Feline Infectious Peritonitis
updated information for breeders Susan Little DVM, Diplomate ABVP (Feline) CFA Health Committee

One of the most poorly understood and enigmatic feline viruses is the feline coronavirus - the virus responsible for feline infectious peritonitis (FIP).

It is no exaggeration to say that this is one of the most feared diseases in catteries. Many catteries that remain operative for several years will have a brush with FIP. Despite the fact that this disease is a shared experience in the cat fancy, affected catteries are wrongly feared and ostracized. All breeders need to make efforts to understand this disease and how to control it.

While the first description of feline infectious peritonitis was reported by Dr. Jean Holzworth in 1963, there are reports of clinical cases that are likely FIP going back to1914. Even though we have known about this virus for a long time, we know frustratingly little about it. However, much new research has been done in the past 5 years that is slowly shedding more light on this ever-present feline health problem. This article is designed to present some of the newer information and change some of the older ideas still found in print and other media.

Feline coronavirus operates differently from any other feline virus in several important ways: a) systemic antibodies have no protective function for the cat and may play a role in the disease FIP itself b) antibody titres are meaningless for diagnosis of FIP or prognosis c) a vaccine is available, but there is no consensus on its efficacy or safety First, some notes on terminology.

FIP is the term for clinical disease associated with feline coronavirus infection.
The common benign form of feline coronavirus is referred to as FECV (feline enteric coronavirus).
When FECV has mutated into a disease-causing form, it is then referred to as FIPV (feline infectious peritonitis virus).
Feline coronaviruses in general are referred to as FCoV.
FECV is a very common, highly infectious feline virus. It belongs to the genus Coronavirus, which has members that infect other species (man, swine, cattle, birds, dogs). The majority of cats with FECV (about 95% or more) remain healthy. But in a small number of cases, FECV infection is the first step in a chain of events leading to FIP.
This happens because coronaviruses are made of large numbers of nucleotides, the basic unit of genetic material, and they are very prone to mutations. As a virus reproduces itself, errors are made in copying these nucleotides. The more nucleotides, the more errors are possible. While most of these errors are harmless, some will have the effect of giving FECV the ability to cause disease. These mutant FECV strains are called FIPV.

Recent research has shown that mutant FECVs arise within an individual cat. Thus, we now know that the vast majority of cats do not "catch" FIP, but they develop it themselves from their own mutant FECV. Transmission of FIP from cat to cat is considered to be rare. This fact has caused leading FIP researchers to state that cats who are ill with FIP are unlikely to be a risk to other cats and thus do not need to be isolated.

It has been estimated that in multi-cat households where FECV has been introduced, 80-90% of all the cats will be infected. Catteries are especially likely to be FECV positive since traffic of cats and kittens in and out of the establishment is common.
However, the incidence of cases of FIP is quite low in comparison. Generally, most catteries experience far less than 10% losses to FIP over the years. Rare instances have been documented where an apparent epidemic of FIP is associated with mortality rates of over 10% in a short period of time. One possible factor in these epidemics is the shedding of virulent virus, an uncommon situation. Usually, losses are sporadic and unpredictable. The peak ages for losses to FIP are from 6 months to 2 years old (with the highest incidence at 10 months of age). Age-associated immunity to FIP appears to be possible. Transmission of FIP from a queen to her unborn kittens has not been shown to occur.

What are the factors that predispose a small percentage of cats with FECV to the development of FIP? Research is currently trying to find more answers to this question, but some facts are becoming clear. Dr. Janet Foley and Dr. Niels Pedersen of the University of California at Davis have identified three key risk factors: genetic susceptibility, the presence of chronic FECV shedders, and cat-dense environments that favour the spread of FECV.

A genetic predisposition to the development of FIP was identified by Drs. Foley and Pedersen in 1996. They examined pedigree and health data from 10 generations of cats in several purebred catteries and found that the heritability of susceptibility to FIP could be very high (about 50%). It is likely a polygenetic trait rather than a simple dominant or recessive mode of inheritance. Inbreeding, by itself, is not a risk factor. Selecting for overall disease resistance is a helpful tool for breeders. The likely defect in immunity to FIP is in cell-mediated immunity. Therefore cats that are susceptible to FIP are also likely susceptible to some other infections as well, especially fungal and viral infections. This finding gives breeders the ability to achieve success in reducing the risk of FIP by using pedigree analysis to select breeding cats from family backgrounds that have strong resistance to FIP and other infectious diseases.

Research has shown that there are two main patterns that occur with FECV infection. Most cats will become infected and recover, but will not be immune. They are susceptible to reinfection the next time they contact the virus. A small number of cats become infected but do not recover. They become persistent shedders of FECV in the cattery and are the source of reinfection for the other cats. Therefore, the key to eliminating FECV (and thus the risk of FIP) in a cattery would be the identification and removal of chronic shedders. Currently, however, there is no easy way to determine which cats in a cattery are persistent shedders. The traditional antibody titre for FECV cannot be used to determine which cats are chronic shedders. The most effective and practical tool is PCR analysis of feces for the presence of FECV, a test which is not yet widely available.

In addition to selecting disease-resistant breeding stock, breeders can initiate husbandry practices that discourage the spread of FECV and development of FIP. Cat-dense environments favour the transmission of the highly contagious FECV. Dr. Diane Addie of the University of Glasgow, Scotland, recommends that the ideal way to house cats in catteries is individually. However, since this is not always possible, she recommends that they be kept in stable groups of no more than 3 or 4. Kittens should remain in groups of similar ages and not be mixed with adults in the cattery. Any measures that reduce environmental and social stress in the cattery population will have a beneficial effect.

FECV is spread primarily by the fecal-oral route and, to a lesser degree, through saliva or respiratory droplets. The virus can persist in the environment in dried feces on cat litter for 3 to 7 weeks, so scrupulous cleaning of cages and litter pans is important to reduce the amount of virus in the environment. It is important to have adequate numbers of litter pans available and that they be scooped at least daily and dumped and disinfected at least weekly. Litter pans should be kept away from food bowls and spilled litter should be regulary vacuumed up from the floor.

Dr. Addie has also described a method for early weaning and isolation of kittens born to FECV positive queens. It involves rigorous barrier nursing techniques to prevent the spread of the highly contagious FECV, and so is not for every breeder or cattery. The procedure involves first isolating the pregnant queen in a separate area to have the kittens. When they are 5-6 weeks old (at the time when their maternal immunity to FECV is waning), the kittens are removed from the queen and isolated by themselves. Some of the difficulties with this method involve the strict infection control procedures needed and possible difficulties in socializing kittens. When properly practiced, not only can FECV-negative kittens can be produced, but the kittens are often less prone to respiratory diseases and other common kitten ailments.

As with so many aspects of FIP, testing remains problematic. To date, there is no way to screen healthy cats for the risk of developing FIP. Antibody titres are poorly correlated with risk of FIP and should not be used to screen cats. As well as problems with interpretation of these antibody tests, there are problems with laboratory quality control. There are newer DNA-based tests offered by a few labs that are purported to be FIP-specific. However, these tests are considered unvalidated by experts as they have not been subjected to scientific scrutiny by researchers outside of the labs that offer them. In addition, there are no published studies that have identified the genetic difference between FECV and FIPV. An article was published by the Cornell Feline Health Center in 1998 warning that the so-called FIP-specific ELISA tests are based on insufficient data and the assays are not yet validated.

The fact remains that we have no screening test for FIP in well cats. Neither do we have a fool-proof way to diagnose FIP in a sick cat. The gold standard remains a biopsy or findings at necropsy. Recently, Dr. Andrew Sparkes and his colleagues at the University of Bristol, England, have suggested that combining several test results (globulin levels, lymphocyte counts) with clinical findings and antibody titre can help rule in or rule out FIP with some degree of certainty. It remains true, however, that a negative antibody titre does not rule out FIP. Neither does a positive antibody titre rule in FIP as a diagnosis. One benefit of the new DNA-based tests may be their use on body fluids, such as effusions from the chest or abdomen of a sick cat. If virus is found in these fluids, it strongly supports the presumptive diagnosis of FIP.

Probably one of the most controversial areas in any discussion of FIP is Primucell FIP, the vaccine made by Pfizer Animal Health, available since 1991. The vaccine is a modified-live termperature-sensitive viral mutant licensed for intranasal use in cats at least 16 weeks of age. The manufacturer recommends annual revaccination although no duration of immunity studies are available. The vaccine stimulates local immunity and will also produce an antibody titre. Evaluation of the risks and benefits associated with this vaccine is a difficult venture and has engendered much controversy.

Since FIP is a severe and fatal disease, the safety of any vaccine is a paramount consideration. Dr. Fred Scott of the Cornell Feline Health Center, concluded in a recently published paper, that the risks associated with the Primucell FIP vaccine are minimal in most situations. He notes that the vaccine has been in use for 7 years with no increase in the incidence of FIP. Troubling reports of a phenomenon called "antibody-dependent enhancement" (ADE) of infection arose from several labs, where cats vaccinated with FIP vaccines and challenged experimentally with virus developed accelerated disease instead of being protected. It is not known whether the phenomenon of ADE occurs in the real world and there is no easy way to find out. If it does occur, it is likely an uncommon event, but the possibility remains troubling.

On the other side of the issue, the benefits of the Primucell FIP vaccine appear to be small. The best reported efficacy for the vaccine is seen when FCoV negative cats at least 16 weeks old were vaccinated twice (3 weeks apart), in a study by Dr. Nancy Reeves published in 1995. In this study, FCoV antibody-negative cats were vaccinated before entering a large cat shelter where FIP was endemic. The vaccinated cats experienced a significantly lower mortality rate than unvaccinated cats. The efficacy of the vaccination was calculated to be 75% (preventable fraction).

In catteries where FIP is endemic, studies have shown the vaccine had no effect on the incidence of disease.
One reason may be that most kittens in catteries are infected between 6 and 10 weeks of age, long before the 16 weeks of age the vaccine is licensed for. Once a cat is infected with FCoV, the vaccine has no benefit. Some cattery owners have been using the vaccine at ages younger than 16 weeks to get around this problem. Dr. Johnny Hoskins has outlined a vaccination protocol for catteries experiencing FIP losses in kittens under 16 weeks of age. He recommends giving the vaccine at 9, 13 and 17 weeks with annual revaccination afterward. Use of this protocol must be made with the knowledge that no controlled studies have been done on kittens under 16 weeks of age and that this is an off label use. It would appear that the use of the vaccine according to the manufacturer's directions is limited to the vaccination of FCoV antibody-negative cats entering high risk situations, such as catteries and shelters.

UPDATES
Introduction by Janet Wolf

Over the past decade, The Winn Feline Foundation has taken a leadership role in investigating the causes, prevention, and treatment of feline infectious peritonitis. Early studies, conducted by Niels Pedersen and the staff at the University of California at Davis, focused on characterization of the disease. When the FIP vaccine was introduced, the Foundation helped fund a scientific evaluation of the vaccine by Dr. Fred Scott at Cornell University.

In 1994, Winn co-sponsored the First International FECV/FIP Conference in cooperation with the Center for Companion Animal Health at the University of California, Davis. Here, for the first time, breeders and practicing veterinarians had an opportunity to interact with the scientists and research veterinarians who were investigating these challenging coronaviruses. The researchers shared their findings, helping to increase the general body of knowledge about FIP. Work groups of breeders, practitioners and scientists conferred and came up with recommendations for catteries to reduce the incidence of FIP. These recommendations have helped many catteries improve conditions and limit the incidence of FIP.

Subsequently, the Winn Foundation has funded a series of studies by Drs. Diane Addie and Oswald Jarrett at the University of Glasgow, Scotland in which they have worked with breeders and other owners of multi-cat households in Great Britain to better understand the mode of transmission and how to raise coronavirus-negative litters. Other studies have included work in Switzerland by Hans Lutz and Daniella Fehr as well as studies which helped develop the polymerase chain reaction or PCR test for the detection of FIP.

A research team led by Dr. Niels Pedersen with the assistance of Dr. Janet Foley at the University of California, Davis (UCD) has undertaken a number of studies which have also increased our body of knowledge about FIP. Their first studies followed cats in eight catteries in an effort to characterize the disease outside the research environment. The Davis studies have added to our understanding of the disease in cattery situations, the role of inheritance, the effectiveness of some cattery management strategies and possible preventive strategies. While there is still much to learn, each new study gives us insights and information. At the end of this introduction is a partial list of the articles on FIP that have resulted from Winn funded research.

With this article, we begin a series of progress reports on Winn-funded FIP research and updates on new testing procedures. John August, MRCVS from Texas A&M University's College of Veterinary Medicine will be reporting on the new tests being commercially marketed for FIP detection. Other progress reports include an article submitted by Diane Addie, who has advocated isolation and early weaning strategies to reduce the incidence of feline infectious peritonitis in multi-cat situations such as catteries. The second progress report is by Janet Foley at UCDavis. It also explores the incidence of coronavirus in multi-cat environments and specifically assesses early weaning as a practical alternative in American catteries.

For further information:
Report from the International FIP/FECV Workshop, University of California, Davis, August 12-14, 1994, Feline Practice, Vol. 23, No. 3, May/June 1995.
(Copies are available from The Winn Feline Foundation for a donation of $10.00; in Spanish $15.00.)
"Risk Factors for Feline Infectious Peritonitis Among Cats in Multiple-cat Environments with Endemic Feline Enteric Coronavirus," by Janet E. Foley, DVM, MS, Amy Poland, Jeff Carlson, Niels Pedersen, DVM, PhD, JAVMA, Vol. 210, No 9, May 1, 1997.
"Patterns of Feline Coronavirus Infection and Fecal Shedding from Cats in Multiple-cat Environments," by Janet E. Foley, DVM, MS, Amy Poland, Jeff Carlson, Niels Pedersen, DVM, PhD, JAVMA, Vol. 210, No 9, May 1, 1997. "The Inheritance of Susceptibility to Feline Infectious Peritonitis in Purebred Catteries," by Janet E. Foley, DVM, MS and Niels Pedersen, DVM, PhD, Feline Practice, Vol. 24, No.1, January/February 1996.
"Evaluation of the Safety and Efficacy of Primucell-FIP Vaccine," F.W. Scott, DVM, PhD, W.V. Corapi, DVM, PhD, C.W. Olsen, DVM, PhD, Perspectives on Cats, Fall 1992.

New Tests Being Commercially Marketed for FIP Detection by John August, MRCVS Texas A&M University's College of Veterinary Medicine

The accurate diagnosis of feline infectious peritonitis (FIP) remains a challenge for practicing veterinarians. Similarly, cat breeders remain frustrated about their inability to identify cats that have been exposed to, and which may be carriers of, pathogenic feline coronaviruses. Presently available immunofluorescent antibody (IFA) tests are non-specific, failing to differentiate between exposure to feline enteric coronavirus (FECV), feline infectious peritonitis virus (FIPV), or coronaviruses from other species.

In the February 1998 edition of their newsletter, Antech Diagnostics describes a new test, the FIP-Specific ELISA, that has been introduced by their laboratories recently. According to Antech, the test is based on the fact that all pathogenic strains of FIPV have an intact 7B region in their genetic code; this region is absent or truncated in many strains of FECV and is not present in the virus included in the commercial vaccine. Demonstration in cats of specific antibodies to the 7B protein, produced by the 7B region, might suggest that the animals have been exposed to a pathogenic FIPV, and may be carriers of the virus or susceptible to disease.

Antech evaluated their new test in a group of 42 cats, including animals exposed to FIPV or FECV, or the FIP vaccine. Also included were cats with proven clinical FIP, specific pathogen-free cats, and cats from two catteries. According to Antech, only the FIPV-infected cats had positive titers with the FIP-Specific ELISA test. Additionally, there was an association in the catteries studied between positive titers (>1:80) and the tendency to develop clinical FIP within three months. From their preliminary data, Antech proposed that cats with titers of 1:160 or greater on their new test are infected with FIPV. Also, cats with titers of 1:320 or greater have a 50% likelihood of dying from the disease within three months. Clearly, Antech's early claims concerning this new test are very intriguing to veterinarians and breeders; however, as with all new tests, the results should be interpreted cautiously until the test has undergone widespread validation on a large number of cats in the general population.

Complicating the interpretation of these new test results is the ongoing concern by some research groups that pathogenic feline coronaviruses (FIPV) cannot be differentiated reliably from their non-pathogenic counterparts through differences in the 7B region of the coronavirus genome. In 1995, Herrewegh and colleagues reported in the journal Virology that deletions in the 7A/7B region did not occur in all FECV isolates. In 1998, Kennedy and colleagues reported in the Journal of Veterinary Diagnostic Investigation that their polymerase chain reaction test was unable to consistently differentiate FECVs and FIPVs when applied to the 7A/7B region. Veterinarians and breeders interested in the control of FIP are encouraged to follow the literature closely to determine how these discrepancies will affect the accuracy of commercial tests being offered for the detection of FIPV.

FeLV is a fragile virus that does not survive in the environment. Ordinary household detergents and bleach effectively kill this virus. There is therefore no danger that cats can be exposed to FeLV in veterinary clinic waiting rooms or exam rooms, or in cages, or at cat shows unless direct contact is made with a positive cat who is shedding virus. Transmission of FeLV requires intimate moist contact. The most common route is contact with infected saliva through grooming, licking, biting and shared dishes and litter pans. FeLV can also be transmitted through a blood transfusion, so all cats who are blood donors are screened for FeLV. Kittens can be infected by their mother before birth or during nursing after birth.

When a cat is exposed to FeLV, there are four possible outcomes. In about 30% of cats, an effective immune response is produced and the infection is resisted. These cats then become naturally immune to FeLV infection for an unknown period of time. In about 40% of cats, the virus is successful and the cat eventually becomes persistently infected and excreting virus in its saliva. Another 30% of cats do not produce immunity but also do not become persistently infected immediately. In these cats, the virus hides in the bone marrow for up to 30 months. Eventually, these cats either overcome the virus or become persistently infected. Finally, some cats can develop latent or sequestered infection. This probably happens to less than 5-10% of cats. These cats, whose virus is hiding in sites such as the bone marrow, will rarely be contagious and are unlikely to develop illness. They will not test positive on routine testing. In general, young cats, especially those under 4 months of age, have the least ability to mount an effective immune response and so are most susceptible to FeLV.

FeLV is capable of producing a wide variety of associated diseases and symptoms. Degenerative diseases, such as anemia, liver disease, intestinal disease and reproductive problems can be seen. In other cats, the virus produces cancerous diseases, such as lymphosarcoma and leukemia. Many cats suffer from suppression of the immune system and other illnesses, depending on which organ is involved. Cats whose immune systems are depressed by FeLV are susceptible to a wide variety of infectious diseases and other problems, such as chronic respiratory infections, chronic gingivitis and stomatitis, feline infectious peritonitis, poor healing of wounds and abscesses and chronic generalized infections.

Testing is the basis for diagnosing and managing FeLV infections
The most common screening test for FeLV is the ELISA, while the immunofluorescent antibody test (IFA) is the most common confirmatory test. Vaccination for FeLV does not affect test results since the tests look for viral antigens, not antibodies. Kittens can be tested at any age because maternal immunity does not interfere with testing. The ELISA is the preferred test for screening cats since it is quick and readily available in vet clinics. It should be performed on a blood sample, since ELISAs done on tears or saliva have been shown to be unreliable. Any positive or equivocal ELISA test results should be confirmed using the IFA test, usually done at a commercial laboratory. It is possible to have results on ELISA and IFA which do not agree for a variety of reasons, and there is a testing protocol to follow in order to determine the status of such cats.

The American Association of Feline Practitioners (AAFP) have published recommendations for FeLV testing. The guidelines state that the FeLV status of all cats should be known because FeLV is responsible for the illness and death of more cats than any other disease condition. Testing and identifying positive cats is the mainstay of FeLV control and is not replaced by vaccination. Cats who have had a recent exposure to a known FeLV positive cat should be tested as should any cats who are ill. Any new kitten or cat should be tested before being added to a household with resident cats. Even if the household does not already have resident cats, new pets should be tested because the emotional bond that forms between owners and pets justifies knowing any future threats to the pet's health.

Cats who test positive for FeLV may live for months to years. Euthanasia of positive cats must be addressed on an individual basis in consultation with the veterinarian. In many cases, it is possible and feasible to keep a positive cat and ensure good quality of life through the combined efforts of the owner and the veterinarian. Positive cats are capable of transmitting their infection to other cats, so they should not live with other cats nor should they be allowed to roam outside. This not only protects other cats from FeLV, but protects the positive cat against the many diseases and illnesses they may contract due to their increased susceptibility.

The mainstays of treating FeLV positive cats are protecting them from exposure to other diseases, ensuring good nutrition, giving regular vaccinations with killed virus vaccines (but not with a feline leukemia vaccine), reducing stress, controlling parasites, and early and aggressive treatment of any symptoms that appear. There is no specific treatment for FeLV and no known cure. A large number of therapies have been investigated for FeLV positive cats, but most have not shown encouraging results. Anti-viral drugs, such as AZT, show some promise, but are associated with many side effects.
A drug that stimulates the immune system, interferon, can be given orally to cats without side effects and may be helpful in many cases. Experimental protocols have been developed that combine AZT with interferon or interferon and another immunostimulant, Propionibacterium acnes (Immunoregulin by ImmunoVet Inc, Tampa FL). Specific cancers associated with FeLV have their own chemotherapy treatment protocols. However, cats with cancer associated with FeLV have an average survival time of 6 months even with aggressive chemotherapy. Drugs that are being developed to treat AIDS in humans are often tested in cats first, so that studies on new drugs for AIDS may produce drugs we can also use to treat FeLV in cats.

The best protection against any infectious disease is eliminating possible exposure. The FeLV test and removal program was developed to remove infected cats from infected households. Using this program, no new cats are added to the household and all resident cats are tested by IFA every 3 months. Any cats with positive tests are removed from the household. When every cat tests negative by IFA for two tests in a row, the household is declared free of FeLV. Any new cats are not admitted to the household without a 3-month waiting period in which they must have two negative IFA tests. This program has proven to be very effective for multi-cat households and catteries.

There are presently a number of companies who make and sell vaccines against FeLV. Vaccines may be against FeLV only, or they may combine FeLV with other components. Many trials have been conducted to compare the effectiveness of the various vaccines, but unfortunately, the studies remain hard to interpret, largely due to inconsistencies in study designs. On average, FeLV vaccines are able to prevent infection in about 80 to 90% of cats. All the vaccines are recommended to be given as a two-dose regimen spaced 2-4 weeks apart, staring with kittens 8 to 9 weeks of age. Thereafter, annual boosters are recommended.

Recently, the American Association of Feline Practitioners has released feline vaccination guidelines.
They divided vaccines into core and non-core groups. Core vaccines are those felt to be necessary for all cats and non-core vaccines are felt to be necessary only for those cats at realistic risk of the disease. FeLV vaccines are designated as non-core vaccines. Vaccination is recommended only for those cats whose lifestyle places them at risk for FeLV. This includes outdoor cats or those that are indoor/outdoor, feral cats, cats in open multi-cat households, cats in FeLV-positive households, and cats in households where the FeLV status of all resident cats is not known.

Since young cats are at the greatest risk and their lifestyle is most likely to change in the future, the AAFP panel felt that it may be appropriate to suggest initial FeLV vaccination for all kittens, with subsequent annual vaccinations only for those that continue to be at-risk. In any case, owners should discuss issues of FeLV testing and vaccination with their veterinarian so the best decision can be reached for each individual cat.