Clinical and molecular links between COVID-19 and feline infectious peritonitis (FIP)

Arjun N. Sweet, Nicole M. André, Alison E. Stout, Beth N. Licitra and Gary R. Whittaker
Julia A. Beatty, Academic Editor and Séverine Tasker, Academic Editor

Original article: Clinical and Molecular Relationships between COVID-19 and Feline Infectious Peritonitis (FIP)

Abstract

The emergence of Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) has led the medical and scientific community to address issues related to the pathogenesis and clinical presentation of COVID-19; however, relevant clinical models other than humans are still lacking. In cats, the ubiquitous coronavirus, described as feline coronavirus (FCoV), can manifest itself as feline infectious peritonitis (FIP) - the leading cause of mortality in young cats, which is characterized by severe systemic inflammation. The diverse extrapulmonary symptoms of FIP and the rapidly progressing course of the disease, together with a close etiological agent, represent a degree of overlap with COVID-19. This article discusses the molecular and clinical relationships between FIP and COVID-19. Although there are key differences between the two syndromes, these similarities support further investigation of feline coronaviruses as a naturally occurring clinical model for coronavirus disease in humans.

Keywords: feline infectious peritonitis, SARS-CoV-2, COVID-19, cats

1. Introduction

In the 1960s, feline infectious peritonitis (FIP) was described as a disease in domestic cats and was subsequently found to be of viral etiology, specifically feline coronavirus (FCoV). ^[1,2]. In most cats, FCoV infection results in mild to moderate clinical signs, but a small proportion of cats develop a serious illness and succumb to a systemic form of the disease known as FIP [3]. In the years since the discovery of FCoV, many features of FCoV have remained misunderstood. Similarly, the COVID-19 pandemic, caused by the occurrence of SARS-CoV-2, has raised many equally challenging issues regarding pathogenesis, transmissibility and treatment. Extensive FCoV / SARS-CoV-2 transmission and the inconspicuous onset of severe symptoms in both FIP and COVID-19 limit the possibility of early detection of the disease - what can only begin as mild or even mild clinical signs or symptoms can quickly lead to systemic disease. ^[3,4]. We believe that FIP may represent a valuable, naturally occurring extrapulmonary model of COVID-19.

Both FCoV and SARS-CoV-2 belong to the family Coronaviridae ^[4,5], although to different genera (Figure 1). FCoV, together with similar animal coronaviruses such as canine coronavirus (CCoV) and porcine gastroenteritis virus (TGEV), belong to the genus alpha-coronaviruses. Community respiratory (CAR) human coronaviruses 229E and NL63 are also included in the genus Alphacoronaviruses. ^[6], the latter being associated with the common cold, hail and possibly Kawasaki disease in children ^[7]. In contrast, SARS-CoV-2 together with SARS-CoV (the cause of the outbreak of severe acute respiratory syndrome in 2002-2003) and coronavirus Middle East Respiratory Syndrome (MERS-CoV) belong to the genus Beta-coronaviruses ^[8], wherein SARS-CoV-2 and SARS-CoV belong to line B (sarbecovirus) and MERS-CoV belong to line C (merbecovirus). Less related beta coronaviruses include human coronavirus CAR OC43 (associated with the common cold), mouse hepatitis virus (MHV), and bovine coronavirus, which is associated with pneumonia and diarrhea in cattle; these viruses are in line A (embekovirus).

FCoV can be classified in two ways, the first of which relates to the form of the disease. Feline enteric coronavirus (FECV) is thought to cause a mild gastrointestinal form of the disease, while feline infectious peritonitis virus (FIPV) is associated with a fatal systemic infection known as FIP. ^[3]. FIPV differs from FECV in its ability to infect and replicate efficiently in monocytes and macrophages ^[9], which causes systemic inflammation. FIPV is associated with a range of clinical consequences. At one end of the spectrum is an effusive or "wet" FIP that progresses rapidly and involves the accumulation of high protein exudate in the abdominal and / or thoracic cavity. At the other end of the spectrum is non-fusive or "dry" FIP, which can affect many organ systems, but is usually characterized by neurological and ocular symptoms. Non-fusive FIP generally has a longer course of the disease and is less common than its effusive counterpart. FCoV can also be divided into two serotypes - type I or type II - based on the major differences in viral spike protein that affect receptor binding and antibody response. ^[10]. The receptor for FCoV type II is feline aminopeptidase N (fAPN) ^[11], while the receptor for type I viruses is not identified. Type I FCoV accounts for the vast majority of FIP cases ^[12].

The classification of SARS-CoV-2 virus into different variants based on genetic mutations is still ongoing as the virus continues to evolve. Viral lines that show the potential for increased transmissibility, treatment resistance, vaccine resistance, or increased morbidity and mortality have been identified as VOCs. The spectrum of diseases associated with COVID-19 is broad, ranging from asymptomatic and mild infections to acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), and multiorgan failure and death. Systemic inflammation in SARS-CoV-2 is not associated with macrophages and monocytes (as in FIP), but is responsible for a wide range of extrapulmonary symptoms. The SARS-CoV-2 receptor, angiotensin converting enzyme-2 (ACE-2), which plays an important role in the renin-angiotensin system and the development of pro-inflammatory status, appears to be involved. ^[13]. Multisystem inflammatory syndrome (MIS) in children and adults, as well as the post-acute course of SARS-CoV-2 (PASC) infection, also known as "long COVID", are potential consequences of COVID-19 infection.

2. Transfer

As a group, coronaviruses are known for their ability to cause both respiratory and intestinal diseases and are usually transmitted in one or both ways. While FCoV is considered faecal-oral and SARS-CoV-2 is primarily respiratory, patients with COVID-19 may excrete the infectious virus in the faeces. ^[14], often for a long time, and FCoV can easily become infected by the oronasal route, which is a common method of experimentally vaccinating cats ^[15].

In most cases, FCoV infection is self-limiting, and although the virus can be detected systemically, replication outside the intestinal epithelium is weak. This form of the virus, referred to as FECV, is easily transmitted by the fecal-oral / oronasal route, with common anchors and swallowing of virus particles during purification being common sources of infection. The current understanding of FIP development involves internal mutation: in a small subset of FECV cases, a complex combination of host and viral factors leads to mutation (s) that allow efficient replication in macrophages and monocytes. ^[16]. These lethal variants are classified as FIPV and are associated with systemic inflammation, organ failure, and death. FIPV is generally considered non-transmissible because factors that increase its tropism on troprophages appear to limit its faecal-oral spread. ^[17]. FIP outbreaks were recorded in kennels and shelters. In these situations, congestion stress and high levels of virus in the environment may promote the conversion of FECV to FIPV. There is evidence that some FCoV strains may be more susceptible to this rebirth than others ^[18,19].

SARS-CoV-2 virus infection is primarily targeted at the respiratory epithelium, but as with FCoV, the virus may appear systemically without appropriate symptoms of infection. ^[20,21]. Asymptomatic individuals are a well-documented source of SARS-CoV-2 ^[22,23,24] and delivery includes inhalation of aerosols as well as contact with droplets ^[25]. The incubation times of SARS-CoV-2 and FECV range from 2 to 14 days ^[26]. The incubation time of FIP is highly variable, influenced by the time to internal mutation and the individual's immune response. The onset of FIP can occur several weeks to months after the initial infection ^{[27,28,29,30]}. Multisystem inflammatory syndrome in children (MIS-C), a severe manifestation of SARS-CoV-2, is also delayed by an initial infection with a median onset of 4 weeks. No viral factors have been associated with the development of MIS-C, but an immune-mediated component is thought.

Vertical transmission of FIP via the placenta or milk is considered rare. In the first experimental study in which a suckling cat was infected, one in four kittens succumbed to FIP ^[28]. Maternal antibodies appear to be effective in preventing transmission until approximately six weeks of age, when antibody levels decrease and kittens are susceptible to fecal-oral transmission. ^[31]. However, this maternally acquired immunity can be overcome at an early age by high levels of FCoV exposure - a Swiss study has shown that large kittens show infection at two weeks of age. ^[32,33]. Vertical transmission poses a risk of SARS-CoV-2 infection. Placental transmission is rare but has been documented in fetuses of SARS-CoV-2 infected mothers. ^[34,35,36], as evidenced by virus detection in amniotic fluid, neonatal blood, umbilical cord blood and placental tissue. Transmission cases have been documented in both early and late pregnancies, but infection of the neonate with SARS-CoV-2 may not always occur in the uterus. Infection can also occur during childbirth or in close contact with the mother. The neonatal outcomes of COVID-19 infected mothers remain under study, and it is difficult to distinguish between the effects of SARS-CoV-2 infection and maternal comorbidities. Nevertheless, neonatal infection does not appear to be without sequelae, with one analysis showing that approximately 50 % infected neonates exhibited COVID-19-related clinical symptoms, including fever and respiratory and gastrointestinal symptoms. ^[37].

3. General clinical presentation

Clinical signs associated with both FIP and COVID-19 include fever, diarrhea, depression, weakness, anorexia, and dyspnoea. ^[1]. Typical manifestations of COVID-19 commonly include non-specific symptoms including fever, dry cough, fatigue, dyspnea, and myalgia [38]. Anosmia (loss of smell) and ageusia (loss of appetite) have also been frequently reported in COVID-19 and are more specific symptomatic indicators of the disease. ^[39]. Pneumonia, acute respiratory distress syndrome (ARDS) and sepsis may occur. Men appear to be at higher risk of developing more severe manifestations of COVID-19 ^[40,41], with several small studies confirming the same relationship between males and the development of FIP in cats ^[42,43].

The classic manifestation of FIP is the formation of effusion in the abdomen and / or thoracic cavity; although this manifestation has also been reported in COVID-19 ^[44], is very rare. In addition, FIP is manifested in various bodily systems that are similar to the extrapulmonary manifestations of COVID-19 (Figure 2 and Figure 3). The most similar feature of both diseases is endothelial dysfunction. Vasculitis is a hallmark of FIP pathology ^[45,46] with lesions characterized by perivascular edema and infiltration, vascular wall degeneration and endothelial proliferation ^[47]. In the case of COVID-19, extrapulmonary symptoms are thought to be caused by virus-mediated endothelitis, which leads to vasculitis, especially in veins with minor arterioles ^[48,49]. In the following sections, we will describe these extrapulmonary symptoms and point out key similarities and differences.

4. Biomarkers

Inflammatory biomarkers are important as prognostic markers in COVID-19 and as a means of differentiating FIP from other diseases. In FIP, IL-6 expression appears to be increased in the ascitic fluid of FIP-infected cats, presumably through increased expression in the heart and liver. ^[50,51]. Other acute phase proteins are also elevated in FIP infection. Alpha-1-acid glycoprotein (AGP) has been studied as a diagnostic marker of FIP, but may be elevated in other conditions, thereby limiting its specificity. ^[52,53]. Serum amyloid A (SAA) is another acute phase protein that appears to distinguish between FIPV and FECV infection, with FIPV-infected cats showing higher levels of SAA compared to FECV-infected cats and control cats without SPF. ^[54], but has limited utility in distinguishing FIP from other effusive conditions ^[55].

As with FCoV, subjects with severe COVID-19 have higher SAA levels compared to subjects with milder COVID-19. ^[56]. Higher SAA levels are also reported in patients who died of COVID-19 compared with those who survived ^[57]. C-reactive protein (CRP) is another marker that has been shown to be a promising biomarker in both FCoV and SARS-CoV-2 infections. Liver CRP synthesis is induced by IL-6 expression in response to inflammation ^[58] and is increased in FIP cases ^[59]. Elevated CRP levels in the early stages of COVID-19 are associated with a more severe course of the disease and higher mortality ^[60,61,62], which led to the recommendation to use it as a prognostic indicator in risk assessment in patients hospitalized for COVID-19. In contrast, one meta-survey found that IL-6 levels were elevated, but at least one order of magnitude lower in patients with COVID-19 than in patients with ARDS and non-COVID-19-related sepsis, suggesting a different mechanism of immune dysregulation. ^[63].

The D-dimer, although not specific for COVID-19 or FIP, is another interesting biomarker. D-dimer is released upon fibrin breakdown and is used as a clinical tool to eliminate thromboembolism ^[64]. Thrombotic events have often been documented in COVID-19 in several organ systems ^[65,66] and elevated D-dimer levels are associated with higher morbidity and mortality ^[67,68]. Similarly, thrombotic events can occur in FIP, and high levels of D-dimers, along with other symptoms of disseminated intravascular coagulation (DIC), can be observed in the final stages of FIP in both natural and experimental infections. ^[69,70].

5. Pathophysiology

5.1. Neurological

FIP is one of the major infectious neurological diseases in cats and the symptoms associated with central nervous system (CNS) infection are well documented. ^[71]. CNS symptoms are reported in approximately 40 % cases of dry FIP and may manifest as nystagmus, torticollis, ataxia, paralysis, altered behavior, altered mentoring, and seizures ^[72]. The wide range of symptoms supports the conclusion that the infection is not limited to a specific part of the CNS ^[73]. CNS infection is restricted to the monocyte and macrophage lines and leads to pyogranulomatous and lymphoplasmacytic inflammation, which usually affects leptomening, choroidal plexus and periventricular parenchyma. ^[74].

Documentation of neurological symptoms associated with SARS-CoV-2 CNS infection is limited compared to other coronaviruses ^[75]. The symptoms observed range from headache and confusion to seizures and acute cerebrovascular events. ^[76]. Virus detection in the brain is rare, suggesting that symptoms may not be directly related to CNS infection. Viral particles have been observed in neural capillary endothelial cells and a subset of cranial nerves, although such detection does not correlate with the severity of neurological symptoms. ^[77]. There is often no clear evidence of direct infection. Instead, inflammatory mediators, such as activated microglia, have been reported to contribute to microvascular damage and disease. ^[78,79].

Further comparison of the neuroinflammatory properties of SARS-CoV-2 and FCoV may provide new insights into the neurological manifestations of COVID-19. Further understanding of the neurological symptoms associated with SARS-CoV-2 is necessary to understand the progression of COVID-19 and the extent of CNS infection.

5.2. Ophthalmological

Ocular manifestations of FIP are more common in the dry form of the disease ^[80]. Mydriasis, iritis, retinal detachment, conjunctivitis, hyphema and keratic precipitates have been observed ^[81]. The most common ocular manifestation of FIP is uveitis, which can affect both the anterior and posterior uvea ^[80]. Viral antigen can also be detected in epithelial cells of the nitrating membrane, but viral antigen detection does not distinguish between FECV and FIPV ^[82].

Ocular manifestations of COVID-19 include conjunctivitis, chemosis, epiphora, conjunctival hyperaemia, and increased tear production ^[83]. Uveitis - a common ocular presentation of FIP - has also been observed in SARS-CoV-2 infection ^[84,85]. Tear fluid virus detection has led to concerns about ocular transmission in the first months of the COVID-19 pandemic [83,86]. SARS-CoV-2 RNA was detected in tear secretions and was isolated from ocular secretions, supporting the possibility of ophthalmic transmission ^[87,88]. Interestingly, in the above case study in China, out of 12 patients with ophthalmic symptoms, only 2 patients returned positive conjunctival tests, suggesting limited sensitivity in detecting virus from conjunctival specimens. ^[83].

5.3. Cardiovascular

Pericardial effusion is a less common manifestation of FIP, but is well documented in the literature ^{[26,89,90,91]}. FCoV was detected in the pericardium of cats with recurrent pericardial effusion, which later developed neurological symptoms ^[92]. Direct FCoV infection of the heart was documented in a 2019 case study of FIP-associated myocarditis with severe left ventricular hypertrophy and atrial enlargement. ^[93]. Immunohistochemistry (IHC) revealed the presence of FCoV-infected macrophages and associated pyogranulomatous lesions. ^[26]. Interestingly, severe SARS-CoV-2 infection with evidence of viral replication in the heart and lungs has recently been documented in cats with pre-existing hypertrophic cardiomyopathy (HCM). ^[94].

Unlike FIP, heart damage associated with SARS-CoV-2 infection appears to be much more prevalent. A study of 187 patients found that 27.8 % cases of COVID-19 showed evidence of myocardial damage, as evidenced by elevated cardiac troponin (TnT) levels. ^[95]. High levels of TnT were in turn associated with higher mortality. In a retrospective multicenter study of 68 patients with COVID-19, 27 deaths were attributable to myocardial damage and / or circulatory failure as one of the leading causes of mortality, with elevated C-reactive protein and IL-6 levels associated with higher mortality ^[96]. The increase in such inflammatory biomarkers in the blood suggests that the rapid inflammatory nature of COVID-19 may have a particularly detrimental effect on heart function. Diffuse edema as well as increased wall thickness and hypokinesis have been reported with COVID-19 infection. ^[97]. Cardiac tamponade was also observed in patients with COVID-19, with SARS-CoV-2 levels detectable in pericardial fluid. ^[98]. In contrast to FIP, in which direct invasion of FCoV-infected macrophages into the myocardium was observed in myocarditis, myocardial infection with SARS-CoV-2 virus is not clearly associated with mononuclear cell infiltration or myocarditis. ^[99]. This leads to considerations of several systemic factors in adverse cardiac outcomes - especially dysregulation of inflammatory cytokines. The impact of SARS-CoV-2 infection on the cardiovascular system is an important element of our deepening understanding of COVID-19-related morbidity and mortality.

5.4. Gastroenterological

FCoV is excreted in the faeces and is transmitted oronasally. The initial FCoV infection is targeted to the intestinal tract - the infection may be subclinical or diarrhea may occur in cats and vomiting may occur less frequently. The primary infection lasts for several months and the virus can be excreted for months to years ^[100,101]. Colonic epithelial cells appear to serve as a reservoir for persistent infection and excretion. ^[21]. The symptoms tend to be mild and spontaneous and only a small proportion of the animals go into the FIP stage. Fibrinous serositis and pyogranulomatous lesions with vasculitis are classic FIP lesions and can be found in the small and large intestines of affected cats. ^[102]. FIP can cause solitary mass lesions in the intestinal wall, although this is considered a rare presentation (26/156 cats in one study) ^[103]. These are usually found in the colon or ileocecal junction and have a pyogranulomatous character.

Gastroenterological symptoms are often reported with COVID-19 infection. ACE2, the cellular receptor for SARS-CoV-2, is widely expressed in glandular cells of the gastric, duodenal and rectal epithelium. Viral RNA and nucleocapsid were detected in these tissues ^[104], which supports their suitability for SARS-CoV-2 replication. Gastrointestinal (GI) symptoms range from general anorexia to diarrhea, nausea, vomiting and abdominal pain ^[105,106]. Excluding a less specific anorexia symptom, multiple meta-analyzes estimate the prevalence of GI symptoms in patients with COVID-19 at approximately 10 % to 20 %, with diarrhea being the most commonly reported symptom. ^{[106,107,108]}. Interestingly, GI symptoms in COVID-19 were observed without accompanying respiratory symptoms ^[105].

Faecal virus excretion is a major concern for COVID-19, as SARS-CoV-2 RNA may continue to be present in faeces even after reaching undetectable levels in upper airway samples. ^[109]. Although the detection of viral RNA in faeces alone does not necessarily indicate the presence of infectious virions, viable viral particles have been detected in faeces. ^[110]. The viral antigen persists in the cells of the gastrointestinal tract as well as in the convalescent phase, up to 6 months after healing ^[20]. In one case study, persistent colon infection was associated with persistent gastrointestinal symptoms in “long COVID” ^[111], which draws a parallel to the role of the colon epithelium as a reservoir for FCoV.

5.5. Dermatological

Dermatological changes have been reported with both SARS-CoV-2 and FIPV infections. Although papular skin lesions are rare, they are the primary dermatological manifestation of FIP, with several available case reports documenting papules. ^{[81,112,113,114]}. On histological examination, pyogranulomatous dermatitis, phlebitis, periflebitis, vasculitis and necrosis were reported in several FIP cases. ^{[81,112,113,114,115]}.

The first report of dermatological manifestations associated with COVID-19 was recorded at Lecco Hospital in Lombardy, Italy ^[116]. In this study, 18/88 patients (20.4 %) developed a skin disorder, with 8/18 patients observed at the onset of the disease and 10/18 after hospitalization ^[116]. Clinical signs included erythematous rash (14/18 patients), diffuse urticaria (3/18 patients) and smallpox-like vesicles (1/18 patients) ^[116]. Lesions were observed mainly on the trunk (torsion) and pruritus was mild or absent ^[116]. The continuation of the pandemic brought better characteristics of the first observed dermatological symptoms, as well as the identification of rarer presentations. The most common dermatological manifestation of COVID-19 appears to be rash, often characterized by maculopapular lesions. ^[117,118]. Another predominant dermatological symptom also appears to be urticaria ^[118,119]. Importantly, neither rash nor urticaria is specific for COVID-19, which limits their positive predictive value. Varicella-like rash has been observed with SARS-CoV-2 infection and may be more specific due to its low prevalence in viral diseases. In particular, with missing lesions in the oral cavity and pruritus observed in COVID-19-associated rash, together with a previous history of varicella infection, the specificity of this presentation is reinforced. ^[118].

5.6. Teriogenological

Orchiditis and periorchitis with fibrinopurulent or granulomatous infiltrates as well as hypoplastic testes have been observed in several cases of FIP. ^[1,26,120]. Inflammatory mediators from the tuna surrounding the testicles caused enlargement of the testicles in cats with FIP ^[26,120]. In effusive FIP, enlargement of the spinal cord due to edema and peritonitis of tuna was observed ^[16]. Despite the apparent pathology of the male reproductive system in cats, FCoV has not been detected in sperm, which reduces the likelihood of sexual transmission. ^[121]. The pathology of the female reproductive system in FIP is less documented in the literature, but macroscopic lesions present in the ovaries of FIPV-infected cats have been observed. The surrounding uterine and ovarian vessels of these cats were surrounded by lymphocytes, macrophages, plasma cells and neutrophils. ^[122].

As with FIP, the pathology of COVID-19 is manifested in the male reproductive system. One study examining the testes of 12 COVID-19 patients found edema as well as lymphocyte and histiocytic infiltration, consistent with viral orchitis. ^[123]. These samples were also characterized by damage to the seminiferous tubules with a significant effect on Sertoli cells, as well as a reduced number of Leydig cells. In a separate study, germ cell damage was more pronounced despite similar Sertoli cell counts between SARS-CoV-2-infected individuals and uninfected controls, which represents a more direct relationship between infection and fertility. ^[124]. The extent to which SARS-CoV-2 may persist in the male reproductive tract is still being investigated. Although SARS-CoV-2 has been detected in human semen, it is questionable whether this is a true testicular infection or a consequence of a disrupted blood-epididymal / deferent barrier. ^[125,126].

Our knowledge of COVID-19 in the female reproductive system is still limited by the amount of literature and sample size of existing studies. Nevertheless, an understanding of the extent of SARS-CoV-2 in the female reproductive tract is essential to recognize any adverse effects on fertility. ACE2 is expressed in the ovaries, oocytes, and uterus, but limited coexpression of proteases such as TMPRSS2 and cathepsins L and B with ACE2 raises questions about the likelihood of ovarian / uterine infection. ^[127,128]. While in one study of 35 women diagnosed with COVID-19, SARS-CoV-2 was not detected in vaginal fluid or in exfoliated cervical cells, in a case study from Italy, SARS-CoV-2 was detected in vaginal fluid by RT-PCR ( Ct 37.2 on day 7 and Ct 32.9 on day 20 from the onset of symptoms), suggesting that infection of the female reproductive system is possible ^[129,130].

5.7. Immunological response

FIP is classically characterized as an immune-mediated disease based on early observations of complement and immunoglobulin circulation, even in the form of immune complexes. ^[131]. Components of type III and IV immune responses have been described ^[132]. Vasculitis and vasculitis-like lesions are thought to play a role in COVID-19 systemic complications that cannot be explained by direct organ infection, such as microthrombosis in the brain, kidney, spleen and liver. ^[133]. One type III hypersensitivity report has been identified in the COVID-19 literature ^[134]; however, immune complexes do not appear to play an important role in COVID-19 pathology. The mechanism of viral clearance and the inflammatory effects of the immune response are important areas of study for both FIP and COVID-19. Previous work investigating SARS-CoV has demonstrated the need for CD4 + T cells for virus clearance ^[135,136]. T-cell depletion was a recognized consequence of FCoV and was observed to be associated with more severe cases of COVID-19 ^{[137,138,139]}. In addition, FIP reduces both regulatory T cells and NK cells in the blood, mesenteric lymph nodes and spleen. ^[140]. High levels of IL-6 have previously been demonstrated in FIP ascites [50], and similarly, elevated levels of IL-6 appear to be related to disease severity and outcome in patients with COVID-19. ^[141]. The cytokine storm, characterized by overexpression of inflammatory cytokines, has been implicated in the pathogenesis of both infections. In FIP, this pathology is associated with monocyte and macrophage activation, while in COVID-19, the association with macrophages and monocytes is less clear. ^[142]. When considering the balance between cell-mediated immunity and humoral immunity, early reports suggested a link to strong humoral immunity leading to FIP ^[143]. However, humoral immunity may play a more beneficial role in patients with COVID-19 ^[144], especially given the potential clinical benefit of convalescent plasma / serum ^[145].

During the development of the SARS-CoV-2 vaccine, the antibody-dependent infection enhancement process (ADE), in which virus-antibody complexes enhance infection, was particularly important. FIPV has been shown to exhibit ADE in the presence of anti-FIPV antibodies ^[146]. This increase in infection appears to be serotype specific, with passive immunization of cats against FIPV type I or type II leading to ADE only after challenge with the same serotype for which the immunization was performed. ^[147]. As a result, ADE is a major challenge for the development of FIP vaccines. In diseases caused by human coronaviruses, ADE has yet to be fully understood. SARS-CoV has been found to have higher concentrations of anti-spike antibodies having a higher neutralizing effect, while more dilute concentrations are thought to contribute to ADE in vitro. ^[148]. In SARS-CoV-2, ADE was observed in monocyte lines but was not related to the regulation of pro-inflammatory cytokines ^[149]. Spike protein sequence modeling has identified possible ADE mechanisms that involve interaction with Fc receptors on monocytes and adipocytes ^[150]. If ADE played a role in SARS-CoV-2, the most likely mechanism would be overactivation of the immune cascade through Fc-mediated innate immune cell activation. ^[151,152]. There is currently insufficient evidence to suggest an ADE with the pathogenesis of SARS-CoV-2 and further research is needed to assess the true extent of the risk.

6. Molecular similarities between FCoV and SARS-CoV-2 spike proteins

Spike protein is a major factor in tissue and cell tropism and binds the cell receptor ^[153]. It is now well known that SARS-CoV-2 binds angiotensin converting enzyme-2 (ACE-2) as a primary receptor, a common feature of SARS-CoV. There are other binding partners for SARS-CoV-2, including heparan sulfate as a non-specific binding and neuropilin-1 (NRP-1), which may cause viral tropism for the olfactory and central nervous systems. ^[154,155]. In contrast, most alpha-virus viruses, including FCoV type II, use aminopeptidase (APN) virus entry. ^[9,153,156]. The receptor for FCoV type I has yet to be elucidated. The spike protein also mediates membrane fusion, which is activated by a complex process controlled by host cell proteases. ^[153]. While type I FCoV has two protease cleavage activation sites, designated S1 / S2 and S2 ′, type II FCoV has only one cleavage activation site (S2 ′). ^[10]. In comparison, SARS-CoV-2 is similar to FCoV-1 (and currently unique to SARS-related viruses) in that it has two identified cleavage sites (S1 / S2 and S2 ′), the first of which, the furin cleavage site or FCS is considered a significant factor in pandemic spread ^{[157,158,159]}. In both cases, the presence of S1 / S2 cleavage sites distinguishes FCoV-1 and SARS-CoV-2 from their close relatives. The importance of the cleavage activation site appears to be directly related to the proteases required for viral infection, and thus to another component of tissue tropism. In FCoV type I, the transition from FECV to macrophage-tropical FIPV was first demonstrated by amino acid substitutions at the S1 / S2 cleavage site in FIP-confirmed pathological specimens that are thought to reduce proteolytic priming of furin by similar proteases prior to S2-mediated fusion process activation. ^[72,160,161]. In SARS-CoV-2, TMPRSS-2 or other trypsin-like related proteases are a major activator of fusion and entry at S2 ′ ^[162] (Table 1), wherein the furin-like proteases prim the tip and S1 / S2 ^[163] and in particular have been shown to be rapidly regulated after adaptation to Vero E6 cells in culture and possibly also in extrapulmonary human tissues ^[164]. Thus, there appear to be remarkable similarities in host cell adaptation between the two viruses.

Virus	Group	Receptor	Consensus sequence S1 / S2 in circulating viruses	Consensus sequence S2 ′ in circulating viruses
SARS-CoV-2	Beta-coronavirus	ACE2	SPRRAR | S (* SHRRAR | S and SRRRAR | S)	SKPSKR | S
FCoV-1	Alphacoronavirus ("clade A")	unknown	SRRSRR | S (in FECV; mutated in FIPV)	KR | S
FCoV-2	Alphacoronavirus ("Clade B")	APN	absent	YRKR | S

7. Prevention and treatment: From social withdrawal to vaccines

Until now, the role of public health / public health measures has been a major driver in mitigating both the spread of FCoV and SARS-CoV-2. ^{[3,31,165,166]}. In this regard, many measures have been introduced for the affected population to reduce social distance, including orders to stay at home, the closure of unnecessary establishments and restrictions on public assemblies. ^[167]. Although not referred to as social distances, similar methods are often introduced or recommended in cat populations. ^[3]. Dreschler et al. summarize the methods that have been recommended in cat populations, especially in a multi-cat environment, including reducing the number of cats per room, frequent cage cleaning, and grouping cats according to excretion and / or serological status. ^[168]. Dreschler argues that quarantining cats exposed to FCoV / FIPV to limit the spread of FCoV in the population is neither effective nor beneficial given the likelihood of widespread FCoV infection in a multi-cat environment as well as the months required for development (and uncertainty in development) FIP. In contrast, quarantine people exposed to SARS-CoV-2 has the potential to reduce the spread of the disease and mortality ^[169]. Regardless of the extent of grouping or separation, the social difficulties caused by separation must be carefully considered for both cats and humans. In the case of cats, especially in connection with the premature weaning of their mothers, special attention must be paid in the weaning process to ensuring adequate socialization of the kittens. Similarly, in the case of COVID-19, the process of quarantine and / or isolation can be psychologically burdensome for individuals. A thorough cost-benefit analysis must often be carried out to compare the benefits of quarantine and isolation for public health with the negative psychological burden on the persons concerned in order to avoid unnecessary / ineffective quarantine. Where appropriate, justification as well as support to improve well-being should be provided ^[170].

Although the FIP vaccine is commercially available (Primucell), the benefit of FIP vaccination is still low. Primucell is an intranasal vaccine that uses an attenuated FIPV serotype 2 isolate. Although the FIP vaccine is commercially available (Primucell), the benefit of FIP vaccination is still low. Primucell is an intranasal vaccine that uses an attenuated FIPV serotype 2 isolate (FIPV-DF2), given in two doses 3 to 4 weeks apart to cats at least 16 weeks old. ^[171]. In a placebo-controlled experimental study in 138 cats, vaccinated cats did not show a significantly lower incidence of FIP compared to controls during the 12-month study period. After adjusting for FCoV titers, cats with lower antibody titers (100 or less) had a significantly lower incidence of FIP at the time of the first vaccination compared to cats with higher titers (400 or more). ^[172]. However, due to the high prevalence of FCoV, especially in multi-cat environments, attempts to alleviate FIP by vaccinating cats that are FCoV-naive at least 16 weeks of age may not be feasible due to the high potential for FCoV infection during the 16 weeks prior to vaccination. As a result, the American Association of Animal Hospitals and the American Association of General Practitioners for Cats do not recommend FIP vaccination. ^[173].

ADE remains a major problem for FIP vaccines. Several studies have attempted to reduce the incidence of FIP in experimentally infected cats with recombinant and other experimental vaccines, but ADE has been repeatedly reported. In one placebo-controlled study in which purebred British shorthair cats and non-specific pathogen-free (SPF) domestic shorthair cats were vaccinated with one of two recombinant FIPV type 2 vaccines (FIPV-DF2), both candidate vaccines showed significantly reduced to no challenge protection. FIPV in non-SPF cats - with most non-SPF animals showing ADE ^[174]. In a separate study, immunization of kittens with a vaccine virus recombined with the FIPV spike glycoprotein gene significantly shortened survival time after FIPV challenge compared to kittens immunized with wild-type vaccine virus. Importantly, low levels of neutralizing antibodies were observed in the group immunized against FIPV ^[175]. Concerns about ADE after FIPV immunization remain a challenging challenge in FIP prevention.

COVID-19 vaccines, in contrast to FIP vaccination, have played a more important role in reducing the spread of infection. Several types of vaccines have been produced that have been shown to be safe and effective in preventing symptomatic infection, serious illness and death from COVID-19 - including mRNA vaccines (Pfizer / BioNTech and Moderna), viral vector vaccines (Janssen, AstraZeneca) and inactivated viral vaccines. (Bharat Biotech, Sinovac) ^{[176,177,178,179,180,181]}. The first two vaccine platforms use the SARS-CoV-2 spike glycoprotein as the immunogen, while inactivated virus vaccines have the potential to elicit an immune response to viral components other than the spike glycoprotein. Despite the favorable safety profile of COVID-19 vaccines, adverse reactions occurred after vaccination, some of which were mediated by antibodies in analogy to ADE concerns with FIP vaccines. Thrombosis has been a documented problem, especially with AstraZeneca and Janssen vaccines. Although the exact mechanisms are being investigated, the inflammatory response is currently thought to lead to increased levels of platelet-activating antibodies, which bind to platelet factor 4 and lead to a hypercoagulable state. ^[182,183]. In contrast to the higher incidence of ADE in experimental FIP vaccines, the incidence of thrombotic events after administration of COVID-19 is low. ^[184].

In addition to the primary endpoints of vaccine studies, which focused on the prevention of symptomatic infection, serious illness, and death from COVID-19, many phase 3 vaccine studies did not address observations to assess the degree of prevention of asymptomatic infection. Beneficial efficacy against asymptomatic infection is important from a public health perspective, especially given that asymptomatic individuals can transmit COVID-19 and that routine monitoring testing is resource intensive and difficult to coordinate on a large scale. ^[22]. An important contribution to this area is real studies that examine the effectiveness of the vaccine, which shows a reduced risk of SARS-CoV-2 infection, as well as a reduced viral load in vaccine "breakthrough" infections. ^{[185,186,187,188]}. Such evidence supports the use of SARS-CoV-2 vaccines as a protective measure not only against severe COVID-19, but also as a crucial contribution in the management of the disease.

8. Clinical care and therapeutic options

In 1963, when the first clinical cases of FIP were described (before understanding the viral etiology), it was found that antibiotic treatment was often tried, but it clearly did not bring any benefit. ^[189]. Since this first report and without an effective vaccine, a number of therapies have been tried in cats with FIP. Ribavirin, a nucleoside analogue, has previously provided promising results against FCoV in an in vitro study ^[190], however, when administered to cats as an experimental treatment, led to poorer results in some cases ^[191]. Similarly, at the onset of the COVID-19 pandemic, ribavirin was used in several doses and in combination with other drugs. ^[192] and a study protocol was designed to examine the benefit in human patients ^[193]. However, another direct-acting antiviral drug (DAA) (remdesivir), a nucleoside analogue that acts as a chain terminator and raises minor toxicity concerns compared to ribavirin, is rapidly gaining prominence in the treatment of hospitalized patients with COVID-19. . Despite initial enthusiasm, remdesivir has not been shown to be effective in patients with such diseases in robust clinical trials; however, several reports have demonstrated the clinical benefit of the related nucleoside analog GS-441524 in the treatment of cats with FIP, including effusive, non-fusive, and neurological forms of the disease. ^{[194,195,196,197]}. At the time of writing, studies on the effectiveness of remdesivir in the treatment of FIP are being conducted in Australia and the United Kingdom. Interestingly, remdesivir is a prodrug form of GS-441524 [195]. Two orally available DAAs have recently entered clinical trials for COVID-19 and are currently awaiting FDA approval; molnupiravir (MK-4482 / EIDD-2801), a modified form of ribavirin, and Paxlovid (a protease inhibitor PF-07321332 in combination with ritonavir, which improves the half-life of PF-07321332) targeting the major protease (Mpro). It is noteworthy that the active substance Paxlovid is related to GC-376 and has previously been shown to be effective in a FIP clinical study. ^[196]. It will be very interesting to follow the development, FDA approval and use of these DAAs in relation to the relevant diseases caused by SARS-CoV-2 and FCoV.

Due to the inflammatory nature of both FIP and COVID-19, treatment often focuses on controlling the immune response. Although cats with FIP are often given glucocorticoids in an effort to alleviate the inflammatory symptoms of the disease, the clinical benefit is negligible. ^[198]. The use of corticosteroids in patients with COVID-19 does not appear to be insignificant, with some studies showing negative profiles ^[199]. However, their administration may be beneficial in severe cases of COVID-19 through the observed reduction in mortality ^[200,201]. Cyclosporine, an immunosuppressive drug that is often used to prevent organ rejection in transplant patients and to treat some autoimmune diseases, has been studied in both FIP and SARS-CoV-2. An in vitro study with cyclosporin A (CsA) using FCoV type II virus showed a reduction in virus replication ^[202], treatment of a 14-year-old cat CsA after unsuccessful IFN treatment resulted in clinical improvement, reduction in viral load and survival of more than 260 days ^[203]. Although there are currently no controlled studies on the use of CsA in the treatment of patients with COVID-19, in addition to safety concerns, potential mechanisms of action have been suggested. ^{[204,205,206]}. In addition, the cyclosporin A analogue, alisporivir, has shown in vitro effects on virus replication ^[207], similar to evidence that cyclophilin A blockade inhibits the replication of other coronaviruses ^[208].

Many antibiotics have been prescribed for both FIP and COVID-19, but not for their antimicrobial properties, but rather for their anti-inflammatory effects. ^[198]. For example, doxycycline may have helped prolong survival in cats with FIP ^[209]. Whether doxycycline would be of benefit to patients with COVID-19 is not currently known, but has been suggested as a possible part of the treatment of the disease. ^[210].

Interferons have also been studied in the treatment of FIP without a clear link to clinical improvement ^[211]. In human patients with COVID-19, combination therapy with interferon-β-1b with lopinavir, ritonavir and ribavirin compared with lopinavir and ritonavir alone was associated with a reduced duration of virus excretion and improved clinical outcomes in mild to moderate cases. ^[212].

Monoclonal antibodies targeting components of the immune response have the potential to reduce inflammatory cytokine levels. A small study in cats experimentally infected with FIPV-1146 demonstrated the benefit of anti-TNF-α in managing the disease ^[213]. Tocilizumab, an anti-IL-6 monoclonal antibody, was administered to patients with COVID-19 [214]. Due to the different clinical results reported, further research is needed with Tocilizumab ^[215,216].

The transfer of knowledge between species will undoubtedly affect cats as well as humans and even other species. Although many compounds are effective when studied in vitro, their use in vivo can lead to different results, including toxicity. In addition, the fact that a compound may show promising results in one species does not mean that the same effect will be observed in other species, especially when comparing similar but different viruses and virus-induced diseases.

9. MIS-C and PASC

In April 2020, the UK National Health Service issued a warning of the increased incidence of multisystem inflammatory syndrome in children - many of whom tested positive for COVID-19. ^[217]. As the pandemic progressed, studies from other countries examining this inflammatory condition provided more detail towards a clinical understanding of what is now referred to as MIS-C, a rare presentation of COVID-19 in pediatric patients. MIS-C includes several organ systems. Cardiovascular dysregulation in MIS-C is often observed in the form of ventricular dysfunction, pericardial effusion and coronary artery aneurysms ^[218,219]. Gastrointestinal symptoms mimic appendicitis and include abdominal pain, vomiting, and diarrhea. Terminal ileitis is a common finding on imaging tests ^[220]. Many patients also experience neurocognitive symptoms, including headache and confusion. More serious neurological complications, including encephalopathy and stroke, are less common ^[218,221].

One of the areas in which FIP and COVID-19 overlap clinically significantly is the rare inflammatory manifestation of SARS-CoV-2 infection, a multisystem inflammatory syndrome in children (MIS-C). MIS-C is observed in the pediatric population, as FIP commonly affects young cats ^[43]. Like FIP, MIS-C has a systemic presentation involving multiple organ systems - including gastrointestinal, cardiovascular and hematological abnormalities. ^[222]. As with the wet form of FIP, pleural effusions and ascites occur in MIS-C. ^[223]. Both syndromes also show overlap in vascular pathology. FIP shows granulomatous vasculitis, which overlaps with Kawasaki vascular syndrome observed in MIS-C ^[224]. MIS-C is thought to be a post-infectious disease associated with a previous SARS-CoV-2 infection ^[223,225]. FIP also has a delayed onset after the first FCoV exposure and occurs only in a small subset of cases. Although cats with FIP may still secrete FCoV in the faeces, mutations associated with biotype transition from FECV to FIPV are thought to be non-transmissible - supporting a degree of similarity in the limited infectious extent of both FIP and MIS-C.

Recently, the post-acute sequelae status of COVID-19 (PASC) has been defined, which includes memory loss, gastrointestinal distress, fatigue, anosmia, dyspnea, etc. and is more commonly referred to as "long-term COVID". Together with MIS-C, PASC is a very active subject of research, summarized by others ^[226], and together represent an excellent starting point for the use of feline medicine as a model of coronavirus-induced pathogenesis, possibly in an unexpected way ^[224].

10. SARS-CoV-2 infection in cats

Cats have now become widespread hosts for SARS-CoV-2 infections, in part due to the relative similarity of human and feline ACE2 receptors. Following cases reported in Hong Kong and Belgium in March 2020, the most notable early natural infection occurred at the Bronx Zoo in New York City, USA. In April, four tigers and three lions showed mild respiratory symptoms from their breeders, and SARS-CoV-2 was detected by PCR and sequencing. ^[227]. Consequently, infection of both domesticated and non-domesticated cats has become relatively common in cases where owners and caregivers are positive for SARS-CoV-2. From a clinical point of view, SARS-CoV-2 infection in cats is considered to be predominantly asymptomatic, with some animals showing mild respiratory symptoms. ^{[228,229,230]}. In general, severe respiratory symptoms do not appear to occur in cats, although severe respiratory distress may in some cases be related to the underlying hypertrophic cardiomyopathy (HCM) of cats. ^[94]. An increased incidence of myocarditis in dogs and cats has also been reported in the United Kingdom, associated with a sharp increase in variant B.1.1.7 (Alpha). ^[231]. There is a clear need for further studies in this area, as well as possible links between coronavirus infections in cats and multisystem inflammatory syndrome in children (MIS-C), which, as mentioned above, is a rare manifestation of COVID-19.

Laboratory animal studies have also been key to understanding SARS-CoV-2 infection in cats, which are very susceptible to infection by oronasal challenge. Experimentally infected cats showed mild respiratory symptoms or asymptomatic infection, virus shedding, virus-to-cat virus transmission, and a strong neutralizing antibody response. Recent studies have shown that long-term immunity exists after re-infection of cats, but cats may develop long-term consequences, including persistence of inflammation and other lung lesions. ^[232]. Overall, as with SARS-CoV in 2003, cats in particular can be an important source of information on the pathogenesis and immune responses elicited by SARS-CoV-2.

Thanks

Thanks to Annette Choi for helping with Figure 1 and all Whittaker Lab members for helpful discussions during the preparation of this manuscript.

Author shares

All authors have contributed to this article. All authors have read and agreed to the published version of the manuscript.

Financing

The work in the author's laboratory is partly funded by research grants from the National Institutes of Health, the EveryCat Foundation and the Cornell Feline Health Center. AES was supported by the NIH Comparative Medicine Training Program T32OD011000. Studies on FIP are also supported by the Michael Zemsky Fund for Cat Diseases.

Conflict of interests

The authors do not indicate any conflict of interest.

Footnotes

Publisher Note: The MDPI remains neutral in terms of jurisdictional claims in published maps and institutional affiliation.

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