Feline infectious peritonitis

Introduction

Feline Infectious Peritonitis (FIP) is the result of a mutation of the ubiquitous and relatively harmless feline coronavirus (FCoV). First described in 1963 1, the rise and increased incidence of FIP since its discovery has been associated with husbandry practices that result in group-housed cats; this includes breeding and sheltering facilities. The first commercial cat litter appeared on the US market in 1947 2 — a reflection of the changing role of the cat as an indoor companion animal — and both breeding and rescue operations increased in the following decades, creating opportunities for transmission and amplification of infectious diseases in groups of cats. To date, FIP has evaded medical prevention modalities as well as a cure; furthermore, ante-mortem diagnosis often remains a clinical challenge. Current research includes enhanced diagnostic tools utilizing molecular sequencing and clinical trials of new therapies; both of these areas suggest promising advances in the field.

Etiology and pathogenesis

Feline coronavirus is a large, enveloped, positive-stranded RNA virus. Coronaviruses in general exhibit a high rate of mutation during replication, which leads to intra-species and cross-species recombination and transmission. Currently, FCoV is considered to have two serotypes: type I, which is the most prevalent form found worldwide in naturally affected cats (with some geographic variation), and type II, which arose from a recombination event between type I FCoV and canine coronavirus. Although type 1 predominates in natural feline infections, the vast majority of research has been conducted on type II because it is more readily propagated in the laboratory for study. Both type I and type II FCoV serotypes have been implicated in FIP development 3. Type I and type II are distinguished by genetic differences in their S (spike) proteins (Figure 1), which are considered important in the transformation of common FCoVs to the FIP-causing FCoVs (FIPVs).

The main route of FCoV transmission is fecal-oral, with oronasal inoculation of the virus via direct transmission or fomites such as litterboxes or surfaces. After inoculation, FCoV moves into intestinal enterocytes, where the virus replicates. Infections with FCoV are often subclinical, but may result in a self-limiting diarrhea as the virus impacts the intestinal epithelium.

The transformation of the common FCoV to the lethal FIPV involves specific point mutations in the RNA genome. Structural features of interest are the viral spike (S) and membrane (M) proteins which act in allowing entry into and exit from cells (Figure 1). An understanding of specific point mutations is thought to be the key in unlocking this lethal transformation; current efforts are focused primarily on the S and 3c genes, with the S gene being most commonly implicated in laboratory studies to date 4.

The macrophage is the primary inflammatory cell in FIP. Point mutations in the FCoV genome switch the virus from an epithelial tropism to a macrophage trophism. The resulting virus is then able to travel and replicate in macrophages, moving into organs and other tissues. Infected macrophages internalize antigen, allowing the virus to evade antibody-dependent lysis, while also activating complement which increases the influx of other inflammatory cells to infected tissues. The humoral branch of the immune response is also activated, resulting in the deposition of antibody-antigen complexes along vessels, causing profound and widespread vasculitis. Approximately 50% of FIP cases develop effusive disease, while the other 50% develop the less-effusive granulomatous presentation; however, the classic dichotomy is a false one, as the disease acts along a spectrum between effusive and non-effusive signs. This variation is theorized to depend on which branch of the immune system is most active in responding: the humoral system results in more effusive disease, and the complement system in the more granulomatous presentation 5.

Epidemiology and risk factors

FCoV is a ubiquitous virus, with sero-prevalence rates ranging from 25% in single cat households to 75-100% in group-housed settings such as catteries and shelters 6 7. The fatal FIPV mutation is a relatively rare occurrence; the reported incidence of FIP in FCoV seropositive cats ranges from 1% to 12%, with the higher rates recorded in older reports that primarily studied cattery populations 8 9. In general, it is estimated (based on the literature) that following FCoV exposure, 5-10% of cats will be resistant to the virus, 70-75% will undergo a transient infection for weeks to months, 10-15% will become chronic shedders, and less than 3% will go on to develop FIP 9.

The commonly supported “internal mutation” hypothesis posits that point mutations resulting in FIPV occur within certain cats based on viral factors (particular FCoV strains and mutability), environmental factors (overcrowding and viral load) and cat factors (genetic predisposition and immune response). Until recently, therefore, FIPV was not considered to be horizontally transmitted between cats; however, rare outbreaks of identical FIPV infections in groups of cats have been documented by molecular sequencing technology 10. FIPV is still not widely believed to be transmissible, although more high-risk strains or intermediate viral strains which are transmissible between cats may signal an increased risk for FIPV development and transmission in a population.

FIP is generally considered a disease of young cats (< 2 years of age). Kittens generally experience higher viral loads than adult cats, encounter more stressful events (including vaccination, neutering, and rehoming), and suffer from immature immune systems. While a subset of cats will eliminate high-risk mutations of the virus (as demonstrated in several laboratory challenge studies), most cats that develop FIP do so after their first exposure to FCoV, which usually occurs as kittens 5 8. Additional risk factors include being purebred and group-housed, especially in over-crowded or insanitary conditions, where high viral loads and physiologic stressors predominate (Figure 2). Finally, older studies demonstrated a higher risk in cats also infected with FeLV or FIV, although this finding has not been consistent 11 12.

Clinical signs

Classically, FIP has been described in two clinical forms: “wet”/effusive and “dry”/non-effusive. However, FIP naturally occurs on a spectrum, with effusive disease at one end and non-effusive granulomatous disease at the other; the majority of cases present with both elements. Difficulties in diagnosing FIP relate to the non-specific clinical signs, the lack of pathognomonic abnormalities in hematology and biochemical tests, and the low sensitivity of current ante-mortem testing methods used in clinical practice.

Waxing and waning or persistent fever and inappetance are the most commonly reported early clinical signs. Particularly in kittens, early FIP can be confused with other more common infectious diseases, including panleukopenia and upper respiratory viruses. When effusion is present, it is the distinguishing feature and a key component of diagnosis. Cats with effusive disease often have abdominal distention, dyspnea, icterus or pallor. Many non-effusive presentations will include ocular lesions (uveitis, iritis, keratic precipitates) and neurologic abnormalities, which can raise the index of suspicion for FIP. Primary differentials for effusive FIP include neoplastic disease (lymphoma in particular), cardiac failure, and other causes of pleuritis and peritonitis. The less effusive form of FIP can mimic toxoplasmosis, FeLV, FIV, and cancer (lymphoma, adenocarcinoma and others).

Clinical signs are a direct result of antigen-antibody complexes binding to blood vessels. The result is the classic fibrinous and/or granulomatous vasculitis found on surgical or necropsy sampling of tissues. Fluid moves out of diseased vessels and into cavities, resulting in pleural, pericardial, and/or abdominal effusion (Figure 3). In solid organs, lesions are primarily multi-focal to coalescing granulomas, which often track blood vessels (Figure 4)(Figure 5).

FIP is a progressive disease. Clinical signs change over time, and serial examinations in close succession (including ophthalmic and neurologic) can help to confirm an early clinical suspicion (Figure 6).

Diagnostic testing

To date, the most definitive diagnosis of FIP is made by identifying FCoV or FIPV in tissue macrophages via immunohistochemistry and/or reverse-transcriptase PCR (RT-PCR). However, this requires collection of surgical biopsies or necropsy samples, which fails to offer non-invasive, ante-mortem means of diagnosis. Ante-mortem diagnosis is often presumptive, and is based on careful consideration of medical history and physical exam findings alongside hematology, clinical chemistry, and (when effusion is present) effusion analysis (Box 1).

There are no pathognomonic bloodwork changes in FIP. Common findings on a complete blood count include a non-regenerative anemia with lymphopenia but usually without the neutrophilic leukocytosis commonly seen in a stress leukogram. Serum biochemistry profiles reflect an elevated total protein due to hyperglobulinemia in a majority of cats 13. Other associated findings include elevated liver enzymes and bilirubin levels due to organ damage.

Effusion analysis and testing provide the best ante-mortem confirmation of FIP. Effusion analysis, which can be accomplished patient-side, provides strong support for an FIP diagnosis when the total protein is greater than 3.5 mg/dL, and the cell count is minimal. An albumin:globulin ratio of less than 0.8 on the effusion is highly supportive of an FIP diagnosis. Immunostaining of effusions for FCoV antigen is not considered a sensitive modality since they contain few cells and/or antigen is often masked by bound antibodies 14.

RT-PCR for FIPV (not FCoV) on effusions is a relatively specific (95.8%) but fairly insensitive (68.6%) laboratory method for FIPV detection. As such, it is currently the best non-invasive method of confirming an FIP diagnosis. When positive, this test identifies particular mutations in the spike protein associated with FIPV. In cats with effusions, in which prevalence for FIP is 50-60%, RT-PCR for FIPV has a positive predictive value of around 95%. This test is not recommended for use on blood, serum or feces due to low presence of antigen and antibody-antigen binding. Additionally, many cats will have multiple coronavirus strains simultaneously, which can limit the interpretive value of this test.

Importantly, a positive serology for FCoV antibodies should never be interpreted as a diagnosis of FIP. Serology cannot distinguish between antibodies induced by the ubiquitous FCoVs and FIP-causing FCoVs.

Treatment

FIP is considered uniformly fatal, although there are rare reports of prolonged disease or even recovery. It is usually rapidly progressive, with a median survival time of 9 days following diagnosis 15. Many antiviral drugs have been suggested in the past based on in vitro studies or use for other species and diseases; these include ribavirin, vidarabine, human interferon-alpha, and feline interferon-omega 13 but have been found to be largely ineffective for FIP. Palliative treatments that are readily available include immunosuppressants, which can have some impact on the progression of clinical signs; most commonly these include prednisolone or dexamethasone, but also include cyclophosphamide or chlorambucil 13. Non-specific immunostimulants have been used with anecdotal success to prolong life in some cats, but numbers are small and these are currently not recommended for FIP 16.

Currently treatment for FIP is a very active area of research, and there is great promise in some ongoing investigations. Polyprenyl immunostimulant (PPI) has undergone multiple laboratory studies and clinical trials, demonstrating success in ameliorating disease in early cases of non-effusive FIP 17; furthermore, PPI is commercially available and licensed for treatment of feline upper respiratory infections in some countries. Other promising work includes a protease inhibitor (GC376) which has successfully resulted in temporary regression of clinical signs in both laboratory studies and clinical trials of affected cats 18. A commercial form of GC376 is expected to be licensed for release in the next few years in the US 19. A recent investigation of RNA transcription inhibitors (EVO984/GS441524) demonstrated dramatic reduction of viral replication in in vitro studies and reversal of clinical disease in 10/10 experimentally infected cats 20.

Vaccination

Currently there is one commercially vaccine available in the US, Europe and Canada for FIP. It is a modified live intranasal product containing a mutated FCoV. The American Association for Feline Practitioners (AAFP) groups vaccines into three general categories: core, non-core, and generally not recommended, and according to the AAFP Feline Vaccination Advisory Panel, the current FIP vaccine is not recommended, as there is “insufficient evidence that it provides clinically relevant protection” 21.

Implications for FIPV-exposed cats

As previously stated, FIPV is not thought to transmit horizontally between cats in most circumstances, which is why outbreaks of FIP are very rare. However, when a cat or kitten develops FIP, there is always concern regarding the degree of risk to other cats with whom that cat had contact. Unrelated cats exposed to a cat with FIP are considered to be at very low risk for developing FIP based on the “internal mutation theory” previously discussed. However, genetically related cats are at higher risk, given likely exposure to the same FCoV strain and similar genetic susceptibility to mutation; this is multiplied by the likelihood that related cats have also shared environments, and perhaps even shared stressors. Therefore, littermates of affected kittens are at highest risk for FIP development, and should be monitored for clinical signs.

The incubation period to FIP development, or course, can be months to years. Currently available diagnostic tests do not aid in predicting the outcome for cats that have been exposed to the virus but are currently nonclinical; however, molecular sequencing of FCoV point mutations may be the tool that changes this in the future.

Implications for FIP prevention in cat populations

FCoV can survive for up to 7 weeks in dry environments, but is easily inactivated by common detergents and disinfectants. In populations of cats, prevention and control measures for FIP are aimed at minimizing risk factors for development, including reducing exposure to FCoV as much as possible. Shelters and rescues should practice routine and thorough sanitation and disinfection protocols. Litter box hygiene should include frequent scooping, at minimum daily, and use of disposable litter boxes for kittens and cats with diarrhea. Avoiding overcrowding of cats is essential, and best practices in sheltering 22 to keep populations at humane levels and healthy should be followed. Ideally, unrelated litters of kittens should not be mixed, in order to avoid opportunities for sharing of viral strains and recombination events. However, an incidence of FIP of up to 1% is generally considered unavoidable in populations of cats. Investigation is warranted in catteries or shelters experiencing higher incidence of FIP; this should include assessment of sanitation and disinfection, handling and husbandry practices, cat housing, and stress management.

FIP is a devastating disease resulting from a complex interaction between mutated strains of FCoV, host immunity, and environmental loads and conditions. Researchers are simultaneously working to elucidate these points of mutation, means of early recognition or risk assessment, and treatments to slow or reverse progression of clinical signs. Promising advances have been made in the area of treatment in the last two years, and for the individual cat afflicted with this condition in private practice, these options may be both available and reasonable means of palliation. Eradicating FCoV is not an attainable goal, but minimizing viral load and exposure is the best method for reducing FIP occurrence in populations of cats.