Feline Infectious Peritonitis: What Do We Know About This Disease? John R. August, BVetMed, MS, MRCVS, Dip ACVIM Dean of Faculties and Associate Provost Texas A&M University I. LEARNING OBJECTIVES A. Describe the relationship between non-pathogenic and pathogenic coronaviruses in the feline population. B. Describe the reasons that some cats infected with non-pathogenic coronaviruses develop feline infectious peritonitis (FIP). C. Discuss the reasons that some cats develop effusive FIP and some develop the non-effusive form of the disease. D. Discuss the diagnostic methods used to confirm a diagnosis of FIP, including the strengths and weaknesses of the various tests. E. Describe the basic therapeutic strategies used to support cats with FIP. F. List the basic principles used to prevent the development of FIP in cat populations. II. KEY FACTS A. Feline coronaviruses (FCOVs) are distributed widely in the feline population. B. Most FCOVs are non-pathogenic, have an affinity for intestinal epithelial cells, and cause no significant clinical disease. C. Rapid replication of non-pathogenic FCOVs in the intestinal tract may give rise to mutant pathogenic FCOVs, with a different tissue tropism and the ability to spread systemically leading to the development of FIP. D. A robust cell-mediated immune response, rather than a strong humoral response, appears to prevent the systemic spread of pathogenic FCOVs. E. The lesions of FIP are associated with an immune-mediated coronaviral vasculitis. The virus causing FIP is one of very few that causes granulomatous disease. F. Effusive FIP appears to be the result of a dominant humoral immune response leading to antibody-mediated inflammation, and an inadequate cell-mediated response. G. Histopathological examination of tissues, the detection of mutated coronavirus in fluids and tissues, and to a lesser extent the careful analysis of effusion fluid, are the gold standards of diagnosis for FIP. H. FIP is a progressive and fatal disease. Some treatments may improve quality of life and longevity. Viral protease inhibitors may offer future promise. I. Prevention of FIP depends much more on good husbandry than on vaccination. 1
III. IV. VIROLOGY A. Feline coronaviruses (FCOVs) are large enveloped positive-stranded RNA viruses. B. FCOVs are relatedly antigenically to coronaviruses from other species (canine coronavirus, transmissible gastroenteritis virus of swine). C. Non-pathogenic FCOVs are ubiquitous in feline populations, especially those in which animal density is high. D. Kittens shed 100 times the amount of virus during primary infection compared to adult cats. Cases of FIP in senior cats are often linked to the introduction of a new kitten to the household to keep the older cat company after a companion has died of other causes. PATHOGENESIS OF INFECTION A. Non-pathogenic FCOVs are highly infectious between cats. B. Non-pathogenic FCOVs also are called feline enteric coronaviruses (FECVs), because of their strong affinity for replication in the epithelial cells of the tips of the villi in the small intestine. C. FECVs are incapable of causing multi-organ systemic disease (feline infectious peritonitis), but may very rarely cause self-resolving diarrhea in kittens. D. FECVs mutate in the intestinal tract of infected cats, giving rise to FCOVs with increased pathogenicity and the ability to cause systemic disease (FIP). The virus mutation that causes this affinity for replication in peritoneal macrophages was identified in 2013 (Licitra et al). E. Chronic stress appears to increase the rate of FECV replication in the intestinal tract, enhancing the chance of mutation. F. Pathogenic mutated FCOVs replicate in peritoneal macrophages, enhancing their ability to spread throughout the body and end up in perivascular locations. G. Mutated FCOVs can be found in up to 20% of asymptomatic cats who are shedding FECV, suggesting that immunity to the mutated form can occur. H. Another theory proposed that it may be the total load of coronavirus with which a cat is infected that predisposes it to disease, rather than any specific mutations that might occur. The recent identification of the virus mutation discredits this theory. I. Systemic disease (FIP) is more likely to occur if the infected cat develops a strong humoral response to pathogenic FCOV, and an ineffective cell-mediated immune response. J. Systemic spread of pathogenic virus may be prevented at this stage of infection if the cat develops a strong cell-mediated immune response. K. Tissue damage occurs due to an inflammatory response in perivascular locations initiated by antigen-antibody-complement complexes. L. The resulting clinical disease is described more accurately as an immune-mediated coronaviral vasculitis, rather than infectious peritonitis. Lesions may be found in many organs beyond the peritoneal cavity. M. FIP is considered a fatal disease; very few cats have recovered from well-documented infection. 2
V. TRANSMISSION AND RISK FACTORS A. FCOVs are transmitted through the fecal-oral route. This may occur directly through grooming (for example, from queen to susceptible kittens), or via contaminated litter boxes or fomites. Some FCOV strains are capable of remaining viable on dry surfaces for several weeks. B. Infection occurs as a result of exposure to non-pathogenic FCOVs. Cats with clinical FIP do not appear to shed pathogenic mutant FCOVs that are transmitted to other in-contact cats. C. Young cats are most likely to become infected with FCOVs, especially if they live in multiple-cat households in which chronic FCOV carriers are present, and if they must share litter boxes and food and water bowls. D. Infection is perpetuated in multiple-cat households by the presence of chronic FCOV carriers who shed virus in their feces, and by continual re-infection of cats as they lose their acquired immunity. New cats added to the group also may introduce non-pathogenic FCOVs. VI. CLINICAL SIGNS A. Enteric coronavirus infection 1. Usually asymptomatic; however, transient diarrhea and occasional vomiting may be noted rarely in some kittens. It is uncommon to make a clinical diagnosis of FECV-induced gastroenteritis in feline patients. B. Feline infectious peritonitis 1. Many cases of FIP occur in cats from 6 months to 3 years of age; however, the disease may be noted at any age. There may be a second smaller peak of incidence in older cats who are becoming immunoincompetent. Both forms of FIP share some common features including chronic antibiotic-resistant fever, weight loss, lymphadenopathy, inflammatory lesions in a variety of tissues due to vasculitis, and a variably progressive course leading to death or euthanasia. 2. Early signs in young cats are non-specific, but may include delayed growth, vague signs of ill health, and abdominal lymphadenopathy at the time they are forming immune responses to viremia. These clinical signs may resolve or the patient may slowly develop signs of FIP. 3. Effusive FIP a. First signs are often noted 1-2 months after a stressful episode (kitten moving to a new home) or exposure to infection with FCOVs. b. The effusive form of FIP is considered to be the more severe manifestation of systemic illness. It probably is associated with a strong (but detrimental) humoral response to a large amount of pathogenic virus that occurs an effective cell-mediated response can develop. c. Clinical signs are associated with widespread immune-mediated vasculitis, leading to the leakage of protein-rich fluid into a variety of body cavities. d. Signs at clinical presentation may include weight loss, antibiotic-resistant fever, dyspnea, icterus, and abdominal masses (mesenteric lymph nodes, omentum with adhesions). Ascites (fluid 3
wave), muffled heart sounds (pleural and/or pericardial effusions), and scrotal enlargement may be noted. e. In spite of supportive treatment, most patients with effusive FIP live only for a few weeks. 4. Non-effusive FIP a. Clinical signs are less obvious and may include progressive weight loss, anorexia, chronic unresponsive fever, lymphadenopathy, and some localizing lesions. May be more common in Burmese and Birman cats. b. The disease is characterized by the development of multiple perivascular pyogranulomas on serosal surfaces and within tissues without effusion. c. Non-effusive FIP is considered to be a more chronic, smoldering form of the disease. The humoral response to virus may be less robust, decreasing antibody-mediated disease. A partial cell-mediated immune response may decrease the severity of the lesions. d. Ocular lesions are common in patients with non-effusive FIP and include iritis, keratic precipitates, hypopyon, retinal perivascular cuffing, retinal hemorrhages, and retinal detachments. e. Neurological signs occur in about 25-33% of cats with non-effusive FIP. Clinical signs include depression, ataxia, tremors, seizures, and paresis. On necropsy, CNS lesions are found in most cats with non-effusive FIP, even in the absence of overt neurologic signs. Hydrocephalus is a common finding on necropsy and from CT scans. f. Occasionally, affected cats may be presented with a solitary large pyogranulomatous mass in the ileocecocolic or colonic areas with regional lymphadenopathy, following a history of chronic vomiting and diarrhea. g. Cats with non-effusive FIP have a progressive illness that is fatal weeks to months after diagnosis. VII. DIAGNOSIS A. Presently, the only definitive method to confirm a diagnosis of FIP is by histopathological examination of tissues, supported ideally by immunohistochemical identification of mutated coronavirus in body cavity fluids or typical pyogranulomatous lesions. B. Current serological tests for coronaviral antibody are incapable of distinguishing between infections caused by nonpathogenic and pathogenic coronaviruses, and should never be used as the basis for making a diagnosis of FIP. Many patients with look-alike diseases (such as lymphocytic cholangitis) may be seropositive from previous exposure to, or current infection with, non-pathogenic coronaviruses that have nothing to do with the presenting illness. C. The recent introduction of a test to detect coronavirus with pathogenic mutations in body cavity fluid or tissues provides important diagnostic information in cats suspected of having FIP. D. A diagnosis of FIP is made by excluding other diseases, and by careful assessment of the patient s signalment, background, history, physical findings (including careful ocular and 4
neurological examinations), laboratory analysis (hematology, serum chemistries, and urinalysis), effusion fluid analysis, coronaviral antibody titer, the detection of coronavirus mutations in fluid or tissue samples, and histopathological analysis of tissues taken by biopsy or at necropsy. E. Algorithms have been developed, in which points are assigned for positive findings in each of these areas. A confident diagnosis of FIP can be made if the cumulative point total exceeds a certain threshold. 1. Hematology a. Lymphopenia, neutrophilia with a left shift, and non-regenerative anemia may be noted. Lymphopenia is considered a poor prognostic sign. 2. Serum chemistries a. Hyperglobulinemia is a common finding. Serum electrophoresis usually reveals a polyclonal gammopathy. b. Other laboratory changes reflect the varying involvement of visceral organs; for example, hyperbilirubinemia (liver) and azotemia (kidneys). 3. Coagulation assays a. Changes indicative of disseminated intravascular coagulation may be noted, resulting from the widespread vascular damage. This is a poor prognostic sign. 4. Urinalysis a. No significant changes noted 5. Effusion fluid analysis a. General characteristics (1) Usually straw-colored and cloudy. A stable froth develops on shaking due to high protein content. May clot when left standing at room temperature or when refrigerated. (2) The fluid is bacteriologically sterile. (3) Classified as non-septic exudate or modified transudate, based on protein level and cell counts. Often erroneously described as a pyogranulomatous fluid. (4) Albumin:globulin ratio is important. A ratio of >0.8 excludes a diagnosis of FIP. A ratio of <0.45, with a protein level of >3.5 g/dl, and typical cytological content (non-degenerative neutrophils, macrophages, a few plasma cells and lymphocytes, and a granular background of stained protein precipitates), is diagnostic for FIP when bacteriologically sterile. (5) The Rivalta test can be used to evaluate effusion fluid for increased levels of acute-phase proteins. A drop of effusion fluid is added to a mixture of water and 98% acetic acid. If the effusion fluid congeals at the top of the test tube and does not sink and disperse, then the suspicion for FIP is increased (see the reference by Hartmann for details). (6) Detection of coronavirus in macrophages in effusion fluid by immunofluorescence is considered strongly supportive of the 5
diagnosis, especially when accompanied by typical cytological and biochemical findings and a negative bacterial culture. 6. Serological testing a. A positive FCOV antibody titer (performed by indirect immunofluorescent antibody techniques) does not indicate that a sick cat has FIP. Healthy cats with titers >1:400 are likely to be shedding FECV. b. The level of FCOV antibody titer does not correlate with the severity of clinical disease, although very high titers (>1:16,000) may support a diagnosis of FIP if other typical changes are present. Rising antibody titers have little diagnostic significance, because of the normal fluctuation in titer levels. c. Low titers do not exclude a diagnosis of FIP, although a result of Ano detectable antibody@ would make the diagnosis unlikely. Many laboratories give the low cut-off point (reported as negative) at titers of 1:100-1:400; some patients with FIP will have titers in this low range. 7. Detection of messenger RNA in circulating macrophages and monocytes a. A relatively new test (available at Auburn University and The University of California, Davis) detects coronavirus mrna in circulating monocytes and macrophages in blood samples from cats suspected of having FIP. Detection of mrna strongly suggests virus replication in these cells - an event that occurs only with pathogenic FCOVs. Positive test results occur in 93% of cats with FIP, 46% of sick cats, and 5% of normal cats. The diagnostic significance of positive tests in the latter two groups is unknown. Our experience with the test using blood has been disappointing. The predictive value of the test may be enhanced if blood, body cavity effusion or lymph node aspirate, and feces are submitted simultaneously for analysis. VIII. TREATMENT A. At the present time, both forms of FIP are considered incurable. Some supportive treatments may extend longevity and improve quality of life temporarily. B. Oral prednisolone (1-2 mg/kg PO q12h) may be used to decrease the adverse inflammatory response and the detrimental humoral immune response; however, the drug may dampen any beneficial cell-mediated response and predispose to opportunistic infections. Corticosteroid treatment seems to improve quality of life, but not increase longevity. C. Pentoxifylline (100 mg PO q12h) has been used anecdotally (in combination with prednisolone) because of its beneficial effects in improving circulation and reducing inflammation in vascular diseases. It is not licensed for use in cats. D. Recombinant feline interferon omega (not available presently in the USA) may ameliorate some of the signs of FIP. E. One report described significant lengthening of life span of three cats with non-effusive FIP using Polyprenyl Immunostimulant. F. Treatment of experimentally infected cats with viral protease inhibitors recently has been reported to be very promising in reducing or eliminating clinical signs (Pedersen N, 6
ACVIM Forum 2015). G. Supportive care is important; for example, antimicrobial therapy to prevent secondary infections, and nutritional and fluid support. IX. PREVENTION A. Most efforts at prevention are directed toward: 1. Minimizing early FCOV infections of kittens in catteries. 2. Preventing the introduction of FCOVs in cat populations in which the virus is not present. 3. Decreasing the incidence of FIP in populations in which cases have occurred. 4. Decreasing the total load of coronavirus in the environment. B. Strategies include early weaning and isolation of kittens, reducing stress and overcrowding, enhancing preventive health care and nutrition, and reducing litter-box and fomite contamination with FCOVs. C. The commercial intranasal vaccine (Primucell FIP) has not gained widespread acceptance as an effective means for preventing FIP. The vaccine induces local surface immunity in the oronasal cavity to prevent primary infection, and stimulates a cell-mediated immune response to prevent systemic infection. Contrary to previous concerns, the vaccine does not appear to cause antibody-enhancement of disease. References 1 Addie D, Jarrett O: Feline coronaviral infections. In Greene CE (ed): Infectious diseases of the dog and cat, ed 3, St. Louis, 2006, Elsevier, pp 88-101. 2. Foley JE: Feline infectious peritonitis and feline enteric coronavirus. In Ettinger SJ, Feldman EC (eds): Textbook of veterinary internal medicine, ed 6, Philadelphia, 2005, Elsevier, pp 663-666. 3. Hartmann K: Diagnosis and treatment of feline infectious peritonitis. In August JR (ed): Consultations in feline internal medicine, vol 6, St. Louis, Saunders Elsevier, 2010, pp 62-76. 4. Licitra BN, Millet JK, Regan AD, et al: Mutation in spike protein cleavage site and pathogenesis of feline coronavirus. Emerg Infect Dis 19(7), 1066, 2013. 5. Disease information fact sheet. Feline infectious peritonitis. J Feline Med Surg 15, 2013 (Suppl). 7
Feline Infectious Peritonitis What do we know about this disease? Colorado VMA Convention Loveland, Colorado Saturday, September 23, 2017 Complicated Unpredictable Difficult to explain Difficult to confirm No proven cure 1
Which abnormalities do you observe? Enveloped RNA viruses Environmentally resistant Fecal-oral spread 2
Feline enteric coronavirus Ubiquitous non-pathogenic form Crowded cat populations Feline infectious peritonitis 3
Genetic predisposition? Infection with enteric coronavirus Stress Increased viral replication Viral mutation Macrophage-associated viremia Inappropriate immune response Breed associations Early CMI response Termination of viremia Early humoral response Effusive FIP Ineffective CMI response Non-effusive FIP 4
Body cavity effusions FIP effusion fluid Renal pyogranulomas 5
Non-effusive FIP The accurate diagnosis of noneffusive FIP is relatively easy in most cats with suspicious clinical signs 1 2 True False The accurate diagnosis of noneffusive FIP is relatively easy in most cats with suspicious clinical signs 2 True False 6
Fever Lymph nodes Weight loss Organ specific CNS disease Cavity effusion Ocular changes Pyogranulomatous lymphadenitis Photo courtesy of Dr. Cynthia Powell Colorado State University Keratic precipitates 7
Chorioretinitis Signalment and Background History Physical exam Laboratory examinations Effusion fluid CBC and chemistry Serology FeLV/FIV/Toxo Titer/mutation Histopathology and virology CSF Tissue biopsy Diagnostic evaluation Body cavity effusion 8
Sterile High protein Low A:G ratio Low cell count Mixed cell population Rivalta test Pyogranulomatous vasculitis 9
Signalment and background Age (and breed?) Multiple-cat facility Environmental stressors Clinical signs Antibiotic-resistant fever, effusion Ocular and CNS signs Abdominal lymphadenopathy Laboratory findings Lymphopenia and hyperglobulinemia Positive titer and detection of mutation Non-septic exudate Palliative Corticosteroids Specific Polyprenyl immunostimulant Anti-viral proteases Minimize kitten infections Isolation Reduce stress Prevent overcrowding Litter box hygiene Confirm cause of deaths Vaccination? 10
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