Feline infectious peritonitis (FIP) is a common disease and a frequent reason for referral; approximately 1 of every 200 new feline cases presented to American veterinary teaching hospitals represents a cat with FIP [1] . It is also a major factor in kitten mortality [2] . FIP is a fatal immune-mediated disease triggered by infection with a feline coronavirus (FCoV) [3] . FCoV belongs to the family Coronaviridae, a group of enveloped positive-stranded RNA viruses that are frequently found in cats [4] . Coronavirus-specific antibodies are present in up to 90% of cats in catteries and in up to 50% of those in single-cat households [5] , [6] , [7] , [8] . Only approximately 5% of FCoV-infected cats develop FIP in a cattery situation, however [5] , [9] , [10] , [11] . Because FIP is not only common but deadly and has no effective long-term management, a rapid and reliable diagnosis is critical for prognostic reasons. A reliable diagnostic test would lessen the suffering of affected patients while avoiding euthanasia of unaffected cats; however, unfortunately, such a test is not currently available. Difficulties in definitively diagnosing FIP arise from nonspecific clinical signs; lack of pathognomonic, hematologic, and biochemical abnormalities; and low sensitivity and specificity of tests routinely used in practice.
It was initially hypothesized that FCoV strains causing FIP are different from avirulent enteric FCoV strains [12] . Those former strains, however, are serologically and genetically indistinguishable [13] , [14] , [15] , [16] , [17] , [18] and represent virulent variants of the same virus rather than separate virus species [19] . It is now known that 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 [20] , [21] , [22] , leading to the ability of the virus to replicate within macrophages, which seems to be a key pathogenic event in the development of FIP [9] , [23] . Although intensive research has continuously led to new knowledge and understanding about FIP, it has produced even more questions that still have to be answered. The objective of this article is to review recent knowledge and to increase understanding of the complex pathogenesis of FIP.
Etiology
The disease FIP was first described in 1963 as a syndrome in cats characterized by immune-mediated vasculitis and pyogranulomatous inflammatory reactions [24] . In 1978, a virus was identified as the etiologic agent, and in 1979, it was classified as a coronavirus labeled “feline infectious peritonitis virus” (FIPV) [25] . FIP has become an increasingly important disease for veterinarians and must now be considered to account for most infectious disease-related deaths in pet cats, thus taking over this title in recent years from feline leukemia virus (FeLV) infection, which is decreasing in prevalence and importance. A possible explanation for an increase in the prevalence of FIP is that management of domestic cats has changed [20] . With the introduction of litter boxes, more cats are kept permanently indoors, exposing them to large doses of FCoV in the feces that would previously have been buried outdoors. More and more cats are spending part of their life in crowded environments, such as at cat breeders or shelters, which increases their stress and exposure to FCoV while in such an environment [26] .
Coronaviruses can cause harmless and mostly clinically inapparent enteral infections in cats, but they can also cause FIP. In earlier days, it was the common hypothesis that two different coronaviruses existed in cats, the “feline enteric coronavirus” (FECV) and the FIPV. Since then, it has become known that FIPV develops out of FECV spontaneously within the infected cat. Both viruses are identical with regard to their antigenetic properties and, with the exception of a single mutation, their genetic properties, but they are different with regard to their pathogenicity. This is why only the term feline coronavirus FCoV should be used to describe all coronaviruses in cats.
FCoV is an RNA virus and belongs to the genus Coronavirus of the family Coronaviridae. Coronaviruses are pleomorphic enveloped particles that average 100 nm in diameter (range: 60–120 nm) and contain single-stranded RNA. Characteristic petal-shaped projections called peplomers (range: 12–24 nm) protrude from the viral surface [29] . These peplomers are responsible for the crown-like (“corona”) appearance of the virus when visualized under the electron microscope, which led to the term coronavirus . The peplomer proteins are used for virus attachment to cellular surface proteins, which act as receptors for the virus. They are shaped so that they can bind specifically to topical enterocytes. Replication of nonmutated FCoV is thus primarily restricted to enterocytes. The mutated FIP-causing FCoV has a broader cell spectrum, including macrophages.
FCoV belongs to the same taxonomic cluster of coronaviruses as transmissible gastroenteritis virus (TGEV), porcine respiratory coronavirus, canine coronavirus (CCV) [16] , [30] , [31] , [32] , and some human coronaviruses [33] . In many species of animals, coronaviruses have a relatively restricted organ tropism, mainly infecting respiratory or gastrointestinal cells [34] . In cats and mice, however, coronavirus infections can, under certain circumstances, involve several organs. Coronaviruses have a relatively low species specificity. CCV that can cause diarrhea in dogs is closely related to FCoV and can also infect cats. After contact with CCV-containing dog feces, cats develop antibodies that cross-react with FCoV. One CCV strain induced diarrhea in laboratory cats after experimental infection. In a cat infected with another CCV strain, histologic changes identical to changes typically seen in enteral FCoV infection were detected. In one study, CCV even caused FIP [35] .
Depending on their antigenetic relation to CCV, FCoV strains can be classified into the subtypes serotype I and serotype II. Antibodies against CCV neutralize FCoV serotype II but not FCoV serotype I. FCoV serotype II strains are genetically more closely related to CCV than are FCoV serotype I strains, and FCoV serotype II strains seem to have arisen by recombination between FCoV serotype I strains and CCV [19] , [21] , [32] . Aside from the different degree of neutralization by antisera to CCV, serotypes I and II are different in their growth characteristics in cell culture and in their cytopathogenicity in vitro. FCoV serotype I strains are difficult to grow in cell culture and cause a slowly developing cytopathogenic effect. FCoV serotype II strains, however, grow more rapidly and produce a pronounced cytopathogenic effect [36] . Serotype I is the more prevalent serotype in field infections; between 70% and 95% of isolated FCoV strains in the field in the United States and Europe belong to serotype I. In Japan, however, serotype II predominates [19] , [37] . Most cats with FIP are infected with FCoV serotype I. Both serotypes can cause FIP, however, and both can cause clinically inapparent FCoV infections [38] .
Epidemiology
FCoV and FIP are major problems in multiple-cat households and, to a much lesser extent, in free-roaming cats.
Prevalence
FCoV is distributed worldwide in household and wild cats [27] , [28] . The virus is endemic especially in environments in which many cats are kept together in a small space (eg, catteries, shelters, pet stores). There is virtually no multiple-cat household without endemic FCoV. At least 50% of cats in the United States and Europe have antibodies against coronaviruses. In Switzerland, 80% of breeding cats and 50% of free-roaming cats tested positive for antibodies. In Great Britain, 82% of show cats, 53% of cats in breeding institutions, and 15% of cats in single-cat households had antibodies [8] , [27] . FCoV is relatively rare in free-roaming ownerless cats because stray cats are usually loners without close contact with each other. Most importantly, they do not use the same locations for dumping their feces, which is the major route of transmission in multiple-cat households. In a study in Gainesville, Florida, 250 adult feral cats in a trap-neuter-return program were tested for antibodies to coronavirus; 88% of the sera were negative, confirming that most of these cats were not infected [39] . In another study, feral cats were tested at the time they were brought into local shelters (in which multiple cats were kept together) and at 1-to 2-week intervals thereafter. At the time of entering, only a small number of cats had antibodies (approximately 15%); the percentage, however, increased rapidly until virtually all cats in the shelters were infected with FCoV [40] .
Although the prevalence of FCoV infection is high, only approximately 5% of cats in multiple-cat household situations develop FIP; the number is even lower in a single-cat environment [5] , [9] , [10] . The risk of developing FIP is higher for young and immune-compromised cats, because the replication of FCoV in these animals is less controlled, and the critical mutation is thus more likely to occur. More than half of the cats with FIP are younger than 12 months of age [41] .
FCoV is also an important pathogen in nondomestic felids [42] . Kennedy et al [43] found evidence of FCoV infection in 195 of 342 investigated nondomestic felids in southern Africa, which included animals from wild populations and animals in captivity. There is also a high incidence of FIP in wild felids in captivity in the United States and Europe (eg, in zoos). Cheetahs are highly susceptible to development of FIP, and a genetic deficiency in their cellular immunity is thought to predispose them to the disease [44] .
Transmission
Infection usually takes place oronasally.
Infection
Cats are usually infected with nonpathogenic FCoV through FCoV-containing feces shed by a cat with a harmless FCoV enteric infection or by a cat with FIP. Mutated FIP-causing FCoV has not been found in secretions or excretions of cats with FIP. Thus, transmission of the mutated FIP-causing FCoV is considered unlikely under natural circumstances. FIP-causing FCoV can, however, be transmitted iatrogenically or under experimental conditions if, for example, effusion from a cat with FIP containing infected macrophages is injected into a naive cat [45] .
FCoV is a relatively fragile virus (inactivated at room temperature within 24 to 48 hours), but in dry conditions (eg, in carpet), it has been shown to survive for up to 7 weeks outside the cat [46] . Indirect fomite transmission is thus possible, and the virus can be transmitted through clothes, toys, and grooming tools. In organ homogenates, it is even resistant to repeated freezing at −70°C for many months. The virus is destroyed by most household disinfectants and detergents, however.
The most common mode of infection is through virus-containing feces. Thus, the major source of FCoV for uninfected cats is litter boxes shared with infected cats [47] . If multiple cats are using the same litter box, they readily infect each other. Continuous reinfection through the contaminated litter box of a cat already infected also seems to play an important role in the endemic survival of the virus. Rarely, virus can be transmitted through saliva, by mutual grooming, by sharing the same food bowl, or through close contact. Sneezed droplet transmission is also possible. Whether or not FCoV transmission occurs to a significant degree at cat shows is still a point of discussion. In one survey, attending cat shows seemed to be a factor of minor significance affecting the incidence of FIP [48] , but in another survey, more than 80% of cats at shows in the United Kingdom were found to have antibodies [8] . Transmission by lice or fleas is considered unlikely [33] . Transplacental transmission can occur, because FIP was found in a 4-day-old kitten and in stillborn and weak newborn kittens born to a queen that had FIP during the later stages of pregnancy [26] . This mode of transmission is uncommon under natural circumstances, however. Most kittens that are removed from contact with adult virus-shedding cats at 5 to 6 weeks of age do not become infected [7] . Most commonly, kittens are infected at the age of 6 to 8 weeks, at a time when their maternal antibodies wane, mostly through contact with feces from their mothers or other FCoV-excreting cats.
Virus shedding
FCoV is shed mainly in the feces. In early infection, it may be found in saliva when the virus replicates in tonsils and, possibly, in respiratory secretions and urine [49] , [50] . It is likely that when naive cats in a multiple-cat household first encounter FCoV all become infected (and develop antibodies) and most probably shed virus for a period of weeks or months. With extremely sensitive reverse transcriptase (RT)–polymerase chain reaction (PCR) techniques, it has been shown that many naturally infected healthy carrier cats shed FCoV for at least up to 10 months [50] . Most cats shed virus intermittently, but some become chronic FCoV shedders for years to lifelong, providing a continuous source for reinfection of other cats [51] . Cats that are antibody-negative are unlikely to shed [51] , [52] , whereas approximately one third of FCoV antibody–positive cats shed virus [10] . It has been shown that cats with high antibody titers are more likely to shed FCoV and to shed more consistently and higher amounts of the virus [51] . Thus, the height of the titer is directly correlated with virus replication and the amount of virus in the intestines. Most cats with FIP also shed (nonmutated) FCoV [53] ; however, the virus load in feces seems to decrease after a cat has developed FIP [51] .
Pathogenesis
Nonmutated FCoV replicates in enterocytes, causing asymptomatic infection or diarrhea, whereas mutated FCoV replicates in macrophages, leading to FIP. It was once believed that avirulent FCoV remained confined to the digestive tract, could not cross the gut mucosa, and was not spread beyond the intestinal epithelium and regional lymph nodes [12] , whereas FIP-causing FCoV disseminated to other organs, most likely via bloodborne monocytes [54] , [55] , [56] . FCoV can be detected in the blood using RT-PCR, however, not only in cats with FIP but in healthy cats from households with endemic FCoV that never develop FIP [50] , [57] , [58] , [59] , indicating that nonmutated FCoV may also cause viremia. It is likely that this viremia in cats that do not develop FIP may be only short term and low grade.
Pathogenesis of enteric feline coronavirus infection
After a cat becomes infected with FCoV by ingestion (or, rarely, by inhalation), the main site of viral replication is the intestinal epithelium. The specific receptor for FCoV (at least FCoV serotype I) is an enzyme, aminopeptidase-N, found in the intestinal brush border [60] , [61] , [62] . Replication of FCoV in the cytoplasm can cause destruction of intestinal epithelium cells. Cats may sometimes develop diarrhea, depending on the degree of virus replication. In many cats, infection persists over a long period without causing any clinical signs. These cats shed FCoV intermittently or continuously and act as a source of infection for other cats.
Pathogenesis of feline infectious peritonitis
FIP itself is not an infectious but a sporadic disease caused by a virus variant that has developed within a specific cat.
Occurrence of the mutation
FIP develops when there is a spontaneous mutation in a certain region of the FCoV genome (the genes 3C and 7B are being discussed as most important) [19] . Whenever FCoV infection exists, so does the potential for the development of FIP [11] , [63] . The critical mutation always occurs in those same genes, but the exact location varies. Comparison of the genome of the mutated virus with the parent virus revealed 99.5% homology [21] , [64] , [65] . The mutation leads to changes in the surface structures of the virus that allow the virus phagocytized by macrophages to bind to the ribosomes in these macrophages. Thus, this mutated virus, in contrast to its harmless relative, is all of a sudden able to replicate within macrophages; this is considered the key event in the pathogenesis of FIP.
Decreased suppression of the virus in the intestines by the immune system may allow for increased virus replication; this, in turn, predisposes the cat to FIP development through increased virus load, because increased virus replication makes the occurrence of a “virulent mutation” more likely [20] , [66] . Any factors that increase FCoV replication in the intestines increase the probability of the mutation to occur. These factors include physical characteristics (eg, young age and breed predisposition); immune status of the cat, which may be compromised by infections (eg, feline immunodeficiency virus [FIV] or FeLV infection); stress; glucocorticoid treatment; surgery as well as dosage and virulence of the virus; and the reinfection rate in multiple-cat households [66] . It is likely that kittens developing FIP do so because they are subjected to a large virus dose at a time of life when their still undeveloped immune systems are also coping with other infections and the stresses of vaccination, relocation, and neutering [11] , [66] . The question as to why one cat develops FIP and many others do not is a subject of intensive research. A recent study failed to detect a correlation between genetic differences in the feline leukocyte antigen complex (class II polymorphisms) and susceptibility to FIP [67] .
Development of the disease
FIP is an immune complex disease involving virus or viral antigen, antiviral antibodies, and complement. It is not the virus itself that causes major damage but the cat's own immune reaction that leads to the fatal consequences. Within approximately 14 days after the mutation has occurred, mutated viruses that have been distributed by macrophages in the whole body, are found in the cecum, colon, intestinal lymph nodes, spleen, liver, and central nervous system (CNS). There are two possible explanations for the events occurring after 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 [20] ; as a consequence, typical granulomatous changes develop. The alternative explanation is that FIP occurs as a result of circulating immune complexes exiting from the circulation into blood vessel walls, fixing complement [68] 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 cats depend on their size, antibody concentration, and antigen content. Immune complex deposition most likely occurs at sites of high blood pressure and turbulence, and such conditions occur at blood vessel bifurcations. FIP lesions are common in the peritoneum, kidney, and uvea, all of which are sites of high blood pressure and turbulence [26] .
Not only virus but chemotactic substances, including complement and inflammatory mediators, are released from infected and dying macrophages. Complement fixation leads to the release of vasoactive amines, which causes 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 [36] . Inflammatory mediators activate proteolytic enzymes that cause tissue damage. The immune-mediated vasculitis leads to activation of the coagulatory system and to disseminated intravascular coagulation (DIC).
An imbalance in certain cytokines (eg, increase in tumor necrosis factor-α [TNFα], decrease in interferon-γ) can be found early in experimentally induced FIP [69] , [70] , [71] . Acute-phase proteins are altered in cats with FIP [72] . It has been suggested that increase of the acute-phase protein α 1 -acid glycoprotein and changes in its glycosylation play a role in the pathogenesis of FIP [73] . The tissue distribution of the α 1 -acid glycoprotein–related protein is, however, not dependent on the presence of FCoV, suggesting that this protein is not directly involved in the pathogenesis of FIP [74] .
Antibody-dependent enhancement
In many infectious diseases, preexisting antibodies protect against subsequent challenge. In experimentally induced FIP, however, an enhanced form of disease may occur in cats that already have preexisting antibodies [75] , [76] , [77] , [78] , [79] . The proposed mechanism of this so-called “antibody-dependent enhancement” (ADE) is that antibodies facilitate the uptake of FCoV into macrophages [18] , [80] , [81] , [82] , [83] . Because of ADE, a higher proportion of antibody-positive cats died compared with antibody-negative controls, and the antibody-positive cats developed disease earlier (12 days compared with 28 days or more for controls) [78] . These findings have complicated the search for an effective and safe vaccine, because ADE occurred after vaccination in many vaccine experiments. ADE does not seem to play a major role in the field, however. Antibody-positive pet cats that were naturally reinfected by FCoV showed no evidence of ADE [26] .
Clinical findings
The clinical signs totally depend on whether the “virulent mutation” occurs or not.
Feline coronavirus infection
After initial FCoV infection, there may be a short episode of upper respiratory tract signs, although these signs are usually not severe enough to warrant veterinary attention [26] . FCoV infection can cause a transient and clinically mild diarrhea or vomiting [20] as a result of replication of FCoV in enterocytes. Kittens infected with FCoV generally more commonly develop diarrhea, sometimes have a history of stunted growth, and occasionally have upper respiratory tract signs [7] . Rarely, the virus can be responsible for severe acute or chronic vomiting or diarrhea with weight loss, which may be unresponsive to treatment and continue for months. Most FCoV-infected cats, however, are asymptomatic.
Feline infectious peritonitis
Clinical signs of FIP can be variable, because many organs, including the liver, kidneys, pancreas, and eyes, as well as the CNS can be involved. The clinical signs and pathologic findings that occur in FIP are a direct consequence of the vasculitis and organ failure resulting 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.
In the case of natural infection, the exact duration of time between mutation and development of clinical signs is unknown and almost certainly depends on the immune system of the individual cat. Most likely, the disease becomes apparent a few weeks to 2 years after the mutation has occurred. The time between infection with “harmless” FCoV and the development of FIP is even more unpredictable and depends on the event of spontaneous mutation. It has been shown that cats are at greatest risk of developing FIP in the first 6 to 18 months after infection with FCoV and that the risk falls to approximately 4% at 36 months after infection [11] .
Three different forms of FIP have been identified: (1) an effusive, exudative, wet form; (2) a noneffusive, nonexudative, dry, granulomatous, parenchymatous form; and (3) a mixed form. The first form is characterized by a fibrinous peritonitis, pleuritis, or pericarditis with effusions in the abdomen, thorax, and/or pericardium, respectively. The second form without obvious effusions is characterized by granulomatous changes in different organs, including the eyes, as well as the CNS. In the meantime, it has been shown that differentiation between these forms is not useful (and is only of value for the diagnostic approach), because there is always effusion to a greater or lesser degree in combination with more or less granulomatous organ changes present in each cat with FIP. In addition, the forms can transform into each other. FIP can thus simply be more or less exudative or productive in a certain cat at a given time point.
Effusions
Many cats with FIP develop effusions. Cats with effusions have ascites ( Fig. 1 ), thoracic effusions, and/or pericardial effusion. In a survey of 390 cats with FIP with effusions, 62% had ascites, 17% had thoracic effusions, and 21% had effusions in both body cavities [41] . Nevertheless, it is important to consider that of all cats with effusions, less than 50% actually have FIP. In a study including 197 cats with effusions caused by various reasons, approximately 30% of cats with thoracic effusions and 30% of cats with both abdominal and thoracic effusions had FIP. Of the cats with ascites, approximately 60% had FIP [84] . Fig. 1 Cat with ascites caused by FIP.
In cats with ascites, an abdominal swelling is commonly noticed by the owner and sometimes may be confused with pregnancy. Fluctuation and a fluid wave may be present; in less severe cases, fluid can be palpated between the intestinal loops. Abdominal masses may sometimes be palpated, reflecting omental and visceral adhesion or enlarged mesenteric lymph nodes. Thoracic effusions usually manifest in dyspnea and tachypnea, and sometimes in open-mouth breathing and cyanotic mucous membranes. Auscultation reveals muffled heart sounds [84] . Pericardial effusions may be present in addition to or without other effusions. In these cats, heart sounds are muffled and typical changes can be seen on EKG and echocardiography. In one survey, FIP accounted for 14% of cats with pericardial effusion, second to congestive heart failure (28%) [85] .
Some cats with effusions may be bright and alert, whereas others are depressed. Some of these cats eat with a normal or even increased appetite, whereas others are anorectic. Some cats have a fever, and some show weight loss. Signs of organ failure can be present in addition to the effusion (eg, icterus). Effusions can be visualized by diagnostic imaging (eg, radiographs, ultrasound). Their presence is verified by tapping the fluid.
Changes in abdominal and thoracic organs
In cats without effusion, signs are often vague and include fever, weight loss, lethargy, and decreased appetite. Cats may be icteric. If the lungs are involved, cats may be dyspneic and thoracic radiographs may reveal patchy densities in the lungs [86] . Abdominal palpation may reveal enlarged mesenteric lymph nodes and irregular kidneys or nodular irregularities in other viscera. Presenting clinical signs can be unusual. In some cats, abdominal tumors are suspected, but FIP is finally diagnosed at necropsy [87] . Other cats are presented with only gastrointestinal obstruction [88] . In one case report, a cat suffered from necrotizing orchitis because of FIP but had no other signs [89] . Although believed to be so in the 1970s, reproductive disorders, neonatal deaths, and fading of kittens are not usually associated with FIP [26] .
Sometimes, the main or only organ affected by granulomatous changes is the intestine. Lesions are commonly found only in the ileocecocolic junction but may also 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 but sometimes vomiting. Obstipation can also occur [26] , [90] , [91] . Palpation of the abdomen often reveals a thickened intestinal area. Hematology sometimes shows increased numbers of Heinz bodies, which is a result of decreased absorption of vitamin B 12 .
Ocular changes
Cats with FIP frequently have ocular lesions. The most common but not obvious ocular lesions are retinal changes. Therefore, a retinal examination should be performed in all cats in which FIP is suspected. 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 [26] . Retinal hemorrhage or detachment may also occur. The changes, however, are not pathognomonic. Similar changes can be seen in other systemic infectious diseases, including toxoplasmosis, systemic fungus infections and FIV and FeLV infection.
Another common manifestation is uveitis ( Fig. 2 ) [92] . Uveitis is an inflammation of the uveal coat of the eye, which consists of the iris, ciliary body, and choroidal vessels. The uveal coat can be seeded by immunologically competent cells that migrate into the eye. The eye can thus undergo all types of immunologically mediated inflammation [93] . Mild uveitis can manifest as color change of the iris. Usually, part of or all the iris becomes brown, although blue eyes occasionally appear to be green. Uveitis may also manifest as aqueous flare, with cloudiness of the anterior chamber, which can sometimes be detected only in a darkened room using focal illumination. Large numbers of inflammatory cells in the anterior chamber settle out on the back of the cornea and cause keratic precipitates, which may be hidden by the nictitating membrane. In some cats, there is hemorrhage into the anterior chamber. If aqueous humor is tapped, it may reveal elevated protein and pleocytosis [26] . Fig. 2 Cat with uveitis caused by FIP.
Neurologic signs
FIP is a common reason for neurologic disorders in cats. In a retrospective study of 286 cats with neurologic signs, more than half of the cats (47) in the largest disease category (inflammatory diseases) had FIP [94] . Of all cats with FIP, approximately 13% have neurologic signs [95] . These are variable and reflect the area of CNS involvement. Usually, the lesions are multifocal [96] . The most common clinical sign is ataxia, followed by nystagmus and seizures [97] . In addition, incoordination, intention tremors, hyperesthesia, behavioral changes, and cranial nerve defects can be seen [98] , [99] . If cranial nerves are involved, neurologic signs like visual deficits and loss of menace reflex may be present, depending on which cranial nerve is damaged. When the FIP lesion is located on a peripheral nerve or the spinal column, lameness, progressive ataxia, tetraparesis, hemiparesis, or paraparesis may be observed [26] . In a study of 24 cats with FIP with neurologic involvement, 75% were found to have hydrocephalus on postmortem examination. Finding hydrocephalus on a CT scan is suggestive of neurologic FIP, because other diseases, such as cryptococcosis, toxoplasmosis, and lymphoma, have not been reported to cause these findings [97] .
Diagnosis
Diagnosing enteral FCoV can be performed by RT-PCR in feces [51] , [100] or by electron microscopy of fecal samples. Intestinal biopsies are of limited value, because the histopathologic features of villus tip ulceration, stunting, and fusion are nonspecific [26] . FCoV infection as the cause of diarrhea can only be confirmed if immunohistochemical or immunofluorescent staining of intestinal biopsies is positive.
Definitively diagnosing FIP antemortem can be extremely challenging in many clinical cases. FIP is often misdiagnosed [29] . Many times, its general clinical signs (eg, chronic fever, weight loss, anorexia, malaise) are nonspecific. A fast and reliable diagnosis would be critical for prognostic reasons and to avoid suffering of the patient. Difficulties in definitively diagnosing FIP, however, arise from unspecific clinical signs; lack of pathognomonic, hematologic, and biochemical abnormalities; and low sensitivity and specificity of tests routinely used in practice. The diagnostic value of frequently used parameters is only known in experimental settings, and some tests have not been widely used in clinical patients. A weighted score system for FIP diagnosis that takes several parameters into account, including background of the cat, history, presence of clinical signs, laboratory changes, and height of antibody titers, has been suggested [95] . This, however, only leads to a certain score or percentage of likelihood of FIP, and thus does not help to confirm the diagnosis definitively. There are, however, certain tests available in the meantime (eg, staining of antigen in macrophages in effusion or tissue) that, at least in the case of a positive result, confirm the diagnosis of FIP 100% [101] .
Laboratory changes
There are a number of laboratory changes that are common in cats with FIP; they are not pathognomonic, however, and FIP cannot be diagnosed based on these findings.
Complete blood cell counts and coagulation parameters
Blood cell counts are often changed in cats with FIP [102] , [103] ; however, changes are not pathognomonic. White blood cells can be decreased or increased. Although it is often stated that lymphopenia and neutrophilia are typical for FIP, this change can be interpreted as a typical “stress leukogram” that occurs in many severe systemic diseases in cats [101] . In up to 65% of cats with FIP, anemia is present, usually with only a mild decrease in hematocrit. The anemia can be regenerative; in these cases, it is caused mainly by a secondary autoimmune hemolytic anemia (AIHA) in which autoantibodies to erythrocytes can be found and Coomb's test results are positive. In cats with severe intestinal changes, Heinz bodies can be found in large numbers in erythrocytes [26] , and this can also lead to hemolysis. Alternatively, anemia can be nonregenerative and is then mainly caused by anemia associated with chronic inflammation [41] . Approximately 50% of cats with FIP have nonspecific reactive changes of the bone marrow at necropsy [104] . Thrombocytopenia can commonly be found in cats with FIP as a result of DIC. In experimental infection, thrombocytopenia was detected as early as 4 days after infection [105] . Other parameters indicating DIC, including fibrinogen degradation products (FDPs) and D-dimers, are also commonly increased.
Serum chemistry
The most consistent laboratory finding in cats with FIP is an increase in total serum protein concentration [41] , [101] , [106] . This is found in approximately 50% of cats with effusion and 70% of cats without effusion [107] . This increase in total protein is caused by increased globulins, mainly γ-globulins, also leading to a decrease in the albumin-to-globulin ratio [101] , [108] , [109] . In experimental infections, an early increase of α 2 -globulins was reported [49] , whereas γ-globulins and antibody titers increase just before the appearance of clinical signs [5] , [49] , [69] , [77] . The characteristically high levels of γ-globulins [110] , [111] and the increased antibody titers [5] , [112] invite the conclusion that hypergammaglobulinemia is caused by a specific anti-FCoV immune response. Antibody titers and hypergammaglobulinemia show a linear correlation, but the wide variation in anti-FCoV titers at a given concentration of γ-globulins indicates that additional (autoimmune) reactions occur during the pathogenesis of FIP [113] , [114] . It has been discussed that stimulation of B cells by interleukin-6, which is produced as part of the disease process, additionally contributes to the increase in γ-globulins [115] . Total protein in cats with FIP can reach high concentrations of up to 12 g/dL (120 g/L) and more. This, however, only reflects the chronic antigenic stimulation that generally can be caused by any chronic infection the cat is not able to clear through its immune response. Even if the serum total protein concentration is 120 g/L or greater, the likelihood of FIP is only 90%. Cats with these high serum protein concentrations that do not have FIP may suffer from severe chronic stomatitis, chronic upper respiratory disease, dirofilariasis, or multiple myeloma [101] .
In a recent study of cats with FIP, comparison of total serum protein concentration, γ-globulins, and the albumin-to-globulin ratio revealed that the albumin-to-globulin ratio has a statistically significantly better diagnostic value than the other two parameters [101] . Thus, not only the increase in globulins but the decrease in albumin concentrations seems to be characteristic of FIP. A decrease in serum albumin occurs through decreased production because of liver failure or through protein loss. Protein loss can be attributed to glomerulopathy caused by immune complex deposition, loss of protein caused by exudative enteropathy in case of granulomatous changes in the intestines, or loss of protein-rich fluid in vasculitis. It can also be explained by decreased production in the liver (without compromised liver function), because not only albumin but globulins contribute (although not as importantly) to the plasma oncotic pressure. Thus, an increase in globulins may cause a negative feedback on albumin production in the liver. An optimum cutoff value (maximum efficiency) of 0.8 was determined for the albumin-to-globulin ratio. If the serum albumin-to-globulin ratio is less than 0.8, the probability that the cat has FIP is high (92% positive predictive value); if the albumin-to-globulin ratio is higher than 0.8, the cat likely does not have FIP (61% negative predictive value) [101] .
Electrophoresis is often performed, and the rational behind it is to quantify γ-globulins and to distinguish a polyclonal from a monoclonal hypergammaglobulinemia so as to differentiate FIP (and other chronic infections) from tumors like multiple myelomas or other plasma cell tumors. Quantification of γ-globulins is not more useful than measurement of total proteins [101] , however. In addition, polyclonal and monoclonal hypergammaglobulinemia can occur in cats with FIP, and the same is true in multiple myeloma. Thus, the value of electrophoresis is limited.
Other laboratory parameters (eg, liver enzymes, bilirubin, urea, creatinine) can be variably increased depending on the degree and localization of organ damage [116] , [117] , but they are not helpful in making an etiologic diagnosis. Hyperbilirubinemia and icterus are often observed and are frequently a reflection of hepatic necrosis, despite the fact that alkaline phosphatase (ALP) and alanine aminotransferase (ALT) activities are often not increased as dramatically as they are with other liver diseases, such as cholangiohepatitis and hepatic lipidosis [26] . Hyperbilirubinemia is caused rarely by hemolysis as a result of secondary AIHA; however, the hemolysis has to be severe to cause icterus. Bilirubin is sometimes increased in cats with FIP without evidence of hemolysis, liver disease, or cholestasis. It has been speculated that the bilirubin metabolism and excretion into the biliary system are compromised in cats with FIP, similar to the findings in sepsis.
Measurement of α l -acid glycoprotein may be helpful in the diagnosis of FIP [118] . This acute-phase protein is increased in several infectious diseases of cats, and thus is not specific for FIP. Nevertheless, α l -acid glycoprotein levels in plasma (or effusion) are usually greater than 1500 μg/mL in cats with FIP, which may help to distinguish FIP from other clinically similar conditions [26] .
Tests on effusion fluid
If there is effusion, the most important diagnostic step is to sample the fluid, because tests of effusion have a much higher diagnostic value than tests performed using blood. Thus, fluid should be collected before blood is taken to avoid a waste of money with expensive blood tests. Only approximately half of the cats with effusions suffer from FIP [84] . Thus, although effusions of a clear yellow color and sticky consistency are often called “typical,” the presence of this type of fluid in body cavities alone is not diagnostic ( Fig. 3 ). The effusion in FIP may be clear, straw-colored, or viscous and may froth on shaking because of the high protein content. The effusion may clot when stored refrigerated [26] . If the sample is bloody, pus filled, or foul smelling or is chylus, FIP is less likely [95] , although effusions in FIP can be different and sometimes red, pink, or almost colorless in appearance. Some cases of cats with FIP with pure chylus effusion have even been reported [119] . Fig. 3 “Typical” effusion in cat with FIP.
The effusion in FIP is usually classified as a modified transudate or exudate typically combining characteristics of both transudates and exudates. The protein content is usually high (>35 g/L), reflecting the composition of the serum, whereas the cellular content is low and approaches that of a pure transudate (<1000 nucleated cells per milliliter). The protein content of effusion is high because of the high concentration of γ-globulins. Other diseases causing similar effusions include lymphoma, heart failure, cholangiohepatitis, and bacterial peritonitis or pleuritis. Measurement of enzyme activity in effusion also is an indication that FIP might be the underlying disease. Lactate dehydrogenase (LDH) is typically high (>300 IU/L) in effusions caused by FIP because it is released from inflammatory cells. Activity of α-amylase also is often high, likely as a result of common pancreatic involvement. The enzyme adenosine deaminase (AD) has been used to distinguish different causes of effusions, and its activity was significantly high in cats with FIP [120] .
Cytologic evaluation of effusion in cats with FIP typically shows a pyogranulomatous character, predominantly with macrophages and neutrophils ( Fig. 4 ). Cytologic findings may appear similar in cats with bacterial serositis or, sometimes, with lymphoma; these effusions often can be differentiated, however, by the presence of malignant cells or bacteria, respectively. Bacterial cultures should be performed in unclear cases. Fig. 4 Typical cytology of the effusion in a cat with FIP.
A simple test, the so-called “Rivalta's test,” ( Fig. 5 ) has been used to differentiate transudates from exudates. This test was originally developed by an Italian researcher named Rivalta around 1900 and was used to differentiate transudates and exudates in human patients [121] . Other methods have replaced this test in human medicine because of its limited diagnostic value in people. It has not been shown to be diagnostically helpful in dogs with effusion [122] . Nevertheless, this test seems to be useful in cats to differentiate between effusions caused by FIP and effusions caused by other diseases [101] . It is not only the high protein content but the high concentrations of fibrin and inflammatory mediators that induce a positive reaction. To perform this test, three quarters of a reagent tube is filled with distilled water, to which one drop of acetic acid (98%) is added and is mixed thoroughly. On the surface of this solution, one drop of the effusion fluid is carefully layered. If the drop disappears and the solution remains clear, the Rivalta's test result 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-like or jellyfish-like), the Rivalta's test result is defined as positive. In a recent study, the Rivalta's test had a positive predictive value of 86% and a negative predictive value of 97% [101] . There are some false-positive results in cats with bacterial peritonitis. Those effusions, however, are usually easy to differentiate (through macroscopic examination, cytology, and bacterial culture). Some cats with lymphoma also have a positive Rivalta's test result, but many of these cases can be differentiated cytologically [101] . Overall, the Rivalta's test is an easy and inexpensive method that does not require special laboratory equipment and can be easily performed in private practice. It provides good predictive values, and thus is a helpful diagnostic test. Fig. 5 Positive Rivalta's test in a cat with FIP.
Tests on cerebrospinal fluid
Analysis of cerebrospinal fluid (CSF) from cats with neurologic signs caused by FIP lesions may reveal elevated protein (50–350 mg/dL, with a normal value of less than 25 mg/dL) and pleocytosis (100–10,000 nucleated cells per milliliter) containing mainly neutrophils, lymphocytes, and macrophages [97] , [123] , [124] , which is a relatively nonspecific finding, however. Many cats with FIP and neurologic signs have normal CSF taps.
Measurement of antibodies
Antibody titers measured in serum are an extensively used diagnostic tool [6] , [125] . In view of the facts that a large percentage of the healthy cat population is FCoV antibody–positive, that high and rising titers are frequently found in asymptomatic cats, and that most of those cats never develop FIP [126] , antibody titers must be interpreted extremely cautiously [7] , [10] , [127] , [128] . From the time when the first “FIP test” was described more than two decades ago [9] to the present, the inadequacies and pitfalls of the test have been the topic of continuous discussion and controversy. Meanwhile, the so-called “FIP test” is referred to as the “feline coronavirus antibody test,” emphasizing that the latter more correctly describes the antibodies that are detected and react with a large group of closely related coronaviruses. At times, clinicians have mistakenly taken a positive titer to equate with a diagnosis of FIP, and it has been assumed that more cats have died of FCoV antibody tests than of FIP [77] . FCoV tests are often performed for inappropriate reasons. There are five major indications to test for FCoV antibodies: (1) for the diagnosis of FCoV-induced enteritis or to narrow the diagnosis of FIP, (2) for a healthy cat that has had contact with a suspected or known excretor of FCoV, (3) for a cat-breeding facility with the aim of obtaining an FCoV-free environment, (4) to screen a cattery for the presence of FCoV, and (5) to screen a cat for introduction into a FCoV-free cattery [26] .
Antibodies in blood
Although frequently criticized, antibody testing has a certain role in the diagnosis and, more importantly, in the management of FCoV infection when it is performed by appropriate methodologies and results are properly interpreted. Antibody testing can only be useful if the laboratory is reliable and consistent. Methodologies and antibody titer results may vary significantly. A single serum sample divided and sent to five different laboratories in the United States yielded five different results [26] . The antigen used in a test, for example, can play an important role in test sensitivity and specificity (eg, if the antigen used for the test is derived from nonfeline viruses, which is practiced by many commercial laboratories). Thus, it is essential that antibody results that are interpreted and compared by the clinician are always obtained with the same method performed by the same laboratory, and it is essential to use antibody tests validated by the scientific community. Evaluating titers of antibodies gives an idea of the amount of antibodies present. In contrast, tests (eg, in-house tests) that only indicate the presence of antibodies without quantification are not useful. They also produce a high number of false-positive and false-negative results [129] . The choice of the laboratory to be used is critical, and only those that perform quantitative titer evaluations should be used. The laboratory should have established two levels: one is its least significant level of reactivity (or lowest positive titer), and the other is its highest antibody titer value. In searching for a reliable laboratory, repeat samples from the same animal should be sent without warning to the same laboratory and to an FCoV-referenced laboratory for comparison to enable useful interpretation. Serum or plasma samples store well at −20°C without loss of antibody concentration [26] .
The presence of antibodies does not indicate FIP, and the absence of antibodies does not exclude FIP. Many authors agree that low or medium titers do not have any diagnostic value [101] , [130] , [131] . Approximately 10% of the cats with clinically manifest FIP have negative results. It has been shown that in cats with fulminant FIP, titers decrease terminally [77] . Cats with effusions sometimes have low titers or even no antibodies. This is because large amounts of virus in the cat's body bind to antibodies and render them unavailable to bind antigen in the antibody test or because the antibodies are lost in effusion when protein is translocated in vasculitis. Extremely high titers are of a certain diagnostic value. If the highest measurable titer is present in a cat (thus, it is important to know what the highest titer in a specific laboratory is), it increases the likelihood of FIP. In a recent study, the probability of FIP was 94% in cats with the highest titer when investigating a cat population in which FIP was suspected [101] . The diagnostic value of a high titer is also dependent on the background of the cat. The highest titer in a cat coming out of a multiple-cat household situation is not extremely predictive, because in those households, FCoV is endemic and many cats have high titers, whereas the highest titer in a cat from a single-cat environment is unusual and a stronger indicator of FIP.
Although antibody testing in sick cats that are suspected to have FIP is of limited value, there are a number of other situations in which antibody testing is a useful tool. A healthy cat that has no antibodies is considered likely to be free of FCoV, and thus is not infectious to others, does not shed FCoV, and does not develop FIP [10] . It has been shown that the height of the antibody titer directly correlates with the amount of virus that is shed with feces; cats with high antibody titers are more likely to shed FCoV and to shed more consistently with higher amounts of the virus [51] . Thus, height of the titer is directly correlated with the virus replication rate and the amount of virus in the intestines. Antibody measurement is important for the common situation in practice in which a cat is presented because it has been in contact with a cat with FIP or a suspected or known virus excretor. The owner wants to know the prognosis for an exposed cat or wishes to obtain another cat and needs to know whether the exposed cat is shedding FCoV. Also, cat breeders may request testing, with the goal of creating an FCoV-free cattery. Screening a cattery for the presence of FCoV and screening a cat before introduction into an FCoV-free cattery are also important indications.
Antibodies in effusion
Some studies have evaluated the diagnostic value of antibody detection in fluids other than serum, such as in effusions [132] . The presence of antibodies in effusion is correlated with the presence of antibodies in blood [133] . In a study by Kennedy et al [132] , antibody titers in effusions were not helpful, because all cats in their study had medium antibody titers irrespective of whether they had FIP or not. In a study by Hartmann et al [101] , however, the presence of anti-FCoV antibodies in effusion had a high positive predictive value (90%) and a high negative predictive value (79%), although height of titers was not correlated with the presence of FIP. The measurement of antibodies in effusions is at least more useful than the measurement of antibodies in blood.
Antibodies in cerebrospinal fluid
Foley et al [134] determined the diagnostic value of antibody detection in CSF and found a good correlation to the presence of FIP when compared with histopathologic findings, whereas in a study by Boettcher et al [135] , there was no significant difference in antibody titers in CSF from cats with neurologic signs caused by FIP compared with cats with other neurologic diseases confirmed by histopathologic findings.
Polymerase chain reaction
Compared with serology, RT-PCR provides the obvious advantage of directly detecting the ongoing infection rather than documenting a previous immune system encounter with a coronavirus.
Polymerase chain reaction in blood
RT-PCR can be performed to reverse-transcribe coronavirus RNA to cDNA and then to make large quantities of DNA visually detectable. Although FIP-causing viruses are genetic mutants of harmless enteric FCoV, numerous sites exist in the 3C and 7B genes that can be mutated or deleted and confer on the virus the capability to infect and replicate within macrophages. Sometimes, the change can be a single RNA base. As a result, PCR primers to discriminate between FIP-causing viruses and harmless enteric FCoV cannot be designed, and it is not possible to distinguish between a mutated and nonmutated virus by PCR [136] . There are a number of reasons why RT-PCR results are not always easy to interpret. There are several plausible explanations for false-negative PCR results. The assay requires reverse transcription of viral RNA to DNA before amplification of DNA, and degradation of RNA could be a potential problem, because RNases are virtually ubiquitous. There may be sufficient strain and nucleotide sequence variation such that the target sequence chosen for the assay may not detect all strains of FIPV [19] . There are also a number of explanations for false-positive results. First, the assay does not distinguish between “virulent” and “avirulent” FCoV strains, nor does it differentiate FCoV from CCV or TGEV. Although the role of these viruses in the field is unknown, cats can be experimentally infected with CCV and TGEV [35] , [137] , [138] ; these infections could result in a positive PCR result. Second, recent studies support the hypothesis that viremia occurs not only in cats with FIP but in healthy carriers. FCoV RNA could be detected in the blood of cats with FIP as well as in the blood of healthy cats that did not develop FIP for a period of up to 70 months [50] , [57] , [58] , [136] , [139] . In a study by Gunn-Moore et al [59] , it was shown that in households in which FCoV is endemic, up to 80% of the cats can be viremic, irrespective of their health status, and that the presence of viremia does not seem to predispose the cats to the development of FIP. Therefore, the results of PCR tests must be interpreted in conjunction with other clinical findings and cannot be used as the sole criterion for diagnosing FIP.
Polymerase chain reaction in effusion
RT-PCR in effusion has been discussed as an interesting diagnostic tool. Data on the usefulness of this approach are limited, however. So far, only one study including information about RT-PCR on ascites fluid of a limited number of cats has been reported. In this study, six of six cats with confirmed FIP had positive RT-PCR results, and one of one cat with ascites caused by another disease had a negative RT-PCR result [101] . These numbers are, however, not sufficient to judge that approach sufficiently.
Polymerase chain reaction in cerebrospinal fluid
CSF has not been recommended for RT-PCR because it may contain low numbers of virus also in cats that do not have FIP if the blood-brain barrier is compromised. Accurate studies are needed, however.
Polymerase chain reaction in feces
RT-PCR has been used to detect FCoV in fecal samples and is sensitive and useful for documenting that a cat is shedding FCoV in feces [100] . Because cats vary in how much FCoV is shed in feces, repeated PCR should be performed daily over 4 to 5 days to detect accurately whether a given cat is shedding FCoV. Samples for RT-PCR must be carefully handled, kept frozen, and protected from RNA-degrading enzymes (which are ubiquitous in most environments). PCR should be performed as quickly as possible after collection, even if samples are frozen; delays in testing may result in false-negative results. Positive RT-PCR results in fecal samples document FCoV infection. The strength of the PCR signal in feces correlates with the amount of virus present in the intestines [51] .
Antibody antigen complex detection
Because FIP is an immune-mediated disease and antibody antigen complexes play an important role, it has been suggested to look for circulating complexes in serum and effusions [113] , [140] . Antibody antigen complex detection can be performed using a competitive ELISA. Usefulness, however, is limited; the positive predictive value of the test was not high (67%) in one study, because there were many false-positive results [101] .
Antigen detection
Other methods to detect the virus include searching for the presence of FCoV antigen ( Fig. 6 ). Fig. 6 Immunofluorescent staining of macrophages.
Immunofluorescence staining of feline coronavirus antigen in effusion
In a study by Parodi et al [141] , an immunofluorescence assay detecting intracellular FCoV antigen in cells within effusion was used; however, the number of cats enrolled in that study was limited. Hirschberger et al [84] detected FCoV antigen in 34 of 34 samples from cats with FIP-induced effusions. In a recent study involving a large number of cats, immunofluorescence staining of intracellular FCoV antigen in macrophages of effusion had a positive predictive value of 100%. There were no false-positive results. This means that if this staining test is positive, it predicts 100% that the cat has FIP. Unfortunately, the negative predictive value was not high (57%). Cases that stained negative (although the cats did have FIP) can be explained by the fact that the number of macrophages on the effusion smear is sometimes insufficient. Another explanation is a potential masking of the antigen by competitive binding of FCoV antibodies in effusion that displace binding of fluorescence antibodies [101] .
Antigen in tissue
Immunohistochemistry can also be used to detect the expression of FCoV antigen in tissue [142] . Tammer et al [143] used immunohistochemistry to detect intracellular FCoV antigen in paraffin-embedded tissues of euthanized cats and found FCoV antigen only in macrophages of cats that had FIP and not in control cats. Hök [144] was able to demonstrate FCoV antigen in the membrana nictitans of cats with FIP. It was shown that positive staining of macrophages in effusion predicts FIP 100% [101] ; the same seems to be true for immunohistochemical staining of tissue macrophages. Immunostaining cannot differentiate between the “harmless” nonmutated FCoV and the mutated FIP-causing FCoV. Obviously, only FIP-causing virus is able to replicate in sufficiently large amounts in macrophages, which results in positive staining. Therefore, in addition to histopathology (if pathognomonic lesions are present), detection of intracellular FCoV antigen by immunofluorescence or immunohistochemistry is the only way to diagnose FIP definitively. This tool should be used whenever possible.
Histology
Diagnosis of FIP can be established in many cases with just histopathologic testing of biopsy or necropsy samples. 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 [26] , [145] , [146] . If histologic testing is not diagnostic, staining of antigen in macrophages [146] or detection of nucleic acids in tissue [147] can be used to confirm FIP ( Fig. 7 ). Fig. 7 Algorithm for the diagnosis of FIP.
Therapy
Virtually every cat with confirmed FIP dies. Fast and reliable diagnosis of FIP and differentiating it from harmless enteric FCoV infection are crucial for prognostic reasons.
Treatment of healthy feline coronavirus antibody–positive cats
There is no indication that any treatment of a healthy antibody-positive cat would prevent development of FIP [26] . Treatment with corticosteroids can conceivably prevent clinical signs from occurring (once the mutation has occurred) for a certain period of time, but immune suppression might have the opposite effect and precipitate clinical FIP because it can increase the risk of mutation (if the mutation has not occurred yet). Thus, immune suppression is contraindicated as long as the cat is only infected with harmless FCoV. Because stress is an important factor in the development of FIP [95] , avoidance of unnecessary stress, such as rehoming, elective surgery, or placement in a boarding cattery, may be beneficial. IFNs (eg, feline IFN-ω, which is available commercially in Europe and Japan) have been discussed in this situation, but controlled studies are missing to date.
Treatment of cats with feline coronavirus–induced enteritis
Most cases of diarrhea caused by nonmutated FCoV are self-limiting. Cats with chronic diarrhea that have antibodies against FCoV, in which other possible causes have been eliminated or in which FCoV has been detected in the feces by electron microscopy, can only be treated supportively with fluid and electrolyte replacement and dietary intervention [20] . Treatment with lactulose or living natural yogurt may be beneficial because it regulates the intestinal bacterial flora and increases passage time. No specific antiviral treatment has yet been demonstrated to cure this condition. These cases can be a challenge because they are sometimes difficult to distinguish from cats with FIP, which can manifest solely as granulomatous changes in the intestines leading to diarrhea. FIP diarrhea can only be treated with immune suppression if it is identified, which, conversely, is contraindicated in harmless FCoV infection. In both cases, cats usually have antibodies and sometimes high titers but can only be differentiated by exploratory surgery, which should be avoided in cats with harmless intestinal FCoV infection.
Symptomatic treatment of cats with feline infectious peritonitis
Treatment for FIP is almost invariably doomed to failure, because cats with clinical FIP eventually die. Some cats with milder clinical signs may survive for several months and enjoy some quality of life with treatment, however. Once clinical signs become debilitating and weight and appetite decline, the owner must be prepared for the reality that the cat is dying.
Because FIP is an immune-mediated disease, treatment is aimed at controlling the immune response to FCoV, and the most successful treatments consist of relatively high doses of immunosuppressive and anti-inflammatory drugs. Immunosuppressive drugs, such as prednisone (4 mg/kg administered orally every 24 hours) or cyclophosphamide (2.5 mg/kg administered orally for four consecutive days every week), may slow disease progression but do not produce a cure. Some cats with effusion benefit from tapping and removal of the fluid and injection of dexamethasone (1 mg/kg) into the abdominal or thoracic cavity (every 24 hours until no effusion is produced anymore). Cats with FIP should also be treated with broad-spectrum antibiotics and supportive therapy (eg, subcutaneous fluids) for as long as they are comfortable. A thromboxane synthetase inhibitor (ozagrel hydrochloride), which inhibits platelet aggregation, has been used in a few cats and has led to some improvement of clinical signs [148] .
Some veterinarians prescribe immune modulators (eg, Propionibacterium acnes , acemannan) to treat cats with FIP, with no documented controlled evidence of efficacy. Immune modulators and IFN inducers are widely used and induce synthesis of IFNs and other cytokines. It has been suggested that these agents may benefit infected animals by restoring compromised immune function, thereby allowing the patient to control viral burden and recover from the disease. Nonspecific stimulation of the immune system is contraindicated however in cats with FIP, because clinical signs develop and progress as a result of an immune-mediated response to the mutated FCoV.
Antiviral chemotherapy in cats with feline infectious peritonitis
The search for an effective antiviral treatment for cats with FIP, unfortunately, has not been successful, although several studies have been performed.
Ribavirin
Ribavirin, 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide (RTCA), is a broad-spectrum triazole nucleoside that has marked in vitro antiviral activity against a variety of DNA and RNA viruses, including FCoV. Ribavirin is a nucleoside analogue, but in contrast to the most common antiviral compounds, which act primarily to inhibit polymerases, ribavirin allows DNA and RNA synthesis to occur but prevents the formation of viral proteins, most likely by interfering with capping of viral mRNA. In vivo, therapeutic concentrations are difficult to achieve because of toxicity, and cats are extremely sensitive to the side effects.
Although active against FCoV in vitro [149] , [150] , ribavirin was not effective in the treatment of cats with FIP. In one study, ribavirin was administered (16.5 mg/kg orally, intramuscularly, or intravenously every 24 hours for 10 to 14 days) to specific pathogen-free kittens 18 hours after experimental challenge exposure with an FIP-causing virus. All kittens, including ribavirin-treated and untreated kittens, succumbed to FIP. Clinical signs of disease were even more severe in the ribavirin-treated kittens, and their mean survival times were shortened [151] . The most common side effect in cats reported in several studies (already using a low dose of 11 mg/kg) is hemolysis. This develops as a result of sequestration of the drug in red blood cells. In addition, a dose-related toxic effect on bone marrow occurs, primarily on megakaryocytes (resulting in thrombocytopenia and hemorrhage), and erythroid precursors. Later on or at higher dosages, neutrophil numbers are suppressed. Liver toxicity has also been reported [152] , [153] . Weiss et al [151] tried to decrease the toxicity of ribavirin by incorporating it into lecithin-containing liposomes and giving it intravenously at a lower dose (5 mg/kg) to cats challenged with an FIP-causing virus. They were, however, not able to reach a therapeutic concentration with this regimen.
Human interferon-α
Human IFNα has immunomodulatory and antiviral activity. IFNα is active against many DNA and RNA viruses, including FCoV. IFNα has a direct antiviral effect by inducing a general “antiviral state” of INFα-containing cells that protects against virus replication. It is not virucidal but merely inhibits viral nucleic acid and protein synthesis. It binds to specific cell receptors that activate enzymes, inhibiting synthesis, assembly, and release of viruses. Human IFNα is marketed as a recombinant product (rHuIFNα) produced by a cloned human IFNα gene expressed in Escherichia coli . There are two common treatment regimens for use of human IFNα in cats: subcutaneous injection of high-dose IFNα (10 4 to 10 6 IU/kg every 24 hours) or oral application of low-dose IFNα (1–50 IU/kg every 24 hours). When given parenterally in high doses, application leads to detectable serum levels. When given parenterally to cats, it becomes ineffective after 3 to 7 weeks because of the development of neutralizing antibodies against the human IFNα, which limits its activity. In a study in which cats were treated with human IFNα subcutaneously, cats became refractory to therapy after 3 or 7 weeks, respectively, depending on whether a high (1.6 × 10 6 IU/kg) or a lower (1.6 × 10 4 IU/kg) dose was used [154] .
In vitro, antiviral activity of human IFNα against FIP-causing FCoV strains was demonstrated. Combination of IFNα with ribavirin in vitro resulted in antiviral effects significantly greater than the sum of the observed effects from ribavirin or IFNα alone, indicating synergistic interactions [149] . Human IFNα treatment was used in 74 cats (52 treated cats, 22 controls) with experimentally induced FIP that received IFNα, P acnes , a combination, or placebo. The prophylactic and therapeutic administration of high doses (10 4 or 10 6 IU/kg) of IFNα did not significantly reduce the mortality in treated versus untreated cats; only in cats treated with IFNα and P acnes at a dose of 10 6 IU/kg, the mean survival time was significantly prolonged by a few days [155] .
Orally, human IFNα can be given for a longer period, because no antibodies develop. Given orally, however, IFNα is inactivated by gastric acid and, like other proteins, destroyed by trypsin and other proteolytic enzymes in the duodenum; therefore, it is not absorbed and cannot be detected in the blood after oral administration [156] . Thus, direct antiviral effects are unlikely after oral administration; instead, it only seems to have immunomodulatory activity. IFNα may bind to mucosal receptors in the oral cavity, stimulating the local lymphoid tissue and leading to cytokine release on lymphatic cells in the oral or pharyngeal area, which triggers a cascade of immunologic responses that finally act systemically [157] . Tomkins [158] showed that orally administered IFNα induced cytokine responses in buccal mucosal lymph nodes, including upregulation of IFNγ expression and downregulation of interleukin-4. In studies in mice, it was shown that subcutaneous administration of murine IFNα had an antiviral effect, whereas oral administration caused an immunomodulatory effect. Infection of mice with encephalomyocarditis virus resulted in death in 100% of mice if not treated, in 40% survival of mice when treated with murine IFNα orally at a dose of 2 × 10 5 IU per mouse, and in 90% survival of mice when given the same dose intraperitoneally [159] confirming the immune modulatory effect after oral application. Therefore, low-dose oral IFNα treatment should not be used in cats with FIP because of its immunomodulatory activity, which may lead to progression of disease.
Feline interferon-ω
Recently, the corresponding feline IFN, feline IFNω, was licensed for use in veterinary medicine in some European countries and Japan. IFNs are species specific, and the human IFN clearly differs from the feline one not only regarding its antigenicity (thus causing antibody development in animals) but with respect to its antiviral efficacy in feline cells. Even if feline IFNω is used long term, cats do not develop antibodies. In addition, because it is the homologous species of IFN in cats, it is expected to be more effective than human IFNα. Feline IFNω is a recombinant product, which is produced by baculoviruses containing the feline sequence for this IFN that replicate in silkworms after infection; subsequently, feline IFNω is purified out of homogenized silkworm preparations [160] . Data on the efficacy of feline IFNω in cats with FIP are limited. FCoV replication is inhibited by feline IFNω in vitro [161] . In one study (not controlled and only including a small number of cats), 12 cats that were suspected of having FIP were treated with IFNω in combination with glucocorticoids and supportive care [162] . IFNω was given at a rate of 10 6 IU/kg subcutaneously every 48 hours initially until clinical improvement and, subsequently, once every 7 days. Glucocorticoids were given in the form of dexamethasone in case of effusion (1 mg/kg intrathoracic or intraperitoneal injection every 24 hours) or prednisolone (initially, 2 mg/kg administered orally every 24 hours until clinical improvement, then gradually tapered to 0.5 mg/kg administered every 48 hours). Although most cats died, 4 cats survived over a period of 2 years; all had initially presented with effusions. Even though there was no control group in this study and FIP was not even confirmed in the 4 surviving cats, these results are somewhat interesting (because cats with other effusion-associated diseases would not be expected to survive for 2 years without proper treatment), and further studies would certainly be interesting.
Prevention
Unfortunately, preventing FIP is extremely difficult. The only way to prevent the development of FIP is to prevent infection with FCoV. Vaccination prevents neither FIP nor FCoV infection effectively. Testing and removing strategies are ineffective. Management of FIP should be directed at minimizing the population impact and accurately diagnosing and supporting individual affected cats. Thus, veterinarians need to be knowledgeable regarding successful and unsuccessful strategies so as to provide useful counsel to their clients.
Management
Different situations have to be considered depending on the environment.
Management of a cat after contact
If a cat with FIP is euthanized and there are no remaining cats, the owner should wait approximately 3 months before obtaining another cat, because FCoV can stay infectious for at least 7 weeks in the environment. If there are other cats in the household, they are most likely infected with and shedding FCoV. In natural circumstances, cats go outside to defecate and bury their feces, in which case the virus remains infectious hours to days (slightly longer in freezing conditions). Domesticated cats have been introduced to litter boxes, however, in which FCoV may survive for several days, and possibly up to 7 weeks in dried-up feces. Thus, FCoV-shedding cats most likely have a better chance to eliminate the virus if allowed to go outside (optimum situation is in a fenced yard).
It is a common practice for clients to present a cat to the veterinarian that has been in 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 may want to obtain another cat and needs to know whether the exposed cat is shedding FCoV. It is likely that the cat is antibody-positive, because 95% to 100% of cats exposed to FCoV become infected and develop antibodies approximately 2 to 3 weeks after FCoV exposure. There are a few cats, however, that may be resistant to FCoV infection. It has been shown that a low number of cats in FCoV endemic multiple-cat households continuously remain antibody-negative [163] . The mechanism of action for this resistance is still unknown. The owner should be advised that the cat in contact is likely to have antibodies and reassured that this is not necessarily associated with a poor prognosis. Most cats infected with FCoV do not develop FIP, and many cats in single- or 2-cat households eventually clear the infection and become antibody-negative in a few months to years. Cats can be retested (using the same laboratory) every 6 to 12 months until the results of the antibody test are negative. Cats exposed only once often have a quicker reduction in antibodies. To exclude any risk at all, the owner should be advised to wait until antibody titers of all cats are negative before obtaining a new cat. Some cats, however, remain antibody-positive for years. A rise in antibody titer or maintenance at a high level does not necessarily indicate a poor prognosis for the cat. In a study following cats with high titers, the titers of 50 of these cats remained at a high level on at least three occasions, yet only 4 cats died of FIP [26] . In contrast, in a situation of endemic infection, a constantly low titer is highly indicative that a cat is not going to develop FIP.
Management of multiple-cat households with endemic feline coronavirus
Households of less than 5 cats can spontaneously and naturally become FCoV-free, but in households of more than 10 cats, this is almost impossible, because the virus passes from one individual cat to another, maintaining the infection. This holds true for virtually all multiple-cat households, such as breeding catteries, shelters, foster homes, and other homes with more than 5 cats.
When a cat in a household develops FIP, all other cats in contact with that cat have already been exposed to the same FCoV. There is virtually nothing to prevent FIP in other cats that are in contact with the cat with FIP. Although the risk is only 5% to 10%, full-sibling litter mates of kittens with FIP have a higher likelihood of developing FIP than other cats in the same environment [164] indicating a certain genetic component.
Various tactics have been used to eliminate FCoV from a household. Reducing the number of cats (especially kittens less than 12 months old) and keeping possibly FCoV-contaminated surfaces clean can minimize population loads of FCoV. Antibody testing and segregating cats are aimed at stopping exposure. Approximately one third of antibody-positive cats excrete virus [10] , [11] , [130] , [165] , [166] ; thus, every antibody-positive cat has to be considered infectious. After 3 to 6 months, antibody titers can be retested to determine whether cats have become negative. Alternatively, RT-PCR testing of (several) fecal samples can be performed to detect shedders. It is important to detect chronic FCoV carriers so that they can be removed. In large multiple-cat environments, 40% to 60% of cats shed virus in their feces at any given time. Approximately 20% shed virus persistently. Approximately 20% are immune and do not shed virus. Repeated PCR testing of feces should be performed at weekly intervals for 2 months or more to document carriers. If the cats remain persistently PCR-positive for more than 6 weeks, they should be eliminated from the cattery and placed in single-cat environments [164] .
Early weaning and isolation
More than any other factor, management of kittens determines whether or not they become infected with FCoV. Kittens of FCoV-shedding queens should be protected from infection by maternally derived antibody until they are 5 to 6 weeks old. An early weaning protocol for the prevention of FCoV infection in kittens has been proposed by Addie and Jarrett [26] , which consists of isolation of queens 2 to 3 weeks before parturition, strict quarantine of queens and kittens, and early weaning at 4 to 6 weeks of age. This procedure is based on the findings that some queens do not shed the virus and some queens stop shedding after several weeks if not re-exposed. Even if queens do shed, young kittens have maternal resistance to the virus [7] . Early removal of kittens from the queen and prevention of infection from other cats may succeed in preventing infection in these kittens. Although straightforward in concept, isolation of queens and early weaning is not as simple as it may seem. The procedure requires quarantine rooms and procedures that absolutely ensure a new virus does not enter. It is an advantage when the isolated queens are not shedding FCoV, when they are shedding low levels, or when they can clear the infection early after being isolated. The single most important factor is the number of animals. The success of early weaning and isolation in FCoV control depends on effective quarantine and low numbers of cats (<5 cats) in the household. Also, human abodes do not easily allow adequate quarantine space for large numbers of queens and kittens, and the time and money required to maintain quarantine increase in proportion to the number of queens and litters under quarantine. In a study in large catteries in Switzerland in which the same protocol was followed, early weaning failed and viral infection of kittens as young as 2 weeks old was demonstrated [167] . It is clear that low FCoV exposure can delay infection, whereas high exposure can overcome maternally derived immunity at an early age.
There are two essential downsides of isolation and early weaning. It is not easy to do, and it fails if appropriate conditions are not maintained. Additionally, some breeders believe that early weaning exacts a social price on the kittens. In recognition of both concerns, it is recommended that early weaning not be undertaken without careful consideration. FCoV-free households do not require routine isolation and early weaning. When kittens are isolated with their queen, special care must be taken during the period from 2 to 7 weeks of age to socialize the kittens. The success of early weaning should also be monitored, and it should not be continued if it is not successful. Kittens that have been successfully reared free of FCoV should be antibody-negative at 12 weeks of age. Even if kittens can be raised free of FCoV, they may become infected sooner or later. Therefore, the objective of isolation and early weaning should not be to prevent infection but to delay it [164] . For early weaning to be effective, it is best for kittens to be taken to a new home (with no other cats) at 5 weeks of age. Even then, however, early weaning is not always successful.
Recommendations for breeding catteries
It has been suggested to maximize heritable resistance to FIP in breeding catteries. Genetic predisposition is not completely understood, however. It is known that susceptible cats are approximately twice as likely to develop FIP as other cats [168] . If a cat has two or more litters in which kittens develop FIP, that cat should not be bred again. Particular attention should be paid to pedigrees of males, in which FIP is overrepresented. Because line breeding often uses valuable tomcats extensively, eliminating such animals may have a small but important effect on improving overall resistance [164] .
Screening of a cattery for the presence of FCoV is important. If there are many cats housed in a group, a random sampling of 3 to 4 cats should indicate whether FCoV is endemic. If cats are housed individually, it may be necessary to test them all. Cats in households with fewer than 10 cats and no new acquisitions and cats that are isolated from each other in groups of 3 or less often eventually lose their FCoV infection [169] . Once they have been established, antibody-negative catteries can be maintained free of FCoV by monitoring new cats before they are introduced. Thus, cats should be screened before introduction, and antibody-positive cats should never be taken into the household. Cat breeders often also request that their cats be screened for FCoV antibodies before mating. If the cat is healthy and antibody-negative, it can be safely mated with another antibody-negative cat. If the cat is antibody-positive, it should not be mated with a cat from an FCoV-free environment [164] .
Recommendations for shelters
Prevention of FIP in a shelter situation is virtually impossible unless cats are strictly kept in separate cages and handled only by means of sterile handling devices (comparable to isolation units). Isolation is often not effective because of the ease with which FCoV is transported on clothes, shoes, dust, and cats. Comparison of shelters with different types of handling revealed a significant correlation between an increase in the number of handling events outside the cages and an increase in the percentage of antibody-positive cats. In a study in which feral cats were tested at the time they were brought into local shelters (in which multiple cats were kept together) and at 1-to 2-week intervals thereafter, only a low number of cats had antibodies at the time point of entering, but the percentage increased rapidly until virtually all cats in the shelters were infected with FCoV [40] .
Shelter managers should use education and communication to minimize adverse effects of FIP in cat populations. Shelter managers should have written information sheets or contracts informing adopters about FCoV and FIP. They should understand that FCoV is unavoidable in multiple-cat environments and that FIP is an unavoidable consequence of endemic FCoV. Shelters need to optimize facilities and husbandry so that the facilities can be cleaned easily and virus spread is minimized. It is essential to decrease viral load and stress levels [164] .
Vaccination
There have been many attempts to develop effective vaccines, but, unfortunately, most have failed, mainly because of ADE [75] , [78] , [170] , [171] . Nevertheless, a vaccine was licensed (Primucell, Pfizer Animal Health) incorporating 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 temperatures [172] , [173] , [174] , [175] . This vaccine, administered intranasally, produces local immunity (IgA antibodies) at the site where FCoV first enters the body (the oropharynx) and also induces cell-mediated immunity. The vaccine has been available in the United States since 1991 and has been introduced in many European countries. The concerns of such a vaccine are safety and efficacy. Safety concerns focus on whether the vaccine could cause FIP or produce ADE. Although some experimental vaccine trials with vaccines that never appeared on the market have recorded ADE on challenge [176] , [177] , field studies have demonstrated that this intranasal vaccine is safe. In two extensive placebo-controlled double-blind field trials there was no development of FIP or ADE [178] , [179] , [180] . There were a few immediate side effects after application, such as sneezing, vomiting, or diarrhea, which were not statistically different in the vaccinated group and the placebo group [178] .
The efficacy of this vaccine is questioned constantly, however. Experimental studies have reported preventable fractions between 0% [176] , [177] and 50% to 75% [175] , [181] , depending on the investigator. In a survey of 138 cats belonging to 15 cat breeders in which virtually all the cats had antibodies, no difference was found in the development of FIP between the vaccinated group and the placebo group [178] . Thus, vaccination in an FCoV endemic environment or in a household with known cases of FIP is not effective. In one of the placebo-controlled double-blind trials that was performed in Switzerland in a group of cats that did not have contact with FCoV before vaccination, a small but statistically significant reduction in the number of cats that developed FIP was noted [178] , [182] . Because the vaccine is ineffective when cats have already had contact with FCoV, antibody testing may be beneficial before vaccination. One disadvantage is that most cats develop antibodies after vaccination, thus making the establishment and control of an FCoV-free household difficult. In conclusion, study results do not clearly identify whether vaccination has no effect versus a small effect. Although only marginally if at all efficacious, the vaccine is at least safe and does not induce ADE.
Public health considerations
Concerns have arisen about a possible danger of FCoV to people because there is a close antigenetic relation between coronaviruses of different domestic animal species (eg, CCV, TGEV) and a coronavirus deriving from animals in close contact with humans recently caused the so-called “severe acute respiratory syndrome” (SARS) that seemed to be a threat to thousands of people. There is, however, no indication that people can be infected with FCoV.
References
1 Rohrbach B.W. Legendre A.M. Baldwin C.A. Epidemiology of feline infectious peritonitis among cats examined at veterinary medical teaching hospitals J Am Vet Med Assoc 218 2001 1111 1115 11318361 10.2460/javma.2001.218.1111
2 Cave T.A. Thompson H. Reid S.W. Kitten mortality in the United Kingdom: a retrospective analysis of 274 histopathological examinations (1986 to 2000) Vet Rec 151 2002 497 501 12430997 10.1136/vr.151.17.497
3 Pedersen N.C. Coronavirus diseases (coronavirus enteritis, feline infectious peritonitis) Holzworth J. Diseases of the cat. Medicine and surgery vol. 1 1987 WB Saunders Philadelphia 193 214
4 Pedersen N.C. Morphologic and physical characteristics of feline infectious peritonitis virus and its growth in autochthonous peritoneal cell cultures Am J Vet Res 37 1976 567 572 1275343
5 Pedersen N.C. Serologic studies of naturally occurring feline infectious peritonitis Am J Vet Res 37 1976 1449 1453 793459
6 Loeffler D.G. Ott R.L. Evermann J.F. The incidence of naturally occurring antibodies against feline infectious peritonitis in selected cat populations Feline Pract 8 1978 43 47
7 Addie D.D. Jarrett O. A study of naturally occurring feline coronavirus infections in kittens Vet Rec 130 1992 133 137 1313617 10.1136/vr.130.7.133
8 Sparkes A.H. Gruffydd-Jones T.J. Harbour D.A. Feline coronavirus antibodies in UK cats Vet Rec 131 1992 223 224 10.1136/vr.131.10.223-a 1332241
9 Pedersen N.C. Feline infectious peritonitis: something old, something new Feline Pract 6 1976 42 51
10 Addie D.D. Jarrett O. Feline coronavirus antibodies in cats Vet Rec 131 1992 202 203 10.1136/vr.131.9.202-a 1332248
11 Addie D.D. Toth S. Murray G.D. Risk of feline infectious peritonitis in cats naturally infected with feline coronavirus Am J Vet Res 56 1995 429 434 7785816
12 Pedersen N.C. Boyle J.F. Floyd K. An enteric coronavirus infection of cats and its relationship to feline infectious peritonitis Am J Vet Res 42 1981 368 377 6267960
13 Pedersen N.C. Black J.W. Boyle J.F. Pathogenetic differences between various feline coronavirus isolates Adv Exp Med Biol 173 1983 365 380 10.1007/978-1-4615-9373-7_36 6331125
14 Boyle J.F. Pedersen N.C. Evermann J.F. Plaque assay, polypeptide composition and immunochemistry of feline infectious peritonitis virus and feline enteric coronavirus isolates Adv Exp Med Biol 173 1984 133 147 6331106 10.1007/978-1-4615-9373-7_12
15 Fiscus S.A. Teramoto Y.A. Antigenic comparison of feline coronavirus isolates: evidence for markedly different peplomer glycoproteins J Virol 61 1987 2607 2613 3599183 10.1128/jvi.61.8.2607-2613.1987 PMC255709
16 Hohdatsu T. Okada S. Koyama H. Characterization of monoclonal antibodies against feline infectious peritonitis virus type II and antigenic relationship between feline, porcine, and canine coronaviruses Arch Virol 117 1991 85 95 1706593 10.1007/BF01310494 PMC7086586
17 Hohdatsu T. Sasamoto T. Okada S. Antigenic analysis of feline coronaviruses with monoclonal antibodies (MAbs): preparation of MAbs which discriminate between FIPV strain 79–1146 and FECV strain 79–1683 Vet Microbiol 28 1991 13 24 1653482 10.1016/0378-1135(91)90096-X PMC7117509
18 Corapi W.V. Olsen C.W. Scott F.W. Monoclonal antibody analysis of neutralization and antibody-dependent enhancement of feline infectious peritonitis virus J Virol 66 1992 6695 6705 1383568 10.1128/jvi.66.11.6695-6705.1992 PMC240165
19 Herrewegh A.A. Vennema H. Horzinek M.C. The molecular genetics of feline coronaviruses: comparative sequence analysis of the ORF7a/7b transcription unit of different biotypes Virology 212 1995 622 631 7571432 10.1006/viro.1995.1520 PMC7131361
20 Pedersen N.C. An overview of feline enteric coronavirus and infectious peritonitis virus infections Feline Pract 23 1995 7 20
21 Vennema H. Poland A. Hawkins K.F. A comparison of the genomes of FECVs and FIPVs and what they tell us about the relationships between feline coronaviruses and their evolution Feline Pract 23 1995 40 44
22 Vennema H. Poland A. Foley J. Feline infectious peritonitis viruses arise by mutation from endemic feline enteric coronaviruses Virology 243 1998 150 157 9527924 10.1006/viro.1998.9045 PMC7131759
23 Ward J.M. Morphogenesis of a virus in cats with experimental feline infectious peritonitis Virology 41 1970 191 194 4986314 10.1016/0042-6822(70)90070-X PMC7131342
24 Holzworth J. Some important disorders of cats Cornell Vet 53 1963 157 160 13961523
25 O'Reilly K. Fishman B. Hitchcock L. Feline infectious peritonitis: isolation of a coronavirus Vet Rec 104 1979 348 10.1136/vr.104.15.348 473531
26 Addie D.D. Jarrett O. Feline coronavirus infections Greene C.E. Infectious diseases of the dog and cat 1990 WB Saunders Philadelphia 300 312
27 Horzinek M.C. Osterhaus A.D. Feline infectious peritonitis: a worldwide serosurvey Am J Vet Res 40 1979 1487 1492 230758
28 Barlough J.E. Jacobson R.H. Downing D.R. Evaluation of a computer-assisted, kinetics-based enzyme-linked immunosorbent assay for detection of coronavirus antibodies in cats J Clin Microbiol 17 1983 202 217 6300184 10.1128/jcm.17.2.202-217.1983 PMC272610
29 Pedersen N.C. Feline infectious peritonitis and feline enteric coronavirus infections. Part I Feline Pract 13 1983 13 19
30 McArdle F. Bennett M. Gaskell R.M. Canine coronavirus infection in cats; a possible role in feline infectious peritonitis Adv Exp Med Biol 276 1990 475 479 1966440 10.1007/978-1-4684-5823-7_66
31 Motokawa K. Hohdatsu T. Aizawa C. Molecular cloning and sequence determination of the peplomer protein gene of feline infectious peritonitis virus type I Arch Virol 140 1995 469 480 7733820 10.1007/BF01718424 PMC7086962
32 Motokawa K. Hohdatsu T. Hashimoto H. Comparison of the amino acid sequence and phylogenetic analysis of the peplomer, integral membrane and nucleocapsid proteins of feline, canine and porcine coronaviruses Microbiol Immunol 40 1996 425 433 8839428 10.1111/j.1348-0421.1996.tb01089.x PMC7168433
33 Barlough J.E. Stoddart C.A. Feline coronaviral infections Greene C.E. Infectious diseases of the dog and cat 1990 WB Saunders Philadelphia 300 312
34 Wege H. Siddell S. Ter Meulen V. The biology and pathogenesis of coronaviruses Curr Top Microbiol Immunol 99 1982 165 200 6178564 10.1007/978-3-642-68528-6_5
35 McArdle F. Bennett M. Gaskell R.M. Induction and enhancement of feline infectious peritonitis by canine coronavirus Am J Vet Res 53 1992 1500 1506 1329586
36 Mochizuki M. Mitsutake Y. Miyanohara Y. Antigenic and plaque variations of serotype II feline infectious peritonitis coronaviruses J Vet Med Sci 59 1997 253 258 9152932 10.1292/jvms.59.253
37 Hohdatsu T. Okada S. Ishizuka Y. The prevalence of types I and II feline coronavirus infections in cats J Vet Med Sci 54 1992 557 562 1322718 10.1292/jvms.54.557
38 Benetka V. Kubber-Heiss A. Kolodziejek J. Prevalence of feline coronavirus types I and II in cats with histopathologically verified feline infectious peritonitis Vet Microbiol 99 2004 31 42 15019109 10.1016/j.vetmic.2003.07.010 PMC7117137
39 Legendre A, Luria BJ, Gorman SP, et al. Prevalence of coronavirus antibodies in feral cats in Gainesville, Florida [abstract]. In: Abstracts of the Second International Feline Coronavirus/Feline Infectious Peritonitis Symposium. Glasgow, Scotland; 2002.
40 Pedersen N.C. Sato R. Foley J.E. Common virus infections in cats, before and after being placed in shelters, with emphasis on feline enteric coronavirus J Feline Med Surg 6 2004 83 88 15123152 10.1016/j.jfms.2003.08.008 PMC7128562
41 Hartmann K, Binder C, Hirschberger J, et al. Predictive values of different tests in the diagnosis of feline infectious peritonitis [abstract]. In: Abstracts of the Second International Feline Coronavirus/Feline Infectious Peritonitis Symposium. Glasgow, Scotland; 2002.
42 Kennedy M. Citino S. McNabb A.H. Detection of feline coronavirus in captive Felidae in the USA J Vet Diagn Invest 14 2002 520 522 12423039 10.1177/104063870201400615
43 Kennedy M. Kania S. Stylianides E. Detection of feline coronavirus infection in southern African nondomestic felids J Wildl Dis 39 2003 529 535 14567213 10.7589/0090-3558-39.3.529
44 Brown E.W. Olmsted R.A. Martenson J.S. Exposure to FIV and FIPV in wild and captive cheetahs Zoo Biol 12 1993 135 142
45 Weiss R.C. Feline infectious peritonitis and other coronaviruses Sherding R.G. The cat diseases and clinical management 2nd edition 1994 Churchill Livingstone New York 449 477
46 Scott FW. Update on FIP. In: Proceedings of the Kal Kann Symposium 1988;12:43–7.
47 Pedersen N.C. Addie D. Wolf A. Recommendations from working groups of the International Feline Enteric Coronavirus and Feline Infectious Peritonitis Workshop Feline Pract 23 1995 108 111
48 Kass P.H. Dent P.H. The epidemiology of feline infectious peritonitis in catteries Feline Pract 23 1995 27 32
49 Stoddart M.E. Whicher J.T. Harbour D.A. Cats inoculated with feline infectious peritonitis virus exhibit a biphasic acute phase plasma protein response Vet Rec 123 1988 622 624 2464231
50 Herrewegh A.A. DeGroot R.J. Cepica A. Detection of feline coronavirus RNA in feces, tissues, and body fluids of naturally infected cats by reverse transcriptase PCR J Clin Microbiol 33 1995 684 689 7751377 10.1128/jcm.33.3.684-689.1995 PMC228014
51 Gut M, Leutenegger C, Schiller I, et al. Kinetics of FCoV infection in kittens born in catteries of high risk for FIP under different rearing conditions [abstract]. In: Abstracts of the Second International Feline Coronavirus/Feline Infectious Peritonitis Symposium. Glasgow, Scotland; 2002.
52 Foley J.E. Poland A. Carlson J. Patterns of feline coronavirus infection and fecal shedding from cats in multiple-cat environments J Am Vet Med Assoc 210 1997 1307 1312 9143535
53 Addie D.D. Toth S. Herrewegh A. Feline coronavirus in the intestinal contents of cats with feline infectious peritonitis Vet Rec 139 1996 522 523 8953694 10.1136/vr.139.21.522
54 Goitsuka R. Hirota Y. Hasegawa A. Release of interleukin 1 from peritoneal exudate cells of cats with feline infectious peritonitis Nippon Juigaku Zasshi 49 1987 811 888 2824907 10.1292/jvms1939.49.811
55 Weiss R.C. Scott F.W. Pathogenesis of feline infectious peritonitis: nature and development of viremia Am J Vet Res 42 1981 382 390 6267961
56 Stoddart C.A. Scott F.W. Intrinsic resistance of feline peritoneal macrophages to coronavirus infection correlates with in vivo virulence J Virol 63 1989 436 440 2521188 10.1128/jvi.63.1.436-440.1989 PMC247703
57 Egberink H.F. Herrewegh A.P. Schuurman N.M. FIP, easy to diagnose? Vet Q 17 1995 24 25 7571296
58 Herrewegh A.A. Mahler M. Hedrich H.J. Persistence and evolution of feline coronavirus in a closed cat-breeding colony Virology 234 1997 349 363 9268167 10.1006/viro.1997.8663 PMC7130968
59 Gunn-Moore D.A. Gruffydd-Jones T.J. Harbour D.A. Detection of feline coronaviruses by culture and reverse transcriptase-polymerase chain reaction of blood samples from healthy cats and cats with clinical feline infectious peritonitis Vet Microbiol 62 1998 193 205 9791867 10.1016/S0378-1135(98)00210-7 PMC7117229
60 Tresnan D.B. Levis R. Holmes K.V. Feline aminopeptidase N serves as a receptor for feline, canine, porcine, and human coronaviruses in serogroup I J Virol 70 1996 8669 8674 8970993 10.1128/jvi.70.12.8669-8674.1996 PMC190961
61 Benbacer L. Kut E. Besnardeau L. Interspecies aminopeptidase-N chimeras reveal species-specific receptor recognition by canine coronavirus, feline infectious peritonitis virus, and transmissible gastroenteritis virus J Virol 71 1997 734 737 8985407 10.1128/jvi.71.1.734-737.1997 PMC191108
62 Hegyi A. Kolb A.F. Characterization of determinants involved in the feline infectious peritonitis virus receptor function of feline aminopeptidase J Gen Virol 79 1998 1387 1391 9634079 10.1099/0022-1317-79-6-1387
63 Hickman M.A. Morris J.G. Rogers Q.R. Elimination of feline coronavirus infection from a large experimental specific pathogen-free cat breeding colony by serologic testing and isolation Feline Pract 3 1995 96 102
64 Rottier R. The molecular dynamics of feline coronaviruses Vet Microbiol 69 1999 117 125 10515281 10.1016/S0378-1135(99)00099-1 PMC7117432
65 Poland A.M. Vennema H. Foley J.E. Two related strains of feline infectious peritonitis virus isolated from immunocompromised cats infected with a feline enteric coronavirus J Clin Microbiol 34 1996 3180 3184 8940468 10.1128/jcm.34.12.3180-3184.1996 PMC229479
66 Foley J.E. Poland A. Carlson J. Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus J Am Vet Med Assoc 210 1997 1313 1318 9143536
67 Addie D.D. Kennedy L.J. Ryvar R. Feline leucocyte antigen class II polymorphism and susceptibility to feline infectious peritonitis J Feline Med Surg 6 2004 59 62 15123149 10.1016/j.jfms.2003.12.010 PMC7129417
68 Nafe L.A. Topics in feline neurology Vet Clin N Am Small Anim Pract 14 1984 1289 1298 10.1016/S0195-5616(84)50159-4 PMC7134428 6097008
69 Gunn-Moore D.A. Caney S.M. Gruffydd-Jones T.J. Antibody and cytokine responses in kittens during the development of feline infectious peritonitis (FIP) Vet Immunol Immunopathol 65 1998 221 242 9839876 10.1016/S0165-2427(98)00156-1 PMC7120021
70 Dean G.A. Olivry T. Stanton C. In vivo cytokine response to experimental feline infectious peritonitis virus infection Vet Microbiol 97 2003 1 12 14637034 10.1016/j.vetmic.2003.08.010 PMC7117329
71 Kiss I. Poland A.M. Pedersen N.C. Disease outcome and cytokine responses in cats immunized with an avirulent feline infectious peritonitis virus (FIPV)-UCD1 and challenge-exposed with virulent FIPV-UCD8 J Feline Med Surg 6 2004 89 97 15123153 10.1016/j.jfms.2003.08.009 PMC7128844
72 Giordano A. Spagnolo V. Colombo A. Changes in some acute phase protein and immunoglobulin concentrations in cats affected by feline infectious peritonitis or exposed to feline coronavirus infection Vet J 167 2004 38 44 14623149 10.1016/S1090-0233(03)00055-8 PMC7128346
73 Ceciliani F. Grossi C. Giordano A. Decreased sialylation of the acute phase protein alpha1-acid glycoprotein in feline infectious peritonitis (FIP) Vet Immunol Immunopathol 99 2004 229 236 15135988 10.1016/j.vetimm.2004.02.003 PMC7120068
74 Paltrinieri S. Giordano A. Ceciliani F. Tissue distribution of a feline AGP related protein (fAGPrP) in cats with feline infectious peritonitis (FIP) J Feline Med Surg 6 2004 99 105 15123154 10.1016/j.jfms.2003.08.012 PMC7129350
75 Vennema H. De Groot R.J. Harbour D.A. Immunogenicity of recombinant feline infectious peritonitis virus spike protein in mice and kittens Adv Exp Med Biol 276 1990 217 222 1966406 10.1007/978-1-4684-5823-7_30
76 Olsen C.W. A review of feline infectious peritonitis virus: molecular biology, immunopathogenesis, clinical aspects, and vaccination Vet Microbiol 36 1993 1 37 8236772 10.1016/0378-1135(93)90126-R PMC7117146
77 Pedersen N.C. The history and interpretation of feline coronavirus serology Feline Pract 23 1995 46 51
78 Scott F.W. Copari W.V. Olsen C.W. Antibody-dependent enhancement of feline infectious peritonitis Feline Pract 23 1995 77 80
79 Hohdatsu T. Yamada M. Tominaga R. Antibody-dependent enhancement of feline infectious peritonitis virus infection in feline alveolar macrophages and human monocyte cell line U937 by serum of cats experimentally or naturally infected with feline coronavirus J Vet Med Sci 60 1998 49 55 9492360 10.1292/jvms.60.49
80 Hohdatsu T. Nakamura M. Ishizuka Y. A study on the mechanism of antibody-dependent enhancement of feline infectious peritonitis virus infection in feline macrophages by monoclonal antibodies Arch Virol 120 1991 207 217 1659798 10.1007/BF01310476 PMC7087175
81 Olsen C.W. Corapi W.V. Ngichabe C.K. Monoclonal antibodies to the spike protein of feline infectious peritonitis virus mediate antibody-dependent enhancement of infection of feline macrophages J Virol 66 1992 956 965 1309922 10.1128/jvi.66.2.956-965.1992 PMC240797
82 Olsen C.W. Corapi W.V. Jacobson R.H. Identification of antigenic sites mediating antibody-dependent enhancement of feline infectious peritonitis virus infectivity J Gen Virol 74 1993 745 749 7682252 10.1099/0022-1317-74-4-745
83 Corapi W.V. Darteil R.J. Audonnet J.C. Localization of antigenic sites of the S glycoprotein of feline infectious peritonitis virus involved in neutralization and antibody-dependent enhancement Virology 5 1995 2858 2862 10.1128/jvi.69.5.2858-2862.1995 PMC188981 7707508
84 Hirschberger J. Hartmann K. Wilhelm N. Clinical symptoms and diagnosis of feline infectious peritonitis Tierarztl Prax 23 1995 92 99 7792783
85 Rush J.E. Keene B.W. Fox P.R. Pericardial disease in the cat: a retrospective evaluation of 66 cases J Am Anim Hosp Assoc 26 1990 39 46
86 Trulove S.G. McCahon H.A. Nichols R. Pyogranulomatous pneumonia associated with generalized noneffusive feline infectious peritonitis Feline Pract 3 1992 25 29
87 Kipar A. Koehler K. Bellmann S. Feline infectious peritonitis presenting as a tumour in the abdominal cavity Vet Rec 144 1999 118 122 10070701 10.1136/vr.144.5.118
88 MacPhail C. Gastrointestinal obstruction Clin Tech Small Anim Pract 17 2002 178 183 12587284 10.1053/svms.2002.36606
89 Sigurdardottir O.G. Kolbjornsen O. Lutz H. Orchitis in a cat associated with coronavirus infection J Comp Pathol 124 2001 219 222 11222021 10.1053/jcpa.2000.0443 PMC7130237
90 Van Kruiningen H.J. Ryan M.J. Shindel N.M. The classification of feline colitis J Comp Pathol 93 1983 275 294 6863613 10.1016/0021-9975(83)90015-4
91 Harvey C.J. Lopez J.W. Hendrick M.J. An uncommon intestinal manifestation of feline infectious peritonitis: 26 cases (1986–1993) J Am Vet Med Assoc 209 1996 1117 1120 8800260
92 Andrew S.E. Feline infectious peritonitis Vet Clin N Am Small Anim Pract 30 2000 987 1000 10.1016/S0195-5616(00)05002-6 PMC7134424 11033870
93 Bistner S. Allergic- and immunologic-mediated diseases of the eye and adnexae Vet Clin N Am Small Anim Pract 24 1994 711 734 10.1016/s0195-5616(94)50080-9 7975044
94 Bradshaw J.M. Pearson G.R. Gruffydd-Jones T.J. A retrospective study of 286 cases of neurological disorders of the cat J Comp Pathol 131 2004 112 120 15276850 10.1016/j.jcpa.2004.01.010 PMC7134559
95 Rohrer C. Suter P.F. Lutz H. The diagnosis of feline infectious peritonitis (FIP): a retrospective and prospective study Kleintierprax 38 1993 379 389
96 Li Y. Kang J. Horwitz M.S. Clinical, cerebrospinal fluid, and histological data from twenty-seven cats with primary inflammatory disease of the central nervous system Can Vet J 35 1994 103 110 8069819 PMC1686724
97 Kline K.L. Joseph R.J. Averdill D.R. Feline infectious peritonitis with neurologic involvement: clinical and pathological findings in 24 cats J Am Anim Hosp Assoc 30 1994 111 118
98 Baroni M. Heinold Y. A review of the clinical diagnosis of feline infectious peritonitis viral meningoencephalomyelitis Prog Vet Neurol 6 1995 88 94
99 Shell L.G. Feline infectious peritonitis viral meningoencephalitis Feline Pract 25 1997 24
100 Addie D.D. Jarrett O. Use of a reverse-transcriptase polymerase chain reaction for monitoring the shedding of feline coronavirus by healthy cats Vet Rec 148 2001 649 653 11400984 10.1136/vr.148.21.649
101 Hartmann K. Binder C. Hirschberger J. Comparison of different tests to diagnose feline infectious peritonitis J Vet Intern Med 17 2003 781 790 14658713 10.1111/j.1939-1676.2003.tb02515.x PMC7197515
102 Paltrinieri S. Grieco V. Comazzi S. Laboratory profiles in cats with different pathological and immunohistochemical findings due to feline infectious peritonitis (FIP) J Feline Med Surg 3 2001 149 159 11876632 10.1053/jfms.2001.0126 PMC7173158
103 Paltrinieri S. Ponti W. Comazzi S. Shifts in circulating lymphocyte subsets in cats with feline infectious peritonitis (FIP): pathogenic role and diagnostic relevance Vet Immunol Immunopathol 96 2003 141 148 14592727 10.1016/S0165-2427(03)00156-9 PMC7119655
104 Breuer W. Stahr K. Majzoub M. Bone-marrow changes in infectious diseases and lymphohaemopoietic neoplasias in dogs and cats—a retrospective study J Comp Pathol 119 1998 57 66 9717127 10.1016/s0021-9975(98)80071-6
105 Boudreaux M.K. Weiss R.C. Toivio-Kinnucan M. Potentiation of platelet responses in vitro by feline infectious peritonitis virus Vet Pathol 27 1990 261 268 2144930 10.1177/030098589002700407
106 Paltrinieri S. Comazzi S. Spagnolo V. Laboratory changes consistent with feline infectious peritonitis in cats from multicat environments J Vet Med A 49 2002 503 510 10.1046/j.1439-0442.2002.00494.x PMC7169676 12549828
107 Sparkes A.H. Gruffydd Jones T.J. Harbour D.A. An appraisal of the value of laboratory tests in the diagnosis of feline infectious peritonitis J Am Anim Hosp Assoc 30 1994 345 350
108 Shelly S.M. Scarlett Kranz J. Blue J.T. Protein electrophoresis on effusions from cats as a diagnostic test for feline infectious peritonitis J Am Anim Hosp Assoc 24 1988 495 500
109 Rohrer C. Suter P.F. Lutz H. The diagnosis of feline infectious peritonitis (FIP): retrospective and prospective study European Journal of Companion Animal Practice 4 1994 23 29
110 Potkay S. Bacher J.D. Pitts T.W. Feline infectious peritonitis in a closed breeding colony Lab Anim Sci 24 1974 279 289 4362875
111 Gouffaux M. Pastoret P.P. Henroteaux M. Feline infectious peritonitis. Proteins of plasma and ascitic fluid Vet Pathol 12 1975 335 348 59451 10.1177/0300985875012005-00601
112 Horzinek M.C. Osterhaus A.D. Ellens D.J. Feline infectious peritonitis virus Zentralbl Veterinarmed B 24 1977 398 405 878736 10.1111/j.1439-0450.1977.tb01013.x PMC7165595
113 Horzinek M.C. Ederveen J. Egberink H. Virion polypeptide specificity of immune complexes and antibodies in cats inoculated with feline infectious peritonitis virus Am J Vet Res 47 1986 754 761 3008607
114 Paltrinieri S. Cammarata M.P. Cammarata G. Some aspects of humoral and cellular immunity in naturally occurring feline infectious peritonitis Vet Immunol Immunopathol 65 1998 205 220 9839875 10.1016/S0165-2427(98)00155-X PMC7119882
115 Goitsuka R. Ohashi T. Ono K. IL-6 activity in feline infectious peritonitis Immunology 144 1990 2599 2603 2156926
116 Weiss R.C. The diagnosis and clinical management of feline infectious peritonitis Vet Med (Praha) 86 1991 308 319
117 Wolf A. Feline infectious peritonitis. Part 2 Feline Pract 25 1997 24 28
118 Duthie S. Eckersall P.D. Addie D.D. Value of alpha 1-acid glycoprotein in the diagnosis of feline infectious peritonitis Vet Rec 141 1997 299 303 9330474 10.1136/vr.141.12.299
119 Savary K.C. Sellon R.K. Law J.M. Chylous abdominal effusion in a cat with feline infectious peritonitis J Am Anim Hosp Assoc 37 2001 35 40 11204475 10.5326/15473317-37-1-35
120 Hirschberger J. Koch S. Validation of the determination of the activity of adenosine deaminase in body effusions of cats Res Vet Sci 59 1995 226 229 8588096 10.1016/0034-5288(95)90007-1
121 Berti-Bock G. Vial F. Premuda L. Exudates, transudates and the Rivalta reaction (1895). Current status and historical premises Minerva Med 70 1979 3573 3580 392338
122 Kasbohm C. Exudates in body cavities of the dog. Clinical and diagnostic study with special reference to punctate cytology Tierarztl Prax 4 1976 501 505 1006661
123 Rand J.S. Parent J. Percy D. Jacobs R. Clinical, cerebrospinal fluid, and histological data from twenty-seven cats with primary inflammatory disease of the central nervous system Can Vet J 35 1994 103 110 8069819 PMC1686724
124 Foley J.E. Rand C. Leutenegger C. Inflammation and changes in cytokine levels in neurological feline infectious peritonitis J Feline Med Surg 5 2003 313 322 14623200 10.1016/S1098-612X(03)00048-2 PMC7128633
125 Barlough J.E. Serodiagnostic aids and management practice for feline retrovirus and coronavirus infections Vet Clin N Am Small Anim Pract 14 1984 955 969 10.1016/S0195-5616(84)50101-6 PMC7134470 6093322
126 Addie D.D. Dennis J.M. Toth S. Long-term impact on a closed household of pet cats of natural infection with feline coronavirus, feline leukaemia virus and feline immunodeficiency virus Vet Rec 146 2000 419 424 10811262 10.1136/vr.146.15.419
127 Sparkes A.H. Gruffydd Jones T.J. Harbour D.A. Feline infectious peritonitis: a review of clinicopathological changes in 65 cases, and a critical assessment of their diagnostic value Vet Rec 129 1991 209 212 1949515 10.1136/vr.129.10.209
128 Sparkes A.H. Gruffydd-Jones T.J. Howard P.E. Coronavirus serology in healthy pedigree cats Vet Rec 131 1992 35 36 1509661 10.1136/vr.131.2.35
129 Addie D.D. McLachlan S.A. Golder M. Evaluation of an in-practice test for feline coronavirus antibodies J Feline Med Surg 6 2004 63 67 15123150 10.1016/j.jfms.2004.01.001 PMC7128989
130 Addie D.D. Jarrett O. Control of feline coronavirus infections in breeding catteries by serotesting, isolation and early weaning Feline Pract 23 1995 92 95
131 Blatter L.A. Niggli E. Detection of feline coronaviruses in cell cultures and in fresh and fixed feline tissues using polymerase chain reaction Vet Microbiol 42 1994 65 77 7839586 10.1016/0378-1135(94)90078-7 PMC7117364
132 Kennedy M.A. Brenneman K. Millsaps R.K. Correlation of genomic detection of feline coronavirus with various diagnostic assays for feline infectious peritonitis J Vet Diagn Invest 10 1998 93 97 9526870 10.1177/104063879801000119
133 Soma T. Ishii H. Detection of feline coronavirus antibody, feline immunodeficiency virus antibody, and feline leukemia virus antigen in ascites from cats with effusive feline infectious peritonitis J Vet Med Sci 66 2004 89 90 14960820 10.1292/jvms.66.89
134 Foley J.E. Lapointe J.M. Koblik P. Diagnostic features of clinical neurologic feline infectious peritonitis J Vet Intern Med 12 1998 415 423 9857333 10.1111/j.1939-1676.1998.tb02144.x PMC7167019
135 Boettcher I, Fischer A, Steinberg T, et al. Comparative evaluation of CSF anti-coronavirus titers and results of postmortem examination in cats [abstract]. In: Abstracts of the Annual Meeting of the European Society of Veterinary Neurology. Prague, Czech Republic; 2003
136 Fehr D. Bolla S. Herrewegh A. Detection of feline coronavirus using RT-PCR: basis for the study of the pathogenesis of feline infectious peritonitis (FIP) Schweiz Arch Tierheilkd 138 1996 74 79 8720731
137 Witte K.H. Tuch K. Dubenkropp H. Antigenic relationships between feline infectious peritonitis (FIP) and transmissible gastroenteritis (TGE) viruses in swine Berl Munch Tierarztl Wochenschr 90 1977 396 401 200217
138 Toma B. Duret C. Chappuis G. Pellerin B. Echec de l'immunisation contre la peritonite infectieuse feline par injection de virus de la gastro-enterite transmissible du porc Rec Med Vet 155 1979 799 803
139 Gamble D.A. Lobbiani A. Gramegna M. Development of a nested PCR assay for detection of feline infectious peritonitis virus in clinical specimens J Clin Microbiol 35 1997 673 675 9041410 10.1128/jcm.35.3.673-675.1997 PMC229648
140 Jacobse Geels H.E. Daha M.R. Horzinek M.C. Isolation and characterization of feline C3 and evidence for the immune complex pathogenesis of feline infectious peritonitis J Immunol 125 1980 1606 1610 7410847
141 Parodi M.C. Cammarata G. Paltrinieri S. Using direct immunofluorescence to detect coronaviruses in peritoneal and pleural effusions J Small Anim Pract 34 1993 609 613
142 Kipar A. Bellmann S. Kremendahl J. Cellular composition, coronavirus antigen expression and production of specific antibodies in lesions in feline infectious peritonitis Vet Immunol Immunopathol 65 1998 243 257 9839877 10.1016/S0165-2427(98)00158-5 PMC7119884
143 Tammer R. Evensen O. Lutz H. Reinacher M. Immunohistological demonstration of feline infectious peritonitis virus antigen in paraffin-embedded tissues using feline ascites or murine monoclonal antibodies Vet Immunol Immunopathol 49 1995 177 182 8588340 10.1016/0165-2427(95)05459-J PMC7119862
144 Hök K. Demonstration of feline infectious peritonitis in conjunctival epithelial cells from cats APMIS 97 1989 820 824 2551353 10.1111/j.1699-0463.1989.tb00483.x
145 Haagmans B.L. Egberink H.F. Horzinek M.C. Apoptosis and T-cell depletion during feline infectious peritonitis J Virol 70 1996 8977 8983 8971027 10.1128/jvi.70.12.8977-8983.1996 PMC190995
146 Kipar A. Kohler K. Leukert W. A comparison of lymphatic tissues from cats with spontaneous feline infectious peritonitis (FIP), cats with FIP virus infection but no FIP, and cats with no infection J Comp Pathol 125 2001 182 191 11578135 10.1053/jcpa.2001.0501
147 Li X. Scott F.W. Detection of feline coronaviruses in cell cultures and in fresh and fixed feline tissues using polymerase chain reaction Vet Microbiol 42 1994 65 77 7839586 10.1016/0378-1135(94)90078-7 PMC7117364
148 Watari T. Kaneshima T. Tsujimoto H. Effect of thromboxane synthetase inhibitor on feline infectious peritonitis in cats J Vet Med Sci 60 1998 657 659 9637307 10.1292/jvms.60.657
149 Weiss R.C. Oostrom-Ram T. Inhibitory effects of ribavirin alone or combined with human alpha interferon on feline infectious peritonitis virus replication in vitro Vet Microbiol 20 1989 255 265 2549687 10.1016/0378-1135(89)90049-7 PMC7117261
150 Barlough J.E. Scott F.W. Effectiveness of three antiviral agents against FIP virus in vitro Vet Rec 126 1990 556 558 2368297
151 Weiss R.C. Cox N.R. Martinez M.L. Evaluation of free or liposome-encapsulated ribavirin for antiviral therapy of experimentally induced feline infectious peritonitis Res Vet Sci 55 1993 162 172 8235082 10.1016/0034-5288(93)90076-R PMC7131103
152 Povey R.C. In vitro antiviral efficacy of ribavirin against feline calicivirus, feline viral rhinotracheitis virus, and canine parainfluenza virus Am J Vet Res 39 1978 175 178 204229
153 Weiss R.C. Cox N.R. Boudreaux M.K. Toxicologic effects of ribavirin in cats J Vet Pharmacol Ther 16 1993 301 316 8230401 10.1111/j.1365-2885.1993.tb00177.x PMC7167023
154 Zeidner N.S. Myles M.H. Mathiason-DuBard C.K. Alpha interferon (2b) in combination with zidovudine for the treatment of presymptomatic feline leukemia virus-induced immunodeficiency syndrome Antimicrob Agents Chemother 34 1990 1749 1756 2178336 10.1128/aac.34.9.1749 PMC171917
155 Weiss R.C. Cox N.R. Oostrom-Ram T. Effect of interferon or Propionibacterium acnes on the course of experimentally induced feline infectious peritonitis in specific-pathogen-free and random-source cats Am J Vet Res 51 1990 726 733 2159739
156 Cantell K. Pyhala L. Circulating interferon in rabbits after administration of human interferon by different routes J Gen Virol 20 1973 97 104 4356685 10.1099/0022-1317-20-1-97
157 Koech D.K. Obel A.O. Efficacy of Kemron (low dose oral natural human interferon alpha) in the management of HIV-1 infection and acquired immune deficiency syndrome (AIDS) East Afr Med J 67 1990 64 70 2226235
158 Tomkins W.A. Immunomodulation and therapeutic effects of the oral use of interferon-α: mechanism of action J Interferon Cytokine Res 19 1999 817 828 10476925 10.1089/107999099313325
159 Schellekens H. Geelen G. Meritet J.-F. Oromucosal interferon therapy: relationship between antiviral activity and viral load J Interferon Cytokine Res 21 2001 575 581 11559435 10.1089/10799900152547830
160 Ueda Y. Sakurai T. Yanai A. Homogeneous production of feline interferon in silkworm by replacing single amino acid code in signal peptide region in recombinant baculovirus and characterization of the product J Vet Med Sci 55 1993 251 258 7685640 10.1292/jvms.55.251
161 Mochizuki M. Nakatani H. Yoshida M. Inhibitory effects of recombinant feline interferon on the replication of feline enteropathogenic viruses in vitro Vet Microbiol 39 1994 145 152 7515537 10.1016/0378-1135(94)90095-7 PMC7117494
162 Ishida T. Shibanai A. Tanaka S. Use of recombinant feline interferon and glucocorticoid in the treatment of feline infectious peritonitis J Feline Med Surg 6 2004 107 109 15123155 10.1016/j.jfms.2003.08.011 PMC7129501
163 Addie DD, Schaap I, Nicolson L, et al. The persistence and transmission of type I feline coronavirus in natural infections [abstract]. In: Abstracts of the Second International Feline Coronavirus/Feline Infectious Peritonitis Symposium. Glasgow, Scotland; 2002.
164 Addie D.D. Paltrinieri S. Pedersen N.C. Recommendations from workshops of the Second International Feline Coronavirus/Feline Infectious Peritonitis Symposium J Feline Med Surg 6 2004 125 130 15123158 10.1016/j.jfms.2003.12.009 PMC7129416
165 Addie DD, Jarrett O. Isolation of immune complexes in feline infectious peritonitis [abstract]. In: Abstracts of the IXth International Congress of Virology. 1993.
166 Addie D.D. Toth S. Feline coronavirus is not a major cause of neonatal kitten mortality Feline Pract 21 1993 13 18
167 Lutz H, Gut M, Leutenegger CM, et al. Kinetics of FCoV infection in kittens born in catteries of high risk for FIP under different rearing conditions [abstract]. In: Abstracts of the Second International Feline Coronavirus/Feline Infectious Peritonitis Symposium. Glasgow, Scotland; 2002.
168 Foley J.E. Pedersen N.C. The inheritance of susceptibility to feline infectious peritonitis in purebred catteries Feline Pract 1 1996 14 22
169 Gonon V. Eloit M. Monteil M. Evolution de la prevalence de l'infection a coronavirus feline dans deux effectifs adoptant des conduites d'elevage differentes Recueil Med Vet 1 1995 33 38
170 Horsburgh B.C. Brown T.D. Cloning, sequencing and expression of the S protein gene from two geographically distinct strains of canine coronavirus Virus Res 39 1995 63 74 8607285 10.1016/S0168-1702(95)00068-2 PMC7133993
171 Glansbeek H.L. Haagmans B.L. Te Lintelo R.G. Adverse effects of feline IL-12 during DNA vaccination against feline infectious peritonitis virus J Gen Virol 83 2002 1 10 11752695 10.1099/0022-1317-83-1-1
172 Christianson K.K. Ingersoll J.D. Landon M. Characterization of a temperature-sensitive feline infectious peritonitis coronavirus Arch Virol 109 1989 185 196 2558634 10.1007/BF01311080 PMC7086852
173 Gerber J.D. Ingersoll J.D. Gast A.M. Protection against feline infectious peritonitis by intranasal inoculation of a temperature-sensitive FIPV vaccine Vaccine 8 1990 536 542 2087874 10.1016/0264-410X(90)90004-6 PMC7131383
174 Gerber J.D. Pfeiffer N.E. Ingersoll J.D. Characterization of an attenuated temperature sensitive feline infectious peritonitis vaccine virus Adv Exp Med Biol 276 1990 481 489 1966441 10.1007/978-1-4684-5823-7_67
175 Gerber J.D. Overview of the development of a modified live temperature-sensitive FIP virus vaccine Feline Pract 23 1995 62 66
176 McArdle F. Bennett M. Gaskell R.M. Independent evaluation of a modified live FIPV vaccine under experimental conditions (University of Liverpool experience) Feline Pract 23 1995 67 71
177 Scott F.W. Copari W.V. Olsen C.W. Independent evaluation of a modified live FIPV vaccine under experimental conditions (Cornell experience) Feline Pract 23 1995 74 76
178 Fehr D. Holznagel E. Bolla S. Evaluation of the safety and efficacy of a modified live FIPV vaccine under field conditions Feline Pract 23 1995 83 88 10.1016/S0264-410X(97)00006-6 PMC7131199 9269053
179 Postorino-Reeves N.C. Vaccination against naturally occurring FIP in a single large cat shelter Feline Pract 23 1995 81 82
180 Postorino-Reeves N.C. Pollock R.V. Thurber E.T. Long-term follow-up study of cats vaccinated with a temperature-sensitive feline infectious peritonitis vaccine Cornell Vet 82 1992 117 123 1320554
181 Hoskins J.D. Taylor H.W. Lomax T.L. Independent evaluation of a modified live feline infectious peritonitis virus vaccine under experimental conditions (Louisiana experience) Feline Pract 23 1995 72 73
182 Fehr D. Holznagel E. Bolla S. Placebo-controlled evaluation of a modified life virus vaccine against feline infectious peritonitis: safety and efficacy under field conditions Vaccine 15 1997 1101 1109 9269053 10.1016/S0264-410X(97)00006-6 PMC7131199