Antiviral drugs to treat enzootic feline coronavirus infection in kennels and why it might not be a good idea

Niels C. Pedersen, DVM PhD,
1.4.2023

Original article: Antiviral Drugs for Control of Enzootic Feline Coronavirus Infection in Pedigreed Catteries and why it may not be a good idea

When discussing feline coronavirus (FCoV) infection in a multi-cat population setting, it is important to understand the correct nomenclature. The term FCoV is a collective term for two historically named viruses. A coronavirus was eventually identified as the causative agent of feline infectious peritonitis (FIP) in cats and was named FIP virus or FIPV (Ward, 1970; Zooket al., 1968). FIPV was subsequently found to be a mutant form of FCoV that was present in cats infected with a widespread and minimally pathogenic enteric coronavirus and was named feline enteric coronavirus (FECV) (Pedersen et al., 1981). To avoid confusion, this author prefers to refer to the form of FCoV that is relevant to the immediate 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 discussing 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 occur in an animal population, while endemic is the corresponding term used for humans. Clinical “signs” are what veterinarians and pediatricians observe on physical examination or what owners/parents report to them, while symptoms are what patients describe to their physicians. Therefore, “epizootic” and “symptoms” are not strictly veterinary terms.

FECV, like many other microbial infections in cats, is maintained in the population as a chronic or recurrent asymptomatic infection. 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 primary signs of enteritis are mild or usually inconspicuous (Pedersen et al., 2008; Vogel et al., 2010). Subsequent faecal excretion occurs from the colon and usually ceases 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 notoriously short-lived, and repeated infections are common throughout life (Pearson et al., 2016; Pedersen et al., 2008). A stronger immunity appears to develop over time and cats over 3 years of age have been shown to be less likely to become reinfected and become faecal shedders (Addie et al., 2003). Although the level of exposure to FECV is the primary risk factor for FIP in cat breeds (Foley et al., 1997), the health of the immune system at the time of emergence of mutant FIPV is a major determinant of the occurrence of FIP in any population or group of cats.¹

FIP is caused by specific mutants that arise during FECV infection (Poland et al., 1996; Vennema et al., 1995).¹ These FlP-causing mutants develop with some frequency in the organism, but fortunately most of them are eliminated by the healthy immune system (Poland et al., 1996).¹ Given the relationship between enzootic FECV infection and FIP, it is logical to prevent FIP by minimizing exposure to FECV. Since “no vaccine can produce better immunity than natural infection” and given what is known about the weakness and short duration of natural immunity to FECV (Pearson et al., 2016; Pedersen et al., 2008), it is unlikely that effective vaccines against FECV will be developed.

Although enzootic FECV infection is not amenable to vaccination, thorough carrier testing and strict quarantine can eliminate FECV in a group of breeding research cats (Hickman et al., 1995). However, FECV is so ubiquitous in nature and easily spread by direct and indirect cat-to-cat contact and on human-borne fomites that the strictest quarantine facilities and procedures are required to prevent its spread. 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 rigorously tightening quarantine procedures for the remaining colony (Hickman et al., 1995). Nevertheless, FECV re-entered this colony for 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 with feline and murine enteric coronaviruses, it is unlikely that FECV could be kept out of any group of domesticated cats with anything less than the strictest isolation and infection prevention practices.

An interesting approach to preventing or delaying FECV infection in kittens in kennels has been referred to as “early weaning and isolation” (Addie et al. 1995²). It was based on the finding that kittens born to FECV-exposed or infected mothers have maternal immunity to infection up to 9 weeks of age (Pedersen et al., 2008). Therefore, kittens weaned a few weeks before the loss of this immunity (4-6 weeks of age) are usually free of infection and, if removed from the mother and isolated from other cats, could theoretically be kept virus-free. This practice was initially popular, but the necessary facilities and quarantine procedures required to prevent later infection were difficult to maintain in kennels with larger numbers of breeding cats (> 5 cats, Hartmann et al., 2005; > 10 cats Addie et al., 1995²). Therefore, elimination of FECV in kittens by early weaning and isolation has been doomed to failure in most common homes/kennels due to the largely unavoidable exposure to FECV that occurs in the breeding, rearing and exhibition of breeding cats.

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 avoided if all the cats could get rid of the infection at the same time. This can be achieved by serially testing faeces for FECV excretion over a period of time and culling all shedding cats. However, since a significant proportion of cats in farms involved in FECV enzootic disease shed FECV in their faeces (Foley et al., 1997; Herrewegh et al., 1997), culling cats can have a serious impact on the gene pool (Hickman et al., 1995). . This begs the question – can FECV be eliminated in all cats in a group at the same time? Interestingly, the relatively recent discovery of effective antivirals against FIP has also provided a possible method of eliminating all the spreaders of the virus at the same time (Pedersen et al., 2018, 2019). Early studies of such use of antivirals such as GS-441524, although of a rather preliminary nature, suggest that FECV can be eliminated from a closed population of cats with relatively short treatment (Addie et al., 2023).

Assuming that FECV can be eliminated as an enzootic virus from a cat population by the use of specific antivirals, what are the pitfalls of such an approach? The first pitfall is the cost of antivirals, the frequent fecal testing required to identify shedding animals, and the establishment and maintenance of adequate quarantine facilities and practices. Therefore, home facilities with weak barrier isolation procedures to keep this population of cats free of FECV for an extended period of time are doomed to failure. The second pitfall is related to the normal activities of breeding and showing pedigree cats. Breeding pedigree cats involves frequent interaction of cats, as well as humans in contact with cats and with each other. It is also difficult to imagine that a pedigree cat breeder and avid cat show attendee would forgo all the joys of breeding and showing their cats by avoiding all such interactions. The ultimate question is, “Now that the cats are free of FECV, what are you going to do with them?” What are the chances that they will remain FECV-free 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 they come from. Finally, the constant antiviral treatment required to keep a group of cats free of FECV infection is likely to cause drug resistance to develop. We now know that resistance to GS-441524 can occur in cats being 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 % cases⁴ and even if resistance to antivirals does develop, it is largely confined to the affected cat. It can be argued that HIV-1 infection in humans is currently prevented by antivirals without any reported concerns about drug resistance. Preventive treatment of HIV-¹ however, it is not a monotherapy, but includes several drugs of different classes.³ This is not done to increase the effectiveness of treatment, but rather to prevent drug resistance. If the virus develops resistance to one drug in the drug mix, 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 longer period of time, are needed before this practice is seriously considered. The overall incidence of FIP in smaller, well-maintained herds with enzootic FECV infection is usually less than 1/10⁴ A practical way to reduce the incidence of FIP is to keep the number of breeding cats and kittens low, to keep more older cats, to not breed individuals and bloodlines that have given rise to cases of FIP, and to minimize the stress of frequent introductions of new cats and changes in placement or relocated.¹ In smaller farms, isolation and early weaning can also be useful.

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, McDonald M, Audhuy S, Burr P, Hollins J, Kovacic R, Lutz H, Luxton Z, Mazar S, Meli ML, 2012. Quarantine protects Falkland Islands (Malvinas) cats from feline coronavirus infection. J Feline Med Surg, 14, 171-176.
• Addie DD, Schaap IA, Nicolson L, Jarrett O, 2003. Persistence and transmission of natural type I feline coronavirus infection. Journal of General Virology 84, 2735-2744.
• Addie, D.; Jarrett, O. Control of feline coronavirus infections in breeding catteries by serotesting, isolation, and early weaning. 1995. Feline Pract. 23, 92-95.
• 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, 1313-1318.
• Hartmann K, 2005. Feline infectious peritonitis Vet Clin North Am Small Anim Pract. 35(1), 3979.
• Herrewegh AAPM, Mahler 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.
• Pearson M, LaVoy A, Evans S, Vilander A, Webb C, Graham B, Musselman E, LeCureux J, VandeWoude S, Dean GA, 2019. Mucosal Immune Response to Feline Enteric Coronavirus Infection. Viruses 11, 906.
• Pedersen NC, Theilen G, Keane MA, Fairbanks L, Mason T, Orser B, Che CH, Allison C, 1977. Studies of naturally transmitted feline leukemia virus infection. American Journal of Veterinary Research 38, 1523-1531.
• Pedersen NC, Boyle JF, Floyd K, Fudge A, Barker J, 1981. An enteric coronavirus infection of cats and its relationship to feline infectious peritonitis. American Journal of Veterinary Research 42, 368-377.
• Pedersen NC, Allen CE, Lyons LA, 2008. Pathogenesis of feline enteric coronavirus infection. Journal of Feline Medicine and Surgery 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. Journal of Feline Medicine and Surgery 20, 378–392.
• 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. Journal of Feline Medicine and Surgery 20, 378–392.
• 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. Journal of Clinical Microbiology 34, 3180–3184.
• 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. Veterinary Research 41, 71.
• Ward JM, 1970. Morphogenesis of a virus in cats with experimental feline infectious peritonitis. Virology 41, 191-194.
• Zook BC, King NW, Robinson RL, McCombs HL, 1968. Ultrastructural evidence for the viral etiology of feline infectious peritonitis. Veterinary Pathology 5, 91-95.

1. 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.pdf-4.29.22.pdf.
2. Addie D. Prevention of feline coronavirus (FCoV) infection. https://www.catvirus.com/PreventionS1.htm.
3. Cornell University blog. Fight FIP. Unraveling feline infectious peritonitis from the ground up. https://blogs.cornell.edu/fightfip/fip-antivirals/.
4. FIP Treatment – Czechia / Slovakia. Basic data, 2023. https://docs.google.com/spreadsheets/d/e/2PACX-1vRAni FV fteWIW1HXsROLuJ7YY1- i Sf81BCmM9JT9LbCT2mcnwD1rL9IBsLCTB1U59CcnalOGiFqq/pubhtml?gid=1340189982&singl e=true