Feline Infectious Peritonitis test NOT confirmatory for FIP

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Feline Infectious Peritonitis test NOT confirmatory for FIP

Postby malernee » Tue Nov 04, 2003 10:10 pm

Feline Infectious Peritonitis,©2001


Alice M. Wolf, DVM, Diplomate ACVIM, ABVP (Feline Practice)

INTRODUCTION

Feline coronavirus disease is a subject of considerable controversy and confusion. Cats are susceptible to infection with several members of the coronavirus group including porcine transmissible gastroenteritis virus (TGEV), canine coronavirus (CCV), and feline coronaviruses.1-4 Infection with TGEV or CCV causes inapparent infection and seroconversion (development of coronavirus antibodies) in cats under experimental conditions, however, natural infection with these viruses is probably rare.1,3 However, canine coronavirus has been found to produce a syndrome that is clinically identical to FIP under experimental conditions.

Many antigenically similar feline coronavirus (FCoV) strains have been isolated from domestic cats.4,5 Feline coronaviruses vary widely in their spectrum of infectivity and virulence. Feline coronavirus isolates of low virulence that are not systemically invasive and replicate only in mature intestinal epithelial cells have been called feline enteric coronaviruses (FECV).4,5 Feline enteric coronaviruses usually cause only mild, self-limiting diarrheic illness in young cats. More virulent, invasive strains of feline coronavirus produce the clinical disease syndrome called feline infectious peritonitis (FIP) and these virulent isolates are known as feline infectious peritonitis viruses (FIPV).3,4 Virulence varies markedly among the FIPVs because some FIPV isolates consistently produce severe disease and others rarely do so.3,4 The virulence of FIPVs is apparently related to their ability to infect and replicate within macrophages.3-5 The "S" protein on the viral envelope is believed to be responsible for viral attachment, membrane fusion, and virus-neutralizing antibody production.6 However, this distinction is artificial and there is considerable experimental evidence accumulating that apparently "enteric" intestinal coronaviruses rapidly mutate and can develop the pathologic and invasive characteristics of "FIP-type" coronaviruses.5a This most likely accounts for the sporadic occurrence of FIP in coronavirus endemic catteries as well as in cats living in isolated environments that develop FIP late in life. There is also evidence that these "enteric" viruses can be found in systemic circulation thus confounding interpretation of even highly sensitive tests like the PCR.5b Recent studies of cat populations with endemic coronavirus infection (eg, catteries) have demonstrated that the major risk factors for the occurrence of FIP are cat population density, the presence and magnitude of coronavirus shedding individuals in the population, and the concentration of genetically more FIP-susceptible lines of cats in the population.5c It is likely that it is the infection and reinfection with coronaviruses generally among cats (as opposed to the spread of an "FIP" virus among cats) that is responsible for the occurrence of FIP in an individual. Any cat that carries any coronavirus is potentially at risk for developing FIP and 30% of household pet cats and 80-90% of cattery cats carry feline coronavirus.

EPIZOOTIOLOGY

FCoV is shed in the secretions and excretions of infected cats.7,8 Feces and oropharyngeal secretions are the most likely sources of infectious virus because large quantities of FCoV are shed from these sites early in the course of infection, usually before clinical signs of FIP appear.8,9 Infection is acquired from acutely infected cats by the fecal-oral, oral-oral, or oral-nasal route.8

Contrary to earlier reports10, recent evidence suggests that FCoV is relatively stable in the environment.9 Dried virus in a 21o C (70o F) environment can remain infectious for at least six weeks.9 Under ideal conditions, fomites and environmental contamination may be sources of contagion for several months. Fortunately, FCoV is readily destroyed by most common disinfectants and detergents and thorough cleaning will substantially reduce the concentration of infectious virus.10

FIP affects both wild and domestic cats.10 In domestic cats, males and females are affected equally but the incidence of FIP is age related and biphasic.10 Cats 6 to 12 months of age have the highest incidence, probably because of exposure and infection of young, susceptible individuals.10 FIP remains fairly common in cats up to 5 years of age but there is a noticeable decline in the incidence of disease in middle age.10 FIP incidence increases again in cats over 13 years10, perhaps due to a decline in cell-mediated immunity (CMI) in these aged individuals.

FIP tends to affect cats bred and/or raised in catteries or multiple cat environments more frequently than those from single cat households. Multiple cat environments are more likely to contain shedding FCoV carrier cats and environmental sources of infectious virus resulting in prolonged exposure of susceptible kittens. Stress, crowding, poor sanitation, parasitism, and concurrent diseases, particularly immunosuppressive diseases such as feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV), may also increase the impact of FIPV on cats in these environments.

PATHOGENESIS

Course of infection

Experimental studies show that FIPV is found in the tonsils and small intestinal mucosa within 24 hours of ingestion.7 Viral infection of the cecum, colon, mesenteric lymph nodes, and liver occurs over the next 14 days.7 Further systemic spread to any body organ or system occurs as the disease progresses.

Feline infectious peritonitis is an immune complex mediated disease and systemic antibodies are not protective.4,5,9,11 Pre-existing circulating coronavirus antibodies accelerate disease symptoms and cats do not die of FIP unless and until they make antibodies to the virus (antibody-dependent enhancement, ADE).4-6 In ADE, binding or opsonization of virus-antibody complexes by monocytes or macrophages results in infection of these cells rather than virus neutralization.6 Virus-infected phagocytic cells disseminate FIPV infection to distant sites.5

The course of disease appears to be established very quickly following pathogenic FCoV infection. The development of CMI is the most crucial factor in determining the ultimate outcome of FIPV infection.4,5,12 Cats that produce humoral antibodies but fail to generate an effective CMI response develop effusive FIP.4,5 Experimental evidence demonstrates that cats with non-effusive FIP often have preceding, transient effusive disease.4 Thus, noneffusive FIP is believed to result from a partially protective CMI response that is unable to wall off and contain the virus.4

Cats that mount a successful and rapid CMI response apparently do not develop active pathogenic FCoV disease although they may harbor latent virus for some period of time.4,5 In fact, the presence of low level of viremia apparently maintains their CMI status (premunition immunity).4 These recovered "immune carriers" are not ill but may have the potential to reactivate their latent infection if immunosuppressed.4 Although not proven under experimental conditions, it is suspected that immune carriers may periodically shed infectious FCoV and may be a source of infection for naive cats.8 If immune carriers completely clear the FCoV infection they may lose their CMI.4 If CMI is lost but humoral immunity is maintained, these cats may then be hypersensitive to challenge-exposure with virulent virus.4

Predisposing factors

Other host factors are important in determining the outcome of infection with FCoV. Genetic control of macrophage susceptibility to viral infection has been demonstrated for some diseases.3 Although there are no specific domestic feline breeds with a known predisposition to FIPV infection, the genetically monomorphic cheetah is very susceptible to FIP infection and disease.3 Recently, enhanced susceptibility to FIP has been demonstrated in some lines of Persian and Birman cats.12a It is therefore apparent that enhanced pathogenic FCoV susceptibility is present in some highly inbred populations of domestic cats. Conversely, enhanced resistance to FIP may be present in individuals in these same populations and it may be possible to reduce the incidence of FIP in coronavirus endemic catteries if the breeders are willing to select breeding individuals from lines that are more resistant to disease.

Immunosuppression may reactivate latent FIPV in immune carrier cats (assuming these actually exist). In experimental studies, suspect latent FIPV immune carrier cats that were subsequently infected with FeLV often develop active FIP disease.4 However, the administration of large doses of corticosteroids alone did not reactivate latent pathogenic FCoV.4 These differences may occur because corticosteroids have a greater immunosuppressive effect on the humoral immune system whereas FeLV has greater potential to suppress CMI. Alternatively, as suggested by the experimental study previously cited,5a it may be that FeLV coinfection merely enhanced the mutation rate of the intestinal coronavirus and promoted the appearance of a more pathogenic mutant viral variant.

As mentioned above, superimposed FeLV can modulate the appearance of FIP under experimental conditions and FeLV has long been considered a common concurrent disease and predisposing factor for naturally-occurring FIP in cats.4,13 A more recent report suggests that FeLV is not significantly more common in FIP-infected cats than in the sick cat population in general.13 Feline leukemia virus and FIP both are diseases of friendly cat populations and cause substantially more disease in catteries or cluster households than in single pet homes. Because FeLV has now been virtually eradicated from most cattery populations with test and removal procedures, the discrepancies in reports associating these two diseases may result from differences in time, sampling populations, or epidemiologic patterns.

CLINICAL PRESENTATION

There are two major forms of FIP. An effusive form characterized by high protein fluid accumulation in body cavities and a noneffusive form characterized by pyogranulomatous lesions in any body organ or system. Signs common to both forms of FIP include fluctuating antibiotic-unresponsive fever, lethargy, anorexia, and weight loss.5,10

Effusive FIP is caused by Arthus-type, immune-complex damage to small blood vessels that permits leakage of serum protein and fluid into body cavities. Cats with effusive FIP usually develop progressive, nonpainful abdominal distention due to peritoneal fluid accumulation.5,10 Pleural fluid is present in up to 25% of cats with effusive FIP.10 If a sufficient amount of fluid is present in the pleural space, these cats may exhibit exercise intolerance and dyspnea. Pericardial or scrotal fluid accumulation has also been observed in cats with effusive FIP.10,14

In noneffusive FIP, vascular damage may produce mild, subclinical effusion early in the course of disease. The major lesions result from immune recruitment causing localized perivascular infiltrations of inflammatory cells (neutrophils, macrophages, lymphocytes, and plasma cells) in tissue parenchyma. These cellular infiltrates cause local tissue necrosis and disruption of normal organ function.

Because nonspecific signs predominate and any organ or system may be affected alone or in combination, the most consistent clinical feature of noneffusive FIP is its variability. The most common sites for lesions in cats with noneffusive FIP are the eyes, central nervous system (CNS), and parenchymatous abdominal organs.5,10,15 Ocular lesions include anterior uveitis, keratic precipitates, hyphema, hypopyon, chorioretinitis, retinal hemorrhages, and retinal detachment.10 Any part of the CNS can be affected and reported signs include seizures, vestibular disorders, ataxia, paresis, behavioral changes, peripheral neuropathies, hyperesthesia, and urinary incontinence.10,15,16 Damage to internal parenchymal organs causes a plethora of signs resulting from the site of the lesions, degree of organ damage, and resultant organ dysfunction.

LABORATORY FINDINGS

Hematologic findings are nonspecific and variable depending on the severity and progression of FIP and other concurrent problems. A neutrophilic leukocytosis and mild, normocytic, normochromic anemia are present in many cats.10 Severe anemia may be found in cats with concurrent FeLV infection.10 Lymphopenia (< 1500/µl) is another common finding.17a

Biochemistry profiles reveal elevated serum protein values in approximately 50% of cats with effusive FIP and 70% of cats with noneffusive FIP.1,10 The increase in serum protein is due to a polyclonal increase in the globulin fraction resulting from uncontrolled inflammatory protein and antibody production in response to the persistent viral immune stimulus.1,10,17 Serum protein electrophoresis has been recommended by some laboratories as a confirmatory test for FIP.1 Although protein electrophoresis can confirm the polyclonal nature of the globulin elevation, there is no FIP-specific pattern and any persistent immunologic stimulus can produce similar findings.

A recent report17b cites criteria for the antemortem diagnosis of FIP as follows:

"In cats with clinical signs attributable to FIP, a combination of:

1. Lymphopenia (<1.5 x 106/Fl)
2. Feline coronavirus antibody titer of $1:160
3. Hyperglobulinemia of > 5.1 g/dl


had a positive predictive value of 88.9% for FIP.

If a cat with signs suggestive of FIP did not fulfill all three of the above criteria, there was a 98.8% probability that the cat did not have FIP."

I disagree strongly with the statements above because they are far too restrictive in ruling out FIP and too loose in ruling in FIP. In particular, since only 70% of cats with the dry form of FIP have hyperglobulinemia, how can one claim that the absence of this finding rules out FIP in 98.8% of patients? Routine coronavirus antibody titers are highly variable in normal and affected cats. In addition, there is great variability in results on the same sample sent to different laboratories and in some laboratories when the same sample is tested on different days. Finally, lymphopenia, while it occurs in many cats, is present in far less than 98.8% of confirmed FIP cats. I urge you not to use these far too rigid criteria to "rule out" or "rule in" FIP on your differential list. Diagnosis of this disease is, unfortunately, just NOT that simple.

Other biochemical findings in FIPV-infected cats depend upon the presence and severity of internal organ involvement. It is often difficult to differentiate primary changes caused by FIPV from the secondary effects of general disease debilitation. Elevated BUN and creatinine levels may reflect dehydration and prerenal azotemia or may indicate FIP-associated renal parenchymal damage. Increased serum liver enzyme and bilirubin values may be caused by pyogranulomatous liver involvement or be secondary to hepatic lipidosis caused by chronic anorexia.

FIP effusion fluid is thick, tenacious, straw-colored to deep golden, and clear to slightly cloudy.1,10 Fluid analysis reveals a nonseptic, exudate (specific gravity 1.017 to 1.047) with a high protein content (5-12 g/dl) and moderate cellularity.1,10 Cytologic examination demonstrates nondegenerate neutrophils, macrophages, variable numbers of lymphocytes, plasma cells, and a few red blood cells.1 A study of protein electrophoresis of pleural and peritoneal effusions from cats demonstrated that a fluid albumin content of >48% or albumin/globulin ratio of greater than 0.81 was highly predictive in ruling out FIP as a cause for the fluid accumulation.18 Alternatively, a gamma globulin fraction of 32% or greater was highly predictive in indicating that the effusion was due to FIP.18 Because FIP effusion fluid is produced by vascular leakage, the effusion protein pattern roughly parallels the serum electrophoretic pattern.1

Cerebrospinal fluid (CSF) obtained from cats with FIP in the CNS may be normal in patients with focal or subependymal lesions. If meningeal involvement is present the CSF often contains increased protein (> 25 mg/dl) and inflammatory cells (> 5 cells/µl).16 Neutrophils and/or lymphocytes predominate the pleocytosis along with lesser numbers of macrophages and plasma cells.16, 16a

Coagulation profiles should be considered prior to performing biopsy procedures in FIP-infected cats. These studies often reveal prolongation of prothrombin and partial thromboplastin times and increased levels of fibrin degradation products indicative of low grade disseminated intravascular coagulation that may interfere with adequate hemostasis during surgery.17

DIAGNOSIS

Clinical diagnosis

A diagnosis of FIP should be considered in all cats with vague signs of illness, antibiotic-unresponsive fever, malaise, and chronic wasting. Unfortunately, there are a number of other diseases that can cause similar signs including (but not limited to) neoplasia, systemic mycoses, inflammatory bowel disease, hepatic disease, renal disease, retroviral diseases, and toxoplasmosis. A diagnosis of the effusive form of FIP can be made with some confidence because of the distinctive characteristics of the effusion fluid. However, the variability and nonspecific nature of clinical signs and lack of distinctive laboratory findings make antemortem diagnosis of the noneffusive form of FIP a formidable challenge. Supportive historical, clinical, and laboratory findings may lead the clinician to strongly suspect FIP as the causative agent of disease, however, organ biopsy is the only diagnostic procedure that can confirm this diagnosis in the living cat.1

Coronavirus serology

The most commonly available serum so-called "FIP test" is only a test for the presence of antibodies generated against any type of coronavirus. Commercial laboratories perform the majority of these tests and there is one serum ELISA coronavirus antibody test (IDEXX) available for in-clinic use. With one possible exception (see later, below), none of the currently available tests are able to differentiate antibodies generated against FECVs (or other coronaviruses: TGEV, CCV) from antibodies developed in response to infection by FIPVs.1,2,12,19, 19a Because of this, a "positive" test means only that the cat has been exposed to some coronavirus at some time.1 It does not mean that the cat has been or is currently infected with FIPV. Coronavirus antibody titers in purebred cats are particularly difficult to interpret because very high titers can frequently be found in clinically healthy cats.19a

In addition, cats vaccinated with some types of modified live virus vaccines can develop antibodies against bovine serum components used in vaccine virus cultures.1,19 These antibodies can cross react in some test systems producing a "positive" test result. Cats vaccinated with the Pfizer intranasal FIPV vaccine may develop systemic antibodies that react positively with this test. Finally, test methodologies differ from laboratory to laboratory.1 Therefore, coronavirus antibody titers obtained from different laboratories cannot be accurately compared.

Alternatively, a cat with histopathologically confirmed FIP may have a negative coronavirus antibody titer.1, 19a False negative results can occur because of the insensitivity of some test systems to low antibody levels, fulminating peracute infection with little opportunity for antibody generation, exhaustion of antibody production in the terminal stages of disease, or as a result of antigen-antibody complexing that leaves little antibody free to react in the test system.10

In summary, a "positive" coronavirus antibody test does not confirm that the cat has FIP and a "negative" coronavirus antibody test does not rule out a diagnosis of FIP.

PCR (polymerase chain reaction) test for FIPV

At least one commercial veterinary laboratory currently offers a PCR test for FCoV. The test is most commonly performed on blood, although body cavity effusions and tissue samples can also be tested. Properly performed, PCR is a very sensitive and specific technique for detecting small amounts of viral nucleoprotein. Nucleoprotein sequences unique to a specific organism can be identified and the quantity amplified by the test methodology so that it can be detected. At present, no nucleoprotein sequences unique to pathogenic FCoV (ie, not also present in nonpathogenic FCoV) have been identified. Thus, because some nonpathogenic FCoVs are capable of systemic invasion, finding coronavirus protein in the systemic circulation is NOT confirmatory evidence that the protein found is due to infection with a pathogenic (FIP-causing) coronavirus. In addition, because the test is so sensitive, contamination with stray DNA resulting in a false positive test is a significant concern if stringent quality control is not practiced in the laboratory. Finally, a report from the laboratory contains the following caution: "The biology of pathogenic FCoV is such that infected cats may not be viremic; therefore samples derived from thoracic or abdominal fluids, peritoneal lavage, or needle biopsies of a lesion are preferable to blood for detecting FIP carrier cats". Cats with noneffusive disease (the most difficult group to diagnose, the ones which we would most like a test to specifically detect) often are not viremic. If classical, high protein, nonseptic exudate is present, the PCR test is probably not needed for diagnosis. Histopathology or immunohistochemical evaluation of needle biopsies should also be sufficient for diagnosis. It is therefore difficult to see what advantage this test has over other more readily available laboratory methods of diagnosis.

The "7B protein" test (FIPSE "FIP-specific ELISA Test?)

This test is performed by Antech Laboratories. The company states that they have identified a specific protein (7B protein) that is important in pathogenic coronavirus infectivity that is only produced by FIP-producing coronaviruses. This test looks for antibody generated against this protein. Very limited controlled experimental studies (10 cats) demonstrated that a standard coronavirus antibody test became positive after cats were vaccinated with an experimental FIP vaccine from a benign FIP strain but that the 7B ELISA test did not become positive until after challenge with one strain of virulent FIP virus. Unfortunately, further recent experimental studies have shown that not all FIP-type coronaviruses have an active 7B and that some non-FIP coronaviruses do have an active 7B so this test, again, is not specific for FIP-coronaviruses regardless of what company advertising may say. In addition, like all other antibody tests, antibody levels are not predictive for morbidity or mortality from FIP.

TREATMENT

Conventional therapy

A number of "successful" treatments for FIP have appeared in the literature only to be disproved over time. It has been difficult to evaluate therapeutic success because some antemortem diagnoses of FIP are questionable (resulting in some "cured" patients that never actually had the disease) and because cats may rarely undergo spontaneous remission of an active FIPV infection.

There is presently no known effective treatment for FIP. Therapy is palliative and is directed at suppressing the immune-complex component of the disease.22 The best candidates for treatment are FeLV-negative cats with effusive disease that are not anorectic and are still in good physical condition. Combination therapy with prednisolone (4 mg/kg PO q24h) and cyclophosphamide (2-4 mg/kg PO q24h x 4 days/week) may produce temporary disease remission in a small number of cats.22 Some clinicians also include a broad-spectrum antibiotic is in the treatment regimen.

Recent developments

Some of the newer immunomodulating agents, recombinant DNA human alpha interferon (rHuIFN-") and feline fibroblastic beta interferon (FIFN-$), have shown significant antiviral effects against FIPV in vitro studies.23 In similar studies, the antiviral agents, ribaviran (Virazole®) and adenine arabinoside (Vidarabine®) appear to be effective against FIPV, however, ribaviran is toxic to feline cells at therapeutic levels.24,25 The antiviral agents AZT (Retrovir®) and acyclovir (Zovirax®) were not effective against FIPV.25 Amphotericin B, a polyene macrolide antibiotic used in the treatment of systemic mycoses, appears in vitro to have antiviral effects against FIPV.25 Unfortunately, the nephrotoxicity of amphotericin B seriously limits its potential as a therapeutic agent in this disease.

In clinical trials, rHuIFN-" alone or in combination Propionibacterium acnes (Immunoregulin®) did not protect experimentally FIP-infected cats against fatal disease but marginally extended their survival time (mean: approximately 10 days).26 Propionibacterium acnes was ineffective as a single agent in these studies.26 Neither of these agents appear to have value in the primary treatment of FIP but rHuIFN-" may be useful as adjunctive therapy.

The most promising approach to effective treatment of FIP is combination therapy with an antiviral agent to inhibit viral replication and an immune response modifier to enhance protective immune defenses.25 Combinations of ribaviran and rHuIFN-" appear to have significant synergistic anti-FIPV in vitro effects.24 Unfortunately, further studies have not shown good clinical results with this combination therapy in naturally or experimentally infected cats.

PREVENTION

Environmental control

The characteristics and persistence of FIPV in the environment have been described above. The coronavirus antibody test may be of value in determining the coronavirus exposure rate in a closed population of cats.1 If the population is negative, the likelihood of FIP is negligible. Unfortunately, the coronavirus seropositivity rate in most multiple cat environments is 80 to 90% and coronavirus infections are ubiquitous in cats.10 Using the coronavirus antibody test with a goal of establishing and maintaining a coronavirus-free commercial cattery is overly optimistic.

Kittens born to FCoV-carrier queens acquire maternal antibodies within the first 24 hours postpartum. Maternal antibody titers wane over the next 4-6 weeks at which time two patterns emerge.4,5,9 If coronavirus antibody levels continue to decline, the kitten has not been exposed to FCoV.5 Rising FCoV antibody levels reflect the response to natural exposure to FCoV.4,5 Kittens may contract FCoV from the queen in utero (rare) or during the period of lactation, or from other contact immune carriers in the household.4

A study performed in FIP-affected, coronavirus seropositive catteries compared the seropositivity rates of kittens raised "under foot" (allowed to mix with all other cats), kittens isolated with the queen, and kittens isolated from all adult cats, including the queen, from the age of 4-6 weeks. Of kittens raised "under foot" and kittens raised with the queen, 52% and 30% respectively were coronavirus seropositive at 12-16 weeks of age.27 All kittens isolated from all adults in the household were coronavirus seronegative at 16 weeks of age.27 This suggests that transmission of coronaviruses to kittens often takes place horizontally after birth by individuals other than the queen.27 Because coronaviruses can be transmitted indirectly, strict attention to hygiene is also essential to achieve success with this method. Control of FCoV is also related to good nutrition, good general health status, sanitation, and other cattery management procedures.10

Vaccine development

Traditional approaches to disease prevention by parenteral vaccination have failed with FCoV because humoral antibody is sensitizing rather than protective.4,5,9,11 In addition, cats that appear to be solidly immune to one or more strains of FCoV can develop FIP when inoculated with another strain.4 The ideal FCoV vaccine should contain an avirulent FCoV strain that is still invasive, is cross protective against all strains of FCoV, and could persist long enough to induce strong cellular immunity.1,4,5,28 The route of vaccination appears to be important because some FCoV strains are protective if administered intranasally but not if given subcutaneously.28 Intranasal vaccination would have the additional advantage of inducing local IgA antibody production on mucosal surfaces where the initial penetration of virulent virus is most likely to occur.

Investigators have isolated a temperature-sensitive strain of FCoV.29 This FCoV strain replicates well at the lower 31o C (87o F) temperature of the upper respiratory tract but not at higher 38-39o C (100-102o F)¬ systemic body temperatures.29 This strain would seem to be ideally suited to intranasal inoculation and its temperature sensitivity would limit systemic invasion.

A commercial FIP vaccine using this temperature-sensitive virus strain is available from Pfizer (formerly - Norden or SmithKline Beecham). Experimental trials by the manufacturer reported reasonable efficacy against several strains of pathogenic FcoV and field studies by the manufacturer reported few adverse effects. However, a report by Drs. Chris Olsen and Fred Scott at Cornell University did not confirm the efficacy claims of the manufacturer.30 In addition, the development of antibody-dependent enhancement of infection in vaccinated cats was demonstrated in several of their studies. The manufacturer insists that the reduced efficacy of the vaccine seen Cornell studies was due to the severity (dose and virulence) of virus challenge under the conditions of the experiments and that virus exposure of this magnitude does not occur in nature. The facts remain that not all of the control (unvaccinated cats) developed FIP following virus challenge while 100% of the vaccinated cats developed the disease and some of them had accelerated disease associated with ADE. Therefore it is unlikely that the severity of the challenge alone accounts for the vaccine failure. In addition, we do not know the true level of virus exposure that occurs in the course of natural infection. It may in fact be as great or greater than that used in the vaccine challenge studies. On the other hand, although anecdotal occurrences have been reported, antibody-dependent enhancement of disease associated with FCoV vaccination has not, as yet, been scientifically confirmed in the field so that it may be primarily a laboratory phenomenon.

Another manufacturer sponsored study of vaccine efficacy was performed in a "no kill" animal shelter.31 Five hundred (500) healthy, FeLV and FIV negative cats, 16 weeks of age or older, were divided into two approximately equal groups and either vaccinated with Primucell-FIP® or sham vaccinated before introduction into the shelter population. All cats that died over the period of 16 months of observation, were subjected to complete necropsy examination. Overall death losses due to all causes were similar in the two groups. Of the FIP-vaccinated cats, only 2 had evidence of FIP at the time of death. Of controls (sham-vaccinated), 8 had evidence of FIP at the time of death indicating a reduction in death losses due to FIP. The drawback to this study was that these cats were all coronavirus antibody negative before vaccination. Therefore, they do not accurately represent the population of cats (particularly in multiple cat households) likely to receive vaccination in practice. On the practical side, one might also wonder what the cost/benefit ratio is to reduce the number of deaths by 6 in a group of 500 non-owned cats.

An further manufacturer sponsored study was performed using Primucell-FIP® in 16 week old SPF kittens.32 Twenty vaccinated and 20 control (unvaccinated) kittens were challenged 28 days post vaccination orally with FIPV (DF-2 strain) and observed for signs of illness for 8 weeks. Kittens becoming seriously ill were euthanized before the end of the study. The remainder were euthanized at the end of the 8 week observation period and all were subjected to complete necropsy and histopathologic examination. In the vaccinated group, 1 of 20 kittens succumbed to FIP during the observation period, however, FIP lesions were found in 6 of them (including the 1 dead kitten) on necropsy examination. In the control (unvaccinated) group, 5 of 20 kittens died from FIP following challenge and 12 of them (including the 5 dead kittens) had FIP lesions at necropsy examination. There are several drawbacks to this study. The study used SPF kittens which are quite different from conventional kittens. The challenge virus was the DF-2 strain which is the same strain from which the vaccine was developed. The efficacy of the vaccine is likely to be best against a homologous strain of virus. Finally, the observation period was only 8 weeks. Clearly, we know that it may take many more weeks, months, or even years for pathogenic FCoV to cause disease. The presence of FIP lesions in many more kittens than had shown clinical signs of disease in this study suggests that disease may have been developing in more kittens than had yet been observed to be ill. Therefore it is difficult to accurately assess the findings of this study.

The question that each clinician must ask of him/herself is whether FIP represents a significant risk to the average household pet in his/her practice. Serologic screening reveals that only about 30% of domestic (nonpurebred) cats in pet households (compared to 80 - 90% of purebred cats in catteries) have antibodies against coronavirus. It is this author's opinion that there is little risk of exposure to or developing FIP in household pets in a suburban environment. It is questionable whether a vaccine against FIP is required under these circumstances.

Cattery cats are those at greatest risk and with the highest incidence of disease. However, if the vaccine has the potential to sensitize cats to enhanced disease as suggested by the Cornell studies, it may not be appropriate to use it under conditions where exposure to high concentrations of infectious virus is likely. In addition, the vaccine is not licensed for use in cats less than 16 weeks of age (because significant efficacy cannot be demonstrated in younger kittens). As demonstrated in the studies by Addie et al, by 16 weeks of age, over 50% of kittens raised in coronavirus endemic, multiple cat environments in contact with adult cats will already be infected with coronavirus.27 If the objective of vaccination is to prevent coronavirus infection, there is no advantage to vaccination after infection has already occurred. Therefore, if a breeder wanted to include FIP vaccination in a cattery management program, it should be done only in combination with the strict isolation program previously described. And if the isolation program is followed assiduously, kittens will be coronavirus free at the time of sale to a new home. If at this time, the kitten is going to a private home without other coronavirus carriers, the benefits of coronavirus vaccination are questionable. If the kitten is likely to be exposed to high levels of coronavirus (eg, remaining in or going to another endemic cattery), the risks and possible benefits of vaccination against FIPV must be weighed carefully.

cont.
malernee
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Postby malernee » Tue Nov 04, 2003 10:11 pm

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