On July 3, 2025, Bova published updated recommendations for the treatment of FIP with various antiviral drugs. It should be noted that the recommended injection dosage of GS-441524 is missing, as Bova does not produce this active ingredient in injectable form.
Bova is a manufacturer of legal FIP medication, although very few veterinarians in the Czech and Slovak Republics use it due to its high price.
Abstract
Feline infectious peritonitis (FIP) was until recently considered a fatal disease of cats with no effective treatment. However, since 2020, there has been a major breakthrough in the treatment of FIP with the legal availability of antivirals such as remdesivir and its active metabolite GS-441524, initially in Australia and the United Kingdom. This expert review summarizes current recommendations for veterinarians regarding the diagnosis, treatment and monitoring of patients with FIP, and presents the growing clinical experience with individual therapeutic approaches.
The treatment focuses on nucleoside analogues (GS-441524, remdesivir, molnupiravir/EIDD-2801, EIDD-1931), whose mechanism of action is based on the inhibition of viral RNA replication. Oral administration of GS-441524 has been shown to be highly effective even as monotherapy, including in neurological and ocular forms of FIP. The recommended duration of treatment is 12 weeks (84 days), although a shorter 6-week regimen may be considered in cases of early diagnosis and rapid clinical response. Dosage must be adjusted to the individual patient's condition, type of FIP, absorption of the active substance and possible weight gain during treatment.
The document also discusses in detail the possible adverse effects of antiviral drugs (e.g. neutropenia, ALT elevation, gastrointestinal symptoms), recommendations for use in specific cases, and emphasizes the importance of therapeutic monitoring using acute phase proteins (AGP, SAA) and albumin/globulin ratio monitoring. A key caveat is the use of unregulated preparations that may be toxic and of unclear active substance content.
In addition to primary treatment, attention is paid to relapse management, supportive care (including nutrition, analgesia, antiemetics), as well as comorbidities such as immune-mediated hemolytic anemia (IMHA) or myocarditis. Owner support in home care, correct weight-based dosing, and appropriate education are essential for a successful treatment outcome.
In conclusion, FIP now appears to be a treatable disease, with long-term survival rates exceeding 90% with early diagnosis, appropriate treatment, and good compliance, thanks to the availability of quality antivirals and comprehensive management. The aim of this document is to support veterinarians in their professional confidence in the treatment of FIP and to increase the availability of effective treatment for affected cats worldwide.
For those who are only interested in the treatment protocol itself, I am attaching a clear table.
Below you will find the full article in PDF format in English.
2024 has been a remarkable year for FIP treatment and research. Although many thousands of cats have been cured of FIP in the past 5 years, antiviral drugs such as GS-441524 and molnupiravir have until now only been available on the unapproved market. Fortunately, both drugs are now available legally in many countries at a price comparable to unapproved sources. The full approval of Remdesivir, Molnupirvir, and Paxlovid for human use against COVID-19 has allowed veterinarians to prescribe them to cats with FIP, but at the price of a human prescription. The price of the unapproved and approved drug GS-441524 has also dropped significantly over the past few years, making it much more affordable for cat owners, cat rescue groups, catteries, and shelters.
SOCK FIP Friends continued their long-term support of FIP research at the University of California, Davis (UCD) School of Veterinary Medicine (SVM), and the ongoing studies were quite diverse. Clinical trials of the treatment, led by Dr. Krystle Reagan, included GS-441524 by oral and subcutaneous routes (equally effective); GS-441524 vs. Molnupiravir (equally effective); GS-441524 vs. Remdesivir (also equally effective); 1, 2 and Paxlovid (very promising preliminary results). Ongoing studies in owned cats have also served as a crucial source for other types of studies. Approximately 20 % cats with FIP die within the first few days of treatment, and the causes of these deaths have been investigated by Dr. Brian Murphy and his team.3 In addition to the typical lesions of severe FIP, cats that died early often had signs of secondary bacterial sepsis (supporting pneumonia, hepatitis) and severe heart disease (myodegeneration, myocarditis/pericarditis). Immune cell phenotypes from blood and lymph nodes and levels of various cytokines in body fluids were analyzed by Dr. Amir Kol and colleagues to determine how the immune system responds to infection. Preliminary results show that immunity is much more complex than previously thought, and that lymph node enlargement and cellular changes persist for a very long time after recovery. A third research team, led by Drs. Patty Pesavento and Teresa Brostoff, set out to investigate how vaccines could help prevent FIP, which, if effective, would be a desirable adjunct to treatment. A messenger RNA vaccine against the core protein of feline coronavirus was developed and has been shown to be highly immunogenic in mice. 4 and these studies will now be extended to laboratory and field cats.
Discovery of an effective treatment for FIP, as first announced in 2018 (GC376)5 and 2019 (GS-441524)6 , has led to a renaissance of clinical knowledge and interest in FIP research. FIP research has also intensified significantly in many countries outside the United States, such as China, Japan, and countries in Southeast Asia and Europe. Recently, the severity of FIP in Mediterranean countries, particularly in feral and rescue cat populations, has been documented, leading to a renewed focus on cats in this region of the world. The ability to effectively treat FIP with antiviral drugs has also stimulated not only knowledge of FIP but also interest in feline medicine among veterinarians worldwide. SVM UC Davis is proud of our contribution to this renewed interest in FIP, and we hope that SOCK FIP contributors are equally proud of the support they have provided to this effort.
On behalf of the entire SOCK FIP board, I would like to wish our supporters happy holidays and a happy and productive year 2025. We look forward to an even more productive year 2025.
–Niels C. Pedersen
References
Cosaro, E.; Pires, J.; Castillo, D.; Murphy, BG; Reagan, KL Efficacy of Oral Remdesivir Compared to GS-441524 for Treatment of Cats with Naturally Occurring Effusive Feline Infectious Peritonitis: A Blinded, Non-Inferiority Study. Viruses2023, 15, 1680. https://doi.org/10.3390/v15081680
Reagan KL, Brostoff T, Pires J, Rose A, Castillo D, Murphy BG. Open label clinical trial of orally administered Molnupiravir as a first-line treatment for naturally occurring effusive feline infectious peritonitis. J Vet Intern Med. 2024; 38(6), 3087. https://doi.org/10.1111/jvim.17187
Murphy, BG; Castillo, D.; Neely, NE; Kol, A.; Brostoff, T.; Grant, CK; Reagan, KL Serologic, Virologic and Pathologic Features of Cats with Naturally Occurring Feline Infectious Peritonitis Enrolled in Antiviral Clinical Trials. Viruses2024, 16, 462. https://doi.org/10.3390/v16030462
Brostoff, T.; Savage, HP; Jackson, KA; Dutra, JC; Fontaine, JH; Hartigan-O'Connor, DJ; Carney, RP; Pesavento, PA Feline Infectious Peritonitis mRNA Vaccine Elicits Both Humoral and Cellular Immune Responses in Mice. Vaccines2024, 12, 705. https://doi.org/10.3390/vaccines12070705
Pedersen NC, Kim Y, Liu H, Galasiti Kankanamalage AC, Eckstrand C, Groutas WC, Bannasch M, Meadows JM, Chang KO. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. J Feline Med Surg. 2018 20, 378. https://doi.org/10.1177/1098612X17729626.
Pedersen NC, Perron M, Bannasch M, Montgomery E, Murakami E, Liepnieks M, Liu H. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg. 2019 Apr;21(4):271-281. https://doi.org/10.1177/1098612X19825701.
Basic information Before the discovery of effective antiviral drugs, feline infectious peritonitis (FIP) was a fatal disease of cats. Multiple antiviral treatments have been identified, but optimization of treatment protocols is needed.
The goal To evaluate the efficacy of PO molnupiravir (MPV; EIDD-2801) in the treatment of effusive FIP.
The animals Ten cats with naturally occurring effusive FIP and 10 cats from the control group were treated PO with GS-441524.
Methods Prospective, open-label, longitudinal, comparative study with a reference control group. Ten cats with FIP were enrolled and treated with PO MPV (10–15 mg/kg PO q12h) for 84 days. Cats were evaluated at weeks 0, 6, and 16, and the proportion of cats in clinical remission at week 16 was determined. Survival and clinicopathological characteristics were compared with control cats with effusive FIP treated with PO GS-441524.
The results Eight of the 10 cats treated with MPV survived and were in remission after 16 weeks. Two cats that did not survive died within the first 24 hours of treatment. No adverse events requiring discontinuation of treatment were observed. Survival of cats treated with PO MPV was not inferior to the historical control group of cats treated with PO GS-441524 (5/9 survived [55 %]), with a survival difference of 25 % (90 % confidence interval, −9.3 % to 59.3 %). Clinicopathological features associated with FIP normalized over the course of the study, and no differences in clinicopathological data were observed at any time point in the study when comparing cats treated with MPV and GS-441524.
Conclusions and clinical significance Molnupiravir is an effective antiviral treatment for effusive FIP.
Complete clinical study: Zuzzi-Krebitz AM, Buchta K, Bergmann M, Krentz D, Zwicklbauer K, Dorsch R, Wess G, Fischer A, Matiasek K, Hönl A, Fiedler S, Kolberg L, Hofmann-Lehmann R, Meli ML, Spiri AM, Helfer-Hungerbuehler AK, Felten S, Zablotski Y, Alberer M, Both UV, Hartmann K. Short Treatment of 42 Days with Oral GS-441524 Results in Equal Efficacy as the Recommended 84-Day Treatment in Cats Suffering from Feline Infectious Peritonitis with Effusion-A Prospective Randomized Controlled Study.Viruses. 2024 Jul 16;16(7):1144. doi: 10.3390/v16071144. PMID: 39066306; PMCID: PMC11281457.
The discovery of GS-441524 as an effective antiviral drug for cats with feline infectious peritonitis (FIP) has enabled feline patients to survive this once incurable, fatal disease. In the UK and Australia, GS-411524 is already legally available, while in the US the drug has only recently been available through selected compounding pharmacies. An 84-day treatment cycle has been shown to be successful in various clinical studies and has become an unofficial standard protocol. From a practical point of view, the daily administration of the drug for 12 weeks, as well as the cost of such treatment, can make it difficult or even impossible for cat owners to complete the entire prescribed treatment.
The aim of the researchers in Germany and Switzerland was to evaluate whether a 42-day treatment with GS-441524 is as effective as the currently recommended 84-day protocol. In a prospective randomized controlled treatment study, 40 cats were randomized to receive 15 mg/kg GS-441524 orally once daily for 42 or 84 days. Patients were diagnosed with FIP based on either FCoV RNA detected by RT-qPCR or RT-PCR in effusion in at least one body cavity with altered laboratory parameters typical of FIP. In addition to the diagnosis of FIP, other inclusion criteria included the presence of abdominal and/or pleural effusion, negative FeLV and FIV status, a body weight of at least 2 kg, and the absence of other serious diseases. The age of the cats ranged from 5.1 to 116.3 months, with 17 of the 40 cats being less than 1 year old. Breed distribution was as follows: 40 % Domestic Shorthairs (DSH), 20 % British Shorthairs (BSH) and 40 % other breeds. At the start of the study, 63 % cats had abdominal effusion, 12 % pleural effusion, and 25 % effusion in both cavities.
Each patient was treated for the first 7 days at the Center for Clinical Veterinary Medicine at the LMU in Munich. Treatment groups were blinded until day 7 of the study. The cats remained in their owners' homes for the remaining days of the study and returned every 2 weeks for follow-up examinations and diagnostic tests at the clinic. Tests included abdominal and thoracic ultrasonography, blood chemistry, hematology, urinalysis, measurement of viral RNA in effusion, blood, and feces, and anti-FCoV antibodies. Detailed cardiological and neurological examinations were performed at study entry. The final re-examination was performed 168 days after the start of treatment.
GS-441524 was supplied as 50mg tablets and was legally imported from the UK. Owners kept diaries documenting items such as activity, stool consistency, food intake and body weight. 19 cats (of 20) in each treatment group completed treatment. Two cats were euthanized during treatment (days 3 and 31) due to secondary complications.
Clinical remission was observed between days 14 and 84 with a median of 28 days, and within the first 42 days 37/40 cats went into complete clinical remission. Every cat that completed treatment showed significant improvement in hematological and clinical chemistry parameters. At the beginning of the study, viral RNA was detected in the blood of 35/40 cats, and by day 28 no more viremia was noted in any cat. During the second phase (days 42 to 84) of the study, in which only the long-term treatment group received the drugs, no significant differences were found in viral load in blood, effusion and feces or anti-FCOV antibodies. By 168 days, all 38 cats remaining in the study were in complete remission. Two cats with neurological or ocular signs also fully recovered during treatment.
The most frequently observed adverse events were diarrhea in 25/40 cats (20 % of which were diagnosed as severe based on stool evaluation), elevation of liver enzymes (mild to moderate) in 24/40 cats between days 1 and 84, lymphocytosis in 27/40 cats and a slight increase in SDMA above the reference interval in 25/40 cats. None of the patients experienced adverse effects related to the administration of GS-441524.
This study demonstrated that a shorter treatment of 42 days with oral GS-441524 was as effective as the currently recommended 84-day treatment. GS-441524 was generally well tolerated, with no significant adverse reactions noted. Limitations include that all patients received continuous professional veterinary care during the first 7 days of treatment, which is not common in most clinical practice. In addition, only patients with wet FIP were included and only the oral form of GS-441524 was used. The preparation used in the study was legally manufactured in a strictly controlled manner by BOVA Specials in London, UK. Many cat owners around the world still purchase oral and/or injectable GS-441524 from "black market" sources, so it is unknown whether the 42-day treatment is equally effective in these patients. -BJP
More details:
Pedersen NC, Perron M, Bannasch M, Montgomery E, Murakami E, Liepnieks M, Liu H. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis.J Feline Med Surg. 2019 Apr;21(4):271-281. doi: 10.1177/1098612X19825701. Epub 2019 Feb 13. PMID: 30755068; PMCID: PMC6435921.
Murphy BG, Perron M, Murakami E, Bauer K, Park Y, Eckstrand C, Liepnieks M, Pedersen NC. The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies.Vet Microbiol. 2018 Jun; 219:226-233.doi: 10.1016/j.vetmic.2018.04.026. Epub 2018 Apr 22. PMID: 29778200; PMCID: PMC7117434.
Although not registered for feline infectious peritonitis (FIP) in Japan, nucleoside analogues have shown efficacy and have been offered to owners of cats with FIP in our clinic since January 2020. The aim of this study was to examine the outcomes in cats with FIP who received GS-441524 or molnupiravir. The diagnosis of FIP was based on clinical signs, laboratory test results, and the presence of feline coronavirus RNA in blood or exudate. After providing oral and written information, owners of cats with a presumptive diagnosis of FIP were offered antiviral treatment with commercially available GS-441524 starting in June 2020 and with either GS-441524 or molnupiravir starting in January 2022. Dosage was 12.5–25 mg/kg/day for GS-441524 and 20–40 mg/kg/day for molnupiravir, depending on the presence of effusion and neurological and/or ocular signs, and continued for 84 days. A total of 118 cats with FIP (76 with effusion), 59 with GS-4421524 and 59 with molnupiravir were treated. Twenty cats died, 12/59 (20.3 %) in the GS-441524 group and 8/59 (13.6 %) in the molnupiravir group (p = 0.326), with the majority of deaths occurring within the first 10 days of treatment initiation. In the survivors, neurological and ocular signs resolved in all but one cat that had persistent seizures. Of the cats that completed treatment, 48/48 in the GS-441524 group and 51/52 in the molnupiravir group achieved remission. Laboratory parameters normalized within 6 to 7 weeks of drug initiation. Adverse events, such as liver function abnormalities, were transient and resolved without specific intervention. Our data suggest that GS-441524 and molnupiravir have similar efficacy and safety profiles in cats with FIP.
The full article can be found in English at https://doi.org/10.3389/fvets.2024.1422408
We thank Richard Malik and Sally Coggins for their advice and assistance in the preparation of this paper.
FIP treatment protocols - what's new?
Antivirals currently legally available in the UK and other countries through importation include remdesivir (injection), GS-441524 (oral suspension and oral tablets) and EIDD-1931 (oral tablets). The following recommendations are based on published and unpublished data and experience. The treatment of individual cases remains within the competence of the attending veterinarian. The dosage below is based on experience with the use of reputable preparations with known antiviral content. The extrapolation does not apply to other oral preparations for which the active ingredient and/or its content is unknown or not provided by the manufacturer.
Use of oral GS-441524 throughout treatment, including initiation of treatment
Oral GS-441524 (available as a 50 mg/ml suspension and 50 mg tablets) can be used from the start of FIP treatment for a full (eg, 12-week/84-day) cycle. It is important to support owners in their cats' medication, which can be difficult. GS-441524 oral suspension or tablets can be given with a small treat (tablets can be crushed for this) or directly into the cat's mouth. Further study is needed to examine the effect of food on absorption, but it is recommended that it be given in a small treat or on an empty stomach, with an hour or more gap before a larger meal.
Fasting cats at night can increase their hunger to facilitate the administration of the medicine in the morning, and similarly for the evening dose. However, starving kittens is never recommended as they will not be able to handle it. Any withholding of food must be adapted to the cat's age.
Injectable remdesivir is intended for cats that cannot be treated orally
Injectable remdesivir (10 mg/ml) is effective in the treatment of FIP but is associated with some side effects (see below), particularly pain on subcutaneous injection occurring in 50 % cats. Previous FIP treatment protocols suggested that this drug be used initially before switching to oral GS-441254. However, we now know that cats with FIP can be successfully treated with oral GS-441524 from the first day of treatment. This avoids injection pain and reduces treatment costs (the dose per cat weight using GS-441524 is cheaper than remdesivir). The use of injectable remdesivir should be reserved for the following situations:
Severe neurological symptoms and inability to swallow or tolerate oral medications;
Extremely dehydrated/unruly cats;
Cats that cannot be treated orally for other reasons.
In certain circumstances, if the cat is hospitalized and has decreased appetite, which affects the ability to administer medication, 48 hours of remdesivir (given intravenously, not subcutaneously) may result in significant clinical improvement that may facilitate subsequent oral treatment with GS-441524. The rest of the treatment cycle can then be administered in the form of oral GS-441524.
The switch between remdesivir and oral GS-441524 can be immediate, ie from one treatment to the other.
The current recommendation is to treat for at least 84 days. Some cats have been successfully treated with shorter courses, but large-scale case studies have not yet been published. If cost constraints require a shorter duration of treatment, the dose used should not be reduced and treatment should last as long as possible.
What dosage of GS-441524 and remdesivir should I use to treat FIP?
With experience and as yet unpublished data on therapeutic drug level monitoring (TDM), dosing recommendations have increased over previous FIP treatment protocols. However, evidence shows that more than 85 % cats respond to previously recommended drug dosing, which is still a high rate. However, based on TDM studies, we now know that individual cats vary in their absorption of oral GS-441524, with those that absorb it poorly requiring higher doses to achieve clinical and biochemical remission. Ideally, dosage should be adjusted based on TDM, if available (see below), or based on response to treatment.
Compared to previous FIP treatment protocols, the following changes in dosing recommendations are important:
GS-441524 is administered orally in divided doses twice daily (every 12 hours) to optimize serum levels of GS-441524;
Higher dosages may overcome malabsorption problems in some cats and have a better chance of crossing the blood-brain barrier and the blood-ocular barrier;
Dosage should be adjusted according to response and TDM if available.
Clinical presentation
GS-441524 PO dosing
Remdesivir IV or SC injection
Effusion present No ocular or neurological symptoms
6-7.5 mg/kg q 12h ie 12-15 mg/kg divided into 2 doses per day
10 mg/kg q 24h
Absence of effusion No ocular or neurological symptoms
6-7.5 mg/kg q 12h
12 mg/kg q 24h
Ocular symptoms
7.5-10 mg/kg q 12h
15 mg/kg q 24h
Neurological symptoms
10 mg/kg q 12h
20 mg/kg q 24h
PO, per os – orally; IV-intravenous; SC – subcutaneously; q – every x hours
Cats should be re-examined after 1-2 weeks (sooner if not improving or worsening) and dosage adjusted depending on monitoring at this point.
NOTE ON WEIGHING CATS: During treatment, it is very important to weigh the cats once a week, using accurate scales, e.g. on cat or baby scales. With successful treatment, the kittens will gain weight and/or grow, necessitating an increase in the dose to ensure that the dose of antiviral given is still adequate for the type of FIP being treated according to Table 1. Failure to increase the dose as the kitten grows appears to be one of the most common causes poor response to treatment and treatment failure.
What should I do if FIP relapses?
e.g. recurrence or insufficient resolution of effusion, pyrexia, development of new ocular or neurological symptoms, or persistent clinicopathological abnormalities:
Make sure you are still sure the cat has FIP; reassess the diagnosis, seek further pathology and consider repeat sampling (eg, external laboratory analysis and culture of any fluid; cytology or lymph node biopsy ± detection of feline coronavirus antigen or RNA, but remember that with treatment the virus is more difficult to find), AGP;
Consider TDM, if available, to monitor GS-441524 serum levels to inform dosing;
If relapse occurs during treatment, increase the dose of GS-441524 (or remdesivir) by 2-3 mg/kg per dose and monitor as above, ensuring that treatment is not stopped before the cat is in normal clinical condition and based on clinical pathology results for at least 2 weeks. Dosage increases depend on the dosage the cat is receiving at the time of relapse, the nature of the relapse and financial resources, but can be up to the recommended dosage for neurological FIP (see dosage chart above) or even higher (seek advice when considering this option );
If relapse occurs after stopping treatment, restart GS-441524 (or remdesivir) at a higher dose (at least 2-3 mg/kg higher than previously used) and ideally continue treatment for an additional 12 weeks. The increased dosage used will depend on the dosage the cat was receiving prior to the relapse and the nature of the relapse, but may be up to the dosage recommended for neurological FIP;
If the cat is already on a high dose of GS-441524 and/or serum TDM levels are adequate, consider switching to EIDD-1931 (see below) and seek advice (email advice for FIP or specialists) as adjunctive therapy such as mefloquine feline interferon or a polyprenyl immunostimulant may be an option (see below).
Treatment with EIDD-1931
This drug is another antiviral effective in the treatment of FIP in cats, although there is much less evidence of its use than GS-441524. The recommended dosage is 15 mg/kg every 12 hours and is available as 60 mg tablets for oral use. Potential adverse effects include cytopenia, especially neutropenia, rarely pancytopenia, decreased appetite/nausea, increased ALT enzyme activity, and potential renal compromise. The use of EIDD-1931 should be reserved for:
cats that do not respond to treatment with GS441524 or remdesivir despite adequate dosing (ideally assessed by TDM);
cats that relapse after treatment with GS-441524 or remdesivir at an appropriate dose.
Treatment with feline interferon (IFN), polyprenyl immunostimulant or mefloquine
In some cats, combinations of IFN omega, the immunostimulant polyprenyl, and mefloquine were used in the post-treatment period with GS-441524 (or remdesivir); however, there is currently no evidence to suggest that they are necessary, as even without this adjunctive treatment, a high success rate of over 85 % has been reported;
Mefloquine is also used to treat cats with FIP when financial constraints make it absolutely impossible to use a full course or increased dosage of more potent antivirals such as GS-441524. Studies are needed to evaluate its effectiveness, but it should only be used when absolutely no alternatives are available, as GS-441524 is known for its high potency.
When discussing feline coronavirus (FCoV) infection in a multi-cat environment, it is important to understand the correct nomenclature. The term FCoV is a collective term for two historically named viruses. The coronavirus was eventually identified as the causative agent of feline infectious peritonitis (FIP) in cats and named FIP virus or FIPV (Ward, 1970; Zook et al., 1968). FIPV was subsequently found to be a mutant form of FCoV that was present in cats infected with the widespread and minimally pathogenic enteric coronavirus and was named feline enteric coronavirus (FECV) (Pedersen et al., 1981). To avoid misunderstanding, this author prefers to refer to the form of FCoV that is relevant to the discussion. Therefore, it is appropriate to use the term FIPV when discussing the form of FCoV that is found in a specific type of white blood cell (monocyte/macrophage) in affected tissues and body fluids of cats with FIP. The term FECV is used when referring to the form of FCoV that causes chronic and intermittent infections of the epithelium in the lower intestine of healthy cats and is shed in large quantities in the feces. Enzootic is the correct term for infections that are maintained at a low and variable level in an animal population, while endemic is the corresponding term used for humans. Epizootic refers to a sudden and significant outbreak of a new infection, usually with rapid direct spread to animals of all ages. The human equivalent of epizootic is epidemic. Clinical “signs” are what veterinarians and doctors observe during a physical examination or what owners/parents convey to them, while symptoms are what people recognize in themselves and tell their doctors about.
FECV, like other feline mucosal pathogens, is maintained in the population as a persistent or recurrent latent infection (ie, enzootic). FECV is first shed in faeces from around 9–10 weeks of life, coinciding with the loss of maternal immunity (Pedersen et al., 2008). Infection occurs via the faecal-oral route and targets the intestinal epithelium, and the primary symptoms of enteritis are mild or mild, transient and rarely chronic or severe (Pedersen et al., 2008; Vogel et al., 2010). Subsequent excretion of feces is from the large intestine and usually stops after several weeks or months (Herrewegh et al., 1997; Pedersen et al., 2008; Vogel et al., 2010) with the development of immunity. The resulting immunity is unfortunately short-lived and repeated infections are common (Pearson et al., 2016; Pedersen et al., 2008. A stronger immunity appears to develop over time and cats older than 3 years appear to be less prone to re-infection and become with faecal excreters (Addie et al., 2003).
FIP is caused by specific FECV mutants that develop during infection (Poland et al., 1996; Vennema et al., 1995).1 A final risk factor for FIP in multifeline settings is the proportion of cats with high titers of antibodies to feline coronavirus and shedding virus in feces (Foley et al., 1997). FIP-causing mutants develop in 10 % or more cases of FECV infection, but only a fraction of these eventually cause disease (Poland et al., 1996). The actual incidence of FIP in a population with enzootic FECV infection appears to range from about 1% to 10% cats, with cases occurring at unpredictable intervals and varying from individual cases to small groups (Addie et al., 1995b; Foley et al. , 1997). The actual incidence appears to be driven by multiple host and environmental factors that somehow compromise the immune system and increase the risk of FIP.1
Given the direct relationship between the presence of FECV and FIP, a logical way to prevent FIP would be to minimize exposure to FECV. A vaccine would be the simplest approach to control FECV infection, but no vaccine can produce better immunity than recovery from natural infection, as demonstrated by the SARS-CoV-II vaccine (Li et al., 2019). Based on what is known about the weakness and short-lived nature of natural immunity to FECV (Pearson et al., 2016; Pedersen et al., 2008), together with the considerable variation in serotypes and strains between different populations and regions (Addie et al., 1995b; Liu et al., 2019), it is unlikely that effective vaccines against FECV will be developed.
Although enzootic FECV infection cannot be easily prevented by vaccination, it is possible to eliminate FECV from a closed group of cats through thorough carrier testing and strict quarantine (Hickman et al., 1995). However, FECV is so ubiquitous in nature and easily spread through direct and indirect cat-to-cat contact and on human-borne fomites that the strictest quarantine facilities and procedures are required to stop it. How strict must the quarantine be? Experience with testing and removal in conjunction with quarantine to eliminate and prevent FECV infection is limited to one report (Hickman et al., 1995). FECV was eliminated from a specific pathogen-free breed of cats at UC Davis by removing the virus shedders and significantly tightening quarantine procedures for the remaining colony (Hickman et al., 1995). Nevertheless, FECV re-entered this colony after several years, despite all attempts to prevent its spread (Pedersen NC, UC Davis, unpublished, 2022). The only example of effective quarantine for FECV was described for cats in the Falkland Islands (Addie et al., 2012). These islands in the remote South Atlantic have fortunately remained free of FECV, probably due to their extreme isolation. Measures have been taken to prevent future inadvertent introduction of FECV to the islands (Addie et al., 2012). Based on this experience, it is unlikely that FECV could be kept out of any group of domesticated cats unless the strictest isolation and infection prevention practices are followed.
An interesting approach to preventing or delaying FECV infection in kittens in catteries has been termed “early weaning and isolation” (Addie et al., 1995a). This approach was based on the observation that kittens born to mothers exposed to or infected with FECV acquired maternal immunity to infection by 9 weeks of age (Pedersen et al., 2008). Therefore, kittens weaned several weeks before the loss of this immunity (4–6 weeks of age) are usually free of infection and, if removed from their mothers and isolated from other cats, could theoretically be maintained free of the virus. This approach was initially popular, but the facilities and quarantine procedures required to prevent the introduction of the virus are difficult to maintain in catteries with larger numbers of breeding cats (≥ 5 dams, Hartmann et al., 2005). Therefore, elimination of FECV in kittens by early weaning and isolation has been doomed to failure in most conventional homes/catteries due to the continued direct and indirect exposure of infected cats to FECV. Another problem with early weaning and isolation is the need to separate virus-free kittens from other cats in a large group. This problem could be circumvented if all cats were cleared of infection at the same time. This can be achieved by serially testing feces for FECV excretion over a period of time and culling all excreting cats, along with strict quarantine. However, since a significant proportion of cats in households involved in enzootic FECV disease excrete feces (Foley et al., 1997; Herrewegh et al., 1997), elimination of cats can have a serious impact on the gene pool (Hickman et al., 1995). This begs the question – is there a way to eliminate FECV in all cats in a group at the same time?
Interestingly, the relatively recent discovery of effective antivirals against FIP (Pedersen et al., 2018, 2019) has also provided a theoretical method to eliminate all shedding viruses at once. Initial studies on this use of antivirals, although relatively preliminary, have suggested that FECV can be eliminated from a closed group of cats with a relatively short course of treatment (Addie et al., 2023). Assuming that FECV can be eliminated as an enzootic virus from a group of cats using specific antivirals, what are the pitfalls of such an approach? The first pitfall concerns the duration of immunity to reinfection that a short course of antivirals might induce. A follow-up study of cats successfully treated for FIP with GS441524 showed a return of low FECV shedding in 5/18 individuals within 3 to 12 months (Zwicklbauer et al., 2023), suggesting that treatment, like recovery from natural infection, does not confer long-term immunity. The second challenge is the cost of antivirals to treat primary and secondary infections, frequent stool testing to monitor shedding, and the establishment and maintenance of adequate quarantine facilities and practices. Therefore, home facilities with weak barrier isolation procedures are doomed to failure to keep this group of cats free of FECV for extended periods. The third challenge relates to the routine activities associated with breeding and exhibiting breeding cats. Breeding breeding cats involves frequent interaction between kittens and older cats, as well as between humans in contact with the cats and each other. It is also difficult to imagine that a breeder of purebred cats and an avid cat showgoer would forgo all the joys of breeding and showing their cats by avoiding all such contact. The ultimate question is – “now that the cats are free of FECV, what should be done with them?” What are the chances that they will remain free of FECV for any length of time after leaving the controlled environment? They will have no immunity to FECV and will be very sensitive to even the slightest exposure. The same will be true for the group of cats from which they come. Finally, and this is the biggest concern, the constant antiviral treatment required to keep a group of cats free of FECV infection will cause drug resistance to develop. We now know that resistance to GS-441524 can occur in cats treated for FIP, and researchers at UC Davis1 and Cornell University3 agree that acquisition of drug resistance in enzootic FECV infections would outweigh any potential benefit of such treatment on FIP incidence. FIP is currently curable in more than 90 % cases3, and even if resistance to antivirals does develop, it is largely confined to the affected cat. Arguably, HIV-1 infection in humans is currently prevented by antivirals, with no reported concerns about drug resistance. However, HIV-1 prevention treatment is not a monotherapy, but includes several drugs of different classes. Treatment with multiple drugs is not carried out with the aim of increasing the effectiveness of the treatment, but rather with the aim of preventing the development of drug resistance. If the virus develops resistance to one drug in the drug cocktail, the other drugs will prevent it from replicating.
In conclusion, I would like to paraphrase: “Just because something can be done, should it be done?” The author believes that much larger and better designed studies, conducted over a long period of time, are needed before treating asymptomatic FECV infection with antivirals is seriously considered as a means of preventing FIP. The overall incidence of FIP in smaller, well-maintained kennels, shelters and research breeding colonies with enzootic FECV infection is often low, and currently more than 90% of the FIP cases that could arise can be cured (Pedersen et al, 2019).3 A practical way to reduce the incidence of FIP is to keep the number of breeding cats and kittens low, to keep a larger number of older cats, not to breed individuals and bloodlines that have given rise to cases of FIP, and to minimize the stress of frequent introductions of new cats and placement/relocation .1 Isolation and early weaning can also be useful in smaller farms (Addie et al., 1995a). The problem of FIP in foster/rescue facilities is a bigger problem because most cats come from the feral population and are often very young when they arrive. They often suffer from malnutrition, a number of other diseases and are exposed to a high degree of stress associated with capture, routine treatment, change of diet, adaptation to a new environment and finally rehoming.1,3
References
Addie DD, Bellini F, Covell-Ritchie J, Crowe B, Curran S, Fosbery M, Hills S, Johnson E, Johnson C, Lloyd S, Jarrett O. 2023. Stopping Feline Coronavirus Shedding Prevents Feline Infectious Peritonitis. Viruses. 15(4), 818.
Addie DD, Schaap IA, Nicolson L, Jarrett O, 2003. Persistence and transmission of natural type I feline coronavirus infection. J Gen Virol. 84, 2735–2744.
Addie, D.; Jarrett, O. Control of feline coronavirus infections in breeding catteries by serotesting, isolation, and early weaning. 1995a. Feline Pract. 23, 92–95.
Addie DD, Toth S, Murray GD, Jarrett O. 1995b. Risk of feline infectious peritonitis in cats naturally infected with feline coronavirus. Am J Vet Res. 56, 429-34.
Foley JE, Poland A, Carlson J, Pedersen NC, 1997. Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus. J Amer Vet Med Assoc. 210, 13131318.
Hartmann K, 2005. Feline infectious peritonitis Vet Clin North Am Small Anim Pract. 35(1), 39– 79.
Herrewegh AAPM, Mähler M, Hedrich HJ, Haagmans BL, Egberink HF, Horzinek MC, Rottier PJM, de Groot RJ, 1997. Persistence and evolution of feline coronavirus in a closed cat-breeding colony. Virology 234, 349–363.
Hickman MA, Morris JG, Rogers QR, Pedersen NC, 1995. Elimination of feline coronavirus infection from a large experimental specific pathogen-free cat breeding colony by serologic testing and isolation, Feline Practice 23, 96–102.
Li C, Liu Q, Kong F, Guo D, Zhai J, Su M, Sun D. 2019. Circulation and genetic diversity of Feline coronavirus type I and II from clinically healthy and FIP-suspected cats in China. Transbound Emerg Dis. 66, 763-775.
Pearson M, LaVoy A, Evans S, Vilander A, Webb C, Graham B, Musselman E, LeCureux J, VandeWoude S, Dean GA, 2019. Mucosal Immune Response to Feline Enteric Coronavirus Infection. Viruses 11, 906.
Pedersen NC, Theilen G, Keane MA, Fairbanks L, Mason T, Orser B, Che CH, Allison C, 1977. Studies of naturally transmitted feline leukemia virus infection. Am J Vet Res. 38, 1523–1531.
Pedersen NC, Boyle JF, Floyd K, Fudge A, Barker J, 1981. An enteric coronavirus infection of cats and its relationship to feline infectious peritonitis. Am J Vet Res. 42, 368-377. 5
Pedersen NC, Allen CE, Lyons LA, 2008. Pathogenesis of feline enteric coronavirus infection. J Feline Med Surg. 10, 529–541.
Pedersen NC, Liu H, Dodd KA, Pesavento PA, 2009. Significance of coronavirus mutants in feces and diseased tissues of cats suffering from feline infectious peritonitis. Viruses 1, 166-184.
Pedersen NC, Kim Y, Liu H, Galasiti Kankanamalage AC, Eckstrand C, Groutas WC, Bannasch M, Meadows JM, Chang KO, 2018. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. J Feline Med Surg. 20, 378-392.
Pedersen NC, Perron M, Bannasch M, Montgomery E, Murakami E, Liepnieks M, Liu H, 2019. Efficacy and
safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg. 21, 271-281.
Poland AM, Vennema H, Foley JE, Pedersen NC, 1996. Two related strains of feline infectious peritonitis virus isolated from immunocompromised cats infected with the feline enteric coronavirus. J Clin Microbiol. 34, 3180-3184.
Uusküla A, Pisarev H, Tisler A., et al., 2023. Risk of SARS-CoV-2 infection and hospitalization in individuals with natural, vaccine-induced and hybrid immunity: a retrospective population-based cohort study from Estonia. Sci Rep 13, 20347.
Vennema H, Poland A, Foley J, Pedersen NC, 1995. Feline infectious peritonitis viruses arise by mutation from endemic feline enteric coronaviruses. Virology 243, 150–157.
Vogel L, Van der Lubben M, , Te Lintelo EG, Bekker CPJ, Geerts T, Schuif LS, Grinwis GCM, Egberink HF, Rottier PJM, 2010. Pathogenic characteristics of persistent feline enteric coronavirus infection in cats. Vet Res. 41, 71.
Ward JM, 1970. Morphogenesis of a virus in cats with experimental feline infectious peritonitis. Virology 41, 191–194.
Zook BC, King NW, Robinson RL, McCombs HL, 1968. Ultrastructural evidence for the viral etiology of feline infectious peritonitis. Vet Path. 5, 91–95.
Zwicklbauer K, Krentz D, Hartmann K, et al., 2023. Long-term follow-up of cats in complete remission after treatment of feline infectious peritonitis with oral GS-441524. J Feline Med Surg. 25(8)
Footnotes
Pedersen NC. History of Feline infectious Peritonitis 1963-2022 – First description to Successful Treatment. https://sockfip.org/wp-content/uploads/2022/04/Review-FIP-1963-2022-final-version.pdf4.29.22.pdf.
Cornell University blog. Fight FIP. Unraveling feline infectious peritonitis from the ground up. https://blogs.cornell.edu/fightfip/fip-antivirals/.
A cat with Feline Infectious Peritonitis (FIP) in Cyprus shows several signs of the disease, including a swollen abdomen due to fluid build-up in the abdominal lining, unkempt fur and poor muscle condition.
The first signs of problems appeared at the end of last year (2022) in Cyprus, an island state in the eastern Mediterranean, known for its abundance of free-roaming cats. Some veterinarians there have begun to see an increase in cases of Feline Infectious Peritonitis (FIP), a fatal disease of cats.
The cats had a fever, were lethargic, losing weight and did not want to eat. Some had swollen abdomens, others had tumor-like lesions. Some were staggering, uncoordinated. Some had inflamed, cloudy or discolored eyes.
FIP usually occurs in cats as a rare reaction to infection with a common pathogen, feline enteric coronavirus (FECV). The virus is shed in the feces of infected cats, from where it can be spread to other cats. FECV is a subtype of feline coronavirus (FCoV), which is one of hundreds of known coronaviruses and does not infect humans. However, this virus is very common among stray cats and cats that live with several other cats. Cats infected with FECV are generally asymptomatic and remain healthy. However, sometimes the virus mutates and causes FIP.
In Cyprus, thousands of cats were diagnosed in the first months of this year. The disease spread rapidly, contradicting common ideas about how FIP develops.
“It’s just not right,” said Dr. Danielle Gunn-Moore, a professor of feline medicine at the Royal (Dick) School of Veterinary Medicine at the University of Edinburgh, when she found out this summer that the number of diagnoses on the island had increased 40-fold compared to the previous year.
So far unpublished work, which was published on the bioRxiv portal in November before being published in a peer-reviewed journal, offers preliminary answers to the question of why so many cats fell ill in Cyprus. Based on RNA sequencing of samples from dozens of cats with FIP, the authors of the paper argue that a strain of coronavirus that arose from separate feline and canine coronaviruses may have combined, linking the fecal excretion and infectivity of the common FECV virus with the virulence of the mutated FIP virus to one pathogen.
"In normal FIP, the FIP virus is rarely spread," said Gunn-Moore, the author of the paper. "That's a huge difference in the new outbreak. Everything suggests it's directly transmitted."
Veterinary researchers asked by VIN to comment on the paper called the evidence “interesting” and “highly suggestive” but not definitive. They say further research is needed, which the authors say is underway.
Concerns are growing on "Cat Island"
In short
Thousands of cats on the Mediterranean island of Cyprus have been diagnosed this year with feline infectious peritonitis, a fatal and usually rare feline disease.
The disease spread quickly among the many free-ranging cats on the island, upsetting the conventional wisdom about how FIP develops.
The authors of the new paper, which has not yet been peer-reviewed, say the outbreak was caused by a new strain of the pathogen that evolved from separate cat and dog coronaviruses, a recombination that increases its ability to spread.
Veterinarians in Cyprus are treating many sick cats with antivirals, some of which have been developed to treat humans with Covid-19.
A cat imported to the UK from Cyprus in August has been confirmed to be infected with the new strain.
Dr. Demetris Epaminondas, vice president of the Pancyprian Veterinary Association (PVA), first learned of the “alarming increase in FIP cases” in December last year from his wife, a practicing veterinarian. He soon began receiving similar reports from other doctors.
The potential rise in the deadly feline disease is of particular concern in an area sometimes called “cat island,” where cats roam, scurry, hunt and sleep everywhere. Large colonies of the cats, revered as holy, live in and around monasteries, where they are cared for by monks. Elsewhere, residents feed and care for neighborhood felines. There is no official estimate of the number of cats on the island.
PVA sent a questionnaire to 150 veterinary clinics in Cyprus to try to find out what was going on. Twenty-four clinics reported a total of approximately 500 cases of FIP in the first three months of 2023, a tenfold increase over the first three months of the previous year. In April, the number of reports peaked at around 2,000 cases.
These numbers only include cats on about half the island, an area of more than 2,000 square miles. Cyprus has been divided since the 1970s: The area to the south and west is under the control of the Republic of Cyprus, which has a Greek Cypriot majority and is a member of the European Union. The area to the north is occupied by Turkish military forces and is not under the effective control of the Cypriot government. There have been no official FIP announcements from the north.
dr. Charalampos Attipa, a veterinary pathologist from Cyprus, noticed the increase in cases in January while reviewing test results for Vet Dia Gnosis Ltd., a veterinary diagnostic laboratory he helped found in 2021.
There is no single test that can diagnose every case of FIP. Therefore, the diagnosis is often made based on a summary of clues from the patient's history, physical examination, and various diagnostic tests, including PCR tests. PCR stands for polymerase chain reaction, a technique that allows users to rapidly amplify a small sample of genetic material for study.
In the diagnosis of FIP, small segments of the genetic material of the coronavirus are identified by PCR in a sample of fluid from the lining of the abdomen (peritoneum) or lungs (pleura) or from the spine, or from a biopsy of tumor-like lesions.
In 2021 and 2022, Vet Dia Gnosis recorded three and four positive PCR tests in cats with FIP in Cyprus. From January to August 2023, 165 positive FIP-related PCR tests were recorded.
"These are just cats whose owners paid to have PCR done," Attipa said. "This is most likely the tip of the iceberg. But we don't really know the size of the iceberg. That's the problem."
Attipa, who started at the University of Edinburgh in April, is the lead author of the preprint paper. He is also a key member of an international collaboration investigating the virology, epidemiology and therapy of the current epidemic.
At the beginning of the year, Attipa, Epaminondas and others focused on raising awareness among veterinarians and the public. The effort led to several missteps, including a report picked up by multiple news outlets that 300,000 cats had died from the disease. Epaminondas said the figure was an unofficial and inaccurate estimate by animal welfare organizations. Additionally, the PVA estimate of 8,000 infected cats by mid-July was incorrectly reported by the Associated Press as 8,000 dead. There is no official estimate of the number of dead.
The number of PCR-confirmed cases began to decline in April, but this may not be cause for celebration just yet.
“Initially, people didn’t know what the disease was, so they took their animals to the vet to get a diagnosis,” Epaminondas said. But as awareness grew, cat owners and caretakers became aware of the rise in FIP and the clinical signs, such as a swollen abdomen, present in one form of the disease. “Because they can find treatment on the black market, they don’t want to spend money to get the disease properly diagnosed,” he said.
In recent years, antiviral compounds have shown remarkable promise in reversing the course of FIP. However, these compounds are not approved for veterinary use in many countries. As a result, a black market for antiviral drugs, mostly made in China, is flourishing, fueled by desperate cat owners who treat their animals on their own. A 2021 study of cats given unlicensed antivirals in the US found a survival rate of 80 % and above.
The number of PCR tests increased again in August, which may be due to the Cypriot government approving the veterinary use of molnupiravir, an antiviral drug used to treat Covid-19 in humans. Cats must be PCR positive for their owners or caretakers to receive a prescription.
According to Epaminondas, caseload data for most of the second half of the year, based on clinic surveys, should be available soon.
Dr. J. Scott Weese, an infectious disease veterinarian at the Ontario Veterinary College at the University of Guelph, said in an email to VIN News that the epidemiology of the outbreak is not well described, adding that it is "a common problem in field studies where information is piecemeal and often anecdotal."
According to Weese, the number of cases confirmed by PCR - 165 - is very small, especially for a country with a lot of feral cats. He also said that the rate of diagnosis based on questionnaires begs the question: Are more diagnoses due to a significant increase in the disease, a significant increase in testing, or both?
"There appears to be an increase in FIP in Cyprus. It's hard to say by how much," he said. "As there is more discussion and awareness, there are also more diagnoses of an endemic disease that may have been there all along, just ignored. Often times these are mixed situations where there is a real increase or a small local cluster, but the increased discussion and testing leads to an overestimation of the rate of change."
He added: "I'm not ruling out that this was a real epidemic or that this is a worrying new strain. We just don't know (or at least I don't know). This work shows that we need to look more closely at this issue."
Introducing FCoV-23
Basic information of FIP
If you find the specifics of feline infectious peritonitis difficult to understand, take a cue from Dr. Brian Murphy: It is. “FIP is probably the most complicated virus in veterinary medicine,” said Murphy, a veterinary pathologist and FIP researcher at the University of California, Davis, School of Veterinary Medicine. Much of what science knows about FIP was pioneered by Murphy’s now-retired mentor, Dr. Niels Pedersen.
FIP is caused by mutations in a ubiquitous and otherwise insignificant pathogen called feline enteric coronavirus. These mutations allow the virus to infect immune system cells called macrophages, which multiply and cause deadly inflammation. FIP is estimated to affect 1.3 % cats, most often kittens in catteries and shelters.
There are two forms of FIP: wet and dry. Cats may initially have one form and later develop another. In wet FIP, the fluid created as a result of inflammation accumulates most often in the abdomen, less often in other parts of the body. In dry FIP, the patient develops tumor-like lesions in the abdomen, chest, eyes, and/or brain. Early symptoms of FIP include fever, loss of appetite, weight loss, and depression. Cats with neurological FIP may develop lack of coordination, seizures, and dementia. Eye disease can cause inflammation, discoloration, or clouding of a cat's eyes, which impairs vision.
No test can diagnose every case of FIP with absolute sensitivity and specificity. Therefore, the diagnosis is often established based on a summary of clues from the patient's history, physical examination, and various diagnostic tests.
First identified in the 1950s, FIP was considered a death sentence for decades. However, in recent years, antivirals – including those used against the coronavirus that causes Covid-19 in humans, such as remdesivir, molnupiravir and Paxlovid – have been shown to reverse the course of FIP in cats. None of these antivirals are approved for veterinary use in the United States (except at universities that are researching these drugs in cats with FIP). These medicines are variously available for veterinary use in several European countries, including Cyprus, Finland, Norway, Sweden and the United Kingdom, as well as Australia and New Zealand.
In countries where the treatment is not approved by regulators, pet owners have resorted to buying unlicensed antivirals, mostly made in China, to treat sick cats themselves.
Understanding why the new strain behaves differently than what some researchers call “traditional FIP” requires a closer look at how FECV leads to FIP.
For reasons that are not fully understood, FECV sometimes mutates inside a cat. These changes allow it to escape from intestinal cells and infect a key cell of the immune system, the macrophage. This macrophage-infecting virus is known as the FIP virus or FIPV. It can now travel throughout the body, “ravaging the environment,” Gunn-Moore says, causing potentially fatal inflammation.
Once established, the FIPV coronavirus has two important characteristics: First, it is no longer an enteric virus, so it can only very rarely return to the gut to be excreted as FIPV in the feces. Second, FIPV has a gene sequence that is unique to a given cat.
FCoV-23, as the new strain has been named, appears to violate both of these schemes. Gunn-Moore said it thrives in the intestines of Cypriot cats. Furthermore, based on RNA sequencing from PCR samples, the virus in many cats had the same genetic sequence. The genetic sequencing was carried out by researchers at the Roslin Institute, an animal science research center at the University of Edinburgh.
Gunn-Moore had some early hypotheses about what might have caused the outbreak, but genetic analysis points to her main theory — that a pantropical canine coronavirus combined with a feline enteric coronavirus. Pantropic viruses can spread to different tissues in the body, a property that would allow FCoV-23 to enter other organs and nerves, as well as continue to multiply in the intestinal tract.
"I think a dog came to Cyprus and defecated on the floor. The cat, who already had FECV, then got dog feces on its feet, licked its paws and got both viruses," she said. "And that's what these viruses do, they recombine, they're party animals. They get together and go, 'Hey, do you want some of this? I'll give you some of that?'"
Gunn-Moore added that further work is planned to confirm the case for their direct transmission.
"We are currently conducting experiments to sequence the virus from feces because we need to sequence the virus and prove that it is the same sequence as in the blood," she explained.
dr. Brian Murphy, a veterinary pathologist and FIP researcher at the University of California, Davis, School of Veterinary Medicine, said the recombinant feline and canine coronavirus described in the Cyprus paper had been identified before, including by a team at Washington State University's School of Veterinary Medicine. Medicine in the 1970s.
"This is a replication of this virus, but it's a highly virulent form of the virus," Murphy said of the evidence so far. He welcomes the scientists' plans for further genetic analysis and suggests further investigation.
“Sequencing an enteric corona or a virus that comes from the gut is compelling, but it’s not proof,” he said. “It wouldn’t be a bad experiment to take fecal material containing the virus that comes from the gut, infect cats with it, and then when they get sick, save those cats with antiviral treatment. That would be good evidence of transmission of a virulent form of the virus.”
Murphy acknowledged that this kind of testing on companion animals is essentially banned in Europe and would likely be very controversial. “I think most people probably wouldn’t agree with me,” he said. “But I think it can be done ethically because we have high-quality, highly effective drugs.”
Dr. Maria Lyraki, an internal medicine specialist in Athens, Greece, who coordinates treatment protocols with veterinarians in Cyprus and is an author of the paper, said Murphy is right that the experiment would be proof, although some of the infected cats may not get sick if they develop an adequate immune response.
"However, it is something that we would not be able to implement from an ethical point of view," she said.
Thousands of sick cats
If the Cypriot epidemic had occurred 10 years ago, countless cats would probably have died because until recently there was no known way to stop the disease.
Antivirals have changed this situation.
Two promising products are remdesivir, made by pharmaceutical company Gilead to treat Covid-19 in humans, and the related compound GS-441524. GS, as it's called for short, was shown to be effective in reversing FIP in cats in an infectious disease study at the University of California, Davis in 2018.
Gilead has not granted a license to develop GS-441524 as a veterinary medicinal product. Remdesivir is not approved as a veterinary medicine in the United States, Canada, and some European countries.
However, since August, Cypriot vets have been able to import compounded versions of GS and remdesivir, manufactured by Bova, a veterinary pharmaceutical company based in the UK and Australia, under a special permit, to based on instructions UK Veterinary Medicines Directorate.
GS and remdesivir “are the first line of drugs that we use because we have the most literature on them,” Lyraki said. “But they are really expensive … which is really challenging, especially for such a large number of stray cats.”
According to Epaminondas, treating one cat with these drugs can cost from €3,000 to €7,000 ($3,250 to $7,580).
“We contacted people around the world who treat FIP cases,” Lyraki said. “And the specialists advised us that they were using molnupiravir. There is published literature on this drug and we have a lot of anecdotal discussion among FIP specialists around the world that it is indeed effective.”
The government's decision to allow veterinary use of molnupivirus has made a huge difference.
“It actually works quite well,” Lyraki said. Initially, boxes of molnupiravir were donated to the PVA to help fight the epidemic. They were available at an exceptionally low price of around 100 euros ($108) per cat, a significant saving. The actual price of the drug is much higher, but still significantly cheaper than GS.
However, the replacement of molnupivir will not last long. Merck Sharp and Dohme BV, which sells the antiviral under the name Lagevrio, will stop making it for Europe next year after the European Medicines Agency decided earlier this year not to support the registration of molnupiravir based on its finding that the antiviral's benefit in treating Covid in adults has not been proven.
"We are now working to find alternatives," Lyraki said.
Limitation of dissemination
A healthy free-roaming cat lies outside a bakery in Paphos, Cyprus. Stray cats are everywhere on the island - although no one knows how many there are. In response to the FIP outbreak, the Cyprus Veterinary Association, together with ThePetzApp, is launching an initiative to engage cat owners and carers in Cyprus to count the cats in their homes or in the stray cat colonies they care for.
In addition to the immediate situation in Cyprus, there are fears that the strain could spread to other countries or that it is already in other countries from which it has reached Cyprus, as yet unrecognized.
The new strain was confirmed in a cat imported to the UK from Cyprus in August. This cat has been quarantined and is responding to treatment.
Keeping the cats on the island under control can be a challenge. Cyprus is home to many cat rescue activities. Stray cats are regularly collected and taken to other parts of Europe where they are given a new home. According to Epaminondas, there are no regulations regarding the export of cats from Cyprus.
But veterinarians like Lyraki are urging rescue groups to be cautious. “Our team of experts has issued a recommendation that cats be tested before traveling outside Cyprus and that only cats with negative antibodies to FCoV be exported,” said Dr. Lyraki. Once the cats arrive at their destination, they should be quarantined for three weeks and then retested for antibodies “until the outbreak is under control and the number of affected cats has significantly decreased.”
Meanwhile, Greece, which has its own large stray cat population, has also seen an increase in FIP cases, according to Lyraki.
"We believe it's a matter of time before this outbreak spreads to Greece because Greece and Cyprus are very, very close culturally, geopolitically. There is a lot of exchange and travel between them," she said. "So it's something we're actively monitoring."
We had hoped that in 2023 one or more antivirals for cats would be legalized. With the exception of a few countries outside the US, this has not happened. Still, there is hope that studies being conducted at the University of California, Davis and elsewhere around the world will help advance conditionally and/or fully approved human drugs such as Remdesivir, Molnupiravir and Paxlovid for use by veterinarians. Even if drugs are approved for use in animals, drugs marketed for human use are not ideal because they must be purchased at the price set for humans. Therefore, the unapproved market will remain the main source of cheaper antivirals for many years to come. However, SOCK FIP appreciates the efforts of countless cat owners and lobbying industry and government agencies to allow the use of effective antivirals for cats. These efforts have had varying degrees of success in many countries outside the US.
FIP research at UC Davis in 2023 supported by SOCK FIP contributions
2023 continues to support SOCK FIP and feline coronavirus research at UC Davis, and we couldn't do it without the help of many donors. Two ongoing research projects receiving SOCK FIP funding are of particular interest. The first project involves testing antiviral drugs and is led by Drs Krystle Regan and Brian Murphy. Patients and owners were drawn from across the US. The first study compared two antiviral drugs in cats with wet FIP to test cure rates with either oral GS-441524 or Remdesivir (Gilead). This study, which was published, showed that oral Remdesivir worked as well as oral GS-441524. So if Remdesivir gets full approval in the United States, veterinarians can safely prescribe it to cats with wet FIP. Other studies comparing GS-441524 and Remdesivir in cats with dry FIP and Molnupiravir (Merck) in cats with wet FIP have also been completed. The results of these studies should be published in early 2024. The latest study involving Paxlovid (Pfizer) was recently fully approved and widely available in the United States, and if it proves to be a safe and effective treatment for cats with FIP, it will a third human antiviral drug to treat FIP that may one day be used by veterinarians. Drs Regan and Murphy also used their field test cases to study the causes of death during the first two weeks of treatment. This population represents up to 10 % treated cases worldwide. Necropsies showed the existence of serious complicating diseases, which often included bacterial sepsis, often with highly resistant organisms to antibiotics, as well as serious heart disease. More work is needed to determine the nature of the heart disease and how much of it may be pre-existing disease and how much is caused by the FIP virus.
The second major research project focused on the prevention of FIP is implemented by Dr. Patricia Pesavento, one of our veterinary pathologists, and her research team, which includes veterinary microbiologist Terza Brostoff, biomedical engineer Randy Carney, immunologist Dennis Hartigan O'Connor, and lab technician Ken Jackson. Their study involves the development of an mRNA vaccine against a portion of the nucleocapsid protein that is common to virtually all known feline coronavirus isolates. The theory is that an immune response to this protein, compared to the spike protein commonly used in COVID-19 vaccines, will protect cats exposed to the common enteric form of feline coronavirus from developing FIP. This would be analogous to the protection against severe and chronic forms of COVID-19 reported with mRNA vaccines. Team Dr. Pesaventa developed a vaccine based on ideal manufacturing parameters and tested it for safety and efficacy in a rodent model. The development of this mRNA vaccine will only be a first step as it will need to be further tested in a limited number of cats as a prelude to much more extensive field testing in larger populations of cats such as breeding stations or temporary/rescue stations experiencing ongoing cases of FIP.
Areas of future FIP research
The discovery of a cure for FIP does not end the need for further FIP research. We hope that veterinary scientists from around the world who are still active in academia and industry will consider some of the other promising areas of research. Such studies cover all aspects of FIP pathogenesis, from the basic enteric coronavirus, which is enzootic in virtually all healthy cat populations and exists in the lower intestinal tract, to mutant forms that have acquired the ability to infect monocytes/macrophages in and outside the abdominal cavity. The exact nature of immunity to feline coronaviruses, both the minimally pathogenic enteric form and the highly lethal form causing FIP, needs to be clarified. We know that immunity to both intestinal and extraintestinal forms of the virus is weak, short-lived and susceptible to weakening by internal and external stressors. Immunity to enteric coronavirus appears to involve locally produced antibodies, whereas immunity to FIP-causing mutant viruses involves more systemic lymphocyte-mediated (cellular) immune responses. Accurate knowledge of the strengths and weaknesses of both types of immunity will be essential for all future vaccine development efforts. Will you prevent FIP by attacking underlying enteric coronavirus infections or by attacking FIP-causing mutants when they emerge?
There is a great need to develop tests that can accurately determine when a cat has been cured by antiviral therapy. We know that some cats can heal in as little as 4-6 weeks, while others need up to 12 weeks. We suggest 12 weeks of treatment because this gives the maximum cure rate, but we know that some cats will be treated for an unnecessarily long time. The only current way to tell when a cat is cured is to stop the treatment and see if the disease returns. Regular complete blood counts and basic serum biochemistry are useful in conjunction with physical health indicators in monitoring and managing treatment, but return to normal test values and general health do not guarantee that treatment will not relapse. On the contrary, the persistence of minor abnormalities in the blood and health status is not always a sign that there has been no cure and that it is necessary to increase the dosage or prolong the treatment. This is especially true for cats with neurological FIP, where blood test results and the state of neurological deficits do not always indicate a cure.
Although there is hope that even more effective antiviral drugs will be found in the future, the well-documented safety and efficacy profiles of current drugs leave little room for further improvement. However, drug resistance is currently being observed in some cats. What is known about how drug resistance develops in chronic infections such as HIV/AIDS should be applied to FIP. The most effective way to combat drug resistance in HIV/AIDS is to combine two or more antivirals with different mechanisms of action before resistance develops.
It appears that some strains of feline coronavirus may be more neurotropic than others. A penchant for infecting the central nervous system can be developed by specific mutations in enteric strains of the coronavirus that are enzootic in the environment or by mutations that occur as part of the FIP biotype. The role of the blood-brain barrier and the apparent compartmentalization of immunity between the central nervous system and the rest of the organism are other areas that require study.
Most cat owners are currently aware of the large outbreak of FIP occurring on the island of Cyprus. It is still uncertain whether this outbreak qualifies as epizootic (epidemic) or enzootic (endemic). Preliminary research suggests that the outbreak is linked to closely related isolates of FIP virus serotype 2 (similar to canine coronavirus). It is clear that for cats in all parts of the world, whether this outbreak is related to the spread of the virus from cat to cat (ie, an epizootic disease) or to factors promoting the disease in the environment (ie, an enzootic disease) is important. The worst possible scenario is a panepizootic disease like COVID-19. Hopefully, researchers in Cyprus, the UK and elsewhere will be able to resolve the nature of this outbreak as quickly as possible.
Between January and April 2023, the Urolite Center in Minnesota received three shipments of atypical stones (Figure 1). All three samples were obtained from cats. All three cats were under 1 year old. Cats came from North and South America. In each case, the infrared spectrographic pattern of the stones was identical. Urinary stones usually contain large amounts of phosphorus, calcium and magnesium. In these cases, electron dispersion spectroscopy revealed a high proportion of nitrogen, carbon and oxygen.
Mystery solved. When asked about their medical history, all three cats were diagnosed with feline infectious peritonitis. All three were treated with either Remdesivir or its metabolite GS-441524. We requested samples of their antiviral drugs for analysis. The antiviral drugs were spectrographically identical (Figure 2). The stones were composed of GS-441524.
Figure 2: FT-IR spectroscopy of urinary stone of patient and reference sample GS-441524
After administration, GS-441524 is excreted primarily in the urine. Although GS-441524 is very soluble in organic solvents such as DMSO (10-59 mg/ml), it is poorly soluble in aqueous solutions such as water (0.0004 to 0.1 mg/ml). Its limited solubility makes GS-441524 a prime candidate for stone formation. Observation of urinary symptoms in cats receiving Remdesivir or GS-441524 is an indication to look for stones. Observation of atypical crystalluria or uroliths may be an indication to limit the dose of the drug (if possible) and increase water consumption to minimize stone formation.
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