Feline Infectious Peritonitis (FIP) and COVID-19: What Do They Have in Common?

Are coronaviruses that infect different host species really that distinct? The recent COVID-19 pandemic has turned the spotlight on a large family of viruses that infect all kinds of animals. Researchers set out to compare the feline coronavirus responsible for feline infectious peritonitis (FIP) with SARS-CoV-2. We take a look at their similarities and differences and the implications for current research.

  SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been making headlines for nearly a year now. The emergence of this virus in humans has radically disrupted our lives, altering our habits and claiming hundreds of thousands of lives. But this is only the tip of the iceberg. It is part of a large family of viruses that infects a myriad of different animals. In the quest for answers and solutions to combat the virus, researchers have turned to insights gained from veterinary medicine regarding the virus’s close relatives. In particular, they have focused on the feline coronavirus (FCoV), which causes feline infectious peritonitis (FIP)—a fatal disease in cats, especially young kittens. According to estimates, it kills up to 1.4% of infected cats worldwide. Information on FCoV could provide context and shed light on certain aspects of SARS-CoV-2 pathogenesis that remain unclear. Here, then, is an overview of the similarities and differences between these coronaviruses.  

Viral Origin

New coronavirus emerge through a recombination mechanism that allows existing strains to fuse and mix, generating new variants capable of infecting species other than their natural reservoir. Genomics and phylogenetic analyses have identified the recombination events that led to the emergence of new CoV species in numerous animal species. Coronaviruses from bats have thus been identified as the ancestors of several CoVs found in pigs, ruminants, birds, and rodents. This is also the case for SARS-CoV-2 and FCoV. SARS-CoV-2 belongs to the genus Betacoronavirus. It is a completely new virus that is believed to have originated from recombination events between CoVs from other species—notably bats—according to the most recent information, potentially via an intermediate host such as the pangolin. In contrast, FCoV belongs to the genus Alphacoronavirus. Two types are currently known: FCoV serotype I and FCoV serotype II. The ancestor of FCoV type I is unknown, but it is known that Alphacoronaviruses likely originate from bats. FCoV type II resulted from a double recombination between FCoV type I and canine coronavirus (CCoV). Although the two serotypes show no difference in pathogenicity, FCoV serotype I remains the most prevalent strain detected in field cases of feline infectious peritonitis. Unlike in other animal species, the number of viral variants in cats is very limited, likely because FCoVs in domestic cats have limited interaction with CoVs from other animal species. Or perhaps due to the social characteristics of feral cats, which tend to have few interspecific interactions. However, despite the low frequency of recombination with other CoVs, FCoV exhibits high variability within the feline population. The mutation rate is very high, and the high rate of FCoV replication in the intestines of infected cats leads to the generation of “quasi-species” in each cat. Some of these new variants may carry mutations that, if associated with a specific immune response in infected cats, are likely to play a key role in the pathogenesis of feline infectious peritonitis. Several variations have also been reported in SARS-CoV-2. However, information on the genetic heterogeneity of SARS-CoV-2 strains is not currently considered conclusive, but rather preliminary and hypothesis-generating. Further studies on the genetic diversity of SARS-CoV-2 populations are needed.    

Epidemiology

Various coronaviruses tend to be highly contagious and spread rapidly within susceptible populations. SARS-CoV-2 and FCoV are no exception. However, their epidemiological patterns differ. Based on current information, the spread of SARS-CoV-2 more closely corresponds to an epidemiological/pandemic profile. In contrast, FCoV—like at least four common human coronaviruses (hCoVs-229E, -NL63, -OC43, and -HKU1) and nearly all bat coronaviruses—follows a more endemic pattern. The number of asymptomatic infected individuals is high, with a lower mortality rate. Today, the proportion of FCoV RT-PCR-positive and/or seropositive cats in a multi-cat household often approaches 100%. In this latter situation, the infection rate depends on the partially protective immunity that cats can develop, which allows them to periodically clear the infection. However, once local immunity wanes, cats can become reinfected, which helps maintain the infection in the environment and among populations. It is unlikely that SARS-CoV-2 will be eradicated and that the infection will enter an endemic phase. But if this scenario were to occur, based on the FCoV model, there is a risk of additional outbreaks of epidemic infection (as occurs in cats when FCoVs enter catteries with low endemicity), as well as a risk of future viral mutations that could alter its virulence.  

Pathogenesis

  Although the virological and epidemiological aspects of FCoV and SARS-CoV-2 infection share common characteristics, their pathogenesis appears to differ. This difference begins at the level of cellular entry. SARS-CoV-2 binds to the human ACE2 receptor. While there is a resemblance between human and feline receptors that would suggest a possible SARS-CoV-2 infection in cats, such cases have been rare. FCoVs bind to different receptors, including fAPN for serotype II, and utilize different membrane molecules. At first glance, the cellular tropism of the two viruses also appears to differ. FCoV is a systemic disease affecting various organs, whereas SARS-CoV-2 appears to primarily affect the lungs. However, the orally transmitted-fecal route can also be a transmission pathway for SARS-CoV-2, just as FCoV can cause mild gastrointestinal symptoms. However, when SARS-CoV-2 mutates, it becomes capable of replicating in macrophages and thus spreads throughout the host, leading to feline infectious peritonitis. Despite these differences, severe acute systemic inflammatory response syndrome (SIRS) is common in both COVID-19 and feline infectious peritonitis (FIP) . Cats can harbor FCoV without showing clinical signs for years, but when feline infectious peritonitis (FIP) develops, the innate immune response is rapidly activated. The immune response leads to an overproduction of pro-inflammatory cytokines responsible for severe clinical and biological changes—a “cytokine storm” also observed in patients with COVID-19. This cytokine storm can lead to fatal multi-organ failure in these patients. Anti-cytokine immunotherapies appear to show promising results against this inflammatory surge. This type of treatment has never been studied in cats, primarily due to cost or the unavailability of drugs approved for felines. However, the good clinical response of cats to steroidal anti-inflammatory drugs supports the hypothesis that suppressing the hyperinflammatory response could temporarily improve their clinical condition. While this is not a complete cure for feline infectious peritonitis (FIP), due to its unique immunopathogenic mechanisms, it may provide COVID-19 patients with valuable time to activate the antiviral immune response or, hopefully, to enhance the effect of antiviral drugs.    

Clinical Signs

FCoV can induce a wide spectrum of clinical and biological changes, ranging from mild gastrointestinal disease without specific biological abnormalities (FECV) to severe and invariably fatal systemic disease (feline infectious peritonitis). Feline infectious peritonitis can present in two main clinical forms, which may sometimes overlap:

• the wet form, characterized by the accumulation of protein-rich fibrinous fluid in body cavities, leading to symptoms consistent with severe, acute hypovolemia and/or organ compression in the affected cavity
• the dry form, which depends on the primary site of granulomatous lesion formation (the kidneys, liver, lungs, intestines, but most commonly in the eye or central nervous system)

In both forms, fever, depression, asthenia, emaciation, as well as anemia, lymphopenia, or elevated serum levels of globulin fractions and acute-phase proteins are commonly observed. Conversely, the most common clinical presentation of COVID-19 involves severe acute respiratory distress associated with interstitial pneumonia, although neurological, hepatic, and gastrointestinal manifestations have been reported in infected patients.  

Diagnosis

Because clinical signs and laboratory findings vary among coronaviruses, the diagnostic approach to the disease differs. No molecular or serological test can distinguish between virulent and non-virulent strains of feline infectious peritonitis (PIF). Consequently, RT-PCR or serology can confirm the infection but not the disease. Only the detection of the virus in the effusion or within lesions can confirm the disease. These challenges do not appear to arise in patients with COVID-19. An RT-PCR swab test is sufficient to make a diagnosis, even for asymptomatic patients.    

Prevention

A feline infectious peritonitis/FCoV vaccine has been developed and marketed, but it is available only in a few countries. This is because there is ongoing debate regarding the risk of stimulating excessive antibody production, which may induce the disease rather than prevent it. For this reason, the World Small Animal Veterinary Association does not recommend this vaccine for feline infectious peritonitis. Several research institutes and pharmaceutical companies are currently working on developing a vaccine to prevent SARS-CoV-2 infection, and approximately 200 vaccine candidates are in various stages of testing. Since the genetic diversity of SARS-CoV-2 strains is lower compared to FCoV, and the humoral immune response appears to be only partially involved in the pathogenesis of COVID-19, vaccination could be a promising preventive tool. In the absence of an effective vaccine, the primary preventive measure adopted worldwide to contain and eventually eradicate SARS-CoV-2 infection relies on isolation and social distancing. To date, these measures have significantly reduced the infection and mortality rates associated with the virus. A similar approach has already been recommended for cats. Although these measures have proven effective in managing the infection within individual catteries, their overall effectiveness has been compromised by the lack of common rules imposed on all cat owners by regulatory agencies. Isolation/quarantine strategies must be implemented on a large scale, as public authorities in many countries are doing for COVID-19.  

Treatment

Although feline infectious peritonitis (FIP) has historically been considered an inevitably fatal disease and no effective medication has been available for decades, effective treatments have recently been developed with promising results. For a long time, cats with feline infectious peritonitis received only supportive or anti-inflammatory treatment, which often improved their quality of life without eliminating the infection or halting the disease’s immunopathogenesis. This is also the approach taken for COVID-19 patients, for whom most therapeutic efforts focus on managing acute respiratory distress or modulating inflammatory responses. Stimulating immunity with interferon in cats with feline infectious peritonitis remains one of the most commonly used therapeutic approaches. The use of interferon against COVID-19 in combination with other molecules (ribavirin) is currently under investigation. However, the therapeutic approach for cats with feline infectious peritonitis has been revolutionized in recent years with the introduction of the peptidomimetic GC-376 and the nucleoside analog GS-441524, both of which are capable of inhibiting FCoV replication in different ways. Although GS-441524 is not approved for use in cats in many countries, this treatment is now widely used. GS-441524 is also the active ingredient in Remdesivir, which has shown promising results against COVID-19. More recently, it has been demonstrated that Mutian® Xraphconn (Mutian X), containing inotodiol—an anti-inflammatory sterol of fungal origin—completely and rapidly eliminates FCoV from the intestines of infected cats, likely by reducing viral replication.    

Why Compare Coronaviruses

FCoV and SARS-CoV-2 share certain characteristics. Both coronaviruses spread rapidly within a population, but their infection rates decrease when infected patients are isolated. Furthermore, common anti-inflammatory or antiviral treatments appear to be effective against these viruses. However, FCoV and SARS-CoV-2 are not identical in every respect. The biology of the viruses, their target cells, pathogenesis, and clinical characteristics differ. Nevertheless, years of research on the cat virus clearly show that deepening our understanding of the virus’s biology and host-virus interactions improves our chances of containing and, eventually, combating the infection. The information obtained to date has already helped us gain a head start against SARS-CoV-2 by serving as a springboard for the rapid, targeted development of preventive or therapeutic strategies against COVID-19. By furthering comparative studies among the various known coronaviruses, it is highly likely that new insights or effective strategies will emerge. TABLE 1. Comparison between FCoV/SARS-CoV-2 infection and FIP/COVID diseases

		FCoV/FIP	SARS-CoV-2/COVID-19
Virology	Genus	Alphacoronavirus	Betacoronavirus
	Presence of serotypes/clades/strains	Yes (serotypes I and II)	Yes (research ongoing)
	Origin	Serotype I: unknown (alphacoronaviruses likely originate in bats)	Suggested spillover from other species (bats, pangolins)
		Serotype II: recombination of FCoV I and CCoV
	Cell Receptor	Serotype I: Unknown (possibly fDC-SIGN)	ACE2 receptor
		Serotype II: fAPN (possibly also fDC-SIGN)
	Mutation frequency	High (quasispecies)	Mutations reported; research ongoing (suggested groups with different levels of virulence)
Epidemiology	Transmissibility	High	High
	Epidemiological pattern	Epidemic → endemic	Epidemic (to date)
	Reinfections	Frequent	Rarely reported (to date)
	Model of infection	SIS (susceptible-infected-susceptible)	Unknown (to date)
	Lethality	Epidemic phase: high; Endemic phase: low	Epidemic phase: high
Pathogenesis	Route of infection	Fecal–oral	Respiratory (oral not excluded)
	Cellular tropism	Enterocytes, monocytes/macrophages	Alveolar macrophages, enterocytes
	Role of mutated viral variants	Probable	Postulated
	Main target organs	FECV: intestine, FIPV: multiple organs/tissues	Lung (less frequently GI tract or other organs)
	Lesions	Granulomatous lesions, vasculitis, and effusions; lymphoplasmacytic infiltrates	Cytopathic effect on lung cells, multinucleated syncytial cells, mononuclear infiltrates
Immunopathogenesis	Type III hypersensitivity	Demonstrated	Postulated
	T-cell lymphopenia	Demonstrated	Demonstrated
	ADE	Hypothesized	Hypothesized
	Cytokine storm/SIRE	Demonstrated	Demonstrated
Prevention	Vaccination	Available but not recommended (risk of ADE)	Not available
	Quarantine/isolation	May eradicate the disease from catteries	May reduce the prevalence of infection/disease
Treatment	Symptomatic medications	Effective as supportive therapy	Effective and curative in mild cases
	Anti-inflammatory drugs	Effective as adjunctive therapy	Possibly curative
	Anti-cytokine drugs	Not tested	Effective, curative in mild cases
	Hyperimmune plasma	Not tested	Possibly curative
	Interferon or Th1 modulators	Rarely effective	Studies in progress
	Antiviral drugs	Effective in a few clinical trials (GS-441524, GS-5734, Xraphconn)	Possibly effective (GS-5734)

• Abbreviations: ACE2, angiotensin-converting enzyme 2; ADE, antibody-dependent enhancement; CCoV, canine coronavirus; fAPN, feline aminopeptidase N; FCoV, feline coronavirus; fDC-SIGN, C-type lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin; SIRE, systemic inflammatory response syndrome.