Current treatment options for FIP and SARS-CoV-2 positive cats

Original article: Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats (13.11.2020)
Authors: Aaron M. Izes, Jane Yu, Jacqueline M. Norris, and Merran Govendir
Translation: 22.1.2021


Feline peritonitis (FIP) is a virus-induced, immune-mediated feline disease caused by virulent feline coronavirus biotypes (FCoV), known as feline infectious peritonitis virus (FIPV). Historically, three major pharmacological approaches have been used to treat FIP: (1) immunomodulators to non-specifically stimulate the patient's immune system to attenuate the clinical effects of the virus through a strong immune response, (2) immunosuppressive agents to temporarily suppress clinical symptoms, and (3) human antiviral medicines originally intended for other purposes, none of which have unfortunately not been reliably demonstrated to be effective in the treatment of FIPV. Recent studies investigating the broad-spectrum coronavirus protease inhibitor GC376 and the adenosine nucleoside analog GS-441524 have shown that they have led to increased survival and clinical cure in many patients. However, doctors' access to these antiviral therapies is currently problematic because they have not yet obtained registration for veterinary use. As a result, FIP treatment remains a major challenge. The purpose of this summary is to provide information on the current status of therapeutics for the treatment of FIP. Furthermore, due to the increased interest in coronaviruses resulting from the current human pandemic, this summary also provides information on domestic cats identified as positive for SARS-CoV-2.

Keywords: Cat, feline infectious peritonitis, FIP, feline infectious peritonitis virus, therapeutics, treatment, SARS-CoV-2

1. Introduction

Feline infectious peritonitis (FIP) is a virus-induced, immune-mediated disease with a high mortality rate that globally affects domestic cats as well as some wild cats (Addie et al. 2009; Drechsler et al. 2011; Pedersen 2014a). The disease is caused by virulent feline coronavirus (FCoV) biotypes, known as feline infectious peritonitis virus (FIPV) (Addie et al. 2009; Drechsler et al. 2011; Pedersen 2014a). FIPV is caused by unidentified genetic changes in FCoV, leading to an increased ability to replicate in monocytes and macrophages (Addie et al. 2009; Pedersen 2009). Although FIP can affect cats of any age, it is most common in cats less than three years of age, especially in cats aged four to sixteen months (Addie et al. 2009; Pedersen 2009). The true prevalence of FIP is unknown. While some authors report that approximately 12%, or one in nine FCoV-infected cats, develop clinical signs of FIP (Addie et al. 2009; Pedersen 2014b), this figure was extrapolated from veterinary clinic studies rather than from domesticated feline population as a whole and does not correspond to field estimates of the number of recorded cases in relation to the population. Other studies provide a lower prevalence of FIP. In a control study lasting ten years from 1986 to 1995, out of 397,182 additions presented to North American Veterinary Teaching Hospitals, approximately 0.55% new cats and 0.36% of the total number of cats were FIP cats (Rohrbach et al., 2001). These patients with FIP were significantly more likely to be purebred, young, and sexually intact males (Rohrbach et al. 2001; Pesteanu-Somogyi et al. 2006). In a study of cat growth at North Carolina State University College of Veterinary Medicine over a 16-year period from 1986 to 2002 from 11,535 cats of known breed, the prevalence of suspected or confirmed FIP in the mixed cat population was 0.35% versus 1.3% in the population. purebred cats (Pesteanu-Somogyi et al. 2006). In some of these studies, the diagnosis of FIP was made on the basis of clinical examination alone and without confirmatory diagnostic tests (Rohrbach et al. 2001; Pesteanu-Somogyi et al. 2006). In an Australian study, young cats were significantly overrepresented among FIP cases (Worthing et al. 2012). Compared to the Australian cat population, domestic crossbred, Persian and Himalayan cats were significantly under-represented, while several breeds were over-represented, including British Shorthair, Devon Rex and Abyssinian cat. A significantly higher proportion of FIP was observed in males (Worthing et al. 2012).

FIP is categorized according to clinical manifestation as either a wet (effusive) or dry (non-fusible) form (Addie et al. 2009; Pedersen 2009, 2014a). The wet form is characterized by immune-mediated fibrinous-granulomatous serositis, often with protein-rich effusions in the thoracic or abdominal cavity (Addie et al. 2009; Pedersen 2009, 2014a). In contrast, the dry form is typical of pyogranulomatous lesions found in multiple body organs and around blood vessels (Addie et al. 2009; Pedersen 2009, 2014a).

FIP-related mortality is extremely high as soon as clinical signs appear (Pedersen 2014b). As Pedersen noted (2014b, p. 1333), "the onset of visible manifestations of the disease is a signal that the cat's fight with the virus is lost." Although some cats may live with FIP for weeks, months, or sometimes years (Pedersen 2014b), times survival generally varies from days to weeks for effusive FIP and weeks to months for nonfusion (dry) FIP (Fischer et al. 2011; Tsai et al. 2011; Hugo and Heading 2015). Determining the definitive ante-mortem diagnosis of FIP is challenging, especially since current diagnostic tests fail to distinguish between FCoV and FIPV (Fischer et al. 2011; Pedersen 2014b). Because the confirmed diagnosis relies on positive immunostaining of the FCoV antigen in cytology and histopathology, invasive diagnostic tests for tissue biopsies may be required in sick cats to confirm the diagnosis. (Tasker 2018). We refer the reader to a recent summary of more detailed information on FIP diagnostics (Drechsler et al. 2011; Pedersen 2014b; Tasker 2018; Kennedy 2020). In exploring treatment options for FIP, many older studies describing potential treatment are mostly based on cases without a confirmed diagnosis of FIP and suffering from a lack of properly controlled clinical trials (Hartmann and Ritz 2008). Also, the use of other reported treatment options is currently only supported by in vitro studies and not by in vivo clinical studies (Choong et al. 2014; Doki et al. 2016; Hu et al. 2017; Takano et al. 2017). Despite recent antiviral studies with GC376 and GS-441524, which hold great promise in the treatment of FIPV in naturally and experimentally infected cats (Murphy et al. 2018; Pedersen et al. 2018, 2019), these substances have not yet been authorized for veterinary use (Wogan 2019a, 2019b). Therefore, there is currently no effective treatment for FIP (Pedersen 2019a) legally available to veterinarians.

2. SARS-CoV-2

We are currently witnessing great interest in the potential of type 2 severe acute respiratory syndrome virus (SARS-CoV-2) to infect animals, including reports of domesticated and zoologous wild cat farms with a positive result for this virus (Hosie et al. 2020; USA). Ministry of Agriculture 2020; Wang et al. 2020). Coronaviruses are single-stranded RNA viruses (Lundstrom 2020) classified into four genera based on genotypic and serological characterization (Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus; Woo et al. 2012). While FCoV is an alpha-coronavirus (Felten and Hartmann 2019), SARS-CoV-2, which causes COVID-19, is a beta-coronavirus (Chakraborty and Maity 2020; Lai et al. 2020). Coronaviruses have a high recombination rate as well as inherently high mutation rates, which allow them to adapt rapidly with an increased potential to infect new hosts (Woo et al. 2006). Viral recombination is mediated in part by the corrective activity of nsp14 exoribonuclease, which has previously been shown to inhibit the development of nucleoside-based coronavirus treatment (Agostini et al. 2018).

Domesticated cats that tested positive for SARS-CoV-2 were associated with SARS-CoV-2 positive or suspected SARS-CoV-2 owners (Halfmann et al. 2020; Newman 2020). A small number of domesticated SARS-CoV-2-positive cats showed upper or lower airway respiratory symptoms (Sailleau et al. 2020), while others did not show obvious clinical symptoms (Newman 2020; Sailleau et al. 2020; Sit 2020; Sit et al. 2020). Limited experimental studies involving a large number of viral vaccines have shown that cats can transmit SARS-CoV-2 to other cats housed in the same facility by air (Shi et al. 2020). Another study reported that vaccination and exposure to SARS-CoV-2 lead to nasal excretion in cats, and that cats without clinical signs are capable of direct virus transmission to other cats (Halfmann et al. 2020). There is currently no evidence that cats can transmit SARS-CoV-2 to humans (Hosie et al. 2020).

As some of the antivirals described below have shown some anti-FCoV efficacy, it is tempting to extrapolate that they may also reduce SARS-CoV-2 excretion in rare cases of feline infection. However, to the best of the authors' knowledge, no in vivo studies have been published to verify their antiviral activity in SARS-COV-2 in cats.

3. FIP therapeutics

In practice, three main approaches are used to treat FIP, either individually or in combination (Pedersen 2014b). The first approach seeks to non-specifically modulate the patient's immune system in order to reduce the clinical effects of the virus through a strong immune response (Pedersen 2014b). The second approach relies on the use of immunosuppressive drugs to suppress the inflammatory response that is at the core of the pathology of the disease (Hartmann and Ritz 2008; Addie et al. 2009; Pedersen 2014b), while the third approach focuses on the use of antiviral agents that inhibit virus replication (Murphy et al., 2018; Pedersen et al., 2018, 2019). Although each of these main approaches can be used simultaneously, we will address each of them in turn.

3.1. Non-specific immunostimulants

Non-specific immunostimulants have been used to treat FIP for many years, often due to unsubstantiated reports that these treatment regimens can either prolong survival or serve as a direct cure for FIP (Pedersen 2014b). The main goal of this approach is to stimulate the patient to develop an immune response strong enough to reduce the viral load sufficiently to suppress the clinical manifestations of the infection. However, it is somewhat paradoxical that the use of immunostimulants is often associated with immunosuppressants, as some of these drugs may be mutually supportive (Pedersen 2014b). Examples of non-specific immunostimulants used to treat FIP include staphylococcal A protein (Pedersen 2014b), Propionibacterium acnes (an immunomodulatory compound derived from gram-positive bacteria) (Weiss et al. 1990), T-cell immunomodulators (such as omega [ω] interferon). ) and plant extracts such as polyprenyl immunostimulant (PI) (Legendre and Bartges 2009; Legendre et al. 2017). All of these substances were unsuccessful or had only a limited effect in the treatment of FIP. For example, with respect to the biological plant extract PI, the use of this agent was originally proposed by Legendre and Bartges (2009) after three cats were reportedly cured of the dry form of FIP after long-term treatment with PI. However, these studies admit that treatment had no effect in cats with more severe FIP (Legendre and Bartges 2009). A later PI field study in 60 cats showed prolonged survival, with four of these cats surviving more than 300 days with improved quality of life (Legendre et al. 2017). The study also showed that PI survival times were significantly longer in cats that were not co-treated with corticosteroids (Legendre et al. 2017).

3.2. Immunosuppressive agents

The use of immunosuppressive agents to suppress the inflammatory response in FIPV is something of a therapeutic surrogate. This means that the lack of access to safe and effective alternatives leaves veterinarians with very few options other than relying on immunosuppressive therapy to suppress the clinical signs of FIP (Hartmann and Ritz 2008; Addie et al. 2009; Pedersen 2014a). Examples of immunosuppressive agents in the treatment of FIP include glucocorticoids (e.g., prednisolone, dexamethasone) (Disque et al. 1968; Addie et al. 2009), cytokine inhibitors (e.g., pentoxifylline and propentophyllin) (Fischer et al. 2011), and alkylating agents (Fischer et al. 2011). e.g., cyclophosphamide) and chlorambucil) (Bilkei 1988; Addie et al. 2009). Although glucocorticoid administration reduces clinical signs in cats with FIP, there is no evidence that they have any therapeutic effect in infected cats (Addie et al. 2009). Claims that substances such as glucocorticoids are effective against FIP have been refuted by placebo-controlled, double-blind studies by Ritz et al. (2007) and Fischer et al. (2011). In these studies examining the effects of feline interferon ω (Ritz et al. 2007) and propentofylline (Fischer et al. 2011) on the survival and quality of life of FIP-affected cats, all cats (including those in the placebo group) received dexamethasone and / or prednisolone. The authors reported that there was no significant difference in survival between cats with FIP that received either feline interferon ω (Ritz et al. 2007) or propentophyllin (Fischer et al. 2011) (median survival time of cats interferon ω and eight days for propentophylline) and those in the control group given glucocorticoids alone (median survival of eight days in both studies). Due to the co-administration of dexamethasone and / or prednisolone in both of these studies, it is difficult to determine the effects of feline interferon ω or propentofylline as the sole therapeutic agent. Feline interferon ω has been shown to inhibit FCoV replication in vitro (Mochizuki et al. 1994). An uncontrolled study with feline interferon ω and glucocorticoids yielded a promising result in 67% cats that achieved complete or partial remission, but FIP was not confirmed in these cases (Ishida et al. 2004). When recombinant human leukocyte interferon alpha or feline fibroblast beta interferon was used alone, neither reduced mortality in treated cats compared to controls (Weiss and Toivio-Kinnucan 1988; Bolcskei and Bilkei 1995; Ritz et al. 2007). However, when a high dose of alpha interferon was used in combination with Propionibacterium acnes, the average survival time was prolonged, but only by three weeks (Weiss et al. 1990). Although interferons are often used in cats with FIP, their effectiveness is questionable. The use of cyclophosphamide in combination with prednisolone and ampicillin has also been studied in cats with FIP (Bilkei 1988). Seventy-six of the 151 cats were considered "healthy" after treatment. However, the cats included in this study did not have a reliably confirmed diagnosis of FIP. Another study investigating the use of cyclophosphamide other than prednisolone and ampicillin in cases of suspected FIP states that 29-80% cats died within three years (Bolcskei and Bilkei 1995). Again, however, FIP was not confirmed in these cats. Ozagrel hydrochloride (a thromboxane synthesis inhibitor) has also been used as an immunosuppressive agent against FIP (Watari et al. 1998). Although two cats have shown beneficial effects, FIP has not been confirmed in either of them (Watari et al. 1998).

3.3. Specific FIP therapeutics

A third approach to FIP treatment involves the administration of antiviral agents targeting either the cellular mechanisms that viruses choose to replicate or, alternatively, a specific aspect of virus activity associated with infection and / or replication (Hartmann and Ritz 2008; Addie et al. 2009; Pedersen 2014a ). Antiviral drugs that inhibit FCoV have been identified, but many have not been successful in infected patients (Weiss et al. 1993; Hartmann and Ritz 2008; Addie et al. 2009; McDonagh et al. 2014; Pedersen 2014b). However, a new therapeutic breakthrough has emerged using the nucleoside analog GS-441524 with a direct effect on FIP virus (Murphy et al. 2018; Pedersen 2019a, 2019b; Dickinson et al. 2020). GS-441524, the active metabolite of remdesivirus, is a terminator of the RNA strand of viral RNA-dependent RNA polymerase (Murphy et al. 2018; Pedersen et al. 2019). naturally occurring FIP (Murphy et al. 2018; Pedersen et al. 2019). Using an in vitro approach, Murphy et al. (2018) determined that GS-441524 did not show toxicity in feline Crandell Rees (CRFK) kidney cells at concentrations of 100 μM, while still able to inhibit FIPV replication in cultured CRFK cells even in naturally infected feline peritoneal macrophages at 1.0 µM concentrations. . In an accompanying in vivo study in FIPV experimentally infected cats (FIPV serotype I strain m3c-2), GS-441524 was administered once daily (5.0 mg / kg BW or 2.0 mg / kg BW as a subcutaneous injection [SC]) after for two weeks (Murphy et al. 2018). This regimen, which required at least two weeks of treatment, resulted in a rapid reversal of clinical symptoms and a return to normal in all patients. No toxicity was observed. Based on this work, Pedersen et al. (2019) investigated the in vivo therapeutic effects of GS-441524 on naturally occurring FIP, including both wet and dry forms of the disease. 31 cats (26 with FUS and 5 with non-fusion FIP) were enrolled in this study and given a dose of 2.0 mg / kg BW SC once daily for at least 12 weeks. The dose was increased to 4.0 mg / kg BW SC once daily as indicated by worsening clinical symptoms. Four cats were euthanized or died during the first five days of the experiment due to the severity of their infection. The fifth cat was euthanized after 26 days due to the lack of response to treatment. The remaining 26 cats successfully completed a twelve-week (or longer) cycle. Eighteen cats remained healthy after one treatment cycle, while the remaining eight relapsed within 3 to 84 days. Three of the eight relapsing cats were treated again with the same dose, while the five cats had their dose increased from 2.0 to 4.0 mg / kg body weight. Five cats treated with the higher dose recovered. Of the remaining three cats treated with the original lower dose, two relapsed a second time and required a third treatment with a higher dose. The two cats recovered. The third cat relapsed after the second round of the lower dose and was sacrificed due to the severity of its neurological disease. The study yielded 25 long-term surviving cats. The most common side effect was injection site reactions (Pedersen et al. 2019). Based on these findings, the authors concluded that GS-441524 is a safe and effective treatment for FIP when administered at a dose of 4.0 mg / kg BW SC once daily for at least 12 weeks (Pedersen et al. 2019). For neurological cases of FIP, a higher dose of 5.0 to 10.0 mg / kg BW SC once daily for 12 weeks was recommended, resulting from the treatment of four clinical cases (Dickinson et al. 2020). Due to the consistency of its reported effectiveness, a growing global black market has emerged with GS-441524, as it has not been formally approved for commercial use anywhere (Pedersen 2019b). Interestingly, GS-441524 also showed in vitro antiviral activity against SARS-CoV (Cho et al. 2012).

Remdesivir (GS-5734), a prodrug of the original adenosine nucleoside analog, GS-441524 (Amirian and Levy 2020), has been approved by the US Food and Drug Administration (FDA) for emergency use in the treatment of suspected or laboratory-confirmed cases of COVID-19 in adults. and children hospitalized with a severe infection. This emergency approval was based on a randomized, double-blind, placebo-controlled study conducted by the National Institute of Allergies and Infectious Diseases (NIAID) (NCT04280705) and a sponsored open-label study evaluating the different duration of remdesivir (NCT04292899). Another randomized, double-blind, placebo-controlled, multicenter study conducted in China also showed that the use of remdesivir in adult patients with COVID-19 was associated with shortened clinical improvement time with early treatment, although no statistically significant clinical benefits were observed (Wang et al. 2020). Clinical trials of remdesivir and many other antiviral drugs for the treatment of COVID-19 are currently underway in many countries (Amirian and Levy 2020).

Although not related to direct treatment of FIP, a drug designed to reduce FCoV excretion may be a likely precursor to FIP prevention. An antiviral product called Mutian® X, a synthetic adenosine analogue whose exact composition is a "trade secret", has been shown to stop fecal coronavirus excretion in chronically infected cats when administered orally at a dose of 4.0 mg / kg body weight once daily. for four days (Addie et al. 2020). Addie et al. (2020) suggest that the combination of probiotics and interferon in the same study reduced coronavirus secretion in two cats. Feline interferon ω has been shown to reduce feline coronavirus viral secretion in retrovirus-infected cats (Gil et al. 2013).

3.4. Other antiviral compounds

Other candidate compounds have also been tested for their antiviral activity against FIPV. For example, antiviral ribavirin has been tested in vivo in cats experimentally infected with FIPV and has been found to have marginal antiviral activity against FIPV and toxicity to cats (Weiss et al. 1993). Cyclosporin A, a cyclophilin inhibitor, has been shown to inhibit feline coronavirus replication in vitro, although the mechanism of its inhibitory effects is unknown (Pfefferle et al. 2011; Tanaka et al. 2012, 2013). Cyclosporine was administered to one cat with effusion FIP, and a decrease in pleural fluid volume and viral load was noted after treatment. The cat died of respiratory failure on day 264, but the cause of death has not been determined (Tanaka et al. 2015). Likewise, two compounds, galanthus nivalis agglutinin (GNA) and nelfinavir (protease inhibitor), were able to inhibit FCoV replication in vitro when combined (Hsieh et al. 2010). Nevertheless, none of these compounds proved to be effective when tested under conditions simulating FIPV infection. Similarly, based on promising findings regarding the efficacy of 3C-like protease inhibitors against FCoV (Kim et al. 2013, 2015, 2016), a field study was performed with GC376 in 20 cats with various forms of FIP, except those with neurological symptoms (Pedersen et al., 2018). Cats were dosed with 15.0 mg / kg BW, SC, twice daily for a minimum of 12 weeks. Although the results were encouraging (seven cats achieved an average disease remission of 11.2 months), side effects occurred, including transient injection pain, subcutaneous fibrosis, alopecia, and abnormal permanent tooth development in cats treated before 16-18. by week of age (Pedersen et al. 2018). There are other protease inhibitors targeting the 3C-like protein of coronaviruses (Rathnayake et al. 2020; Theerawatanasirikul et al. 2020).

The antifungal itraconazole demonstrated in vitro anti-FIPV activity at low drug concentrations (2.5 μM) (Takano et al. 2019). A recent in vivo study examined the effects of a combination of itraconazole (50 mg / animal orally, once daily) and an anti-human TNF-alpha monoclonal antibody (10 mg / animal) on the treatment of three cats experimentally infected with FIPV (Doki et al. 2020). Although two of the three cats showed improvement in FIPV-related clinical symptoms, an increase in peripheral blood lymphocytes and a decrease in alpha-1-acid glycoproteins were observed after initiation of treatment. A third cat was killed for not responding to treatment. The authors concluded that this combination of drugs may be useful until more effective anti-FIPV agents are available. Itraconazole was used in combination with prednisolone to treat effusion FIP in a three-month-old Scottish Fold kitten, resulting in a reduction in pleural effusion (Kameshima et al. 2020). However, this cat showed neurological manifestations and was euthanized due to status epilepticus after 38 days of treatment (Kameshima et al. 2020). Other agents, including anti-feline TNF-alpha monoclonal antibody, have also been shown to have antiviral activity against FCoV (Doki et al. 2016); U18666A (cholesterol transport inhibitor) (Takano et al. 2017; Doki et al. 2020); difylline (vacuolar ATPase blocker) and its nanoformulation (Hu et al. 2017) and a circular triple helix forming oligonucleotide RNA (Choong et al. 2014). However, no in vivo studies using these compounds have been published.

The human antimalarial drug chloroquine also inhibits FIPV replication in vitro (Takano et al. 2013; McDonagh et al. 2014). Chloroquine has long been known to have anti-inflammatory and in vitro antiviral properties against a wide range of viruses (Takano et al. 2013). Despite good in vitro activity, chloroquine showed weak antiviral activity against in vivo experimentally induced FIP infection (Takano et al. 2013). In their study, Takano et al. (2013) found that chloroquine treatment was associated with improved clinical scores and a slightly increased but not statistically significant survival time of cats infected with highly virulent FCoV FIPV 1146. Further increased levels of alanine aminotransferase activity in the chloroquine-treated groups indicated a potential liver damage problem. A dose of 10 mg / kg body weight twice weekly SC was extrapolated from human dosing protocols and was not based on any known pharmacokinetic studies in cats. The antiviral activity of hydroxychloroquine against FIPV has also recently been the subject of an in vitro study. When hydroxychloroquine was used with recombinant feline IFN-ω, it showed increased antiviral activity against FIPV infection (Takano et al. 2020). Hydroxychloroquine has also been studied in clinical trials for the treatment of COVID-19 in humans (Lundstrom 2020). However, this drug has yielded controversial results, leading to the current conclusion that its clinical efficacy in patients with COVID-19 has not been established (Lundstrom 2020).

McDonagh et al. (2014) examined 19 candidate compounds used in the treatment of other coronavirus infections for their cellular toxicity and efficacy in inhibiting FIPV replication in infected CRFK cells. In this in vitro study, a resazurin-based cytopathic effect inhibition (CPE) screening assay was developed to determine antiviral activity against two FCoV strains: FECV 1683 and FIPV 1146. Other assays, including plaque reduction, reduction in virus excretion, and viricidal suspension, were used to evaluate the antiviral effects of candidate compounds. The study finally identified three compounds (chloroquine, mefloquine and hexamethylene amiloride) that significantly reduced FIPV viral load in infected CRFK cells without cytotoxic effects at 10 μM concentrations. In addition, preliminary experiments suggest that the antiviral mechanisms of all three compounds act at an early stage of viral replication.

Due to the potential impact of these results on the treatment of FIP, further investigation of these compounds is needed (McDonagh et al. 2014). Both chloroquine and mefloquine are commercially available pharmaceuticals registered for use in humans. Behind each of them is a wealth of supporting literature on their pharmacokinetics and safety in non-feline species. Some information on the pharmacokinetic profile of mefloquine in cats is already available (Izes 2019; Izes et al. 2020a, 2019, 2020b; Yu et al. 2020). Hexamethylene amiloride is significantly less known, especially with regard to its safety (McDonagh et al. 2014). Since Takano et al. (2013), who previously questioned the in vivo efficacy of chloroquine against FIP, consider clinical trials of mefloquine for the treatment of infected cats. Recent in vitro pharmacokinetic studies have suggested that mefloquine undergoes phase I hepatic metabolism but not phase II glucuronidative metabolism when catalysed by feline liver microsomes and is therefore unlikely to cause delayed elimination in cats (Izes et al. 2020a). The pharmacokinetic profile of mefloquine in cats has been investigated in anticipation of clinical studies to inhibit feline coronavirus and feline calicivirus in cats clinically affected by these viral infections (Yu et al. 2020). Further studies of the clinical efficacy of mefloquine in FIP-confirmed cats are ongoing.

With respect to all of these antiviral agents, it is important to note that it may be necessary to administer a combination of therapeutics to inhibit the selection of viral resistance in monotherapy.

4. Conclusion

Despite the lack of their commercial availability, antiviral agents such as GS-441524 and GC376 have been shown to be effective treatment options for FIP. While pending approval of these substances, other commercially available substances, such as mefloquine and itraconazole, need to be further investigated through in vivo studies to determine their true potential as antivirals for the treatment of FIPV. In addition, while the current SARS-CoV-2 pandemic has been of little benefit to veterinary medicine, One Health's global approach tells us the need to monitor therapeutic progress in the fight against coronaviruses, as information may ultimately be useful among species.


  1. Addie D, Belák S, Boucraut-Baralon C, Egberink H, Frymus T, Gruffydd-Jones T, Hartmann K, Hosie MJ, Lloret A, Lutz H, et al. . 2009. Feline infectious peritonitis. ABCD guidelines on prevention and management. J Feline Med Surg. 11 (7): 594–604. [PMC free article] [PubMed] [Google Scholar]
  2. Addie DD, Curran S, Bellini F, Crowe B, Sheehan E, Ukrainchuk L, Decaro N .. 2020. Oral Mutian® X stopped faecal feline coronavirus shedding by naturally infected cats. Res Vet Sci. 130: 222–229. [PMC free article] [PubMed] [Google Scholar]
  3. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R, et al. . 2018. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. MBio. 9 (2): e00221-18. [PMC free article] [PubMed] [Google Scholar]
  4. Amirian ES, Levy JK .. 2020. Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. One Health. 9: 100128. [PMC free article] [PubMed] [Google Scholar]
  5. Bilkei G. 1988. Contribution to FIP therapy. Tierärztl Umschau. 43: 192–196. [Google Scholar]
  6. Bolcskei A, Bilkei G .. 1995. Langzeitstudie iiber behandelte FIP-verdachtige katzen. Tierarztliche Umschau. 50: 721–728. [Google Scholar]
  7. Chakraborty I, Maity P .. 2020. COVID-19 outbreak: migration, effects on society, global environment and prevention. Sci Total Environ. 728: 138882. [PMC free article] [PubMed] [Google Scholar]
  8. Cho A, Saunders OL, Butler T, Zhang L, Xu J, Vela JE, Feng JY, Ray AS, Kim CU .. 2012. Synthesis and antiviral activity of a series of 1′-substituted 4-aza-7,9- dideazaadenosine C-nucleosides. Bioorg Med Chem Lett. 22 (8): 2705–2707. [PMC free article] [PubMed] [Google Scholar]
  9. Choong OK, Mehrbod P, Tejo BA, Omar AR .. 2014. In vitro antiviral activity of circular triple helix forming oligonucleotide RNA towards feline infectious peritonitis virus replication. Biomed Res Int. 2014: 654712. [PMC free article] [PubMed] [Google Scholar]
  10. Dickinson PJ, Bannasch M, Thomasy SM, Murthy VD, Vernau KM, Liepnieks M, Montgomery E, Knickelbein KE, Murphy B, Pedersen NC, et al. . 2020. Antiviral treatment using the adenosine nucleoside analogue GS-441524 in cats with clinically diagnosed neurological feline infectious peritonitis. J Vet Intern Med. 34 (4): 1587–1593. [PMC free article] [PubMed] [Google Scholar]
  11. Disque D, Case M, Youngren J .. 1968. Feline infectious peritonitis. J Am Vet Med Assoc. 152 (4): 372–375. [PubMed] [Google Scholar]
  12. Doki T, Takano T, Kawagoe K, Kito A, Hohdatsu T .. 2016. Therapeutic effect of anti-feline TNF-alpha monoclonal antibody for feline infectious peritonitis. Res Vet Sci. 104: 17–23. [PMC free article] [PubMed] [Google Scholar]
  13. Doki T, Tarusawa T, Hohdatsu T, Takano T .. 2020. In vivo antiviral effects of U18666A against type I feline infectious peritonitis virus. Pathogens. 9 (1): 67. [PMC free article] [PubMed] [Google Scholar]
  14. Doki T, Toda M, Hasegawa N, Hohdatsu T, Takano T .. 2020. Therapeutic effect of an anti-human-TNF-alpha antibody and itraconazole on feline infectious peritonitis. Arch Virol. 165 (5): 1110–1197. [PMC free article] [PubMed] [Google Scholar]
  15. Drechsler Y, Alcaraz A, Bossong FJ, Collisson EW, Diniz PPVP .. 2011. Feline coronavirus in multicat environments. Vet Clin North Am Small Anim Pract. 41 (6): 1133–1169. [PMC free article] [PubMed] [Google Scholar]
  16. Felten S, Hartmann K .. 2019. Diagnosis of feline infectious peritonitis: a review of the current literature. Viruses. 11 (11): 1068. [PMC free article] [PubMed] [Google Scholar]
  17. Fischer Y, Ritz S, Weber K, Sauter-Louis C, Hartmann K .. 2011. Randomized, placebo controlled study of the effect of propentofylline on survival time and quality of life of cats with feline infectious peritonitis. J Vet Intern Med. 25 (6): 1270–1276. [PMC free article] [PubMed] [Google Scholar]
  18. Gil S, Leal RO, Duarte A, McGahie D, Sepúlveda N, Siborro I, Cravo J, Cartaxeiro C, Tavares LM .. 2013. Relevance of feline interferon omega for clinical improvement and reduction of concurrent viral excretion in retrovirus infected cats from a rescue shelter. Res Vet Sci. 94 (3): 753–763. [PMC free article] [PubMed] [Google Scholar]
  19. Halfmann PJ, Hatta M, Chiba S, Maemura T, Fan S, Takeda M, Kinoshita N, Hattori Si, Sakai-Tagawa Y, Iwatsuki-Horimoto K, et al. . 2020. Transmission of SARS-CoV-2 in domestic cats. N Engl J Med. 383 (6): 592–594. [PubMed] [Google Scholar]
  20. Hartmann K, Ritz S .. 2008. Treatment of cats with feline infectious peritonitis. Vet Immunol Immunopathol. 123 (1-2): 172–175. [PMC free article] [PubMed] [Google Scholar]
  21. Hosie MJ, Hartmann K, Hofmann-Lehmann R, Addie DD, Truyen U, Egberink H, Tasker S, Frymus T, Pennisi MG, Möstl K, et al. . 2020. SARS-Coronavirus (CoV) -2 and cats. European Advisory Board on Cat Diseases (ABCD) [Google Scholar]
  22. Hsieh LE, Lin CN, Su BL, Jan TR, Chen CM, Wang CH, Lin DS, Lin CT, Chueh LL .. 2010. Synergistic antiviral effect of Galanthus nivalis agglutinin and nelfinavir against feline coronavirus. Antiviral Res. 88 (1): 25-30. [PMC free article] [PubMed] [Google Scholar]
  23. Hu C-MJ, Chang WS, Fang ZS, Chen YT, Wang WL, Tsai HH, Chueh LL, Takano T, Hohdatsu T, Chen HW, et al. . 2017. Nanoparticulate vacuolar ATPase blocker exhibits potent host-targeted antiviral activity against feline coronavirus. Sci Rep. 7 (1): 1–11. [PMC free article] [PubMed] [Google Scholar]
  24. Hugo TB, Heading KL .. 2015. Prolonged survival of a cat diagnosed with feline infectious peritonitis by immunohistochemistry. Can Vet J. 56 (1): 53–58. [PMC free article] [PubMed] [Google Scholar]
  25. Ishida T, Shibanai A, Tanaka S, Uchida K, Mochizuki M .. 2004. Use of recombinant feline interferon and glucocorticoid in the treatment of feline infectious peritonitis. J Feline Med Surg. 6 (2): 107–109. [PMC free article] [PubMed] [Google Scholar]
  26. Izes AM. 2019. Comparative studies of in vitro hepatic metabolism of mefloquine by feline microsomes and those of other selected species [PhD thesis]. The University of Sydney;; [Google Scholar]
  27. Izes AM, Kimble B, Norris JM, Govendir M .. 2020. a. In vitro hepatic metabolism of mefloquine using microsomes from cats, dogs and the common brush-tailed possum. PLoS One. 15 (4): e0230975. [PMC free article] [PubMed] [Google Scholar]
  28. Izes AM, Kimble B, Govendir M .. 2019. Intrinsic clearance rate of O-desmethyltramadol (M1) by glucuronide conjugation and phase I metabolism by feline, canine and common brush-tailed possum microsomes. Xenobiotica. 50 (7): 776–77. [PubMed] [Google Scholar]
  29. Izes AM, Kimble B, Norris JM, Govendir M .. 2020. b. Assay validation and determination of in vitro binding of mefloquine to plasma proteins from clinically normal and FIP-affected cats. PLoS One. 15 (8): e0236754. [PMC free article] [PubMed] [Google Scholar]
  30. Kameshima S, Kimura Y, Doki T, Takano T, Park CH, Itoh N .. 2020. Clinical efficacy of combination therapy of itraconazole and prednisolone for treating effusive feline infectious peritonitis. J Vet Med Sci. 82 (10): 0049-1492. [PMC free article] [PubMed] [Google Scholar]
  31. Kennedy MA. 2020. Feline infectious peritonitis: update on pathogenesis, diagnostics, and treatment. Vet Clin North Am Small Anim Pract. 50 (5): 1001–1011. doi: 10.1016 / j.cvsm.2020.05.002. [PubMed] [CrossRef] [Google Scholar]
  32. Kim Y, Liu H, Galasiti Kankanamalage AC, Weerasekara S, Hua DH, Groutas WC, Chang KO, Pedersen NC .. 2016. Reversal of the progression of fatal coronavirus infection in cats by a broad-spectrum coronavirus protease inhibitor. PLoS Pathog. 12 (3): e1005531. [PMC free article] [PubMed] [Google Scholar]
  33. Kim Y, Mandadapu SR, Groutas WC, Chang KO .. 2013. Potent inhibition of feline coronaviruses with peptidyl compounds targeting coronavirus 3C-like protease. Antiviral Res. 97 (2): 161-168. [PMC free article] [PubMed] [Google Scholar]
  34. Kim Y, Shivanna V, Narayanan S, Prior AM, Weerasekara S, Hua DH, Kankanamalage ACG, Groutas WC, Chang KO .. 2015. Broad-spectrum inhibitors against 3C-like proteases of feline coronaviruses and feline caliciviruses. J Virol. 89 (9): 4942–4950. [PMC free article] [PubMed] [Google Scholar]
  35. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR .. 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and corona virus disease-2019 (COVID-19): the epidemic and the challenges. Int J Antimicrob Agents. 55 (3): 105924. [PMC free article] [PubMed] [Google Scholar]
  36. Legendre AM, Bartges JW .. 2009. Effect of polyprenyl immunostimulant on the survival times of three cats with the dry form of feline infectious peritonitis. J Feline Med Surg. 11 (8): 624–626. [PMC free article] [PubMed] [Google Scholar]
  37. Legendre AM, Kuritz T, Galyon G, Baylor VM, Heidel RE .. 2017. Polyprenyl immunostimulant treatment of cats with presumptive non-effusive feline infectious peritonitis in a field study. Front Vet Sci. 4 (Article 7): 7. [PMC free article] [PubMed] [Google Scholar]
  38. Lundstrom K. 2020. Coronavirus pandemic — therapy and vaccines. Biomedicine. 8 (5): 109. [PMC free article] [PubMed] [Google Scholar]
  39. McDonagh P, Sheehy PA, Norris JM .. 2014. Identification and characterization of small molecule inhibitors of feline coronavirus replication. Vet Microbiol. 174 (3-4): 438–447. [PMC free article] [PubMed] [Google Scholar]
  40. Mochizuki M, Nakatani H, Yoshida M .. 1994. Inhibitory effects of recombinant feline interferon on the replication of feline enteropathogenic viruses in vitro. Vet Microbiol. 39 (1-2): 145–152. [PMC free article] [PubMed] [Google Scholar]
  41. Murphy BG, Perron M, Murakami E, Bauer K, Park Y, Eckstrand C, Liepnieks M, Pedersen NC .. 2018. The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies . Vet Microbiol. 219: 226–233. [PMC free article] [PubMed] [Google Scholar]
  42. Newman A. 2020. First reported cases of SARS-CoV-2 infection in companion animals — New York, March – April 2020. Morb Mortal Wkly Rep. 69 (23): 710–713. [PMC free article] [PubMed] [Google Scholar]
  43. 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 (4): 378–392. [PMC free article] [PubMed] [Google Scholar]
  44. 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 the treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg. 21 (4): 271–281. [PMC free article] [PubMed] [Google Scholar]
  45. Pedersen NC. 2009. A review of feline infectious peritonitis virus infection: 1963-2008. J Feline Med Surg. 11 (4): 225–258. [PMC free article] [PubMed] [Google Scholar]
  46. Pedersen NC. 2014. a. An update on feline infectious peritonitis: virology and immunopathogenesis. Vet J. 201 (2): 123–132. [PMC free article] [PubMed] [Google Scholar]
  47. Pedersen NC. 2014. b. An update on feline infectious peritonitis: diagnostics and therapeutics. Vet J. 201 (2): 133–141. [PMC free article] [PubMed] [Google Scholar]
  48. Pedersen NC. 2019. a. Fifty years' fascination with FIP culminates in a promising new antiviral. J Feline Med Surg. 21 (4): 269–270. [PubMed] [Google Scholar]
  49. Pedersen NC. 2019. b. Blackmarket production and sale of GS-441524 and GC376.
  50. Pesteanu-Somogyi LD, Radzai C, Pressler BM .. 2006. Prevalence of feline infectious peritonitis in specific cat breeds. J Feline Med Surg. 8 (1): 1–5. [PMC free article] [PubMed] [Google Scholar]
  51. Pfefferle S, Schöpf J, Kögl M, Friedel CC, Müller MA, Carbajo-Lozoya J, Stellberger T, von Dall'Armi E, Herzog P, Kallies S, et al. . 2011. The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors. PLoS Pathog. 7 (10): e1002331. [PMC free article] [PubMed] [Google Scholar]
  52. Rathnayake AD, Zheng J, Kim Y, Perera KD, Mackin S, Meyerholz DK, Kashipathy MM, Battaile KP, Lovell S, Perlman S, et al. . 2020. 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV – infected mice. Sci. Transl. Med. 12 (557): eabc5332. [PMC free article] [PubMed] [Google Scholar]
  53. Ritz S, Egberink H, Hartmann K .. 2007. Effect of feline interferon ‐ omega on the survival time and quality of life of cats with feline infectious peritonitis. J Vet Intern Med. 21 (6): 1193–1197. [PMC free article] [PubMed] [Google Scholar]
  54. Rohrbach BW, Legendre AM, Baldwin CA, Lein DH, Reed WM, Wilson RB .. 2001. Epidemiology of feline infectious peritonitis among cats examined at veterinary medical teaching hospitals. J Am Vet Med Assoc. 218 (7): 1111–1115. [PubMed] [Google Scholar]
  55. Sailleau C, Dumarest M, Vanhomwegen J, Delaplace M, Caro V, Kwasiborski A, Hourdel V, Chevaillier P, Barbarino A, Comtet L, et al. . 2020. First detection and genome sequencing of SARS ‐ CoV ‐ 2 in an infected cat in France. Transbound Emerg Dis. doi: 10.1111 / tbed.13659 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  56. Shi J, Wen Z, Zhong G, Yang H, Wang C, Huang B, Liu R, He X, Shuai L, Sun Z, et al. . 2020. Susceptibility of ferrets, cats, dogs, and different domestic animals to SARS-coronavirus-2. Science. 368 (6494): 1016–1020. [PMC free article] [PubMed] [Google Scholar]
  57. Sit T. 2020. OIE COVID-19 (SAR-COV-2), Hong Kong (SAR-PRC).
  58. Sit THC, Brackman CJ, Ip SM, Tam KWS, Law PYT, To EMW, Yu VYT, Sims LD, Tsang DNC, Chu DKW, et al. . 2020. Infection of dogs with SARS-CoV-2. Nature. 586 (7831): 776–778. 10.1038 / s41586-020-2334-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  59. Takano T, Akiyama M, Doki T, Hohdatsu T .. 2019. Antiviral activity of itraconazole against type I feline coronavirus infection. Vet Res. 50 (1): 5. [PMC free article] [PubMed] [Google Scholar]
  60. Takano T, Endoh M, Fukatsu H, Sakurada H, Doki T, Hohdatsu T .. 2017. The cholesterol transport inhibitor U18666A inhibits type I feline coronavirus infection. Antiviral Res. 145: 96–102. [PMC free article] [PubMed] [Google Scholar]
  61. Takano T, Katoh Y, Doki T, Hohdatsu T .. 2013. Effect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo. Antiviral Res. 99 (2): 100-107. [PMC free article] [PubMed] [Google Scholar]
  62. Takano T, Satoh K, Doki T, Tanabe T, Hohdatsu T .. 2020. Antiviral effects of hydroxychloroquine and type i interferon on in vitro fatal feline coronavirus infection. Viruses. 12 (5): 576. [PMC free article] [PubMed] [Google Scholar]
  63. Tanaka Y, Sato Y, Osawa S, Inoue M, Tanaka S, Sasaki T .. 2012. Suppression of feline coronavirus replication in vitro by cyclosporin A. Vet Res. 43 (1): 41. [PMC free article] [PubMed] [Google Scholar]
  64. Tanaka Y, Sato Y, Sasaki T .. 2013. Suppression of coronavirus replication by cyclophilin inhibitors. Viruses. 5 (5): 1250–1260. [PMC free article] [PubMed] [Google Scholar]
  65. Tanaka Y, Sato Y, Takahashi D, Matsumoto H, Sasaki T .. 2015. Treatment of a case of feline infectious peritonitis with cyclosporin A. Vet Rec Case Rep. 3 (1): e000134. [Google Scholar]
  66. Tasker S. 2018. Diagnosis of feline infectious peritonitis: Update on evidence supporting available tests. J Feline Med Surg. 20 (3): 228–243. [PubMed] [Google Scholar]
  67. Theerawatanasirikul S, Kuo CJ, Phetcharat N, Lekcharoensuk P .. 2020. In silico and in vitro analysis of small molecules and natural compounds targeting the 3CL protease of feline infectious peritonitis virus. Vet Res. 174: 104697. [PMC free article] [PubMed] [Google Scholar]
  68. Tsai HY, Chueh LL, Lin CN, Su BL .. 2011. Clinicopathological findings and disease staging of feline infectious peritonitis: 51 cases from 2003 to 2009 in Taiwan. J Feline Med Surg. 13 (2): 74–80. [PMC free article] [PubMed] [Google Scholar]
  69. United States Department of Agriculture. 2020. Confirmed cases of SARS-CoV-2 in Animals in the United States [accesed 2020 July 2]. Available from:
  70. Wang L, Mitchell PK, Calle PP, Bartlett SL, McAloose D, Killian ML, Yuan F, Fang Y, Goodman LB, Fredrickson R, et al. . 2020. Complete genome sequence of SARS-CoV-2 in a tiger from a US zoological collection. Microbiol Resour Announc. 9 (22): e00468-20. [PMC free article] [PubMed] [Google Scholar]
  71. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, et al. . 2020. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicenter trial. Lancet. 395 (10236): 1569–1578. [PMC free article] [PubMed] [Google Scholar]
  72. Watari T, Kaneshima T, Tsujimoto H, Ono K, Hasegawa A .. 1998. Effect of thromboxane synthetase inhibitor on feline infectious peritonitis in cats. J Vet Med Sci. 60 (5): 657–659. [PubMed] [Google Scholar]
  73. Weiss R, Cox N, Martinez M .. 1993. Evaluation of free or liposome-encapsulated ribavirin for antiviral therapy of experimentally induced feline infectious peritonitis. Res Vet Sci. 55 (2): 162–172. [PMC free article] [PubMed] [Google Scholar]
  74. Weiss R, Cox N, Oostrom-Ram T .. 1990. Effect of interferon or Propionibacterium acnes on the course of experimentally induced feline infectious peritonitis in specific-pathogen-free and random-source cats. Am J Vet Res. 51 (5): 726–733. [PubMed] [Google Scholar]
  75. Weiss RC, Toivio-Kinnucan M .. 1988. Inhibition of feline infectious peritonitis virus replication by recombinant human leukocyte (alpha) interferon and feline fibroblastic (beta) interferon. Am J Vet Res. 49 (8): 1329–1335. Aug [PubMed] [Google Scholar]
  76. Wogan L. 2019. a. Legal treatment for cat disease known as FIP still years away.
  77. Wogan L. 2019. b. Hope, despair fuel black market for drugs in fatal cat disease.
  78. Woo PCY, Lau SKP, Lam CSF, Lau CCY, Tsang AKL, Lau JHN, Bai R, Teng JLL, Tsang CCC, Wang M, et al. . 2012. Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus. J Virol. 86 (7): 3995–4008. [PMC free article] [PubMed] [Google Scholar]
  79. Woo PCY, Lau SKP, Yip CCY, Huang Y, Tsoi HW, Chan KH, Yuen KY .. 2006. Comparative analysis of 22 coronavirus HKU1 genomes reveals a novel genotype and evidence of natural recombination in coronavirus HKU1. J Virol. 80 (14): 7136–7145. [PMC free article] [PubMed] [Google Scholar]
  80. Worthing KA, Wigney DI, Dhand NK, Fawcett A, McDonagh P, Malik R, Norris JM .. 2012. Risk factors for feline infectious peritonitis in Australian cats. J Feline Med Surg. 14 (6): 405–412. [PubMed] [Google Scholar]
  81. Yu J, Kimble B, Norris JM, Govendir M .. 2020. Pharmacokinetic profile of oral administration of mefloquine to clinically normal cats: a preiminary in-vivo study of a potential treatment for feline infectious peritonitis (FIP). Animals. 10 (6): 1000. [PMC free article] [PubMed] [Google Scholar]

Leave a Reply

Your email address will not be published.