Feline Infectious Peritonitis (FIP): More Complex Than We Thought!
World Small Animal Veterinary Association World Congress Proceedings, 2015
Richard Ford1, DACVIM, DACVPM (hon)
North Carolina State University, Raleigh, NC, USA

The first references to the fact that cats infected by this virus developed disease were described as early as 1960. However, it was not until 1966 that feline infectious peritonitis (FIP) was described as a distinct clinical entity and the infectious nature of the disease was described. And 25 years later, the first (and still only) FIP vaccine was introduced in the US (and is now available in some European countries). Although the initial name, "feline infectious peritonitis," has remained the popular name for this disease, the virus by no means is restricted to the peritoneum.

In fact, coronaviruses are a widely distributed group of viruses capable of infecting several species of birds and mammals. They can cause upper respiratory and gastrointestinal disease, hepatitis, vasculitis, peritonitis, pleuritis, and encephalitis. Perhaps the best known of these viruses are the FIP virus in cats, canine coronavirus in dogs, and transmissible gastroenteritis virus of swine.

Epizootiology

The overall prevalence of FIP is not precisely known. In the general population, it has been reported by some sources to be less than 1% of all cats presented to university teaching hospitals. In multiple cat households and catteries, the prevalence is probably considerably higher. Under the worst conditions, the morbidity (clinical illness) due to FIP is typically around 3–4% in cluster households. (Note: that compares to 28–30% for FeLV endemic households). Nonetheless, the disease we call FIP is highly lethal and carries a poor prognosis for survival.

The Clinical Disease

Generally speaking, FIP occurs in two distinct forms: an effusive form characterized by peritonitis or pleuritis, or both, and a noneffusive or dry form that causes granulomatous lesions in major organs, such as lymph nodes, kidneys, the eyes, and the central nervous system (CNS).

Effusive FIP is characterized by a widespread vasculitis that is responsible for the outpouring of protein- and fibrin-rich fluid. Although antibody titers do not correlate with immunity, titers will rise simultaneously with the development of lesions of effusive FIP. The presence of effusion in cats with FIP has been attributed to a strong humoral immune response to the virus, but a weak cell-mediated immune (CMI) response. Note: CMI is key in protecting cats from FIP.

The noneffusive form of FIP, clearly the most difficult to diagnose, is characterized by a dramatic granulomatous reaction in localized tissues, such as the nervous system or the eye. Again, antibody is not protective. An "intermediate" CMI and humoral response is responsible for the lack of effusion.

Cell-mediated immunity does not always lead to complete elimination of the virus. Apparently, virus can persist in the body of some cats for an indefinite period of time. With advancing age or drug-induced immunosuppression (FeLV infection or steroids), the FIP infection may again become active.

Transmission

The actual route by which feline coronavirus (FCoV) is spread is generally believed to be via the fecal-oral route (esp., queen-to-kitten). Transmission in utero has been suggested; however, this route has not been definitely proven. The virus is probably excreted into the environment by a number of routes, including oral and respiratory secretions, feces, and possibly, urine. It appears that close, sustained contact between cats (esp. a carrier queen and her kittens) is required for effective transmission of the virus. Note: the virus appears to remain infectious for up to 7 weeks in a dry environment...it's more resilient than originally thought. Therefore, cluster households where breeding is prevalent (lots of kittens) pose the greatest risk of transmission of FCoV.

Important: FCoV is commonly found in individual as well as households of cats; up to 90% of healthy cats living in a household can be found to have FCoV (fecal shedding).

The clinical disease we call 'FIP' is apparently subsequent to 3 factors:

1.  Exposure to and infection with FCoV (which is very common)...and

2.  Mutation of the "very common" FCoV into a virulent coronavirus called the FIP virus (FIPV), (Note: this mutation appears to occur within the individual cat...mutated virus does not appear to spread among cats)...and

3.  A genetic predisposition of the individual cat to develop disease once the mutation occurs. (Persian and Burmese are at the top of the genetic predisposition list...but other breeds and mixed-breed cats can certainly be susceptible).

(Note: some studies have challenged the mutagenesis concept of FIP pathogenesis).

Diagnosis of Clinical FIP

The effusive form of FIP is easier to diagnose than the noneffusive form. Once a pleural or peritoneal effusion develops, gross and microscopic examination of the fluid is usually sufficient to make a clinical diagnosis. In the noneffusive form, the disease is far more difficult to diagnose because of the virus's ability to localize in discrete organs and the absence of obvious clinical signs.

Hematology and Biochemistry

In both the effusive and noneffusive forms of FIP, the total white blood cell (WBC) count is typically elevated with an absolute neutrophilia and a normal to low lymphocyte count. Cats with concurrent feline leukemia virus (FeLV) infection may have profound panleukopenia. In most cases of FIP, a mild to moderately severe anemia exists.

Fluid Analysis

Peritoneal and pleural effusions (if present!) are characteristic and essentially diagnostic. The fluid is light to dark yellow in color and has a sticky, viscous consistency. The fluid is technically an exudate since it is high in protein (characteristically from 5 to 12 g/dL) and has a high specific gravity ranging from 1.017 to 1.047. Cytological assessment of the fluid: expect the fluid to be relatively hypocellular consisting principally of WBCs, predominantly neutrophils and macrophages, with occasional mesothelial cells.

An albumin:globulin ratio (determined on abdominal fluid) that is greater than 0.81 is highly predictive for ruling out a diagnosis of FIP.

An albumin concentration (in the abdominal effusion) greater than 48% of the total protein (or a gammaglobulin less than 32% of total protein) is a relatively good predictor that the effusion is not caused by FIP.

On the other hand, an effusion in which the globulin fraction is greater than 32% of the total protein (in the fluid) is highly predictive of FIP.

Plasma Proteins

Of particular importance in the diagnosis of the noneffusive form of FIP is the fact that approximately 75% of the cats affected have plasma proteins that are greater than 7.8 g/dl. Characteristically, the albumin is lower than normal and the globulin fraction is abnormally high.

Important: Electrophoresis of the serum proteins, available through most commercial clinical pathology labs, will demonstrate an increase in the gammaglobulin fraction of serum in about 75% of cats affected with the NONEFFUSIVE form of FIP.

Histopathology

Biopsy is the only "test" that CAN confirm an antemortem diagnosis of FIP. Any FIP diagnosis made without histologic confirmation must be considered presumptive.

Antibody vs. Antigen Testing

Several assays are currently available to detect coronavirus antibody in serum. Remember: There is no "FIP test." Commercial laboratories offering "FIP-antibody titers" are actually reporting "coronavirus antibody titers." While it has been proposed that the disease can be diagnosed by virtue of a high antibody titer, none of the so-called antibody tests for FIP are diagnostic. A negative titer, on the other hand, can indicate lack of exposure to a coronavirus and therefore be interpreted as not FIP... (but...the high incidence of FCoV exposure among normal cats makes a negative FCoV titer pretty rare!)

A "positive" coronavirus titer does not define a diagnosis of FIP.

Titer Applications

Despite all the frustration associated with interpreting coronavirus antibody tests, there are some situations in which determination of antibody titers can be of use to the practitioner:

1.  Based on the current knowledge of feline coronavirus serology, there is little or no value in performing routine antibody titer screening. In fact, cats dying of FIP typically have a low or "negative" titer.

2.  Determination of coronavirus antibody titers is a poor clinical aid in the diagnosis of a sick cat with signs suggestive of FIP. A positive coronavirus titer may be the least significant test to perform compared to any other diagnostic procedure available.

3.  Recently available through commercial laboratories is the reverse transcriptase-polymerase chain reaction (RT-PCR) assay for coronavirus antigen. The assay offers the ability to detect viral antigen in effusions, serum, plasma, and in feces. This is not an FIP test! The value of RT-PCR is that it can detect viral antigen (compared to antibody). It does not distinguish between FIPV and FECV or any other feline coronaviruses.
The RT-PCR assay does not distinguish between FIPV and the FECV; however, it has allowed investigators to study feline coronavirus shedding patterns of cats living in cluster households. This, combined with evidence that FECV is, in fact, the parent of FIPV, has provided new, clinically germane information about this complex disease:


 

...another ('new-and-improved') RT-PCR test is commercially available. Investigators have discovered that RT-PCR technology can be utilized to identify mRNA (messenger RNA) of replicating feline coronaviruses inside circulating monocytes of infected cats. The biological point of significance here is that even cats with benign (so-called) 'enteric' coronavirus can have circulating coronavirus in their plasma...but that's NOT necessarily an indication of FIP. However, if mRNA can be identified in macrophages, the coronavirus is replicating...and that's characteristic of FIP...only the FIPV replicates inside cells.

Note: False-positive test results have been observed (i.e., the test is not always correct!)

The FIP Vaccine (Topical)

Zoetis currently sells the only approved vaccine for FIP (Felocell® FIP, also Primucell®) which is available in a limited number of markets. It is a temperature-sensitive, modified-live virus "designed" to grow only at the cooler temperatures of the upper respiratory tract. The vaccine virus will not replicate at core body temperatures. Therefore, it is effective only if exposure is via the oronasal mucous membranes (and this is the presumed most common route of infection); the vaccine is administered intranasally (applied directly onto the oral-nasal mucosa). Protection is apparently mediated by secretory IgA produced at the level of the upper respiratory tract and oral mucous membranes combined with an enhanced cell-mediated immune response.

The efficacy of the vaccine in preventing FIP has not been definitively established. Challenge studies offer conflicting results but generally cite the value when the vaccine can be administered to kittens that have never been exposed to coronavirus. The vaccine is not recommended by the World Small Animal Veterinary Association Vaccine Guidelines Group.

The search for an effective vaccine is still ongoing.

References

1.  Addie DD, Jarrett O. Feline coronavirus infections. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 4th ed. Chapter 10. St. Louis, MO: Saunders-Elsevier; 2012:92–108.

2.  Addie DD, Ishida T. Feline infectious peritonitis: therapy and prevention. In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy XIV. Chap 285. St. Louis, MO: Saunders Elsevier; 2009:1295–1299.

  

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Richard B. Ford, DVM, MS, DACVIM, D(Hon)ACVPM
North Carolina State University
Raleigh, NC, USA


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