitated development of FIP. If this were true, it seems likely that the dramatic decrease in the incidence of FeLV would be accompanied by a parallel decrease in the incidence of FIP. Because the incidence of FIP has remained the same despite a decrease in the incidence of FeLV, the correlation between the two viruses is much weaker than once imagined.

• 11. How is FIP diagnosed?

  Histology of affected tissues is considered the only way to reach an indisputable diagnosis of FIP. Immunohistochemical staining of tissues allows identification of viral antigen associated with inflammation and therefore provides a specific diagnosis.

• 12. How can effusions be used to aid in the diagnosis of FIP?

  If the cat has ascites or pleural effusion, centesis and fluid analysis are valuable diagnostic tools. Typically the fluid is pale yellow and has increased viscosity. Evaluation of protein content yields a total protein > 3.5 gm/dl, over 50% of which is composed of gammaglobulins. Cytology of the fluid reveals an exudate with cellularity (< 5000 cells/μl) consisting primarily of nondegenerative neutrophils. In rare cases, the effusion is pink and chylous. With a combination of the above protein content, globulin predominance, and cytology, the positive predictive value for diagnosis of FIP based on fluid analysis is > 90%. In addition, the albumin-to-globulin ratio of the effusion is usually < 0.8; a ratio < 0.45 is usually predictive of effusive FIP. Documentation of coronaviral RNA by reverse transcriptase polymerase chain reaction (see question 15) supports the diagnosis of effusive FIP.

• 13. Can noneffusive FIP be diagnosed without obtaining tissue?

  Clinicians strive to arrive at a diagnosis with less invasive methods because of the patient's often compromised condition. The noninvasive approach to diagnosis can prove to be difficult. Currently no single test of serum or effusion fluid can give a definitive diagnosis of FIP; therefore, the clinician must rely on careful history and observation, thorough physical examination, and multiple diagnostic tests. If the history and physical examination are suggestive of FIP, diagnostic tests can aid in confirmation.

  Cats with clinical signs consistent with FIP and the combination of lymphopenia (< 1.5 × 103 cells/μl), FCoV antibody titer > 1:160, and hyperglobulinemia (> 5.1 gm/dl) have an 88.9% probability of having FIP. If the cat has clinical signs of FIP but does not have all three of the above diagnostic criteria, there is a 98.8% probability that the cat does not have FIP. Therefore, these tests can be quite helpful in excluding the diagnosis of FIP.

  In cats with neurologic FIP, cerebrospinal fluid (CSF) analysis can provide helpful information to aid in diagnosis. CSF analysis in cats with neurologic FIP usually reveals increased protein concentrations and neutrophilic pleocytosis. Detection of coronavirus antibodies in CSF has not correlated consistently with a diagnosis of FIP and does not seem to correlate with serum titers.

• 14. What kind of serologic tests are available? How reliable are they in diagnosing FIP?

  No available serologic test can differentiate between strains of FCoV. A positive test result reveals that the cat has been exposed to a coronavirus but does not predict that the cat will develop FIP. One study reported that cats with high coronavirus antibody titers had only a 38.9% probability of having FIP. In addition, cats that have been vaccinated for FIP can become seropositive. Although negative titers strongly suggest that the cat does not have FIP, some studies have reported negative antibody titers in cats with histologically confirmed FIP. A possible explanation is that, with widespread immune complex formation, the antibody may be bound in the complex and prevented from reacting in the test. Alternatively, the cat may have had fulminant FIP and died before mounting a humoral response. For these reasons, clinicians are urged not to rely on serology as a single diagnostic test. Many cats have been euthanized because of misconceptions about the validity of serologic tests as the sole determinant of disease.

• 15. What other tests are available for FIP?

  Reverse transcriptase polymerase chain reaction (RT-PCR) test is available. Because coronaviruses are RNA viruses, reverse transcriptase is used first to convert RNA to DNA. The DNA is then amplified in the polymerase chain reaction. Positive results of this test on whole blood may support the diagnosis of FIP in a clinically ill, seronegative cat. However, as with serologic tests, RT-PCR does not distinguish between FCoV strains; a positive test indicates only exposure to a coronavirus. In one study, cats with enteric coronavirus infections were just as likely to be PCR-positive as cats with FIP. In addition, false positives and false negatives have been reported. Whether RT-PCR performed on aqueous humor or CSF aids in the diagnosis of FIP is currently unknown.

• 16. What is the prognosis for cats with FIP?

  Clinical FIP is almost always a fatal disease with a mortality rate > 95%. Cats with the effusive form of FIP usually progress more quickly and often die within 2 months of initial clinical signs. The noneffusive form may run a slower course; some cats live for months to years.

• 17. What treatment is recommended for FIP?

  Because FIP is an immune complex disease, immunosuppression is the mainstay of treatment. High doses of glucocorticoids are commonly used for their immunosuppressive and antiinflammatory properties. Cytotoxic drugs such as cyclophosphamide and chlorambucil have been used in conjunction with glucocorticoids. Success is greater with noneffusive FIP. Cats with effusive FIP are thought to have poor immunity and heavy viral load; glucocorticoid administration may exacerbate disease. In addition, although these drugs are needed to help control the immune response associated with clinical FIP, they also may cause susceptibility to bacterial infections due to myelosuppression and general immunosuppression. Therefore, broad-spectrum antibiotic therapy may be necessary as a prophylactic treatment. Reasonable choices include amoxicillin and cefadroxil. If an infection is documented, antibiotic selection should be based on culture and sensitivity.

• 18. What other drugs are used for treatment of FIP?

  Antiviral drugs and immune-modulating drugs have been evaluated for the treatment of FIP. Recombinant human interferon-alpha has been given to cats in experimental settings and has slowed progression of disease. For debilitated cats with the effusive form, recombinant human interferon-alpha at high doses has been recommended. For cats with the noneffusive form, lower doses have been recommended. To date, no antiviral drugs have proved effective that can be tolerated by cats without severe side effects.

  Treatment Recommendations for Feline Infectious Peritonitis

  DRUG	DOSE
  Immunosuppressive drugs
  Prednisolone	2–4 mg/kg orally every 24 hr
  Cyclophosphamide	200–300 mg/m2 orally every 2–3 wk or 2.2 mg/kg every 24 hr for 4 consecutive days each week
  or
  Chlorambucil	20 mg/m2 orally every 2–3 wk
  Antibiotic therapy
  Amoxicillin/clavulanic acid	10–20 mg/kg orally every 12 hr
  or
  Cefadroxil	20 mg/kg orally every 12 hr
  Immune-modulating drugs
  Recombinant human interferon-alpha
  Effusive form	2×104 IU/kg intramuscularly or subcutaneously every 24 hr for up to 3 wk
  Noneffusive form	30 IU orally every 24 hr for life

• 19. What measures should be taken to aid in prevention of FIP?

  Prevention strategies should be based on the housing and exposure possibilities of each patient. Cats living in a single cat household need a much less rigid prevention protocol than cats in a cattery or multiple cat household.

• 20. What prevention strategies are appropriate for seronegative single cat households?

  Seronegative cats living in a single cat household are at low risk for developing FIP (incidence = 1 in 5000). Prevention is aimed at limiting exposure to other cats. Any new cat to be introduced to this household should be seronegative 30 days before entrance. Optimally, new cats should be quarantined for 3 weeks, then retested before free access to the household is given. Kittens should be tested after 12 weeks of age to allow time for clearance of lactationally derived antibodies and to allow seroconversion if they have been naturally exposed.

• 21. What prevention strategies are appropriate for seronegative multiple cat households?

  Prevention is geared toward the same goal as the single cat seronegative household—limiting exposure. New additions to the household should be seronegative 30 days before entrance and should be quarantined for 3 weeks, then retested before gaining access to other cats in the household. Kittens should be tested at 12 weeks of age. Fecal contamination should be minimized by keeping food away from litterboxes and cleaning litterboxes daily.

• 22. Describe the appropriate prevention strategies for seropositive multiple cat households.

  Decreasing stress and fecal-oral contamination are main concerns. Care should be taken to decrease fecal contamination of food by keeping food bowls and litterboxes in separate areas. Litterboxes should be cleaned daily and disinfected with a 1:32 dilution of bleach weekly. There should be one litterbox for every 1 or 2 cats. Cats should be kept in stable groups of three or four to decrease stress. In boarding or rescue facilities, cats should be housed singly.

• 23. Describe the appropriate prevention strategies for catteries.

  In catteries or other breeding colonies, cleanliness guidelines should be enforced without exception. The kitten room should be kept separate from other rooms in the cattery, and exposure to other cats should be eliminated. The room should be cleaned with 1:32 dilute bleach solution before the queen is introduced into the room before parturition. Seropositive queens should be separated from their kittens at 5 weeks to limit exposure to the kittens. Kittens that are seronegative at 12–14 weeks of age can be assumed to be FoCV-naive.

• 24. When should vaccination for FIP be used?

  Vaccination with the commerically available intranasal FIP vaccine is not recommended for all cats. Because cats from one- or two-cat households have such a low risk for development of FIP, vaccination is not recommended. In multicat households where FCoV is enzootic, vaccination of resident or incoming seronegative cats potentially decreases the incidence of FIP. Vaccination in these settings has been shown to decrease the incidence only in cats that were seronegative before vaccination.