Feline corona virus (FCoV) and Feline infectious peritonitis (FIP)
Andy Pachikerl, Ph.D
Introduction:
Feline coronavirus (FCoV) is a widely known positive-stranded RNA virus is infecting many cats worldwide (Satoshi, Takehisa and Motonobu 2012). This virus belongs to the species Alphacoronavirus 1 of the genus Alphacoronavirus from within the virus family Coronaviridae (Antoniw and Adams 2013). Alphacoronavirus 1 also includes the canine coronavirus (CCoV), which has been previously reported (link) and the porcine transmissible gastroenteritis coronavirus (TGEV) (Satoshi, Takehisa and Motonobu 2012). There are just two different forms of FCoV namely, the FECV (feline enteric coronavirus) that infects the intestines and FIPV (feline infectious peritonitis virus) that causes the disease feline infectious peritonitis (FIP).
Feline coronavirus can typically be found in feces of infected cats and it can be transmitted to healthy cats via coming in contact by means of the fecal-oral route (Hartmann, Feline infectious peritonitis 2005). In environments with multiple cats, the transmission rate is higher as compared to a single-cat environment (Satoshi, Takehisa and Motonobu 2012). The virus is actually symptomless and insignificant until specific mutations occur that can cause complications such as FIP (Satoshi, Takehisa and Motonobu 2012). FIPV is the complication that can be the result of FCoV and causes FIP in cats, for which treatment is generally symptomatic and palliative only. The drug GS-441524 shows promise as an antiviral treatment for FIP, but now it’s still under further research development.
Virology
Feline enteric coronavirus (FECV)
This is caused when the coronavirus becomes prominent in the mature gastrointestinal epithelial cells i.e. enterocytes, brush border, microvilli and villi of the cat (Rottier Peter, et al. 2005). This intestinal infection can show some outward symptoms and is usually chronic. The virus is excreted in the faeces of the symptomless carrier and can solely be detected by polymerase chain reaction (PCR) of faeces or by PCR testing of rectal samples.
Cats that are raised in group can infect one another or each other with various strains of the virus. Some cats do show resistance to the virus and are not infected or even become a carrier, while others may become a FECV carrier (Rottier Peter, et al. 2005). Carriers may heal spontaneously but acquired immunity may be short and they may go on to being reinfection. Usually within a few weeks, if they are living in a group with healthy but persistent, excretory carriers; some cats will never heal, and the excretory phase remain permanent.
Feline infectious peritonitis (FIPV) and Feline infectious peritonitis (FIP)
The virus can further complicate into what is known as FIPV when random errors occur during when the virus infects an enterocyte, causing the virus to mutate from FECV to FIPV (Rottier Peter, et al. 2005). FIPV causes lethal, incurable disease such as: feline infectious peritonitis (FIP).
Prior to being domesticated, cats are solitary animals and do not like to share space (i.e. hunting areas, rest areas and defecation sites). Domestic cats living in group therefore have a much higher epidemiological risk of mutation. After this mutation, the FCoV acquires a tropism for macrophages while losing intestinal tropism (Rottier Peter, et al. 2005).
Regardless of the source of FIPV and uncertainty about the significance of genetic differences, the relationship between virulence and macrophage/monocyte tropism has been firmly established (Pedersen 2009). While both FIPV and FECV may cause viremia (Gunn-Moore, Bruffydd-Jones and Harbour 1998, Febr, et al. 1996), only FIPV replicates in macrophages and causes the disease (Vennema, et al. 1998, Stoddart and Scott 1989). Complex immune reactions between the virus, antiviral antibodies, and complement cause disseminated vasculitis, which is the hallmark of FIP (Hartmann 2005, Pedersen 2009).
In a large group of cats, n, the epidemiological risk of mutation is higher and expressed theoretically as: E = n2 – n. A house hosting 2 cats therefore has a risk of E = 2. When 4 kittens (6 in total) are born into this group, the risk increases from 2 to 30. Overcrowding increases the risk of mutation and conversion from FECV to FIPV, which constitutes a very high-risk factor for the development of FIP cases. FIP has been shown to develop in cats whose immunity is low, such as younger kittens, old cats, immunosuppressed due to viral-FIV (feline immunodeficiency virus) and/or FeLV (Feline leukaemia virus) and stress such as: separation and adoption (Rottier Peter, et al. 2005).
The incidence of disease is bimodal, occurring most commonly in cats younger than 18 months and older than 12 years of age. There is a genetic component that contributes to the risk of developing FIP, thus littermates of kittens that have developed FIP are at increased risk. Unfortunately, there is no way to predict, out of a group of FCoV seropositive cats at risk for FIP, which ones are most likely to develop the disease.
Infection of macrophages by FIPV is responsible for development of a fatal granulomatous vasculitis, or FIP (see granuloma). Development of FIP depends on two factors: virus mutation and low immunity where virus mutation depends on the rate of mutation of FECV to FIPV and the immune status depends on the age, gene pool and the stress level of the cat. High immune status will be more effective at slowing down the virus (Rottier Peter, et al. 2005).
How does FCoV cause FIP?
Infections with FCoV are usually limited to the intestinal tract, with very limited viral replication elsewhere. Strains of FCoV causing these infections are referred to as feline enteric coronavirus (or FECV). During infection, and while the virus replicates in the intestine, it undergoes spontaneous mutations. This leads to the development of different strains of the virus, and occasionally a strain may develop that has dramatically altered disease-causing potential – this viral strain is referred to as feline infectious peritonitis virus (FIPV). FIPV strains of FCoV differ from FECV in that they no longer replicate well in the intestine, but rather preferentially infect macrophages – one of the important cells of the immune system. The virus spreads throughout the body, and if replication is not contained by a good immune response, a cat will develop clinical signs of FIP.
In most cases, it appears that an FIP-producing strain of FCoV probably arises within a cat already infected with FCoV. In many (or even most) cases of FIP, the FIP-producing strains of the virus are not shed in the faeces of a cat with FIP.
When an FIP-producing strain of FCoV emerges, whether a cat will develop FIP or will remain healthy depends on the quality of its immune response. A strong immune response (especially the type of immunity termed ‘cell mediated immunity’) may enable the cat to control the infection and prevent signs developing.
Symptoms and types
Feline infectious peritonitis (FIP) can be spotted in both a “wet” and a “dry” form. One sign of FIP would be the irresponsiveness of a fever to antibiotics, anorexia, weight loss and lethargy. Additionally, the wet form of FIP is characterized by the accumulation of fluid in the abdominal cavity (Fig. 1), the chest cavity and sometimes both. Cats with fluid in the chest usually show laboured breathing. Cats with fluid in the abdomen can present progressive painless abdominal distension. The dry form of FIP usually presents minute accumulations of inflammatory cells or granulomas, and these are formed in several organs. Clinical signs of the dry form usually depend on which organ it is affecting. If the kidneys are affected, excessive thirst and urination, vomiting and weight loss are seen, if the liver, jaundice. The eyes and the neurologic system are frequently affected, as well.
Figure 1 Exudative of FIP. (A) granulomatous vasculitis form (B) exudate form. Figure taken from (Sanja and Marinković 2004).
Wet FIP usually presents a clear to yellow high protein exudate that contains a low number of nucleated cells (protein levels > 3.5 g/dl, low cellularity of < 5000 cells per microliter). Protein content can be readily surveyed via refractometer. High protein and fibrin content make FIP exudate characteristically viscous, an egg-white consistency that often exhibits threading.
Moreover, Rivalta Test can be done to further assess suspicious exudate from the cat’s peritoneum. One drop of effusion is added and watched carefully: if the drop disappears, the test is negative. If the drop retains its shape, the test is positive. A negative test is more powerful in ruling out disease than a positive test is in supporting FIP diagnosis. It is important to remember that other rule outs for an exudate in the abdomen are all serious conditions, and therefore in a shelter it may be reasonable to euthanize cats based on a strong suspicion of an untreatable condition rather than investing resources on further testing. We strongly recommend Bioguard Rivalta Test ® kit with instruction shown previously in the canine peritonitis report (link).
Suspicious effusion can be analysed for antibodies to FCoV; however, the presence of FCoV antibodies and the magnitude of the titter do not strongly correlate with diagnosing FIP. Studies focused on localizing antibodies in CSF are contradictory, and CSF should not be used in order to determine a diagnosis.
Diagnoses
Diagnosing FCoV and FIP is challenging. Despite the claims made by some laboratories and test manufacturers, there is currently no test that can distinguish between the harmless intestinal coronavirus and the deadly FIP coronavirus. A positive test may support the veterinarian’s suspicions, but by itself is inconclusive. It means only that a cat has been exposed to and may be harbouring a coronavirus. A negative test usually (but not always) indicates that the cat is unlikely to have FIP.
If a cat has what appears to be the wet form of the disease, laboratory analysis of some of the fluid can support a diagnosis of FIP. A 1994 study reported that cats with signs suggestive of FIP, who also had a high coronavirus antibody level, reduced numbers of lymphocytes and high levels of globulins in the bloodstream, had an 88.9 percent probability of having FIP. Diagnosing the dry form of the disease is even more challenging, often requiring biopsy of affected organs.
Diagnosis by PCR:
PCR can be used to detect viral genetic material in tissue or body fluid; there are no effective PCR tests for detecting virus in the blood. Historically, PCR testing could not distinguish between FCoV and FIPV, and results lacked clinical significance like FCoV titter testing. Recently, Idexx developed a Real-PCR that detects a FIPV specific protein, in tissue or body fluid, that correlates well with FIP infection and can be used as a confirmatory diagnostic tool.
To date, it is virtually impossible to screen healthy cats for risk of developing FIP.
| Table 1. Summary of diagnostic tests and interpretation that can help aid in the diagnosis of FIP | |
| Diagnostic Tests | Interpretation |
| Coronavirus Titers | In general, a positive titer only indicates exposure to FCoV, not FIPV. If the titer is negative at <1:25, it is likely the cat is truly negative for FIP. Very high titers, >1:1,600, are suggestive of FIP |
| Rivalta Test | A negative test indicates the fluid is a transudate and not supportive of FIP. |
| Visualization of FCoV within macrophages in effusion or tissue samples (by immunohistochemistry) | Diagnostic for FIP. |
| PCR | Positive FCoV PCR indicates exposure to coronavirus, not FIPV. Negative PCR does not rule out FIP. |
| IDEXX RealPCR™ | Positive result in a sick cat is suggestive of FIP. |
Treatment
Although once considered 100% fatal, promising anti-viral medications, including viral protease inhibitors and a viral RNA inhibitor, have demonstrated FIP remission in clinical trials. Unfortunately, these drugs are not yet approved by the Food and Drug Administration (FDA) and are not publicly available. Black market versions are appearing, but it is important to remember there is no regulation of these drugs including no verification of their authenticity or safety. This puts veterinarians in a difficult position of being aware of possible life-saving treatment but unable to recommend it. In response, cat owners have banded together through groups such as “FIP warriors” on Facebook to share knowledge and experiences.
Until these drugs are approved and legally available, FIP will remain an essentially untreatable disease in shelters. Infected cats likely pose a minimal contagious risk to others and can be cared for in hospice where resources exist, and foster care can be assured. However, the inexorable course of the disease means that euthanasia is still often considered as a humane choice for clinically affected cats in shelters.
Prevention
The best protection against FIP is operating within your shelter’s capacity for care, practicing good husbandry with humane housing, and managing disease in the population and within individuals. These practices minimize the vulnerability of cats to pathogens, like feline coronavirus, by minimizing their exposure, infectious dose and transmission.
- Capacity for care practices important to prevent overcrowding and decrease LOS:
- Manage population size so each cat or litter has a humane housing unit and the staff available to adequately provide care
- Minimize length of stay so each cat stays in the shelter only as long as needed to meet their needs for adoption
- Prioritize fast track animals, like kittens, through your shelter processes so their shelter stay (and disease exposure) is lowered
- Housing and husbandry practices important to decrease stress and minimize viral dose are:
- Humane housing units include:
- Double-sided housing for all cats
- Group housing is limited to adult cats >5 months and related litters
- Each cat in group housing has a minimum of 18 square feet of floor space and their own litterbox
- No comingling of kittens or mixing of litters in the shelter or in foster
- Minimize movement of cats between different housing units
- Manage stress by providing hiding places for all cats and decreasing noise levels
- Practices to minimize overall disease burden are:
- Intake protocols that include vaccination and dewormers
- Work with a DVM to develop treatment protocols for common shelter diseases like diarrhea and upper respiratory disease
- Have in place a robust monitoring and rounds system so sick animals are noted quickly and brought to the attention of medical staff for care
Vaccination for FCoV/FIP
There are inherent challenges to creating a truly reliable vaccine for FCoV, given that even natural infection does not convey lasting immunity. There is currently only one vaccine available for feline coronavirus, a modified live intranasal product labeled for use in cats > 16 weeks of age, which is given as a series of two vaccines 3-4 weeks apart.
Results of studies regarding the efficacy of this vaccine have been variable, some showing no efficacy and others showing limited efficacy under certain circumstances. One study showed a significantly decreased risk of FIP in cats that were seronegative for FCoV at the time of vaccination. Although there may be some benefit to giving the vaccine to cats that have never before been exposed to a multi-cat environment (and are therefore relatively likely to be seronegative), most shelter cats will have long since been exposed by the time the recommended booster vaccine can be administered. Based on this information, vaccination is not recommended by the American Association of Feline Practitioners (AAFP).
Cleaning and Disinfection
Fortunately, the most commonly used disinfectants will inactivate feline coronavirus. Best cleaning practices include:
- Spot-cleaning for daily cleaning and deep cleaning only between cats
- Litterbox care includes:
- Use low-dust litter
- Provide a scoop for each cat clean scoops between each cage, and scoop litterboxes as frequently as possible
- Minimize contamination of floors (don’t empty litter onto floor during cage cleaning)
- Change tops or gowns between groups of animals.
References
- Antoniw, John, and Mike Adams. 2013. Members of Genus: Alphacoronavirus. Hangzhou: Association of Applied Biologist.
- Febr, D., S. Bolla, A. A. Herrewegh, M. C. Horzinek, and H. Lutz. 1996. “Detection of feline coronavirus using RT-PCR: basis for the study of the pathogenesis of feline infectious peritonitis (FIP).” Schweizer Archiv fur Tierheilkunde 74–79.
- Gunn-Moore, D. A., T. J. Bruffydd-Jones, and D. A. Harbour. 1998. “Detection of feline coronaviruses by culture and reverse transcriptase-polymerase chain reaction of blood samples from healthy cats and cats with clinical feline infectious peritonitis.” Veterinary Microbiology 193–205.
- Hartmann, Katrin. 2005. “Feline infectious peritonitis.” Veterinary Clinics of North America: Small Animal Practice 39–79.
- Hartmann, Katrin. 2005. “Feline infectious peritonitis.” Veterinary Clinics of North America: Small Animal Practice 39–79.
- Pedersen, N. C. 2009. “A review of feline infectious peritonitis virus infection: 1963–2008.” Journal of Feline Medicine and Surgery 225–258.
- Rottier Peter, J. M., Kazuya Nakamura, Pepjin Schellen, Haukeline Volders, and Jan Haijema Bert. 2005. “Acquisition of Macrophage Tropism during the Pathogenesis of Feline Infectious Peritonitis is Determined by Mutations in the Feline Coronavirus Spike Protein.” Journal of Virology 14122–30.
- Sanja, Aleksić-Kovačević, and Darko Marinković. 2004. “Feline infectious peritonitis (FIP) in our section material.” Veterinarian Glasnik 121 – 12.
- Satoshi, Taharaguchi, Soma Takehisa, and Hara Motonobu. 2012. “Prevalence of Feline Coronavirus Antibodies in Japanese Domestic Cats during the Past Decade.” Journal of Veterinary Medical Science 1355–8.
- Stoddart, C. A., and F. W. Scott. 1989. “Intrinsic resistance of feline peritoneal macrophages to coronavirus infection correlates with in vivo virulence.” Journal of Virology 436–440.
- Vennema, H., A. Poland, J. Foley, and N. C. Pedersen. 1998. “Feline infectious peritonitis viruses arise by mutation from endemic feline enteric coronaviruses.” Virology 150–157.
