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.
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.
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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.
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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.
Analysis of anti-FIP drugs with detected Molnupiravir content
We have received information that several Chinese drug manufacturers, in an effort to reduce the production costs of drugs and their sales price as much as possible while maintaining the largest possible margin, have started to use Molnupiravir (EIDD-2801) as an active ingredient.
The information came from the global group FIP Warriors 5.0, which published several analyzes of drugs declaring GS441524 or GC376 as the active ingredient, but the results of the analyzes show that the drugs contain the already mentioned Molnupiravir. You can see one of the analyzes below. If someone would object that analytics are some means of competitive struggle, it is not so. There were several independent analyses, we also know about the analysis from Bulgaria, one analysis also took place in Slovakia, but the one published by the global FIP Warriors group is the most complex.
Medicines in the CR/SR with the declared content of GS441524 containing EIDD-2801
Figure 1: Suyi 20mg/ml - The manufacturer declares the content of GS441524, but it actually contains Molnupiravir.
This fact also affects our group. One of the drugs where the presence of EIDD-2801 was detected is the widely used brand Suyi. The fact that the drug contains another active ingredient is not a problem in itself. The problem is that the manufacturer concealed this fact and declared it as the active ingredient of its products GS441524. This fact should apply to injectable solutions on a "water" basis, which do not sting when applied and their pH is around 6.
Figure 2: The drug used in the "How We Defeated FIP" group, for which the manufacturer declares GS441524, but in fact also contains Molnupiravir.
It should be emphasized here that both EIDD2801 and GS441524 are very effective in the treatment of FIP. However, some specifics apply to their use. For example, they have different pharmacokinetics. The one with GS441524 allows application once every 24 hours, while Molnupiravir should be administered twice a day. Anyway, GS441524 is already a very well-proven drug with a minimum of side effects. EIDD-2801 has been used in the treatment of FIP for a shorter time and the official clinical trial is only ongoing, or has not yet been published. That is why other drug manufacturers have so far only recommended it for the treatment of relapses, or in case the cat does not respond to treatment with GS441524. In other words, the drug of first choice is still GS441524. On the other hand, precisely because of the policy of Gilead, which holds the patent for GS441524, hope has dawned for the official treatment of FIP with Molnupiravir, as it has been registered and approved for the treatment of Covid-19 in humans. As a result, a legally available drug (Lagevrio) also appeared in the Czech Republic, but its price was and still is very high and its availability for veterinary use is very complicated.
In an effort to ensure the cheapest possible medicines in order to save as many cats as possible, very cheap medicines also entered our market. The truth is that medication works. We also encountered versions of the solutions that really stung a lot, so it's quite possible that Suyi actually contained GS441524, but over time the manufacturer decided to arbitrarily change the active ingredient, but still declared that it supplied GS441524.
But Suyi is not the only drug containing EIDD-2801 available on our market about which its manufacturer provided misleading information. The drugs in Figure 2 are used in the "How We Defeated FIP" group.
Why is information about the active substance important?
GS441524 and Molnupiravir have a slightly different mechanism of action. GS441524 acts as a terminator of the viral RNA chain, thereby preventing the virus from replicating. EIDD-2801 integrates into the virus's genome, where it causes an accumulation of virus mutations known as a viral error catastrophe, rendering the virus unable to replicate.
The pharmacokinetics of GS441524 allows application once a day, while EIDD-2801 in oral form should be applied twice a day according to current knowledge. Official information on the frequency of application of the injection form does not yet exist.
GS441524 has already been used for several years in the treatment of FIP, several clinical trials, while the use of EIDFD-2801 in clinical practice is relatively new.
The cytotoxicity of GS441424 is lower than that of EIDD-2801. However, it should be noted here that both substances are safe if the recommended dosage is not exceeded. However, if the dosage is significantly exceeded, side effects may appear in the form of significant neutropenia, drooping/dropped ears, etc.
GS441524 was originally created for injection use, later a tablet form was added. EIDD-2801 was initially intended only for oral use (tablets), while the injectable form was never the subject of a clinical trial. It is only assumed that EIDD and GS have similar bioavailability limits as GS. This means that approximately 50% of the active substance is used for the tablet.
There is a lack of information on the potential side effects of EIDD-2801 in the long term. Considering that the active substance - N4-hydroxycytidine - is a strong mutagen, it is not clear whether after a treatment lasting 12 weeks, which is much longer than the recommended period of 5 days in human medicine, the side effects cannot manifest/accumulate more significantly way.
What is the impact of using another active substance to treat FIP?
Pills In principle, there is no problem with tablets, provided that the content of Molnupiravir corresponds to the stated content of GS. The dosage remains the same, we only recommend dividing the dose calculated for GS into 2x a day. This means, for example, that if you administered 1 tablet of Suyi once a day, you will administer 1/2 tablet twice a day. Actually, even with GS, it is recommended, especially with higher dosages, to administer the medication twice a day.
Injection solutions The situation is a little more complicated for them, as the stated concentration of 20mg/ml differs significantly from the measured concentration (Suyi 40mg/ml, while the real measured concentration for the second solution "Cat rehabilitation nutrition supplement" is up to 70mg/ml). Given the relatively unclear dosage of EIDD in injectable form and the significantly higher concentration, we recommend not to overdo the dosage. The manufacturer of Suyi rejects the accusation of changing the active ingredient.
Previous experience with the use of Suyi medicines
Given that the manufacturer still claims that Suyi products contain GS441524, the drug was used and dosed as GS441524, including application only once a day. After more than 9 months, we can declare that its therapeutic effect is indisputable, we register a large number of cured cases, the price of the treatment is favorable, so it would probably be a hasty decision to stop recommending this medicine. However, due to the manufacturer's attitude, we cannot really guarantee the active ingredient in Suyi products. Again, I emphasize that both GS441524 and EIDD-2801 are effective in treating FIP, so it cannot be said that the drug itself is a scam. Of course, it would be better if the manufacturer, instead of ignoring the analyses, simply and clearly declared the active substance according to reality. Until that happens, it is important that you share your experiences with this medicine. For example, in the form of reviews on the website, or directly in the FIP Warriors CZ/SK group.
We certainly do not want to cause panic with this warning. The truth is that the drop in the price of treatment has made it available even for cases where their owners would otherwise have decided on euthanasia. However, in light of the above findings, it is up to you which medication you decide to use. In any case, pay extra attention to checking/monitoring the cat's condition.
Medicines with directly declared EIDD-2801 content
If the manufacturer openly produces drugs containing EIDD-2801, this is of course a good and serious approach. You can find some medicines containing EIDD-2801 here:
Basic information Feline infectious peritonitis (FIP) is a viral disease of cats caused by certain strains of the coronavirus that has a high mortality rate.
The goal This case series reports the results of treatment of cats with FIP with molnupiravir.
The animals Eighteen cats diagnosed with FIP at You-Me Animal Clinic, Sakura-shi, Japan between January and August 2022 and whose owners gave informed consent for this experimental treatment.
Methods In this prospective observational study, molnupiravir tablets were prepared directly at the You-Me Animal Clinic. Owners administered 10-20 mg/kg PO twice daily. The standard duration of treatment was 84 days.
The results Of the 18 cats, 13 cats had effusive FIP and 5 cats had non-effusive FIP. Three cats had neurological or ocular signs of FIP before treatment. Four cats, all with effusive FIP, died or were euthanized within 7 days of starting treatment. The remaining 14 cats completed treatment and were in remission at the time of writing (139-206 days after initiation of treatment). Elevated serum alanine transaminase (ALT) activity was found in 3 cats, all on days 7–9, and all recovered without intervention. Two cats with jaundice were hospitalized, 1 during treatment (day 37) and 1 with severe anemia at the start of treatment.
Conclusions and clinical significance This case series suggests that molnupiravir may be an effective and safe treatment for domestic cats with FIP at a dose of 10–20 mg/kg twice daily.
1. Introduction
Feline infectious peritonitis (FIP) is a viral infectious disease occurring mainly in domesticated cats.1, 2 FIP is an aberrant immune response to infection with feline coronavirus (FCoV), which is ubiquitous, especially in breeding and rescue breeds, usually with no or mild clinical signs. Fecal-oral transmission of FCoV often occurs, especially in environments with multiple cats3 and the incidence of FIP in cats exposed to FCoV is up to 14 %.4, 5
Feline infectious peritonitis is usually classified as either effusive or non-effusive based on clinical presentation.1, 6, 7 Until the development of specific antiviral therapy, the case fatality rate associated with FIP was high, and most affected cats died within weeks to months of the onset of clinical signs.
Some nucleoside analogs, including remdesivir (GS-5734) and its active metabolite GS-4415248, inhibit viral RNA synthesis and have high antiviral activity against FCoV causing FIP in cats.9, 10 Despite the expectations of veterinarians and cat owners, the developer decided not to apply for approval of GS-441524 for the treatment of FIP. As a result, many cats with FIP are being treated with the unapproved drug GS-441524, and concerns have been raised about the quality, purity, and efficacy of the unapproved products available on the world market. Mutian has excellent efficacy and safety.11-14 Although the manufacturer did not disclose the chemical structure of the active substance and its exact concentration, its active substance is GS-441524.12
Molnupiravir is an oral nucleoside antiviral prodrug with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease (COVID-19). As of 2021, molnupiravir is approved in Japan to treat people with COVID-19. There are published reports on the efficacy and safety of molnupiravir in cats15 , but sufficient data on the use of molnupiravir in cats with FIP are lacking. Due to the lack of treatment options for FIP, we began offering molnupiravir to clients at our clinic, using small tablets prepared in-house for easy administration to cats. Here we present the results of the first 18 cats that underwent this FIP treatment in our clinic.
2 MATERIALS AND METHODS
2.1 Cats
All cats attending the You-Me Animal Clinic in Sakura-shi, Japan since January 2022 diagnosed with FIP and whose owners provided informed consent were included in this case series. Feline infectious peritonitis was diagnosed based on a combination of clinical signs (decreased appetite, enlarged abdominal lymph nodes, weight loss, fever, effusions, or uveitis) and laboratory test results for anemia and hyperglobulinemia, including the albumin-to-globulin (A/G) ratio and values of α1-acid glycoprotein (AGP). The presumptive diagnosis of FIP was based on the identification of FCoV RNA in samples from abdominal or pleural effusion (effusive FIP) or whole blood (non-effusive FIP), or from fine needle aspiration (FNA) of pyogranulomatous lesions. Virus detection was performed by reverse transcription polymerase chain reaction (RT-PCR) in the following testing laboratories: abdominal effusion and FNA samples at IDEXX, Japan (using a LightCycler 480 System II, Roche Diagnostics KK, Basel, Switzerland) and whole blood at Canine Lab., Japan (using CFX Connect, Bio-Rad Laboratories, Inc, Irvine, CA, USA). Abdominal or pleural effusion samples (1 ml each) were taken by ultrasound-guided abdominocentesis, respectively. by thoracentesis and were evaluated for the total number of nucleated cells, protein content, A/G ratio and cytology. Whole blood samples (1 ml) were collected and sent in ethylenediaminetetraacetic acid (EDTA) tubes.
2.2 Preparation of the medicine
Tablets containing molnupiravir 20 mg were prepared at the You-Me Animal Clinic. Briefly, molnupiravir powder was extracted from 20 commercially produced molnupiravir 200 mg capsules (MOVFORE, Lot No. HH2201001 [HETERO HEALTHCARE, Hyderabad, India]) and mixed with powdered cellulose (microcrystalline cellulose powder, NICHIGA, Takasaki, Japan) using a mortar and pestle (Matsuyoshi Medical Instruments Co, Ltd, Tokyo, Japan) to make a total of 12 g of powder mixture. The powder was shaped into approximately 200 6 mm wide sectional scored tablets using a generic tablet press made in China.
2.3 Treatment
Treatment with molnupiravir was initiated when FIP was highly suspected on the basis of clinical presentation or when FCoV RNA was detected by PCR; this date was marked as the first check. The following dosages were chosen: 20 mg/kg/d (10 mg/kg twice daily) for cats with effusive type, 30 mg/kg/d (15 mg/kg twice daily) for cats with non-effusive type and cats with pyogranulomatous lesions, and 40 mg/kg/d (20 mg/kg twice daily) for cats with neurological or ocular signs of FIP. Dosage may be increased or decreased in animals showing clinical deterioration or adverse reactions. Dosage was chosen based on estimated animal dosages listed on the Internet16, 17 and based on the adult human COVID-19 dose of molnupiravir, which is 800 mg every 12 hours.18 This would correspond to a dose per kilogram of 10 to 13.3 mg/kg twice daily for adults weighing 60 to 80 kg. As no pharmacokinetic information is available in relation to cats, we have chosen the dosage for cats based on the assumption that metabolism of drugs in cats is equivalent to metabolism in humans.
Owners were instructed to administer the tablets twice a day with 12 hours between doses. The expected standard duration of treatment was 84 days according to study GS-441524.10
2.4 Measurements
Owners were instructed to record body weight, body temperature, physical activity, appetite, and voiding/urinating daily and were asked to visit the clinic at 1, 2, 6, and 10 weeks. The following laboratory tests were required at each visit: red and white blood cell count, hemoglobin, hematocrit (HCT), AGP, total protein, albumin, aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, creatinine, blood urea nitrogen (BUN ) and the A/G ratio. Samples were analyzed in the clinic using a Catalyst One chemistry analyzer and a ProCyte One hematology analyzer (both IDEXX Laboratories, Westbrook, Maine). The A/G ratio was determined either from a whole blood plasma sample or from a fractionated protein sample. We performed abdominal and thoracic ultrasound evaluation of each cat at baseline and after 2, 6, and 10 weeks of treatment using a Prosound α7 (Aloka, Japan), including assessment of cardiac function (fractional shortening, left atrial to aortic diameter ratio, and valvular regurgitation).
2.5 Adverse Events
Any abnormal laboratory test values or medical events that occurred during treatment were considered adverse events and decisions were made to continue/discontinue treatment.
2.6 Statistical analysis
As this is a case series, no statistical calculations were performed other than descriptive statistics.
2.7 Ethics
All owners provided written informed consent prior to initiation of treatment. The experimental use of molnupiravir was approved by our Institutional Animal Study Review Committee.
3 RESULTS
3.1 Characteristics of the disease and treatment
Eighteen cats completed treatment by August 4, 2022 and are included in this summary report.
The presentation of the 18 cats is summarized in Table 1 and Table S1. The median age was 6.5 (range: 3-93) months. All 18 cats had a low serum A/G ratio, 16 cats had a loss of appetite, and 14 cats had mild to severe anemia by hemoglobin level and HCT. Thirteen cats had effusive FIP and 5 cats had non-effusive FIP. Neurological or ocular signs suggestive of FIP were present in 3 cats before treatment, including epileptic seizures/neurological signs (No. 8), blunted postural reflexes (No. 10), and slow pupillary reflex (No. 18) (Table S1). All but 2 cats (#8 and #15) were treated exclusively on an outpatient basis. Cat no. 8 was hospitalized from day 37 for 3 days due to jaundice. Cat no. 15 required hospitalization for 5 days after starting treatment due to anemia and jaundice accompanied by increased bilirubin concentration and ALT activity. During hospitalization, the cat received molnupiravir as scheduled, was hydrated with Ringer's solution, and treated with oral ursodeoxycholic acid (Towa, Japan) 10–15 mg twice daily to reduce bilirubin. There was no evidence of intravascular hemolysis (HCT remained stable), and microscopic examination of blood smears was negative for hemotropic mycoplasma infection.
TABLE 1. Basic characteristics of the cats in the described case series.
Age at disease onset, months, median (range)
6.5 (3-93)
Breed, n (%)
Housecat
9 (50.0)
Exotic shorthair
2 (11.1)
British Shorthair
2 (11.1)
Other
5 (27.8)
Sex, n (%)
Male not neutered/male neutered
4 (22.2)/7 (38.9)
Female not spayed/female spayed
2 (11.1)/2 (11.1)
Weight in kg, mean (SD)
2.72 (0.77)
Duration from onset of illness to initiation of treatment, days, median (range)
16.5 (2-49)
Effusive type, n (%)
13 (72.2)
Pyogranulomatous lesions in the abdominal cavity, n (%)
5 (27.8)
Neurological manifestations of FIP, n (%)
2 (11.1)
Ocular symptoms of FIP, n (%)
1 (5.6)
Temperature, °C, mean (SD)
39.3 (0.9)
Hematocrit, %, mean (SD)
27.3 (8.1)
Albumin/globulin ratio, mean (SD)
0.35 (0.10)
Sample type, n (%)
Abdominal effusion
11 (61.1)
Pleural effusion
1 (5.6)
FNA of a pyogranulomatous lesion
2 (11.1)
Full blood
3 (16.7)
None
1 (5.6)
The attending physician decided to extend the treatment to 99 days for cat no. 1. Consciousness disturbances appeared on day 8 in this cat and the dose was subsequently increased to 40 mg/kg. This symptom disappeared on the 15th day; however, the A/G ratio with the fractionated protein sample did not return to normal. On day 99, although the A/G ratio was still below the reference range (0.6), the clinician decided to stop treatment because the cat showed no clinical progression or deterioration.
3.2 Outputs
Clinical response in 14 cats was rapid. Dosing, findings during treatment, and outcomes in these animals are summarized in Tables S2 and S3. The fever subsided and the appetite returned within 2-3 days after the start of treatment. Remissions were also achieved in cats with severe clinical signs. Among them were cats no. 8, 17 and 18, which had pyogranulomatous lesions ≥ 2 cm in size, cat no. 4, which had severe anemia and a low A/G ratio, cat no. 14, which had a pleural effusion and difficulty breathing, and cat no. 15, who had an enlarged kidney. The pyogranulomatous lesions shrank or were undetectable on ultrasound in all 5 cases, and laboratory values returned to normal in all cats. Three cats had neurological signs of FIP before treatment. Cat no. 12 had no neurological symptoms of FIP before treatment, but had an epileptic seizure on day 7. The dosage was subsequently increased to 40 mg/kg. On the 2nd day, on the slit lamp at cat no. 7 found anisocoria that was probably related to uveitis. The dosage of molnupiravir was increased to 40 mg/kg from day 15, and all neurological or ocular signs of FIP resolved within 15 days.
Of the 14 cats that achieved remission, no relapses occurred through August 3, 2022, during 55 to 107 days of post-treatment follow-up. Three cats died (No. 2, No. 11 and No. 16) and one (No. 13) was euthanized; all these cats had the effusive form of FIP but had no neurological or ocular signs of the disease. All died within one week of starting treatment.
3.3 Security
Alanine transaminase activity higher than the reference value was found in 4 cats; the value of each of them was 286 U/l (cat #8 on day 37), 283 U/l (cat #9 on day 9), 154 U/l (cat #10 on day 7), and 117 U/l (cat No. 17 on the 9th day). Three cats with early ALT elevations on days 7 to 9 recovered without the need for intervention. In cat no. 8 developed jaundice on day 37 and was hospitalized for 3 days.
No abnormalities in BUN or creatinine concentrations were noted during treatment with molnupiravir.
4 DISCUSSION
In our series of cats with presumptive FIP treated off-label with a molnupivir compound, 14 of 18 cats achieved remission and remained in remission for up to 107 days of observation at the time of writing. Four cats showed signs of potential hepatic adverse effects; 3 cats developed ALT activity above the reference range during the first 7 to 9 days of treatment, all of which resolved without treatment, and 1 cat developed jaundice requiring hospitalization on day 37 of treatment.
The approved human formulation of molnupiravir is in 200 mg capsule form, but for animals it must be divided into smaller doses to facilitate administration of an appropriate dose based on body weight. We decided to prepare molnupiravir in the form of small tablets to simplify administration. We hypothesized that cats might refuse to swallow the drug in powder form or in aqueous solution, and it might be difficult for owners to administer the entire powder dose each time.
The minimum effective dose of molnupiravir in FIP is recommended to be 4.5 mg/kg PO every 12 hours for cats without neurological/ocular signs of disease, increasing to 12 mg/kg PO every 12 hours for cats developing ocular or neurological signs. symptoms of FIP.17 Others recommend a dose of 25 mg/kg every 24 hours for dry/wet FIP, 37.5 mg/kg every 24 hours for ocular FIP, and 50 mg/kg every 24 hours for neurological FIP.16 Since none of these recommended dosages have been established in prospective controlled studies, the dosage in this case series was determined by the author based on these estimates, adult dosages, and his experience. Nevertheless, the dosage used in our case series (10 mg/kg twice daily for cats with effusive FIP, 15 mg/kg twice daily for cats with non-effusive FIP or pyogranulomatous lesions, and 20 mg/kg twice daily for cats with neurological or ocular signs FIP) appears to be effective and safe and may help guide dosing in future clinical trials.
Four cats died during this study. Each of these cats had the effusive type of FIP; however, considering that some cats that survived had symptoms as severe or even more severe than those that died, no signs were found to predict early death. Unfortunately, the attending veterinarian was given little information about the deaths of the 3 cats that died at home, and no post-mortem examinations were performed. One cat (#2) died after vomiting the drug on day 6, so it is possible that this animal had swallowing problems.
The use of GS-441524 in 31 cats with FIP, of which 26 cats completed at least 12 weeks of treatment, resulted in remission in 25. 10 Eight of the 26 cats relapsed or became reinfected within 3 to 84 days after this period. . The length of observation in our case series is shorter than in study GS-44152410; however, observation of cats in our series is currently ongoing and more cats with FIP are being treated with molnupiravir. Further observation will provide data on longer-term efficacy. The major adverse events reported with injection in study GS-441524 were injection site reactions in 16 of 26 cats.10 Because the treatment in our study was administered orally, no injection site reactions occurred in any of the cats in our series. In our series, the most frequent adverse event during treatment was an increase in ALT activity. However, longer-term follow-up is necessary to more adequately assess liver-related reactions, and a larger group of animals is needed to more fully assess the adverse effects of molnupiravir.
Molnupiravir is active against SARS-CoV-2 and other RNA viruses19 and in cell culture it creates only low resistance.20 – 22 The efficacy of oral molnupiravir was evaluated in a phase 3 randomized control trial in 1,433 people with COVID-19, with a lower percentage of hospitalizations or deaths by day 29 in the molnupiravir group compared to placebo.18 Another important clinical question is whether molnupiravir-resistant viruses can develop and how many cats relapse or reinfection after treatment.
All owners who provided informed consent to participate were included in this study, so the risk of any bias should be minimal. Nevertheless, selection bias should be considered as this case series was enrolled in a single center in Chiba Prefecture, Japan. Another potential limitation of our case series is that the diagnosis of FIP was probable in all cases. Cats can have FCoV viremia without FIP, so RT-PCR detection of FCoV RNA is not specific for FIP.7 although this technique has a high sensitivity (90 %) and specificity (96 %) for FIP when applied to FNA specimens.23 In our series, the combination of RT-PCR with clinical signs and other serum biochemical tests, including a low A/G ratio, was highly suggestive of FIP.7 This case series suggests that molnupiravir may be an effective and well-tolerated treatment for FIP.
Table S1. Feline demographics and disease status before treatment. Table S2. Overview of the course of treatment. Table S3. Test values obtained at the first visit and the last test, based on which the decision was made to stop treatment.
References
Addie D, Belák S, Boucraut-Baralon C, et al. Feline infectious peritonitis. ABCD guidelines on prevention and management. J Feline Med Surg. 2009; 11: 594-604.
Wang YT, Su BL, Hsieh LE, Chueh LL. An outbreak of feline infectious peritonitis in a Taiwanese shelter: epidemiologic and molecular evidence for horizontal transmission of a novel type II feline coronavirus. Vet Res. 2013; 44: 57.
Addie DD, Toth S, Murray GD, Jarrett O. Risk of feline infectious peritonitis in cats naturally infected with feline coronavirus. Am J Vet Res. 1995; 56: 429-434.
Foley JE, Poland A, Carlson J, Pedersen NC. Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus. J Am Vet Med Assoc. 1997; 210: 1313-1318.
Murphy BG, Perron M, Murakami E, et al. The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Vet Microbiol. 2018; 219: 226-233.
Pedersen NC, Perron M, Bannasch M, et al. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg. 2019; 21: 271-281.
Jones S, Novicoff W, Nadeau J, Evans S. Unlicensed GS-441524-like antiviral therapy can be effective for at-home treatment of feline infectious peritonitis. Animals (Basel). 2021; 11: 2257.
Krentz D, Zenger K, Alberer M, et al. Curing cats with feline infectious peritonitis with an oral multi-component drug containing GS-441524. Viruses. 2021; 13: 2228.
Katayama M, Uemura Y. Therapeutic effects of Mutian([R]) Xraphconn on 141 client-owned cats with feline infectious peritonitis predicted by total bilirubin levels. Vet Sci. 2021; 8: 328.
Katayama M, Uemura Y. Prognostic prediction for therapeutic effects of Mutian on 324 client-owned cats with feline infectious peritonitis based on clinical laboratory indicators and physical signs. Vet Sci. 2023; 10: 136.
Roy M, Jacque N, Novicoff W, Li E, Negash R, Evans SJM. Unlicensed molnupiravir is an effective rescue treatment following failure of unlicensed GS-441524-like therapy for cats with suspected feline infectious peritonitis. Pathogens. 2022; 11: 1209.
Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in non-hospitalized patients. N Engl J Med. 2022; 386: 509-520.
Agostini ML, Pruijssers AJ, Chappell JD, et al. Small-molecule antiviral β-dN (4)-hydroxycytidine inhibits a proofreading-intact coronavirus with a high genetic barrier to resistance. J Virol. 2019; 93:e01348.
Dunbar D, Kwok W, Graham E, et al. Diagnosis of non-effusive feline infectious peritonitis by reverse transcriptase quantitative PCR from mesenteric lymph node fine-needle aspirates. J Feline Med Surg. 2019; 21: 910-921.
A new strain of feline coronavirus is ravaging the cat population in Cyprus CREDIT: CHRISTINA ASSI/AFP via Getty Images
Experts have warned that Cyprus risks turning into an "island of dead cats" following the outbreak of the feline coronavirus epidemic.
Feline infectious peritonitis (FIP), a strain of coronavirus, has been killing stray and domestic cats since January, with experts warning that "many cats" could die if the virus, which is circulating in Cyprus, reaches Britain.
The country, sometimes called the “island of cats,” is home to the earliest evidence of animal domestication. But there is growing concern about the threat posed by “feline Covid” – which does not infect humans but is usually fatal in felines if left untreated.
“Local veterinarians are reporting an alarming increase in FIP cases, which began in January in the capital Nicosia and spread throughout the island within three to four months,” said Dr. Demetris Epaminondas, vice-president of the Pancyprian Veterinary Association.
Veterinarian Kostis Larkou treats a sick cat at a clinic in Nicosia CREDIT: CHRISTINA ASSI/AFP via Getty Images
In a recent blog post, he added that this is the first “outbreak of this magnitude” ever recorded, with previous cases of FIP generally confined to catteries. Symptoms include fever, an enlarged abdomen, loss of energy and sometimes increased hostility. The virus typically affects kittens and young cats.
Professor Danièlle Gunn-Moore, an expert in feline medicine at the University of Edinburgh, told the Telegraph that an epidemic of this scale had “never been seen in history”, with reports of dead cats lying on the streets and suspicions that it could be a new, deadlier strain of FIP. Tests are currently underway to confirm this.
She added that local authorities have set up an advisory team, launched a media information campaign and are working to change legislation so that drugs can be used to treat cats, but stressed that no feline should be allowed to leave the country without negative tests.
"There is already some evidence - albeit anecdotal - that the disease may have also appeared in Turkey, Lebanon and potentially Israel. If this virus were to reach the UK, it could cause the death of many of our cats. It would be heartbreaking. We need to take this seriously."
The country, sometimes called the "Island of Cats," contains the oldest evidence of animal domestication CREDIT: CHRISTINA ASSI/AFP via Getty Images
Cyprus is a cat-loving country, and its history has a long history with these furry animals – archaeologists have found evidence of their domestication dating back 9,500 years.
However, locals who feed stray cats on the island report that their regulars are increasingly disappearing as they succumb to the virus. Although only 107 cases have been officially reported, veterinarians and animal rights activists estimate that the true number is much higher.
“We have lost 300,000 cats [to FIP] since January,” Dinos Ayiomamitis, head of Cats PAWS Cyprus and vice-chairman of Cyprus Voice for Animals, told Agence France-Presse. The island’s cat population is estimated at around one million.
He said part of the problem with counting cases is that with so many stray animals living in Cyprus, it is almost impossible to diagnose and document all cases of the disease.
Dr. Epaminondas said that “the only way to stop the disease is through treatment,” but even that proved difficult.
Experts want to start using the two treatments on cats, but bureaucratic hurdles and costs have prevented further progress.
These are the drugs remdesivir, which is used to treat Covid-19, and the closely related drug GS-441524. Although approved for use on animals in the UK and for import into Cyprus, they are expensive - from £2,500 to £6,000 for a 3-4kg cat.
Experts want to start using two treatments on cats CREDIT: CHRISTINA ASSI/AFP via Getty Images
Another option is a cheaper antiviral used to treat Covid-19 in humans called molnupiravir. Dr Epaminondas estimates it would cost around £170 per animal - but the Veterinary Association's application for permission to treat the cats was rejected in May because the government said human medicines could not be imported for use in veterinary care.
Professor Gunn-Moore urged the Cypriot government to make the drugs GS-441524, remdesivir and molnupiravir available to all cats, but said the ultimate control tool would be a vaccine.
"This is about the coronavirus, so based on the Covid epidemic, it could very well happen if the pharmaceutical companies want to do it," she said.
With the government taking no action, some people are buying the drugs themselves – and Dr Epaminondas told Cypriot news in May that a black market in cheap, unlicensed drugs is “thriving”.
Among those looking for their own solutions is Vasiliki Mani, 38, a member of several animal welfare organisations who has spent around £3,000 of her savings on treating two sick strays. She told AFP that unless FIP is stopped soon, Cyprus will become an "island of dead cats".
Local residents who feed stray animals report that their resident cats are increasingly disappearing as they succumb to the virus CREDIT: CHRISTINA ASSI/AFP via Getty Images
What to do when your cat gets FIP?
A huge outbreak of Feline Infectious Peritonitis (FIP) has raised concerns in Cyprus, particularly with reports that a slightly different version of the virus may be circulating, but is not unique to the country and has previously been reported in the UK.
If your cat shows symptoms such as fever, abdominal distension, loss of energy and sometimes aggressive behavior, experts recommend that you take it to the vet immediately. Kittens and cats under two years of age are most at risk.
An antiviral drug used to treat Covid-19 called remdesivir is available in the UK, as well as a closely related drug called GS-441524, approved for use in cats with FIP.
Veterinarians say the “gold standard” treatment is a three- to four-day infusion of remdesivir, followed by up to two weeks of injections, followed by oral GS-441524 to prevent relapse — for a total of about 12 weeks.
Article provided and translated with permission Danielle Gunn-Moore. Original article: VetRecord, Volume192, Issue 11, 3/10 June 2023, Pages 449-450, published 6/2/2023.
Colleagues and the public are alerted to an outbreak of Feline Infectious Peritonitis (FIP) in Cyprus that broke out in the capital city of Nicosia in January 2023. An increasing number of cases have been reported in the districts of Larnaca, Limassol and Famagusta. Within 12 weeks, the number of PCR-confirmed FIP cases increased more than 20-fold compared to the previous year.
Biopsies of cavitary fluids, abdominal lymph nodes by fine needle aspiration or tissue biopsies of cats with clinical signs consistent with FIP were sent to Vet Dia Gnosis in Limassol. After cytological or histopathological examination, samples were subjected to automated extraction of total nucleic acid and RT-PCR for the detection of feline coronaviruses (FCoV) at Laboklin Bad Kissingen, Germany. 1
Three and four PCR-confirmed FIP cases were reported in 2021 and 2022, respectively, while 98 PCR-confirmed FIP cases were reported from January to April 2023.
Outbreaks of FIP have already been documented in the UK, USA and Taiwan, but only in breeding facilities and trapping centres. 2-4 This outbreak spread very quickly in different districts of the island, with local veterinarians reporting clinical cases even in cats living exclusively indoors. This is extremely alarming and suggests that there is a highly virulent strain of FCoV in Cyprus that can potentially be transmitted by mechanical vectors. We therefore recommend that cats be kept indoors.
Paphos district is geographically the farthest from Nicosia and has not yet seen an increase in cases.
To prevent the spread of this strain of FCoV outside the island, we encourage veterinarians to serologically test every cat before it travels outside Cyprus. No seropositive cat should travel outside of Cyprus until we have a better understanding of the current outbreak. Ideally, if the cat is allowed to travel, it should be kept indoors for 10 to 14 days and retested, as acutely infected cats are likely to seroconvert later. 5
The disease spread very quickly in different districts of Cyprus, indicating that a highly virulent strain of feline coronavirus is present on the island.
Introducing travel measures for cats traveling from Cyprus must be a priority for the UK. This is due to the high number of animals traveling between the two countries, which reflects the existing historical ties; parts of Cyprus are British Overseas Territories and there are significant numbers of British expatriates residing in Cyprus permanently or seasonally. In the past we have seen the introduction of other infectious agents into the UK via dogs traveling from Cyprus, for example Hepatozoon canis and Leishmania infantum. 6
We are currently analyzing FCoV before and during the outbreak, and we are implementing an epidemiological monitoring system. This will provide us with important information regarding this highly virulent strain and help us understand what is causing this epidemic and how we can control its impact on the cat population and the risk of spreading to other countries.
The high number of stray and free-ranging domestic cats in Cyprus is something that could potentially have played a key role in the outbreak, but there are other factors to consider, including the recent introduction of FIP treatment and the recent Covid-19 pandemic.
Charalampos Attipa, senior lecturer in veterinary clinical pathology Danielle Gunn-Moore, professor of feline medicine Stella Mazeri, EBVS European Specialist in veterinary public health Royal (Dick) School of Veterinary Studies and The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG email: charalampos.attipa@ed.ac.uk Demetris Epaminondas, vice president of the Pancyprian Veterinary Association Veterinary Services, Ministry of Agriculture, Natural Resources and Environment, Cyprus Maria Lyraki, EBVS European Specialist in small animal internal medicine Vets4Life Referral Hospital, Athens, Greece Alexandros Hardas, lecturer in veterinary anatomic pathology Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, Hertfordshire AL9 7TA Stavroula Loukaidou, veterinary surgeon Vet Dia Gnosis Ltd, Limassol, Cyprus Michaela Gentil, veterinary surgeon Laboklin GmbH and Co KG, Bad Kissingen, Germany
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Wang YT, Su BL, Hsieh LE, et al. An outbreak of feline infectious peritonitis in a Taiwanese shelter: epidemiologic and molecular evidence for horizontal transmission of a novel type II feline coronavirus. Vet Res 2013;44:57
Barker EN, Tasker S, Gruffydd-Jones TJ, et al. Phylogenetic analysis of feline coronavirus strains in an epizootic outbreak of feline infectious peritonitis. J Vet Intern Med 2013;27:445–50
Healey EA, Andre NM, Miller AD, et al. Outbreak of feline infectious peritonitis (FIP) in shelter-housed cats: molecular analysis of the feline coronavirus S1/S2 cleavage site consistent with a 'circulating virulent-avirulent theory' of FIP pathogenesis. JFMS Open Rep 2022;8:20551169221074226
Stoddart ME, Gaskell RM, Harbor DA, et al. Virus shedding and immune responses in cats inoculated with cell culture-adapted feline infectious peritonitis virus. Vet Microbiol 1988;16:145–58
Attipa C, Maguire D, Solano-Gallego L, et al. Hepatozoon canis in three imported dogs: a new tick-borne disease reaching the United Kingdom. Vet Rec 2018;183:716
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