NIELS C. PEDERSEN DVM, PHD, DISTINGUISHED PROFESSOR EMERITUS, UC DAVIS
FIP is ultimately caused by a ubiquitous and otherwise innocuous feline enteric coronavirus (FECV). FECV is similar to coronaviruses causing diarrhea or bronchitis in humans, piglets, foals, calves and poultry. In about 10% of cats, mainly kittens, the enteric coronavirus will undergo specific mutations that allow it to escape the cells lining the lower intestine and infect the most basic cell of the immune system, the macrophage. This mutant virus is known as feline infectious peritonitis virus (FIPV) and is initially contained to local lymphatic tissues associated with the lower intestine. FIPV infected macrophages can then spread the infection to other sites within the abdominal and chest cavities and to distant organs such as the eyes and brain. More detailed information on FECV infection and clinical manifestations of FIPV disease can be found at: ccah.vetmed.ucdavis.edu. Owners interested in a more historical, in-depth and graphic portrayal of FIP can download the FIP Synopsis from the CCAH or SOCK FIP websites.
This initial macrophage infection is eliminated in all but 0.3-1.4% of cats, which for unknown reasons are unable to develop the required protective immunity. The disease that occurs in this unfortunate small group of cats can clinically manifest within days, several weeks, sometimes months, and rarely a year or more. The form of disease that is manifested is referred to simply as wet (effusive) or dry (non-effusive). The wet form occurs in about two-thirds of cats and the dry form in one-third. These two forms are easily distinguishable, although there may also be transition forms between the two.
Wet FIP tends to be more acute in onset and heralded by onset of a cyclical and antibiotic resistant fever, depression, decreased appetite, weight loss and the accumulation of a yellowish and somewhat sticky fluid in the abdomen, or less commonly in the chest cavity (Table 1). Cats with abdominal effusions usually manifest with abdominal swelling, while cats with thoracic effusions often manifest breathing problems (dyspnea). Many of these cats will be noticeably jaundiced due to high levels of bilirubin and/or have strongly yellow-tinged serum and urine. Neurological and ocular signs are seen in less than 1 in 10 cats with wet FIP (Table 1). Almost all cats with wet FIP will either be euthanized or die within two to 24 weeks, although a rare individual may live with severe abdominal effusions for even longer.
Table 1. Variability in clinical signs of effusive (wet) FIP from cats necropsied at UC Davis
|Signs referable to:||% affected|
|Peritoneal & pleural cavity||22.0|
|Peritoneal cavity, eyes||2.8|
|Peritoneal cavity, CNS*||1.9|
|Peritoneal and pleural cavity, CNS||0.9|
|Peritoneal and pleural cavity, eyes||0.9|
|Pleural cavity, CNS, eyes||0.9|
|Peritoneal cavity, CNS, eyes||0.9|
|*Central nervous system =||brain, spine|
Cats suffering the dry form of FIP tend to be more chronically ill, less apt to have elevated serum bilirubin, and to suffer from more vague clinical signs of disease, inappetence, failure to thrive, and weight loss. The dry form of FIP is characterized, not by diffuse inflammation and fluid effusion, but by less numerous and larger tumor-like lesions (i.e., granulomas) in organs (e. g., kidney, cecum, colon, liver, lung, lymph nodes) within the abdominal or thoracic cavities, or in the eyes and brain (Table 2). Whereas the brain and/or eyes are only involved in 9% of the cases, neurological and-or ocular disease is seen as the main presenting clinical sign in 70% of cats with dry FIP.
Many cats with dry FIP have been subclinically ill for weeks or months prior to diagnosis and are more apt to be treated symptomatically for weeks or months before they are euthanized or die naturally. Subclinical illness is often manifested by failure to grow normally, poor hair coat, recurrent bouts of secondary respiratory or intestinal infections, and other vague signs. Some cats may present with signs of dry FIP but later develop wet FIP, or vice versa. Overall, about 75% of cats will present with wet FIP and 25% will present with dry FIP. Less than 5% of cats, usually those with milder forms of dry FIP to start, will survive longer than one year with the best symptomatic care.
Table 2. Variability in clinical signs of non-effusive (dry) FIP from cats necropsied at UC Davis
|Signs referable to:||% affected|
|CNS & eyes||8|
|Peritoneal cavity, eyes||7|
|Peritoneal & pleural cavities||4|
|Peritoneal & pleural cavities, CNS||3|
|Peritoneal & pleural cavities, eyes||2|
|Peritoneal cavity, CNS, eyes||2|
Details on neurological and ocular FIP can be found in the “About FIP” link in the SOCK FIP website. The main clinical signs of neurological FIP are fever, inappetence, weight loss, and incoordination (most intense in posterior). Some cats may also develop seizures and varying degrees of dementia. Ocular disease often accompanies neurological FIP due to the intimate relationship of eyes and brain. Ocular disease is most often manifested by inflammation of the anterior uveal tract (iris and ciliary body) with discoloration of one or both irises, precipitates on the back side of the cornea, and cloudiness of the aqueous humor. Ophthalmoscopic examination may also demonstrate inflammation in the retina and optic nerve.
Diagnosis of FIP
Veterinarians find FIP to be either an easy or extremely difficult diagnosis, depending mainly on how often it occurs in their cat practice population and on how knowledgeable they are on the disease forms and common laboratory findings. There is often a reluctance to diagnose FIP without overwhelming clinical evidence due to its previously high mortality. However, the diagnosis of FIP should be relatively simple for the wet form and only a little more difficult for the dry forms. FIP tends to be a disease of cats less than 3 years of age with a majority presenting in the 3 to 8-month age range. Affected cats usually come directly from high density cat housing (rescues, catteries, shelters) or have been adopted from such environments within the last 1-6 months. Common presenting signs include stunted growth, acute or chronic inappetence and weight loss, antibiotic unresponsive fever, abdominal distension, dyspnea, jaundice, intra-ocular eye lesions, neurological signs (e.g., posterior incoordination), and chronic diarrhea (often mucus-laden and blood tinged). Physical examination, including palpation and/or ultrasound, will detect abdominal or thoracic effusions, masses in organs within the abdomen or chest cavity, and lesions within the eye (anterior chamber, iris, retina), and neurological signs such as posterior weakness/incoordination. Blood abnormalities commonly observed in to both wet and dry FIP include unresponsive anemia, elevated white blood cell count, absolute lymphopenia, elevated total protein and globulin, low albumin, low A:G ratio, hyper-bilirubinemia. The feline coronavirus antibody test by indirect fluorescent antibody (IFA) is often higher (≥1:3200) than expected for FECV exposed cats (1:25-1:1600). Fluid obtained from abdomen or chest will be weakly or strongly yellow-tinged, watery to mucinous, contain low to high levels of protein, semi-clear to cloudy, and contain low to high numbers of non-toxic neutrophils, lymphocytes, monocytic cells, and large multi-vacuolated macrophages. Polymerase chain reaction (PCR) or immunohistochemistry (IHC) on cells from effusions will be positive for coronavirus RNA or antigen in 70% or so of cases. Whole blood contains very little virus and is not good for PCR or IHC.
The neurological and/or ocular forms of FIP can be confused with feline systemic toxoplasmosis, which is why so many cats with these forms of FIP are tested for toxoplasmosis and treated with Clindamycin or other antibiotics. However, systemic toxoplasmosis is an exceedingly rare disease of cats, especially when compared to FIP. FIP can be easily differentiated origin (cattery, foster/rescue, shelter), signalment (age, gender, breed), and basic blood test results. Deep fungal infections (coccidioidomycosis, blastomycosis, histoplasmosis) can cause similar clinical signs to dry FIP but are still uncommon even in their endemic regions. Lymphoma may also be a differential diagnosis for dry FIP, but this disease is usually sporadic and in older cats. The diagnosis may be confirmed if there is still doubt, by characteristic changes in cerebrospinal fluid (CSF) and aqueous humor (high protein, high cells, neutrophils, lymphocytes, macrophages), suggestive lesions on MRI, PCR or immunohistochemistry on CSF, or high serum coronavirus antibody titer by IFA (>1:3200).
Treatment of FIP
Non-specific (symptomatic) treatment of FIP – There is currently no licensed effective treatment for cats with confirmed FIP. In lieu of approved antiviral drugs, treatment has been mainly symptomatic. A low to moderate dosage of prednisolone or prednisone (starting at 2 mg/kg, orally, once a day for two weeks and then 0.5-1 mg/kg indefinitely), coupled with a diet high in animal protein (e.g., 1/2 cooked chicken, turkey or rabbit and 1/2 a favorite commercial cat food) and a lot of personal care, is the simplest and possibly most effective symptomatic treatment. Symptomatic treatment ultimately depends on the cat’s immune system to cure the infection. Some cats may have mild or subclinical disease isolated to a single intestinal lymph node, which may be detected as an abdominal mass upon routine physical examination or during a spay operation. Cats with more severe clinical signs will often go into a more chronic and less severe stage of disease after several weeks. As we gain more experience with treating rather than euthanizing cats when FIP is diagnosed, we begin to appreciate that a proportion of cats may survive for many weeks, months, and rarely a year or more. However, it is still fair to say that FIP is ultimately fatal to most cats if left to run its natural course.
Antibiotics, in particular doxycycline and clindamycin, are often prescribed for cats with FIP. However, such treatment is not effective against FIP virus and should only be used if there is evidence of secondary bacterial infections that are clinically active (doxycycline) or systemic toxoplasmosis (clindamycin).
There are misconceptions on the value of removing fluid effusions. Cats with chest involvement and breathing difficulties can benefit greatly by removal of pleural fluid. Chest fluid also tends to be slowly replaced, especially when cats are treated with prednisolone. Removal of abdominal fluid should be discouraged unless it is so massive that it interferes with breathing. Abdominal effusions tend to be rapidly replaced at the expense of body fluids and proteins. Owners can be encouraged to maintain symptomatic and palliative treatment for as long as weight and activity are maintained. This can be days, weeks, sometimes months, and rarely a year or more. However, owners should be apprised of the extremely high morality that occurs among cats with clinically active FIP.
There is some debate on whether certain non-steroidal anti-inflammatory drugs (e.g., TNF-alpha blockers such as pentoxifylline, thalidomide), specific immunomodulators (e.g., feline interferon omega, human recombinant alpha or beta interferon), and non-specific immunostimulants (e.g., several plant- or microbial-based biologics) have any efficacy against FIP. Although an initial study with feline interferon omega indicated efficacy, a subsequent large double blind and placebo-controlled trial showed it to be without efficacy. Human alpha and beta interferon are also of doubtless benefit and are immunogenic to cats and will be ultimately destroyed by the resulting antibodies. A similar large-scale trial with pentoxifylline also showed it to be non-effective against FIP. Our research also does not support the efficacy of such treatments. Non-specific immunostimulants such as polyprenyl immunostimulant (PI), Peritan, Acemannan, Immulan, Staphylococcal protein A, have been touted as treatments for chronic viral diseases of cats such as FeLV, FIV and FIP, but have not proven to be very effective. The most commonly promoted of these substances for FIP has been PI. One report compared the survival of 60 cats with milder dry FIP with 59 historical control cats. Eight of the 60 PI treated cats survived over 200 days, and 2 of 60 survived over 365 days, while no historical control cat lived longer than 200 days. However, this difference was not statistically significant.
Treatment with specific antiviral drugs – Two small molecules have been recently shown to inhibit FIPV replication and to cure cats with both experimentally induced and naturally occurring FIP. The first of these drugs to be reported was GC376, an inhibitor of the FIPV protease . This drug was able to cure 7 of 21 cats with naturally occurring FIP. It was successful with both wet and dry FIP, but not with cats with neurological involvement. A second drug, GS-441524, was found to be even more successful in curing cats with wet and dry FIP, and even many cats with neurological disease . GS-441524 is a nucleoside analog that acts to prevent the replication of FIPV RNA and therefore acts at an earlier stage of virus replication than GC376. GC376 is undergoing commercialization by a company called Anivive and may not be marketed for several more years. The patents for GS-441524 are held by Gilead Sciences, Inc., and the company has so far been reluctant to grant rights for animal use.
As a result of delays and uncertainties in the legal development of these two drugs, a vigorous Chinese black market has developed (Black-Market Production and Sale of GS-441524 and GC376 in the “About FIP” link). The use of black market GC376 and GS-441524 has been facilitated by cat owner groups active on social networks and highly committed to the cure of cats with FIP. However, veterinarians will be resistant, rightfully so, to purchase and resale of black-market drugs and will either refuse to help with treatment or only assist if owners take responsibility for the purchase and their unapproved veterinary use. There may be a temptation, therefore, for owners to do the treatment on their own. However, it is important for the success of treatment that owners have a personal veterinarian who is knowledgeable about FIP, that the cat be confirmed to suffer from FIP and not another disease, and that they have assistance in assuring proper administration of the drug and correct monitoring for a response. I must also warn owners seeking antiviral drug treatment, that they are expensive, stressful for owners and cats, requires proper monitoring, and is not always successful. Cats with neurological FIP are the most difficult to treat and often require an even higher dosage. Black market sources of these drugs may also cease at any time.