Antiviral Drugs for Control of Enzootic Feline Coronavirus Infection in Pedigreed Catteries & Why It May Not Be a Good Idea
Niels C. Pedersen, DVM PhD
April 1, 2023
It is important in discussing feline coronavirus (FCoV) infection in multi-cat environments to understand correct nomenclature. The term FCoV is a collective term for two historically named viruses. A coronavirus was ultimately identified as the cause 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 occurred within the body of cats infected with widespread and minimally pathogenic enteric coronavirus and named feline enteric coronavirus (FECV) (Pedersen et al., 1981). To avoid confusion, this author prefers to refer to whichever form of FCoV is applicable to the immediate discussion. Therefore, it is appropriate to use the term FIPV when discussing the form of FCoV that is found within a specific type of white blood cell (monocyte/macrophage) in diseased tissues and fluids of cats with FIP. The term FECV is used when referring to the form of FCoV that causes chronic and intermittent infections of epithelium in the lower bowel of healthy cats and is shed in the feces in large amounts. Enzootic is the correct term for infections that maintain themselves in a population of animals, while endemic is the corresponding term used for humans. Clinical “signs” are what veterinarians and pediatricians either observe in a physical examination or relayed by owners/parents, while symptoms are what patients describe to their doctors. Therefore, “epizootic” and “symptoms” are strictly not veterinary terms.
FECV, like many microbial infections of cats, is maintained in the population as a chronic or frequently recurrent nonapparent infections. FECV is first shed in feces starting at around 9-10 weeks of age coincident with the loss of maternal immunity (Pedersen et al., 2008). Infection is by the fecal-oral route and targets the intestinal epithelium, and primary signs of enteritis are mild or usually inapparent (Pedersen et al., 2008; Vogel et al., 2010). Subsequent fecal shedding is 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 resultant immunity is notoriously short-lived, and recurrent infections are common during a lifetime (Pearson et al., 2016; Pedersen et al., 2008). A stronger immunity appears to develop over time and cats older than 3 years appear less likely to be reinfected and become fecal shedders (Addie et al., 2003). Although the level of FECV exposure is the primary risk factor for FIP in catteries (Foley et al., 1997), the health of the immune system at the time a mutant FIPV’s arise is the main determinant of FIP incidence in any given population or group of cats. ¹
FIP is caused by specific mutants that generated during infection with FECV (Poland et al., 1996; Vennema et al., 1995). 1 These FIP-causing mutants of evolve in the body with some frequency but fortunately, most are eliminated by a 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 the natural infection” and given what is known about the weakness and short-lived nature of natural FECV immunity (Pearson et al., 2016; Pedersen et al., 2008), it is unlikely that effective vaccines against FECV will be developed.
Although enzootic FECV infection does not lend itself to vaccination, it is possible with vigorous testing for carriers and strict quarantine to eliminate FECV from a group of pedigreed research cats (Hickman et al., 1995). However, FECV is so ubiquitous in nature and easily spread both by direct and indirect cat-to-cat contact and on fomites carried on personages, the strictest of quarantine facilities and procedures are needed to keep it out. How strict must the quarantine be? Experience with test and removal coupled 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 cat breeding facility at UC Davis by removing virus shedders and seriously increasing quarantine procedures for the remaining colony (Hickman et al., 1995). Nevertheless, FECV re-entered this colony several years despite all attempts to keep it out (Pedersen NC, UC Davis, unpublished, 2022). The only example of an effective quarantine for FECV was described for cats on the Falkland Islands (Addie et al.,2012). These islands in the distant South Atlantic Ocean have fortuitously remained free of FECV, presumably from their extreme isolation. Steps have been initiated to prevent future inadvertent introduction of FECV to the islands (Addie et al., 2012). Based on these experiences with cats and mice enteric coronaviruses, it is unlikely that FECV can be kept out of any group of cats kept in home type environments with anything less than the strictest isolation and infection prevention procedures.
An interesting approach to either preventing or delaying FECV infection in kittens in pedigreed catteries was referred to as “early weaning and isolation” (Addie et al. 1995).2 It was based on the finding that kittens born to FECV exposed or infected queens conferred maternal immunity to the infection up 9-weeks of age (Pedersen et al., 2008). Therefore, kittens weaned several weeks prior to the loss of this immunity (4-6 weeks of age) are usually free of infection and if removed from their mother and isolated from other cats they could theoretically be kept free of the virus. This procedure was popular at first, but the necessary facilities and quarantine practices necessary to prevent later infection was difficult to maintain in catteries with larger number of breeding cats (≥ 5 queens, Hartmann et al., 2005; ≥ 10 queens Addie et al., 19952 ). Therefore, eliminating FECV from kittens by early weaning and isolation was doomed for failure in most conventional homes/catteries given the largely unavoidable FECV exposures encountered in breeding, rearing, and showing of pedigreed cats.
Another problem with early weaning and isolation is the need to segregate virus free kittens from the rest of cats in a large group. This problem could be circumvented if all the cats could be freed of infection at the same time. This can be done by serial fecal testing for FECV shedding over a period and elimination of all shedders. However, because a significant proportion of cattery cats involved in an FECV enzootic are fecal shedders of FECV (Foley et al., 1997; Herrewegh et al., 1997), eliminating cats can have a serious effect on the gene pool (Hickman et al. 1995). This begs the question – can FECV be eliminated from all cats in a group at the same time? Interestingly, the relatively recent discovery of effective antivirals against FlP has also provided a possible method to eliminate all virus shedders at one time (Pedersen et al.,2018, 2019). The first studies on such use of antivirals like GS-441524, although quite preliminary in nature, indicate that FECV can be cleansed from a closed group of cats with relatively short treatment (Addie et al., 2023).
Assuming that FECV can be eliminated as an enzootic from a group of cats using specific antiviral drugs, what are the pitfalls of such a practice? The first pitfall is the cost of the antiviral drugs, frequent fecal testing required to identify shedders, and creation and maintenance of reasonable quarantine facilities and practice. Therefore, home-orientated facilities with weak barrier containment procedures to maintain this group of cats free of FECV for extended periods of time are doomed to failure. The second pitfall has to do with the normal activities of pedigreed cat breeding and showing. Pedigreed cat breeding involves frequent interaction of cats, as well as people in contact with cats and with each other. It is also difficult to conceive that a pedigreed cat breeder and avid show participant would forego all the joys of raising and displaying their cats by avoiding all such interactions. The ultimate question is “now that cats are freed of FECV, what do you do with them?” What are the chances they will remain FECV free for any period after leaving a controlled environment? They will have no immunity to FECV and will be highly susceptible to the smallest of exposures. The same will be true of the group of cats from which they originated. Finally, the constant antiviral drug treatment required to maintain a group of cats free of FECV infection is likely to generate drug resistance. We now know that resistance to GS-441524 can occur in cats treated for FIP and researchers at both UC Davis1 and Cornell University ³ agree that the acquisition of drug resistance in enzootic FECV infections would outweigh any potential benefit of such treatment on the incidence of FIP. FIP is now curable in over 90% of cases,4 and even when antiviral drug resistance occurs, it is contained largely to the affected cat. It can be argued that HIV-1 infection of humans is now being prevented with antiviral drugs, with no advertised concern with drug resistance. However, HIV-1 prevention treatment is not a monotherapy, but involves several drugs of different classes. ³ This is done not to increase the efficacy of the treatment, but rather to prevent drug resistance. If a virus develops resistance to one drug in a mixture (cocktail) of drugs, it will be prevented from replicating by the others.
In conclusion, and to paraphrase, “just because something can be done, should it be done?” The author believes that much larger and better designed studies, done over a long period of time, are needed before this practice is even seriously considered. The overall incidence of FIP in smaller and well-maintained pedigreed catteries with enzootic FECV infection is usually below 1% and it is now possible to cure over 90% of FIP cases that might arise.4 Keeping the numbers of breeding cats and resultant kittens low, maintaining more older cats, not breeding individuals and bloodlines that have produced FIP cases, and minimizing the stresses of frequent introductions of new cats and housing/re-housing changes, is a practical way to lower FIP incidence. 1 Isolation and early weaning may also be useful in smaller catteries.