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Feline infectious peritonitis (FIP) is an immune-mediated disease triggered by infection with a feline coronavirus (FCoV). FCoV belongs to the family Coronaviridae, a group of enveloped, positive-stranded RNA viruses that are frequently found in cats. Coronavirus-specific antibodies are present in up to 90% of cats in catteries and in up to 50% of those in single-cat households. However, only about 5% of FCoV-infected cats develop FIP in a cattery environment.
Geographic Distribution
FCoV infection and FIP occur worldwide with similar prevalence, and are found in domestic and wild cats. FCoV strains can be classified into serotypes I and II, depending on their antigenetic relationship to canine coronavirus (CCV), and these subtypes vary in proportion among different countries. Among FCoV strains isolated in the field in USA and Europe, 70–95% are serotype I. In contrast, in Japan serotype II predominates. Most cats with FIP are infected with FCoV serotype I. However, both serotypes can cause FIP and both can cause clinically inapparent FCoV infections.
FCoV belong to the same taxonomic cluster of coronaviruses as transmissible gastroenteritis virus, porcine respiratory coronavirus, CCV, and some human coronaviruses. In many species, coronaviruses have a relatively restricted organ tropism, mainly infecting respiratory and/or GI cells. In cats and mice, however, coronavirus infections can, under certain circumstances, involve several organs. Coronaviruses have a relatively low species specificity. For example, CCV can also infect cats. FIP, however, can only occur in felids.
Besides cats, other felid species are susceptible, and FCoV is also an important pathogen in nondomestic felids. There was evidence of FCoV infection in 195 of 342 nondomestic felids in Southern Africa, which included both wild and captive animals. There is also a high incidence of FIP in wild felids in captivity in the USA and Europe, eg, in zoos. Cheetahs in captivity seem to be highly prone to developing FIP; a genetic deficiency in their cellular immunity is thought to predispose them to the disease.
Etiology and Pathogenesis
FIP is caused by a coronavirus named feline infectious peritonitis virus (FIPV). FIP accounts for most infectious disease-related deaths in cats. A possible explanation for the increase in the prevalence of FIP is that the management and housing conditions of domestic cats are changing. With the introduction of litter boxes, more cats are kept permanently indoors, exposing them to large doses of FCoV in the feces, which previously would have been buried outdoors. Crowded environments, such as those at cat breeders or shelters, also may increase stress and exposure to FCoV.
It was originally thought that FCoV strains that cause FIP were different from avirulent enteric FCoV strains. FCoV strains were therefore subdivided into two distinct biotypes, feline enteric coronavirus and feline infectious peritonitis virus. However, it is now known that those biotypes are not different species, but represent virulence variants of the same virus. For this reason FCoV should be used to describe all coronaviruses in cats.
After a cat becomes infected with FCoV by ingestion (or rarely inhalation), the main site of viral replication is the intestinal epithelium. Replication of FCoV in the cytoplasm can cause destruction of intestinal epithelial cells, leading to diarrhea in some cats. In many cats, infection persists over a long period without causing any clinical signs. These cats shed FCoV either intermittently or continuously and act as a source of infection for other cats. Previously, it was believed that avirulent FCoV remain confined to the digestive tract, did not cross the gut mucosa, and did not spread beyond the intestinal epithelium and regional lymph nodes. However, PCR can detect FCoV in the blood of healthy cats from households with endemic FCoV, indicating that avirulent FCoV may also cause viremia. It is likely that this viremia in cats that do not develop FIP may only be short term and low grade.
FIP is a sporadic disease caused by viral variants that develop within a specific cat. Wherever FCoV infection exists, so does the potential for the development of FIP. The pathogenesis of FIP is unclear, but there are 2 main hypotheses. The “internal mutation theory” is based on the fact that a mutation that favors viral replication in macrophages is necessary, and cats are infected with the primarily avirulent FCoV that replicates in enterocytes. In some instances, however, a mutation occurs in a certain region of the FCoV genome that creates a new phenotype with the ability to replicate within macrophages. The presence of highly virulent strains of FCoV that are capable of consistently inducing FIP support this theory, albeit under experimental conditions. However, no consistent mutation has yet been identified.
The second hypothesis for the development of FIP is that any FCoV can cause FIP, but the viral load and the cat's immune response determine whether or not FIP will develop. It is likely that both viral genetics and host immunity play a role. In both hypotheses, the key pathogenic event in the development of FIP is the massive replication of FCoV in macrophages. If the cat fails to eliminate macrophages infected with replication-competent virus early in infection, the presence of the virus within macrophages initiates an ultimately fatal Arthus-type immune-mediated reaction, which defines FIP.
Factors that increase FCoV replication in the intestines (and increase the probability of the mutation) include young age, breed predisposition, immune status, stress, corticosteroid treatment, and surgery, as well as dosage and virulence of the virus and re-infection rate in multiple cat households. Kittens that develop FIP likely do so because they are subjected to a large virus dose at a time of life when their immature immune system is also coping with other infections and the stress of vaccination, relocation, and neutering.
FIP is an immune complex disease involving viral antigen, antiviral antibodies, and complement. Within weeks after mutation occurs, mutated viruses are found in the cecum, colon, intestinal lymph nodes, spleen, and liver after distribution by macrophages in the whole body including the CNS. There are two possible explanations for the events following viral dissemination from the intestines. The first proposed mechanism is that FCoV-infected macrophages leave the bloodstream and enable virus to enter the tissues. The virus attracts antibodies, complement is fixed, and more macrophages and neutrophils are attracted to the lesion; as a consequence, typical granulomatous changes develop. The alternative explanation is that FIP occurs as a result of circulating immune complexes entering blood vessel walls, fixing complement, and leading to the development of the granulomatous changes. It is assumed that these antigen–antibody complexes are recognized by macrophages but are not, as they should be, presented to killer cells and thus are not destroyed.
The consequences of the formation of immune complexes in the cats depend on their size, antibody concentration, and antigen content. Immune complex deposition most likely occurs at sites of high blood pressure and turbulence, conditions that are present at blood vessel bifurcations. FIP lesions are very common in the peritoneum, kidney, and uvea.
In addition to virus, chemotactic substances, including complement and inflammatory mediators, are released from infected and dying macrophages. Complement fixation leads to the release of vasoactive amines, which cause endothelial cell retraction and thus increased vascular permeability. Retraction of capillary endothelial cells allows exudation of plasma proteins, hence the development of characteristic protein-rich exudates. Inflammatory mediators activate proteolytic enzymes that cause tissue damage. The immune-mediated vasculitis leads to activation of the coagulatory system and disseminated intravascular coagulation (DIC). Imbalances in several cytokines (eg, increase of TNF-α, decrease of interferon-γ) appear early in experimentally induced FIP.
Epidemiology and Transmission
FCoV and FIP are a major problem in multiple cat households. The virus is endemic in environments in which many cats are kept together in a narrow space (eg, catteries, shelters, pet stores). FCoV is rare in free-roaming stray cats, which are usually loners without close contact to each other. Most importantly, they do not use the same locations for burying their feces, which is the major source of transmission in multiple cat households.
Although the prevalence of FCoV infection is very high in multiple cat households, only about 5% of cats in these situations develop FIP; the number is even lower in a single cat environment. The risk of developing FIP is higher for young and immuno-compromised cats as the replication of FCoV in these animals in less controlled and thus, the critical mutation is more likely to occur. More than half of the cats with FIP are <12 mo old.
FCoV is shed mainly in the feces. Infection is generally via the oronasal route. In very early infection, it may be found in saliva and in respiratory secretions and urine. When naive cats in multiple cat households first encounter FCoV, it is likely that all will become infected (and develop antibodies); most will shed virus intermittently for a period of weeks or months. Some cats become chronic FCoV shedders, providing a continuous source for re-infection of other cats. Cats that are antibody-negative are very unlikely to shed, whereas approximately one-third of all FCoV antibody-positive cats shed virus. It has been shown that cats with high antibody titers are more likely to shed FCoV. They also are more likely to shed consistently and higher amounts of the virus. Most cats with FIP also shed non-mutated FCoV; however, the virus load in feces seems to decrease after a cat has developed FIP.
The major source of FCoV for naive cats are litter boxes shared with shedding cats. Also, continuous re-infection through the contaminated litter box of a cat already infected seems to play an important role in the endemic survival of the virus. Rarely, virus can be transmitted through saliva, by mutual grooming, sharing the same food bowl, and through close contact. Sneezed droplet transmission is also rare but possible. It is uncertain whether FCoV transmission occurs to a significant degree at cat shows. Transmission by lice or fleas is considered unlikely. Transplacental transmission can occur, but this is very uncommon under natural circumstances. Most kittens that are removed from contact with adult virus-shedding cats at 5–6 wk of age do not become infected. Most commonly, kittens are infected at the age of 6–8 wk at a time when their maternal antibodies wane, mostly through contact with feces from their mothers or other FCoV-excreting cats.
FCoV is a relatively fragile virus that is inactivated at room temperature within 24–48 hr. It is destroyed by most household disinfectants and detergents. However, it can survive in dry conditions (eg, in carpet) for up to 7 wk outside the cat. Indirect fomite transmission is therefore possible, and the virus can be transmitted via clothes, toys, and grooming tools.
Clinical Findings
FCoV Infection
FCoV infection can cause a transient and clinically mild diarrhea and/or vomiting due to replication of FCoV in enterocytes. Kittens infected with FCoV may have a history of stunted growth or, rarely, upper respiratory tract signs. Occasionally the virus may cause severe diarrhea with weight loss, which may be unresponsive to treatment and continue for months. However, most FCoV-infected cats do not show clinical signs.
FIP
Clinical signs of FIP vary depending on organ involvement. Many organs, including the liver, kidneys, pancreas, CNS, and eyes, can be involved. The clinical signs and pathologic findings are a consequence of the vasculitis and organ failure resultant from damage to the blood vessels that supply them. In all cats with nonspecific clinical signs, such as chronic weight loss or fever of unknown origin resistant to antibiotic treatment or recurrent in nature, FIP should be on the list of differential diagnoses.
The length of time between mutation and development of clinical signs is unknown and depends on the immune system of the individual cat. Disease generally becomes apparent from a few weeks to 2 years after the mutation has occurred. The time between infection with FCoV and the development of FIP is even more unpredictable and depends on the occurrence of the spontaneous mutation. Cats are at greatest risk of developing FIP in the first 6–18 mo after infection with FCoV; the risk decreases to about 4% at 36 mo post infection.
Previously, 3 different forms of FIP were distinguished, 1) an effusive, exudative, wet form; 2) a noneffusive, nonexudative, dry, granulomatous, parenchymatous form; and 3) a mixed form. The first form was characterized by a fibrinous peritonitis, pleuritis, and/or pericarditis with effusion in the abdomen, thorax, and/or pericardium, respectively. The second form was characterized by granulomatous changes in different organs including eyes and CNS. It has now been determined that a differentiation between these forms is not useful (and is only of value for the diagnostic approach) as there is always effusion to a greater or lesser degree in combination with more or less granulomatous organ changes present in cats with FIP. In addition, the forms can transform into each other. FIP, therefore, can simply be more or less exudative or productive in a certain cat at a given time.
Many cats with FIP develop effusions. These are most commonly seen as ascites and/or thoracic effusions. Rarely, effusions in other regions, including pericardial and scrotal effusions, are seen. However, fewer than 50% of all cats with effusions actually have FIP.
In cats with ascites, an abdominal swelling is commonly noticed. Fluctuation and a fluid wave may be present; in less severe cases, fluid can be palpated between the intestinal loops. Abdominal masses can sometimes be palpated, reflecting omental and visceral adhesion, or enlarged mesenteric lymph nodes. Thoracic effusions may cause dyspnea, tachypnea, open-mouth breathing, or cyanotic mucous membranes. Auscultation reveals muffled heart sounds. In cats with pericardial effusions, heart sounds are muffled and typical changes can be seen on ECG and echocardiography. Cats with effusions may be alert or depressed. Some eat with a normal or even increased appetite; others are anorectic. Fever, weight loss, and/or icterus may be noted. Effusions can be visualized by diagnostic imaging (eg, radiographs, ultrasound) and verified by a fluid tap.
In cats without obvious effusion, in which mainly granulomatous changes are present, signs are often vague and include fever, weight loss, lethargy, and decreased appetite. Cats may be icteric. If the lungs are involved, cats can be dyspneic, and thoracic radigraphs may reveal patchy densities in the lungs. Abdominal palpation may reveal enlarged mesenteric lymph nodes and irregular kidneys or nodular irregularities in other viscera. Presenting clinical signs sometimes can be unusual. In some cats, abdominal tumors are suspected but FIP is finally diagnosed at necropsy.
Cats with FIP frequently have ocular lesions. The most common ocular lesions are retinal changes. A retinal examination should be performed in all cats with suspected FIP. FIP can cause cuffing of the retinal vasculature, which appears as fuzzy grayish lines on either side of the blood vessels. Occasionally, granulomatous changes are seen on the retina. Retinal hemorrhage or detachment may also occur. These changes, however, are not pathognomic; similar changes can be seen in other systemic infectious diseases including toxoplasmosis, systemic fungal infections, and FIV or FeLV infection.
Uveitis is another common manifestation. Mild uveitis can manifest by color change of the iris. Usually part or all of the iris becomes brown, although occasionally blue eyes appear green. Uveitis may also manifest as aqueous flare, with cloudiness of the anterior chamber, which can be detected in a darkened room using focal illumination. Large numbers of inflammatory cells in the anterior chamber settle on the back of the cornea and cause keratic precipitates, which may be hidden by the nictitating membrane. Hemorrhage into the anterior chamber can occur. If aqueous humor is tapped, it may reveal elevated protein and pleocytosis.
Neurologic signs are common in cats with FIP. These are variable and reflect the area of CNS involvement. Usually, the lesions are multifocal. The most common clinical sign is ataxia followed by nystagmus and seizures. In addition, incoordination, intention tremors, hyperesthesia, behavioral changes, and cranial nerve defects can be seen. If cranial nerves are involved, neurologic signs such as visual deficits and loss of menace reflex may be present. When FIP lesions are located on a peripheral nerve or the spinal column, lameness, progressive ataxia, or paresis may be observed. Finding hydrocephalus on a CT scan is suggestive of neurologic FIP. In a study of 24 cats with FIP with neurologic involvement, 75% were found to have hydrocephalus on postmortem examination.
A rare nodular enteric form of FIP seen in young cats with diarrhea and vomiting is associated with intestinal granulomatous lesions. The main or only organ affected in these cases is the intestine. Lesions are commonly found only in the ileocecocolic junction but may be present in other areas (eg, colon or small intestine). Cats may have a variety of clinical signs as a result of these lesions, most commonly chronic diarrhea. Vomiting or obstipation can also occur, and some cats present with only GI obstruction. Palpation of the abdomen often reveals a thickened intestinal area. Hematology may show increased numbers of Heinz bodies as a result of decreased absorption of vitamin B12.
Skin fragility syndrome was described in a cat with FIP, and other skin lesions (eg, nodular skin lesions, papular skin lesions, pododermatitis) may be present as well. Reproductive disorders, neonatal deaths, and fading kittens are not usually associated with FIP.
Lesions
Histology of lesions is usually pathognomonic. Hematoxylin and eosin-stained samples typically contain localized perivascular mixed inflammation with macrophages, neutrophils, lymphocytes, and plasma cells. Pyogranulomas may be large and consolidated, sometimes with focal tissue necrosis, or numerous and small. Lymphoid tissues in cats with FIP often show lymphoid depletion caused by apoptosis.
Diagnosis
Reliable and rapid diagnosis of FIP is important but can be challenging. Difficulties arise from the lack of noninvasive confirmatory tests in cats without obvious effusion. Obtaining and analyzing effusion is minimally invasive and much more sensitive than diagnostic tests in blood. In cats with no effusion, several parameters including history, clinical signs, laboratory changes, and level of antibody titers should be considered to determine whether to use invasive confirmative diagnostic methods.
Hematology and Serum Biochemistry
WBC counts can be decreased or increased. Lymphopenia is commonly present, mainly caused by apoptosis of uninfected T cells, primarily CD8+ T cells, as a result of high TNF-α concentrations produced by virus-infected macrophages. However, lymphopenia in combination with neutrophilia can occur in many severe diseases in cats. A mild to moderate nonregenerative anemia is another non-specific finding that may occur in almost any chronic disease in cats.
The most common laboratory abnormality in cats with FIP is an increase in total serum protein concentration caused by increased globulins, mainly γ-globulins. Total protein in cats with FIP can reach very high concentrations of up to 120 g/L (12 g/dL) and higher. The albumin to globulin ratio, however, has a significantly higher diagnostic value to distinguish FIP from other diseases than total serum protein or γ-globulin concentrations, because a decrease in serum albumin also may occur through a decrease in production in association with liver failure or protein loss. Protein loss in cats with FIP may be caused by glomerulonephritis secondary to immune complex deposition, by loss of protein due to exudative enteropathy in case of granulomatous changes in the intestines, or by extravasation of protein-rich fluid during vasculitis. An optimum cut-off value of 0.8 was determined for the albumin to globulin ratio. Serum protein electrophoresis may be performed in cats with suspected FIP to distinguish a polyclonal from a monoclonal hypergammaglobulinemia in order to differentiate FIP (and other chronic infection) from tumors such as multiple myelomas or other plasma cell tumors. However, its value is limited.
Other laboratory parameters, including liver enzymes, bilirubin, urea (or BUN), and creatinine, can be variably elevated depending on the degree and localization of organ damage, but are not helpful in establishing an etiologic diagnosis. Hyperbilirubinemia and icterus are often observed and frequently reflect hepatic necrosis. Sometimes, bilirubin concentration is increased in cats with FIP without evidence of hemolysis, liver disease, or cholestasis; this unusual finding is otherwise observed only in septic animals. Bilirubin metabolism and excretion into the biliary system is compromised in these cats, likely due to high levels of TNF-α that inhibit transmembrane transports. Thus, high bilirubin in the absence of hemolysis and elevation of liver enzyme activity should raise the suspicion of FIP.
High serum levels (>3 mg/mL) of α-1-acid glycoprotein (AGP), a serum acute phase protein that is elevated in cats with FIP, can support diagnosis, but levels also are raised in other inflammatory conditions and thus, these changes are not specific. Additionally, AGP may also be high in asymptomatic cats infected with FCoV, especially in households where FCoV is endemic.
Effusion Fluid
Tests on effusion have a much higher diagnostic value than tests performed on blood. Fluid can be obtained through ultrasound-guided fine-needle aspiration or using the “flying cat technique” in case of ascites. Although effusions of clear yellow color and sticky consistency are considered typical, the presence of this type of fluid in body cavities alone is not diagnostic. Fluid may have a different appearance, and some cases with pure chylous effusion have been reported. Usually, the protein content is very high (>3.5 g/dL), consistent with an exudate, whereas the cellular content is low (<5000 nucleated cells/mL), resembling a modified transudate or even pure transudate. Major differential diagnoses for these effusions include inflammatory liver disease, lymphoma, heart failure, and bacterial peritonitis or pleuritis. Lactate dehydrogenase (LDH) activity typically is high (>300 IU/L). Cytology is variable but often consists predominantly of macrophages and neutrophils, similar to cytology in cats with bacterial serositis or sometimes lymphoma; these effusions usually can be differentiated by the presence of malignant cells or intracellular bacteria in cytology and bacterial growth on culture, respectively.
Rivalta's test is a simple, inexpensive method that does not require special laboratory equipment and can be easily performed in private practice. It is very useful in cats to differentiate between effusions due to FIP and effusions caused by other diseases. The high protein content and high concentrations of fibrin and inflammatory mediators lead to a positive reaction. To perform the test, a transparent reagent tube (10 mL) is filled with approximately 8 mL distilled water, to which 1 drop of acetic acid (highly concentrated vinegar, 98%) is added and mixed thoroughly. On the surface of this solution, 1 drop of the effusion fluid is carefully layered. If the drop disappears and the solution remains clear, the Rivalta's test is defined as negative. If the drop retains its shape, stays attached to the surface, or slowly floats down to the bottom of the tube (drop- or jelly-fish-like), the test is defined as positive. Rivalta's test has a high positive predictive value (86%) and a very high negative predictive value (96%) for FIP. Positive results can sometimes occur in cats with bacterial peritonitis or lymphoma. Those effusions, however, are usually easy to differentiate through macroscopic examination, cytology, and/or bacterial culture.
Cerebrospinal Fluid
Analysis of cerebrospinal fluid (CSF) from cats with neurologic signs due to FIP lesions may reveal elevated protein (50–350 mg/dL with a normal value of <25 mg/dL) and pleocytosis (100–10,000 nucleated cells/mL) containing mainly neutrophils, lymphocytes, and macrophages (a relatively non-specific finding). Many cats with neurologic signs caused by FIP have normal CSF.
Measurement of Antibodies
There is no FIP antibody test; all that can be measured is antibodies against FCoV. Antibody titers measured in serum are extensively used as a diagnostic tool. However, most FCoV antibody-positive cats never develop FIP. Thus, antibody titers must be interpreted extremely cautiously. Antibody testing still has a certain role in the diagnosis and, more importantly, in the management of multiple-cat households, when done by appropriate methodologies and when results are properly interpreted. However, antibody testing can only be useful if the laboratory is reliable and consistent. Low or medium titers have no diagnostic value. If interpreted carefully, however, very high titers can be of certain diagnostic value. Cats with high antibody titers are more likely to shed FCoV and to shed more consistently higher amounts of the virus. Thus, the titer is directly correlated with virus replication rate and the amount of virus in the intestines. Antibody measurement may also be useful in practice, eg, to determine the prognosis of an exposed cat or whether an exposed cat is shedding FCoV. Screening a cattery for the presence of FCoV or screening a cat before introduction into an FCoV-free cattery are additional indications.
Measuring antibodies in fluids (eg, effusion, CSF) other than blood has been investigated. Presence of antibodies in effusion is correlated with the presence of antibodies in blood; thus, antibody titers in effusions are not very helpful. One study investigating the diagnostic value of antibody detection in CSF reported a very good correlation to the presence of FIP when compared to histopathology; however, 2 recent studies investigating a large number of cats presented to veterinary teaching hospitals revealed no significant difference in antibody titers in CSF from cats with neurologic signs due to FIP compared to cats with other neurologic diseases confirmed by histopathology.
FCoV Reverse Transcriptase PCR
FCoV reverse transcriptase PCR in blood is used with increasing frequency as a diagnostic tool for FIP. However, so far, no PCR has been developed that can definitively diagnose FIP. Additionally, PCR results are not easy to interpret, and PCR can be false negative (eg, because the assay requires reverse transcription of viral RNA to DNA prior to amplification of DNA, and degradation of RNA can be a potential problem because RNAases are virtually ubiquitous) or false-positive results (eg, the assay does not distinguish between virulent and avirulent FCoV strains, nor will it discriminate FCoV from coronaviruses of other species). Furthermore, viremia appears to occur not only in cats with FIP but also in healthy carriers. FCoV RNA has been detected in the blood of cats with FIP but also in healthy cats that did not develop FIP for a period of up to 70 mo. Therefore, the results of PCR tests in general must be interpreted carefully, and PCR cannot be used as a tool for definitively diagnosing FIP.
PCR has been used to detect FCoV in fecal samples, and it is sensitive and useful for documenting that a cat is shedding FCoV in feces. The strength of the PCR signal in feces correlates with the amount of virus present in the intestines. These results can be useful in detecting cats that chronically shed high virus loads and that pose a high risk in multi-cat households.
Antibody–Antigen Complex Detection
Because FIP is an immune-mediated disease, and antibody-antigen complexes play an important role in the pathogenesis, it has been suggested that it may be useful to look for specific circulating immune complexes in serum and effusions. Coronavirus-specific antibody-antigen complex detection can be performed using a competitive ELISA. Usefulness, however, is limited, and the positive predictive value of this test is not very high (67%).
Immunostaining of FCoV Antigen
Other methods to detect the virus include detection of FCoV antigen in macrophages using immunofluorescence (in effusion) or immunohistochemistry (in tissue). Immunostaining cannot differentiate between the “harmless” FCoV and FIP-causing FCoV, but only FIP-causing virus is able to replicate in sufficiently large amounts in macrophages to yield a positive staining. In a recent study in which a large number of cats with confirmed FIP and controls with other (confirmed) diseases were investigated, positive immunofluorescence staining of intracellular FCoV antigen in macrophages of the effusion was 100% predictive of FIP. Unfortunately, the negative predictive value of the test is not very high (57%), which can be explained by low numbers of macrophages on effusion smears resulting in negative staining. Immunohistochemistry can be used to detect the expression of FCoV antigen in tissue and is also 100% predictive of FIP if positive. However, invasive methods (eg, laparotomy or laparoscopy) are usually necessary to obtain appropriate tissue samples. Either histology itself is confirmative, or immunohistochemistry staining of FCoV antigen in tissue macrophages can be used to diagnose FIP.
Treatment, Control, and Prevention
Treatment of cats with FIP remains frustrating and is limited to the cases that respond favorably within the first few days. The prognosis for a cat with FIP is very poor. In a prospective study including 43 cats with confirmed FIP, the median survival after the definitive diagnosis was 9 days. Some cats, however, may live for several months. Factors that indicate a poor prognosis and a short survival time are low Karnofsky's score (index for quality of life), low platelet count, low lymphocyte count, high bilirubin concentration, and a large amount of effusion. Seizures should be considered an unfavorable prognostic sign; they are significantly more frequent in animals with marked extension of the inflammatory lesions to the forebrain. Cats that show no improvement within 3 days after treatment initiation are unlikely to show any benefit from therapy, and euthanasia should be considered.
Supportive treatment is aimed at suppressing the immune overreaction, usually using corticosteroids. However, there are no controlled studies that indicate whether corticosteroids have any beneficial effect. Occasional cats treated with corticosteroids have shown anecdotal improvement for up to several months. Immunosuppressive drugs such as prednisone (2–4 mg/kg, PO, sid) have been suggested. Some cats with effusion benefit from tapping and removal of the fluid and injection of dexamethasone into the abdominal or thoracic cavity (1 mg/kg bid until no effusion is present).
Cats with FIP should additionally be treated with broad-spectrum antibiotics and supportive therapy (eg, SC fluids). A thromboxane synthetase inhibitor (ozagrel hydrochloride) that inhibits platelet aggregation has been used in a few cats and has led to some improvement of clinical signs. There are anecdotal reports that pentoxifylline, a drug that decreases vasculitis and inhibits several cytokines (such as interleukins and TNF-α), may be beneficial in some cats.
Immune modulators (eg, Propionibacterium acnes, acemannan) have been used to treat cats with FIP with no documented controlled evidence of efficacy. It has been suggested that these agents may benefit infected animals by restoring compromised immune function. However, a nonspecific stimulation of the immune system would seem to be contraindicated in FIP, because clinical signs develop and progress as a result of an immune-mediated response. Some older reports suggest that tylosin, which has immunomodulatory effects, may provide some treatment benefit in cats with FIP. Remissions of varying lengths were reported in individual cats; however, FIP was not confirmed in many of these cases. The immune modulator promodulin was used in 52 cats with suspected FIP that responded favorably to treatment; a rapid remission of clinical signs (anorexia, fever, effusion) was seen. However, FIP again was not confirmed, and there was no control group or longterm follow-up included in the study.
In one study, 29 cats suspected to have FIP were treated in 5 groups over 6 wk. Cats received either ampicillin (100 mg/kg/day), prednisolone (4 mg/kg/day), and cyclophosphamide (4 mg/kg/day); dexamethasone (2 mg/kg at day 1 and day 5) and ampicillin (20 mg/kg tid for 10 days); human interferon-α (6 × 105 IU/cat 5 days/wk for 3 wk); a paraimmunity inducer (0.5 mL/cat/wk for 6 wk); or nothing. Between 29% and 80% (depending on the group) of the cats died within 3 yr. However, FIP was not confirmed in these cats either, and inclusion criteria remain unclear.
A number of studies have investigated effectiveness of various antiviral treatments in cats with FIP. To date, none have proved to be very successful. One cat treated with melphalan, an alkylating agent of the nitrogen mustard group that irreversible interacts with DNA, responded well to treatment for 9 mo, then developed a myeloproliferative disorder and died. The FIP diagnosis was not confirmed in this case, however.
Interferons have been used frequently in cats with FIP. Human interferon-α has a direct antiviral effect and in vitro antiviral efficacy against an FIP-causing FCoV strain has been demonstrated. In a controlled study, cats with confirmed FIP treated with 106 IU/kg interferon-α in combination with Propionibacterium acnes had a significantly prolonged survival time (~3 wk). Feline interferon-ω has been licensed for use in veterinary medicine in some European countries and Japan. Cats can be treated with the feline interferon-ω paren-terally over long periods without developing antibodies. FCoV replication is inhibited by feline interferon-ω in vitro, but treatment results are mixed. In a recently performed randomized placebo-controlled double-blind treatment trial, there was no statistically significant difference in the mean survival time of cats treated with interferon-ω vs placebo. Cats survived for a period of 3–200 days.
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Table 1
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| Drugs That Have Been Suggested for Use in FIP Cases a
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Drug
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Comment
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ABCD Recommendation (EBM Level b)
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Antivirals
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Ribavirin
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Active in vitro but toxic in cats
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Not recommended (2)
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Vidarabin
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Active in vitro but toxic in cats
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Likely ineffective (4)
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Human interferon-α, SC, high dose
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Although effective in vitro against FCoV, SC treatment did not work in an experimental trial
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Ineffective (2)
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Human interferon-α, PO, low dose
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No trials. Only acts as immunostimulant if given orally; immune stimulation should be avoided in cats with FIP
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Contraindicated (4)
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Feline interferon-ω
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Single placebo-controlled study of naturally occurring cases and 1 uncontrolled study
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No benefit was observed (level 1 study); may require further studies in view of anecdotal clinical evidence (4)
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Polyprenyl immunostimulant (investigational drug)
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Upregulation biosynthesis of mRNA of TH1 cytokines, uncontrolled study treating 3 noneffusive cases, long survival
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May have some beneficial effect in noneffusive FIP (3); controlled studies required
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Immunosuppressants
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Prednisolone/dexamethasone (immunosuppressive doses)
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No controlled studies; some cats improved during treatment and survived for several months; does not cure FIP
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Currently supportive treatment of choice (3); if effusion is present, dexamethasone IT or IP may be helpful
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Pentoxifylline
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Aimed at treating vasculitis
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Ineffective in one case study (4)
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Ozagrel hydrochloride
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Thromboxane synthesis inhibitor aimed at treating inflammatory response; only used in 2 cases with beneficial effect
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Controlled studies needed (3)
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Cyclosporin A
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Immunosuppressive; no published studies
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Not recommended; more directed against cellular immunity than humoral (lack of data) (4)
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Cyclophosphamide
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Immunosuppressive; no published studies
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Might be considered in combination with glucocorticoids (4)
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Chlorambucil
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Immunosuppressive; no published studies
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Might be considered in combination with glucocorticoids (4)
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Azathioprine
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Toxic in cats; immunosuppressive; no published studies
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Not recommended (4)
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Acetyl-salicylic acid (aspirin), platelet inhibitory dosage
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To treat inflammatory response as well as vasculitis; no published studies
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May have some beneficial effect, but adverse effects possible if used in combination with high-dose glucocorticoids
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a Many of the treatments listed represent extra-label use for treatment of FIP.
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b Evidence-based medicine (EBM) level 1 = confirmed by randomized controlled clinical trials in target species; EBM level 2 = confirmed by randomized controlled experimental studies in target species; EBM level 3 = supported by case series, other experimental studies, nonrandomized clinical trials; EBM level 4 = based on expert opinion, case reports, studies in other species. Modified, with permission, from Feline infectious peritonitis. Guidelines of The European Advisory Board on Cat Diseases, © 2010 Advisory Board on Cat Diseases.
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Management of Exposed Cats
When a cat in a household develops FIP, all in-contact cats will have already been exposed to the same FCoV. Under natural circumstances, it appears that the FIP-causing virus is not excreted in such cases, and FIP is not transmitted from cat to cat. After FIP has developed, a cat even will shed less “harmless” FCoV than before development of FIP. However, under experimental conditions it has been possible to transmit FIP-causing virus from a cat with FIP to in-contact cats. Still, it appears to be relatively safe to take the cat with FIP back in the same household with cats that have already been in contact to the FCoV strain, as these cats will have a certain immunity to that specific strain. It is not recommended to allow contact between a cat with FIP and any new “naive” cat, however.
If a cat has been euthanized or has died due to FIP, the owner should wait ~3 mo before obtaining another cat. FCoV can remain infectious for at least 7 wk in the environment particularly where litter boxes are in use. Other cats currently in the household are most likely infected with and shedding FCoV. Cats are commonly presented to the veterinarian for evaluation after contact with a cat with FIP or a suspected or known virus excretor. The owner may want to know the prognosis for the exposed cat or whether it is shedding FCoV. Such cats will likely be antibody positive, because 95–100% of cats exposed to FCoV become infected and develop antibodies ~2–3 wk after exposure. A few cats may be resistant to FCoV infection. It has been shown that some cats in FCoV-endemic multiple-cat households continuously remain antibody negative. The mechanism of action for this resistance is unknown.
Although exposed cats will most likely have antibodies, this is not necessarily associated with a poor prognosis. Most cats infected with FCoV will not develop FIP, and many cats in single- or two-cat households will eventually clear the infection and become antibody negative in a few months to years (usually ~6 mo). Owners should be advised to wait until antibody tests of all cats are negative or until fecal PCR (4 fecal samples tested over a 2-wk period) are negative before obtaining a new cat. If antibody testing is used, cats should be retested (using the same laboratory) every 6–12 mo until the antibody test is negative. Some cats will remain antibody positive for years.
Management of Multiple-cat Households
In most multiple-cat households, FCoV is endemic and FIP is almost inevitable. Households of <5 cats may spontaneously and naturally become FCoV-free, but in households of >10 cats per group this is almost impossible because the virus passes from one cat to another, maintaining the infection. In these FCoV-endemic environments, such as breeding catteries, shelters, foster homes, and other multi-cat homes, there is virtually nothing to prevent FIP.
Various tactics have been used to eliminate FCoV from an endemic cattery. Reducing the number of cats (especially of kittens <12 mo old) and keeping suspected FCoV-contaminated surfaces clean can minimize population loads of the virus. Antibody or fecal PCR testing and segregating should be performed to stop exposure. Approximately one-third of antibody-positive cats excrete virus; thus, every antibody-positive cat should be considered infectious. After 3–6 mo, antibody titers can be retested. Alternatively, PCR testing of (several) fecal samples can be performed to detect chronic FCoV carriers; these cats can be removed. In large multiple-cat environments, 40–60% of cats shed virus in their feces at any given time. About 20% will shed virus persistently. If a cat remains persistently PCR-positive for >6 wk, it should be placed in a single-cat environment.
Kittens of FCoV-shedding queens should be protected from infection by maternally derived antibodies until they are 5–6 wk old. An early weaning protocol for the prevention of FCoV infection in kittens has been proposed and consists of isolation of queens 2 wk before parturition, strict quarantine of queen and kittens, and early weaning at 5 wk of age. Early removal of kittens from the queen and prevention of infection from other cats may succeed in keeping kittens free of infection. Kittens should be taken to a new home (with no FCoV-infected cats) at 5 wk of age. Although straightforward in concept, the protocol requires quarantine rooms and procedures to ensure that new virus does not enter. Special care must be taken during this period to socialize the kittens. The success of early weaning and isolation depends on effective quarantine and low numbers of cats (<5) in the household.
Another possible approach is to maximize heritable resistance to FIP in breeding catteries. Genetic predisposition plays a role in the disease but is not completely understood. Full-sibling littermates of kittens with FIP have a higher likelihood of developing FIP than other cats in the same environment. A cat that has 2 or more litters in which kittens develop FIP should not be bred again. Particular attention should be paid to pedigrees of toms where FIP is over-represented. Because line breeding often uses valuable tomcats extensively, eliminating such animals may have an effect on improving overall resistance.
In shelters, prevention of FIP is virtually impossible unless cats are strictly separated and handled only through sterile handling devices (comparable to isolation units). Isolation is often not effective because FCoV is easily transported on clothes, shoes, dust, and cats. There appears to be significant correlation between the number of handling events outside the cages and the percentage of antibody positive cats. Shelters should have written information sheets or contracts informing adopters about FCoV and FIP. Personnel should understand that FCoV is unavoidable in multiple-cat environments and that FIP is an unavoidable consequence of endemic FCoV. Good husbandry practices and facilities that can be cleaned easily may minimize virus spread.
Vaccination
Attempts to develop effective vaccines have met with little success. However, a vaccine has been licensed that incorporates a temperature-sensitive mutant of the FCoV strain DF2-FIPV, which can replicate in the cool lining of the upper respiratory tract but not at higher internal body temperature. This vaccine is admin-istered intranasally and produces local immunity (IgA antibodies) at the site where FCoV first enters the body (the oropharynx), as well as cell-mediated immunity. It is available in the USA and many European countries. Efficacy of the vaccine has been questioned. Vaccination in an FCoV-endemic environment or in a household with known cases of FIP is not effective. Antibody testing may be beneficial before vaccination because the vaccine will not be effective in cats with prior contact with FCoV. Most cats develop antibodies after vaccination, thus making the establishment and control of an FCoV-free household difficult.
Zoonotic Risk
Because of the close antigenetic relationship between coronaviruses of different domestic animal species, and because a coronavirus deriving from animals in close contact to humans caused the so-called severe acute respiratory syndrome (SARS) outbreak of 2003 that threatened the health of thousands of human beings, concerns arose about the possible danger of FCoV to people. However, there is no indication that FCoV is infectious to people.
Last full review/revision March 2012 by Katrin Hartmann, DECVIM-CA, DrMedVet, DrMedVetHabil
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