Feline infectious peritonitis (FIP) is a highly fatal viral disease of cats with a worldwide incidence. Several antiviral agents have recently been shown to be promising in the treatment of cats with FIP. Despite these findings, there is currently no legal FIP treatment approved by the Food and Drug Administration (FDA), so many owners turn to unlicensed antivirals purchased online. Due to the ongoing COVID-19 pandemic, several antiviral drugs have recently been approved for oral use in human patients. One of these antivirals is the nucleoside analog EIDD-2801 (molnupiravir). EIDD-2801 causes hypermutation of developing viral RNA, effectively terminating the viral replication of many different RNA viruses. This antiviral agent has been developed for oral use in human patients at home. The use of EIDD-2801 in human medicine may facilitate veterinary use. An orally administered antiviral compound would be advantageous for the treatment of cats with FIP administered to a client. We will determine the effective oral dosage of EIDD-2801 and evaluate the efficacy of this compound in the home treatment of cats owned by a client with naturally occurring effusive FIP.
Feline coronaviruses (FCoV) are found in the intestines of most domestic cats and usually do not cause any problems. Unfortunately, under certain circumstances, they can move into the immune cells in the blood and mutate, causing infectious feline peritonitis (FIP). Unfortunately, FIP affects 5-10 % domestic cats, especially young breeding cats and cats in rescue centers. Until recently, she was always deadly.
FIP is a mysterious and dreaded disease; in addition to the fact that its cause is not sufficiently known, it is difficult to reliably diagnose it and, until recently, it has responded poorly to all treatments. However, COVID-19 has resulted in the development of Remdesivir and its co-drug GS-441524, and these drugs appear to be remarkably effective and have, in preliminary studies, cured> 70 % cats with FIP after 12 weeks of treatment. Unambiguous diagnosis is becoming increasingly important nowadays.
Accurate diagnosis has long been a holy grail for FIP research: our goal is to i) examine the profile of certain proteins in the blood (known as acute phase or APP proteins) that increase in response to infection ii) while focusing for the first time on the potential role of micro -RNA (miRNA) signatures, which could prove successful in a new and sensitive diagnostic test.
We hope that this study will allow us to better understand FIP and diagnose it more accurately. We also hope to be able to identify which profiles suggest that the cat will respond well to treatment and which will not, thus saving it from the suffering associated with FIP and the potential inconveniences associated with treatment that will not help it.
The emergence of severe acute respiratory syndrome 2 (SARS-CoV-2) has led the medical and scientific community to address questions regarding 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 as feline infectious peritonitis (FIP), a leading cause of mortality in young cats characterized by severe systemic inflammation. The diverse extrapulmonary symptoms of FIP and the rapidly progressive course of the disease, together with the proximate etiologic agent, represent a degree of overlap with COVID-19. This article reviews the molecular and clinical relationships between FIP and COVID-19. Although there are key differences between the two syndromes, these similarities encourage further investigation of feline coronaviruses as a naturally occurring clinical model for human coronavirus disease.
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, infection with FCoV results in mild to inconspicuous clinical signs, but a small proportion of cats develop severe disease and succumb to the systemic form of the disease known as FIP . In the years since the discovery of FCoV, many features of FCoV have remained misunderstood. Similarly, the COVID-19 pandemic, caused by the emergence of SARS-CoV-2, has raised many equally challenging questions regarding pathogenesis, transmissibility, and treatment. The widespread transmission of FCoV/SARS-CoV-2 and the insidious onset of severe symptoms in both FIP and COVID-19 limit the ability to detect the disease early—what may 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. , the latter being associated with the common cold, hail and possibly Kawasaki disease in children . In contrast, SARS-CoV-2, together with SARS-CoV (the causative agent of the severe acute respiratory syndrome outbreak in 2002-2003) and the Middle East respiratory syndrome coronavirus (MERS-CoV) belong to the genus betacoronaviruses , 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. . FIPV differs from FECV in its ability to infect and replicate efficiently in monocytes and macrophages , causing systemic inflammation. FIPV is associated with a spectrum of clinical sequelae. At one end of the spectrum is effusive or “wet” FIP, which progresses rapidly and involves the accumulation of a highly proteinaceous exudate in the abdominal and/or thoracic cavity. At the other end of the spectrum is non-effusive or “dry” FIP, which can affect many organ systems but is usually characterized by neurological and ocular symptoms. Non-effusive FIP generally has a longer course of disease and is less common than its effusive counterpart. FCoV can also be divided into two serotypes – type I or type II – based on major differences in the spike protein of the virus that affect receptor binding and antibody response . The receptor for FCoV type II is feline aminopeptidase N (fAPN) , while the receptor for type I viruses is not identified. Type I FCoV accounts for the vast majority of FIP cases .
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. . Multisystem inflammatory syndrome (MIS) in children and adults, as well as the post-acute course of SARS-CoV-2 infection (PASC), also known as "long COVID", are potential consequences of infection with COVID-19.
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. , often for a long time, and FCoV can easily become infected by the oronasal route, which is a common method of experimentally vaccinating cats .
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. . 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. . 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 . The incubation times of SARS-CoV-2 and FECV range from 2 to 14 days . 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 . 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. . However, this maternally acquired immunity can be overcome early in life by high levels of exposure to FCoV – a Swiss study showed that kittens in large herds show infection as early as 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. .
3. General clinical presentation
Clinical signs associated with both FIP and COVID-19 include fever, diarrhea, depression, weakness, anorexia, and dyspnoea. . Typical manifestations of COVID-19 commonly include non-specific symptoms including fever, dry cough, fatigue, dyspnea, and myalgia . 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. . 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 , 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 . 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.
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. , but has limited utility in distinguishing FIP from other effusive conditions .
As with FCoV, subjects with severe COVID-19 have higher SAA levels compared to subjects with milder COVID-19. . Higher SAA levels are also reported in patients who died of COVID-19 compared with those who survived . 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  and is increased in FIP cases . 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. .
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 . 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].
FIP is one of the major infectious neurological diseases in cats and the symptoms associated with central nervous system (CNS) infection are well documented. . 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 . The wide range of symptoms supports the conclusion that the infection is not limited to a specific part of the CNS . 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. .
Documentation of neurological symptoms associated with SARS-CoV-2 CNS infection is limited compared to other coronaviruses . The symptoms observed range from headache and confusion to seizures and acute cerebrovascular events. . 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. . 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.
Ocular manifestations of FIP are more common in the dry form of the disease . Mydriasis, iritis, retinal detachment, conjunctivitis, hyphema and keratic precipitates have been observed . The most common ocular manifestation of FIP is uveitis, which can affect both the anterior and posterior uvea . Viral antigen can also be detected in epithelial cells of the nitrating membrane, but viral antigen detection does not distinguish between FECV and FIPV .
Ocular manifestations of COVID-19 include conjunctivitis, chemosis, epiphora, conjunctival hyperaemia, and increased tear production . 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. .
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 . 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. . Immunohistochemistry (IHC) revealed the presence of FCoV-infected macrophages and associated pyogranulomatous lesions. . 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). .
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. . 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 . 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. . Cardiac tamponade was also observed in patients with COVID-19, with SARS-CoV-2 levels detectable in pericardial fluid. . 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. . This leads to considerations of multiple systemic factors in adverse cardiac outcomes – particularly dysregulation of inflammatory cytokines. The impact of SARS-CoV-2 infection on the cardiovascular system is an important element in our increasing understanding of the morbidity and mortality associated with COVID-19.
FCoV is excreted in feces and transmitted by the oronasal route. Initial FCoV infection targets the intestinal tract – infection may be subclinical or cats may develop diarrhea and, less commonly, vomiting. The primary infection lasts for several months and the virus can be shed for months to years [100,101]. Colonic epithelial cells appear to serve as a reservoir for persistent infection and excretion. . 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. . FIP can cause solitary mass lesions in the intestinal wall, although this is considered a rare presentation (26/156 cats in one study) . 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 , 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 .
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. . 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. . The viral antigen persists in the cells of the gastrointestinal tract as well as in the convalescent phase, up to 6 months after healing . In one case study, persistent colonic infection was associated with persistent gastrointestinal symptoms in a case of "long COVID" , which draws a parallel to the role of the colon epithelium as a reservoir for FCoV.
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 . 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 . Clinical signs included erythematous rash (14/18 patients), diffuse urticaria (3/18 patients) and smallpox-like vesicles (1/18 patients) . Lesions were observed mainly on the trunk (torsion) and pruritus was mild or absent . 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. .
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 . 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. . 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. .
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. . 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. . 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. . Components of type III and IV immune responses have been described . 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. . One type III hypersensitivity report has been identified in the COVID-19 literature ; 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. . High levels of IL-6 have previously been demonstrated in FIP ascites , and similarly, elevated levels of IL-6 appear to be related to disease severity and outcome in patients with COVID-19. . 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. . When considering the balance between cell-mediated immunity and humoral immunity, early reports suggested a link to strong humoral immunity leading to FIP . However, humoral immunity may play a more beneficial role in patients with COVID-19 , especially given the potential clinical benefit of convalescent plasma / serum .
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 . 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. . 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. . In SARS-CoV-2, ADE was observed in monocyte lines but was not related to the regulation of pro-inflammatory cytokines . Spike protein sequence modeling has identified possible ADE mechanisms that involve interaction with Fc receptors on monocytes and adipocytes . 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 . 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. . 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 ′). . 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 ′  (Table 1), wherein the furin-like proteases prim the tip and S1 / S2  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 . Thus, there appear to be remarkable similarities in host cell adaptation between the two viruses.
Consensus sequence S1 / S2 in circulating viruses
Consensus sequence S2 ′ in circulating viruses
SPRRAR | S (* SHRRAR | S and SRRRAR | S)
SKPSKR | S
Alphacoronavirus (“clade A”)
SRRSRR | S (in FECV; mutated in FIPV)
KR | S
Alphacoronavirus (“clade B”)
YRKR | S
Table 1 Summary of SARS-CoV-2 and two FCoV serotypes. The coronavirus spike glycoprotein, mediated by proteolytic cleavage, is a major driver of cell receptor binding and membrane fusion. The Taxonomic classification, host receptor, and amino acid sequences of the proteolytic cleavage site S1 / S2 and S2 ′ are summarized below. *, Replaced in common variants.
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. . Although not referred to as social distances, similar methods are often introduced or recommended in cat populations. . 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. . 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 . 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 .
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. . 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). . 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. .
ADE remains a major concern of FIP vaccines. Several studies have attempted to reduce the incidence of FIP in experimentally infected cats with recombinant and other experimental vaccines, but ADEs have been reported repeatedly. In one placebo-controlled study in which purebred British Shorthairs and Specific Pathogen Free (SPF) Domestic Shorthairs were vaccinated with one of two recombinant FIPV type 2 (FIPV-DF2) vaccines, both candidate vaccines showed significantly reduced to no protection against challenge FIPV in non-SPF cats - with the majority of non-SPF animals showing ADE . 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 . Concerns about ADE after FIPV immunization remain a challenging challenge in FIP prevention.
Unlike the FIP vaccination, the COVID-19 vaccines have played a more significant role in reducing the spread of the infection. Several types of vaccines have been produced that have demonstrated safety and efficacy in preventing symptomatic infection, severe disease, and death from COVID-19—including, but not limited to, mRNA vaccines (Pfizer/BioNTech and Moderna), viral vector vaccines (Janssen, AstraZeneca), and inactivated virus 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. .
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. . An important contribution towards this field is the real-world studies investigating the efficacy of the vaccine, which show 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. . 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 , however, when administered to cats as an experimental treatment, led to poorer results in some cases . Similarly, at the onset of the COVID-19 pandemic, ribavirin was used in several doses and in combination with other drugs.  and a study protocol was designed to examine the benefit in human patients . 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 . 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. . 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. . The use of corticosteroids in patients with COVID-19 does not appear to be insignificant, with some studies showing negative profiles . 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 , 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 . 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 , similar to evidence that cyclophilin A blockade inhibits the replication of other coronaviruses .
Many antibiotics have been prescribed for both FIP and COVID-19, but not for their antimicrobial properties, but rather for their anti-inflammatory effects. . For example, doxycycline may have helped prolong survival in cats with FIP . 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. .
Interferons have also been studied in the treatment of FIP without a clear link to clinical improvement . 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. .
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 . Tocilizumab, an anti-IL-6 monoclonal antibody, was administered to patients with COVID-19 . 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's National Health Service issued an alert about an increased incidence of multisystem inflammatory syndrome in children - many of whom tested positive for COVID-19 . 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 . Many patients also experience neurocognitive symptoms, including headache and confusion. More serious neurological complications, including encephalopathy and stroke, are less common [218,221].
One area of significant clinical overlap between FIP and COVID-19 is the rare inflammatory manifestation of SARS-CoV-2 infection – multisystem inflammatory syndrome in children (MIS-C). MIS-C is seen in the pediatric population, just as FIP commonly affects young cats . Like FIP, MIS-C has a systemic presentation involving multiple organ systems—including gastrointestinal, cardiovascular, and hematologic abnormalities . As with the wet form of FIP, pleural effusions and ascites occur in MIS-C. . Both syndromes also show overlap in vascular pathology. FIP shows granulomatous vasculitis, which overlaps with Kawasaki vascular syndrome observed in MIS-C . 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 exposure to FCoV and occurs only in a small subset of cases. Although cats with FIP can still shed FCoV in their feces, the mutations associated with the biotype switch from FECV to FIPV are thought not to be transmissible—supporting some degree of similarity in the limited infectious range of both FIP and MIS-C.
Recently, post-acute sequelae of COVID-19 (PASC) has been defined, which includes memory loss, gastrointestinal distress, fatigue, anosmia, dyspnea, etc. and is more often referred to as "long-term COVID". Along with MIS-C, PASC is a very active subject of research, which has been summarized by others , 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 .
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. . 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. . 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). . 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. . 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 to Annette Choi for helping with Figure 1 and all Whittaker Lab members for helpful discussions during the preparation of this manuscript.
All authors have contributed to this article. All authors have read and agreed to the published version of the manuscript.
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.
Publisher Note: The MDPI remains neutral in terms of jurisdictional claims in published maps and institutional affiliation.
Chen, J .; Qi, T .; Liu, L .; Ling, Y .; Qian, Z .; Li, T .; Li, F .; Xu, Q .; Zhang, Y .; Xu, S .; et al. Clinical progression of patients with COVID-19 in Shanghai, China. J. Infect.2020, 80, e1 – e6. [Google Scholar] [CrossRef] [PubMed]
Coronaviridae Study Group of the International Committee on Taxonomy of Virus. The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol.2020, 5, 536–544. [Google Scholar] [CrossRef]
Perlman, SMK Coronaviruses, Including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Disease, 9th ed .; Bennett, JE, Dolin, R., Blaser, MJ, Eds .; Elsevier: Amsterdam, The Netherlands, 2020; pp. 2072–2080. [Google Scholar]
Abdul-Rasool, S .; Fielding, BC Understanding Human Coronavirus HCoV-NL63. Open Virol. J.2010, 4, 76–84. [Google Scholar] [CrossRef]
Letko, M .; Marzi, A .; Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat. Microbiol.2020, 5, 562–569. [Google Scholar] [CrossRef]
Rottier, PJ; Nakamura, K .; Schellen, P .; Volders, H .; Haijema, BJ Acquisition of macrophage tropism during the pathogenesis of feline infectious peritonitis is determined by mutations in the feline coronavirus spike protein. J. Virol.2005, 79, 14122–14130. [Google Scholar] [CrossRef]
Jaimes, JA; Millet, JK; Stout, AE; Andre, NM; Whittaker, GR A Tale of Two Viruses: The Distinct Spike Glycoproteins of Feline Coronaviruses. Viruses2020, 12, 83. [Google Scholar] [CrossRef]
Tresnan, DB; Levis, R .; Holmes, KV Feline aminopeptidase N serves as a receptor for feline, canine, porcine, and human coronaviruses in serogroup I. J. Virol.1996, 70, 8669–8674. [Google Scholar] [CrossRef]
Benetka, V .; Kubber-Heiss, A .; Kolodziejek, J .; Nowotny, N .; Hofmann-Parisot, M .; Mostl, K. Prevalence of feline coronavirus types I and II in cats with histopathologically verified feline infectious peritonitis. Vet. Microbiol.2004, 99, 31–42. [Google Scholar] [CrossRef]
Iwasaki, M .; Saito, J .; Zhao, H .; Sakamoto, A .; Hirota, K .; Ma, D. Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications. Inflammation2021, 44, 13–34. [Google Scholar] [CrossRef]
Xiao, F .; Sun, J .; Xu, Y .; Li, F .; Huang, X .; Li, H.; Zhao, J .; Huang, J .; Zhao, J. Infectious SARS-CoV-2 in Feces of Patient with Severe COVID-19. Emerg. Infect. Dis.2020, 26, 1920–1922. [Google Scholar] [CrossRef]
Sykes, JE Feline Coronavirus Infection. In Canine and Feline Infectious Diseases; Elsevier: Amsterdam, The Netherlands, 2014; pp. 195–208. [Google Scholar] [CrossRef]
Pedersen, NC A review of feline infectious peritonitis virus infection: 1963-2008. J. Feline Med. Surg.2009, 11, 225–258. [Google Scholar] [CrossRef] [PubMed]
Pedersen, NC; Liu, H .; Scarlett, J .; Leutenegger, CM; Golovko, L .; Kennedy, H .; Kamal, FM Feline infectious peritonitis: Role of the feline coronavirus 3c gene in intestinal tropism and pathogenicity based upon isolates from resident and adopted shelter cats. Virus Res.2012, 165, 17–28. [Google Scholar] [CrossRef] [PubMed]
Brown, MA Genetic determinants of pathogenesis by feline infectious peritonitis virus. Vet. Immunol. Immunopathol.2011, 143, 265–268. [Google Scholar] [CrossRef] [PubMed]
Healey, EA; Andre, NM; Miller, AD; Whittaker, GR; Berliner, EA An outbreak of FIP in a cohort of shelter-housed cats: Molecular analysis of the feline coronavirus S1 / S2 cleavage site consistent with a “circulating virulent-avirulent” theory of FIP pathogenesis. J. Feline Med. Surg. Open Rep.2022, 8, 20551169221074226. [Google Scholar] [CrossRef]
Cheung, CCL; Goh, D .; Lim, X .; Tien, TZ; Lim, JCT; Lee, JN; Tan, B .; Tay, ZEA; Wan, WY; Chen, EX; et al. Residual SARS-CoV-2 viral antigens detected in GI and hepatic tissues from five recovered patients with COVID-19. Good2022, 71, 226–229. [Google Scholar] [CrossRef] [PubMed]
Kipar, A .; Meli, ML; Baptiste, KE; Bowker, LJ; Lutz, H. Sites of feline coronavirus persistence in healthy cats. J. Gen. Virol.2010, 91, 1698–1707. [Google Scholar] [CrossRef] [PubMed]
Rothe, C .; Schunk, M .; Sothmann, P .; Bretzel, G .; Froeschl, G .; Wallrauch, C .; Zimmer, T .; Thiel, V .; Janke, C .; Guggemos, W .; et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N. Engl. J. Med.2020, 382, 970–971. [Google Scholar] [CrossRef]
Bai, Y .; Yao, L .; Wei, T .; Tian, F.; Jin, DY; Chen, L .; Wang, M. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA2020, 323, 1406–1407. [Google Scholar] [CrossRef] [PubMed]
Hu, Z .; Song, C .; Xu, C .; Jin, G .; Chen, Y .; Xu, X .; Ma, H .; Chen, W .; Lin, Y .; Zheng, Y .; et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci. China Life Sci.2020, 63, 706–711. [Google Scholar] [CrossRef]
Jin, YH; Cai, L .; Cheng, ZS; Cheng, H .; Deng, T .; Fan, YP; Fang, C .; Huang, D .; Huang, LQ; Huang, Q .; et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med. Res.2020, 7, 4. [Google Scholar] [CrossRef] [PubMed]
Wolfe, LG; Griesemer, RA Feline infectious peritonitis: Review of gross and histopathologic lesions. J. Am. Vet. Med. Assoc.1971, 158 (Suppl S2), 987. [Google Scholar]
Wege, H .; Siddell, S .; ter Meulen, V. The biology and pathogenesis of coronaviruses. Curr. Top. Microbiol. Immunol.1982, 99, 165–200. [Google Scholar] [CrossRef]
Hardy, WD, Jr .; Hurvitz, AI Feline infectious peritonitis: Experimental studies. J. Am. Vet. Med. Assoc.1971, 158 (Suppl S2), 994. [Google Scholar]
Robison, RL; Holzworth, J .; Gilmore, CE Naturally occurring feline infectious peritonitis: Signs and clinical diagnosis. J. Am. Vet. Med. Assoc.1971, 158 (Suppl. 2), 981–986. [Google Scholar]
Sherding, R. Feline Infectious Peritonitis (Feline Coronavirus). Saunders Man. Small Anim. Pract.2006, 132–143. [Google Scholar] [CrossRef]
Addie, DD; Jarrett, O. A study of naturally occurring feline coronavirus infections in kittens. Vet. Rec.1992, 130, 133–137. [Google Scholar] [CrossRef]
Lutz, H .; Gut, M .; Leutenegger, CM; Schiller, I .; Wiseman, A .; Meli, M. Kinetics of FCoV infection in kittens born in catteries of high risk for FIP under different rearing conditions. In Proceedings of the Second International Feline Coronavirus / Feline Infectious Peritonitis Symposium, Glasgow, Scotland, 4–7 August 2002. [Google Scholar]
Addie, DD; Paltrinieri, S .; Pedersen, NC Secong international feline coronavirus / feline infectious peritonitis, symposium Recommendations from workshops of the second international feline coronavirus / feline infectious peritonitis symposium. J Feline Med. Surg.2004, 6, 125–130. [Google Scholar] [CrossRef]
Vivanti, AJ; Vauloup-Fellous, C .; Prevot, S .; Zupan, V .; Suffee, C .; Do Cao, J .; Benachi, A .; De Luca, D. Transplacental transmission of SARS-CoV-2 infection. Nat. Commun.2020, 11, 3572. [Google Scholar] [CrossRef]
Shende, P .; Gaikwad, P .; Gandhewar, M .; Ukey, P .; Bhide, A .; Patel, V .; Bhagat, S .; Bhor, V .; Mahale, S .; Gajbhiye, R .; et al. Persistence of SARS-CoV-2 in the first trimester of the placenta leading to transplacental transmission and fetal demise from an asymptomatic mother. Hum. Reprod.2021, 36, 899–906. [Google Scholar] [CrossRef]
Fenizia, C .; Biasin, M .; Cetin, I .; Vergani, P .; Mileto, D .; Spinillo, A .; Gismondo, MR; Perotti, F .; Callegari, C .; Mancon, A .; et al. Analysis of SARS-CoV-2 vertical transmission during pregnancy. Nat. Commun.2020, 11, 5128. [Google Scholar] [CrossRef]
Raschetti, R .; Vivanti, AJ; Vauloup-Fellous, C .; Loi, B .; Benachi, A .; De Luca, D. Synthesis and systematic review of reported neonatal SARS-CoV-2 infections. Nat. Commun.2020, 11, 5164. [Google Scholar] [CrossRef]
Lovato, A .; de Filippis, C. Clinical Presentation of COVID-19: A Systematic Review Focusing on Upper Airway Symptoms. Ear Nose Throat J.2020, 99, 569–576. [Google Scholar] [CrossRef] [PubMed]
Wee, LE; Chan, YFZ; Teo, NWY; Cherng, BPZ; Thien, SY; Wong, HM; Wijaya, L .; Toh, ST; Tan, TT The role of self-reported olfactory and gustatory dysfunction as a screening criterion for suspected COVID-19. Eur. Arch. Otorhinolaryngol.2020, 277, 2389–2390. [Google Scholar] [CrossRef]
Peckham, H .; de Gruijter, NM; Raine, C .; Radziszewska, A .; Ciurtin, C .; Wedderburn, LR; Rosser, EC; Webb, K .; Deakin, CT Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat. Commun.2020, 11, 6317. [Google Scholar] [CrossRef] [PubMed]
Vahidy, FS; Pan, AP; Ahnstedt, H .; Munshi, Y .; Choi, HA; Tiruneh, Y .; Nasir, K .; Kash, BA; Andrieni, JD; McCullough, LD Sex differences in susceptibility, severity, and outcomes of coronavirus disease 2019: Cross-sectional analysis from a diverse US metropolitan area. PLoS ONE2021, 16, e0245556. [Google Scholar] [CrossRef] [PubMed]
Riemer, F.; Kuehner, KA; Ritz, S.; Sauter-Louis, C.; Hartmann, K. Clinical and laboratory features of cats with feline infectious peritonitis–a retrospective study of 231 confirmed cases (2000–2010). J. Feline Med. Surg.2016, 18, 348–356. [Google Scholar] [CrossRef]
Hambali, NL; Mohd Noh, M .; Paramasivam, S .; Chua, TH; Hayati, F .; Payus, AO; Tee, TY; Rosli, KT; Abd Rachman Isnadi, MF; Manin, BO A Non-severe Coronavirus Disease 2019 Patient With Persistently High Interleukin-6 Level. Front. Public Health2020, 8, 584552. [Google Scholar] [CrossRef]
August, JR Feline infectious peritonitis. An immune-mediated coronaviral vasculitis. Vet. Clin. U.S. Small Anim. Pract.1984, 14, 971–984. [Google Scholar] [CrossRef]
Hayashi, T .; Goto, N .; Takahashi, R .; Fujiwara, K. Systemic vascular lesions in feline infectious peritonitis. Nihon Juigaku Zasshi1977, 39, 365–377. [Google Scholar] [CrossRef]
Stout, AE; Andre, NM; Zimmerberg, J .; Baker, SC; Whittaker, GR Coronaviruses as a cause of vascular disease: A comparative medicine approach. eCommons2021. [Google Scholar] [CrossRef]
Varga, Z .; Flammer, AJ; Steiger, P .; Haberecker, M .; Andermatt, R .; Zinkernagel, AS; Mehra, MR; Schuepbach, RA; Ruschitzka, F .; Moch, H. Endothelial cell infection and endotheliitis in COVID-19. Lancet2020, 395, 1417–1418. [Google Scholar] [CrossRef]
Becker, RC COVID-19-associated vasculitis and vasculopathy. J. Thromb. Thrombolysis2020, 50, 499–511. [Google Scholar] [CrossRef]
Goitsuka, R .; Ohashi, T .; Ono, K .; Yasukawa, K .; Koishibara, Y .; Fukui, H .; Ohsugi, Y .; Hasegawa, A. IL-6 activity in feline infectious peritonitis. J. Immunol.1990, 144, 2599–2603. [Google Scholar] [PubMed]
Malbon, AJ; Fonfara, S .; Meli, ML; Hahn, S .; Egberink, H .; Kipar, A. Feline Infectious Peritonitis as a Systemic Inflammatory Disease: Contribution of Liver and Heart to the Pathogenesis. Viruses2019, 11, 1144. [Google Scholar] [CrossRef]
Mestrinho, LA; Rosa, R .; Ramalho, P .; Branco, V .; Iglesias, L .; Pissarra, H .; Duarte, A .; Niza, M. A pilot study to evaluate the serum Alpha-1 acid glycoprotein response in cats suffering from feline chronic gingivostomatitis. BMC Vet. Res.2020, 16, 390. [Google Scholar] [CrossRef] [PubMed]
Selting, KA; Ogilvie, GK; Lana, SE; Fettman, MJ; Mitchener, KL; Hansen, RA; Richardson, KL; Walton, JA; Scherk, MA Serum alhpa 1-acid glycoprotein concentrations in healthy and tumor-bearing cats. J. Vet. Intern. Med.2000, 14, 503–506. [Google Scholar] [CrossRef]
Giordano, A .; Spagnolo, V .; Colombo, A .; Paltrinieri, S. Changes in some acute phase protein and immunoglobulin concentrations in cats affected by feline infectious peritonitis or exposed to feline coronavirus infection. Vet. J.2004, 167, 38–44. [Google Scholar] [CrossRef]
Hazuchova, K .; Held, S .; Neiger, R. Usefulness of acute phase proteins in differentiating between feline infectious peritonitis and other diseases in cats with body cavity effusions. J. Feline Med. Surg.2017, 19, 809–816. [Google Scholar] [CrossRef] [PubMed]
Li, H.; Xiang, X .; Ren, H.; Xu, L .; Zhao, L .; Chen, X .; Long, H.; Wang, Q .; Wu, Q. Serum Amyloid A is a biomarker of severe Coronavirus Disease and poor prognosis. J. Infect.2020, 80, 646–655. [Google Scholar] [CrossRef] [PubMed]
Zinellu, A .; Paliogiannis, P .; Carru, C .; Mangoni, AA Serum amyloid A concentrations, COVID-19 severity and mortality: An updated systematic review and meta-analysis. Int. J. Infect. Dis.2021, 105, 668–674. [Google Scholar] [CrossRef] [PubMed]
Nehring, SM; Goyal, A .; Bansal, P .; Patel, BC C Reactive Protein; StatPearls: Treasure Island, FL, USA, 2020. [Google Scholar]
Vanderschueren, S .; Deeren, D .; Knockaert, DC; Bobbaers, H .; Bossuyt, X .; Peetermans, W. Extremely elevated C-reactive protein. Eur. J. Intern. Med.2006, 17, 430–433. [Google Scholar] [CrossRef]
Yang, M .; Chen, X .; Xu, Y. A Retrospective Study of the C-Reactive Protein to Lymphocyte Ratio and Disease Severity in 108 Patients with Early COVID-19 Pneumonia from January to March 2020 in Wuhan, China. Med. Sci. Monit.2020, 26, e926393. [Google Scholar] [CrossRef]
Liu, F .; Li, L .; Xu, M .; Wu, J .; Luo, D .; Zhu, Y .; Li, B .; Song, X .; Zhou, X. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J. Clin. Virol.2020, 127, 104370. [Google Scholar] [CrossRef]
Sharifpour, M .; Rangaraju, S .; Liu, M .; Alabyad, D .; Nahab, FB; Creel-Bulos, CM; Jabaley, CS; Emory, C.-Q .; Clinical Research, C. C-Reactive protein as a prognostic indicator in hospitalized patients with COVID-19. PLoS ONE2020, 15, e0242400. [Google Scholar] [CrossRef]
Leisman, DE; Ronner, L .; Pinotti, R .; Taylor, MD; Sinha, P .; Calfee, CS; Hirayama, AV; Mastroiani, F.; Turtle, CJ; Harhay, MO; et al. Cytokine elevation in severe and critical COVID-19: A rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir. Med.2020, 8, 1233–1244. [Google Scholar] [CrossRef]
Adam, SS; Key, NS; Greenberg, CS D-dimer antigen: Current concepts and future prospects. Blood2009, 113, 2878–2887. [Google Scholar] [CrossRef]
Wichmann, D .; Sperhake, JP; Lutgehetmann, M .; Steurer, S .; Edler, C .; Heinemann, A .; Heinrich, F .; Mushumba, H .; Kniep, I .; Schroder, AS; et al. Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study. Ann. Intern. Med.2020, 173, 268–277. [Google Scholar] [CrossRef]
Ackermann, M .; Verleden, SE; Kuehnel, M .; Haverich, A .; Welte, T .; Laenger, F .; Vanstapel, A .; Werlein, C .; Stark, H .; Tzankov, A .; et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N. Engl. J. Med.2020, 383, 120–128. [Google Scholar] [CrossRef] [PubMed]
Yu, HH; Qin, C .; Chen, M .; Wang, W .; Tian, DS D-dimer level is associated with the severity of COVID-19. Thromb. Res.2020, 195, 219–225. [Google Scholar] [CrossRef] [PubMed]
Kermali, M .; Khalsa, RK; Pillai, K .; Ismail, Z .; Harky, A. The role of biomarkers in diagnosis of COVID-19-A systematic review. Life Sci.2020, 254, 117788. [Google Scholar] [CrossRef] [PubMed]
Tholen, I .; Weingart, C .; Kohn, B. Concentration of D-dimers in healthy cats and sick cats with and without disseminated intravascular coagulation (DIC). J. Feline Med. Surg.2009, 11, 842–846. [Google Scholar] [CrossRef] [PubMed]
Marioni-Henry, K .; Vite, CH; Newton, AL; Van Winkle, TJ Prevalence of diseases of the spinal cord of cats. J. Vet. Intern. Med.2004, 18, 851–858. [Google Scholar] [CrossRef] [PubMed]
Andre, NM; Cossic, B .; Davies, E .; Miller, AD; Whittaker, GR Distinct mutation in the feline coronavirus spike protein cleavage activation site in a cat with feline infectious peritonitis-associated meningoencephalomyelitis. JFMS Open Rep.2019, 5, 2055116919856103. [Google Scholar] [CrossRef]
Diaz, JV; Poma, R. Diagnosis and clinical signs of feline infectious peritonitis in the central nervous system. Can. Vet. J.2009, 50, 1091–1093. [Google Scholar]
Crawford, AH; Stoll, AL; Sanchez-Masian, D .; Shea, A .; Michaels, J .; Fraser, AR; Beltran, E. Clinicopathologic Features and Magnetic Resonance Imaging Findings in 24 Cats With Histopathologically Confirmed Neurologic Feline Infectious Peritonitis. J. Vet. Intern. Med.2017, 31, 1477–1486. [Google Scholar] [CrossRef]
Zhou, L .; Zhang, M .; Wang, J .; Gao, J. Sars-Cov-2: Underestimated damage to nervous system. Travel Med. Infect. Dis.2020, 101642. [Google Scholar] [CrossRef]
Asadi-Pooya, AA; Simani, L. Central nervous system manifestations of COVID-19: A systematic review. J. Neurol. Sci.2020, 413, 116832. [Google Scholar] [CrossRef] [PubMed]
Matschke, J .; Lutgehetmann, M .; Hagel, C .; Sperhake, JP; Schroder, AS; Edler, C .; Mushumba, H .; Fitzek, A .; Allweiss, L .; Dandri, M .; et al. Neuropathology of patients with COVID-19 in Germany: A post-mortem case series. Lancet Neurol.2020, 19, 919–929. [Google Scholar] [CrossRef]
Paniz-Mondolfi, A .; Bryce, C .; Grimes, Z .; Gordon, RE; Reidy, J .; Lednicky, J .; Sordillo, EM; Fowkes, M. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J. Med. Virol.2020, 92, 699–702. [Google Scholar] [CrossRef] [PubMed]
Lee, MH; Perl, DP; Nair, G .; Li, W .; Maric, D .; Murray, H .; Dodd, SJ; Koretsky, AP; Watts, JA; Cheung, V .; et al. Microvascular Injury in the Brains of Patients with Covid-19. N. Engl. J. Med.2021, 384, 481–483. [Google Scholar] [CrossRef] [PubMed]
Andrew, SE Feline infectious peritonitis. Vet. Clin. U.S. Small Anim. Pract.2000, 30, 987–1000. [Google Scholar] [CrossRef]
Cannon, MJ; Silkstone, MA; Kipar, AM Cutaneous lesions associated with coronavirus-induced vasculitis in a cat with feline infectious peritonitis and concurrent feline immunodeficiency virus infection. J. Feline Med. Surg.2005, 7, 233–236. [Google Scholar] [CrossRef] [PubMed]
Hok, K. Demonstration of feline corona virus (FCV) antigen in organs of cats suspected of feline infectious peritonitis (FIP) disease. APMIS1990, 98, 659–664. [Google Scholar] [CrossRef] [PubMed]
Wu, P .; Duan, F .; Luo, C .; Liu, Q .; Qu, X .; Liang, L .; Wu, K. Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China. JAMA Ophthalmol.2020, 138, 575–578. [Google Scholar] [CrossRef]
Mazzotta, C .; Giancipoli, E. Anterior Acute Uveitis Report in a SARS-CoV-2 Patient Managed with Adjunctive Topical Antiseptic Prophylaxis Preventing 2019-nCoV Spread Through the Ocular Surface Route. Int. Med. Case Rep. J.2020, 13, 513–520. [Google Scholar] [CrossRef] [PubMed]
Francois, J .; Collery, AS; Hayek, G .; Sot, M .; Zaidi, M .; Lhuillier, L .; Perone, JM Coronavirus Disease 2019-Associated Ocular Neuropathy With Panuveitis: A Case Report. JAMA Ophthalmol.2021, 139, 247–249. [Google Scholar] [CrossRef]
Loon, SC; Teoh, SC; Oon, LL; Se-Thoe, SY; Ling, AE; Leo, YS; Leong, HN The severe acute respiratory syndrome coronavirus in tears. Br. J. Ophthalmol.2004, 88, 861–863. [Google Scholar] [CrossRef]
Arora, R .; Goel, R .; Kumar, S .; Chhabra, M .; Saxena, S .; Manchanda, V .; Pumma, P. Evaluation of SARS-CoV-2 in Tears of Patients with Moderate to Severe COVID-19. Ophthalmology2021, 128, 494–503. [Google Scholar] [CrossRef]
Colavita, F .; Lapa, D .; Carletti, F .; Lalle, E .; Bordi, L .; Marsella, P .; Nicastri, E .; Bevilacqua, N .; Giancola, ML; Corpolongo, A .; et al. SARS-CoV-2 Isolation From Ocular Secretions of a Patient With COVID-19 in Italy With Prolonged Viral RNA Detection. Ann. Intern. Med.2020, 173, 242–243. [Google Scholar] [CrossRef] [PubMed]
Fischer, Y .; Wess, G .; Hartmann, K. Pericardial effusion in a cat with feline infectious peritonitis. Switzerland Arch. Tierheilkd.2012, 154, 27–31. [Google Scholar] [CrossRef] [PubMed]
Rush, JE; Keene, BW; Fox, PR Pericardial disease in the cat: A retrospective evaluation of 66 cases. J. Am. Anim. Hosp. Assoc.1990, 26, 39–46. [Google Scholar]
Hall, DJ; Shofer, F .; Meier, CK; Sleeper, MM Pericardial effusion in cats: A retrospective study of clinical findings and outcome in 146 cats. J. Vet. Intern. Med.2007, 21, 1002–1007. [Google Scholar] [CrossRef]
Baek, S .; Jo, J .; Song, K .; Seo, K. Recurrent Pericardial Effusion with Feline Infectious Peritonitis in a Cat. J. Vet. Clin.2017, 34, 437–440. [Google Scholar] [CrossRef]
Ernandes, MA; Cantoni, AM; Armando, F .; Corradi, A .; Ressel, L .; Tamborini, A. Feline coronavirus-associated myocarditis in a domestic longhair cat. JFMS Open Rep.2019, 5, 2055116919879256. [Google Scholar] [CrossRef]
Carvallo, FR; Martins, M .; Joshi, LR; Caserta, LC; Mitchell, PK; Cecere, T .; Hancock, S .; Goodrich, EL; Murphy, J .; Part, DG Severe SARS-CoV-2 Infection in a Cat with Hypertrophic Cardiomyopathy. Viruses2021, 13, 1510. [Google Scholar] [CrossRef]
Guo, T .; Fan, Y .; Chen, M .; Wu, X .; Zhang, L .; He, T .; Wang, H .; Wan, J .; Wang, X .; Lu, Z. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol.2020, 5, 811–818. [Google Scholar] [CrossRef]
Ruan, Q .; Yang, K .; Wang, W .; Jiang, L .; Song, J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med.2020, 46, 846–848. [Google Scholar] [CrossRef]
Inciardi, RM; Lupi, L .; Zaccone, G .; Italy, L .; Raffo, M .; Tomasoni, D .; Cani, DS; Cerini, M .; Farina, D .; Gavazzi, E .; et al. Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol.2020, 5, 819–824. [Google Scholar] [CrossRef]
Farina, A .; Uccello, G .; Spreafico, M .; Bassanelli, G .; Savonitto, S. SARS-CoV-2 detection in the pericardial fluid of a patient with cardiac tamponade. Eur. J. Intern. Med.2020, 76, 100. [Google Scholar] [CrossRef] [PubMed]
Lindner, D .; Fitzek, A .; Brauninger, H .; Aleshcheva, G .; Edler, C .; Meissner, K .; Scherschel, K .; Kirchhof, P .; Escher, F .; Schultheiss, HP; et al. Association of Cardiac Infection With SARS-CoV-2 in Confirmed COVID-19 Autopsy Cases. JAMA Cardiol.2020, 5, 1281–1285. [Google Scholar] [CrossRef] [PubMed]
Gunn-Moore, DA; Gruffydd-Jones, TJ; Harbor, DA Detection of feline coronaviruses by culture and reverse transcriptase-polymerase chain reaction of blood samples from healthy cats and cats with clinical feline infectious peritonitis. Vet. Microbiol.1998, 62, 193–205. [Google Scholar] [CrossRef]
Addie, DD; Jarrett, O. Use of a reverse-transcriptase polymerase chain reaction for monitoring the shedding of feline coronavirus by healthy cats. Vet. Rec.2001, 148, 649–653. [Google Scholar] [CrossRef] [PubMed]
Stranieri, A .; Scavone, D .; Paltrinieri, S .; Giordano, A .; Bonsembiante, F .; Ferro, S .; Gelain, ME; Meazzi, S .; Lauzi, S. Concordance between Histology, Immunohistochemistry, and RT-PCR in the Diagnosis of Feline Infectious Peritonitis. Pathogens2020, 9, 852. [Google Scholar] [CrossRef]
Harvey, CJ; Lopez, JW; Hendrick, MJ An uncommon intestinal manifestation of feline infectious peritonitis: 26 cases (1986–1993). J. Am. Vet. Med. Assoc.1996, 209, 1117–1120. [Google Scholar]
Xiao, F .; Tang, M .; Zheng, X .; Liu, Y .; Li, X .; Shan, H. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology2020, 158, 1831–1833. [Google Scholar] [CrossRef]
Pan, L .; Mu, M .; Yang, P .; Sun, Y .; Wang, R .; Yan, J .; Li, P .; Hu, B .; Wang, J .; Hu, C .; et al. Clinical Characteristics of COVID-19 Patients With Digestive Symptoms in Hubei, China: A Descriptive, Cross-Sectional, Multicenter Study. Am. J. Gastroenterol.2020, 115, 766–773. [Google Scholar] [CrossRef] [PubMed]
Parasa, S .; Desai, M .; Thoguluva Chandrasekar, V .; Patel, HK; Kennedy, KF; Roesch, T .; Spadaccini, M .; Colombo, M .; Gabbiadini, R .; Artifon, ELA; et al. Prevalence of Gastrointestinal Symptoms and Fecal Viral Shedding in Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis. JAMA Netw. Open2020, 3, e2011335. [Google Scholar] [CrossRef] [PubMed]
Rokkas, T. Gastrointestinal involvement in COVID-19: A systematic review and meta-analysis. Ann. Gastroenterol.2020, 33, 355–365. [Google Scholar] [CrossRef] [PubMed]
Akin, H.; Kurt, R .; Tufan, F .; Swi, A .; Ozaras, R .; Tahan, V .; Hammoud, G. Newly Reported Studies on the Increase in Gastrointestinal Symptom Prevalence withCOVID-19 Infection: A Comprehensive Systematic Review and Meta-Analysis. Diseases2020, 8, 41. [Google Scholar] [CrossRef] [PubMed]
Chen, L .; Lou, J .; Bai, Y .; Wang, M. COVID-19 Disease With Positive Fecal and Negative Pharyngeal and Sputum Viral Tests. Am. J. Gastroenterol.2020, 115, 790. [Google Scholar] [CrossRef] [PubMed]
Wang, W .; Xu, Y .; Gao, R .; Lu, R .; Han, K .; Wu, G .; Tan, W. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA2020, 323, 1843–1844. [Google Scholar] [CrossRef]
Arostegui, D .; Castro, K .; Schwarz, S .; Vaidy, K .; Rabinowitz, S .; Wallach, T. Persistent SARS-CoV-2 Nucleocapsid Protein Presence in the Intestinal Epithelium of a Pediatric Patient 3 Months After Acute Infection. J. Pediatr. Gastroenterol. Nutr.2022, 3, e152. [Google Scholar] [CrossRef]
Declercq, J .; De Bosschere, H .; Schwarzkopf, I .; Declercq, L. Papular cutaneous lesions in a cat associated with feline infectious peritonitis. Vet. Dermatol.2008, 19, 255–258. [Google Scholar] [CrossRef]
Bauer, BS; Kerr, ME; Sandmeyer, LS; Grahn, BH Positive immunostaining for feline infectious peritonitis (FIP) in a Sphinx cat with cutaneous lesions and bilateral panuveitis. Vet. Ophthalmol.2013, 16 (Suppl. 1), 160–163. [Google Scholar] [CrossRef]
Redford, T .; Al-Dissi, AN Feline infectious peritonitis in a cat presented because of papular skin lesions. Can. Vet. J.2019, 60, 183–185. [Google Scholar]
Trotman, TK; Mauldin, E .; Hoffmann, V .; Del Piero, F .; Hess, RS Skin fragility syndrome in a cat with feline infectious peritonitis and hepatic lipidosis. Vet. Dermatol.2007, 18, 365–369. [Google Scholar] [CrossRef] [PubMed]
Recalcati, S. Cutaneous manifestations in COVID-19: A first perspective. J. Eur. Acad. Dermatol. Venereol.2020, 34. [Google Scholar] [CrossRef] [PubMed]
Galvan Casas, C .; Catala, A .; Carretero Hernandez, G .; Rodriguez-Jimenez, P .; Fernandez-Nieto, D .; Rodriguez-Villa Lario, A .; Navarro Fernandez, I .; Ruiz-Villaverde, R .; Falkenhain-Lopez, D .; Llamas Velasco, M .; et al. Classification of the cutaneous manifestations of COVID-19: A rapid prospective nationwide consensus study in Spain with 375 cases. Br. J. Dermatol.2020, 183, 71–77. [Google Scholar] [CrossRef] [PubMed]
Tomsitz, D .; Biedermann, T .; Brockow, K. Skin manifestations reported in association with COVID-19 infection. J. Dtsch. Dermatol. Ges.2021, 19, 530–534. [Google Scholar] [CrossRef]
Welsh, EC; Alfaro Sanchez, AB; Ortega Gutierrez, GL; Cardenas-de la Garza, JA; Cuellar-Barboza, A .; Valdes-Espinosa, RA; Pasos Estrada, AA; Miranda Aguirre, AI; Ramos-Jimenez, J .; Moreno Gonzalez, J .; et al. COVID-19 dermatological manifestations: Results from the Mexican Academy of Dermatology COVID-19 registry. Int. J. Dermatol.2021, 60, 879. [Google Scholar] [CrossRef]
Foster, RA; Caswell, JL; Rinkardt, N. Chronic fibrinous and necrotic orchitis in a cat. Can. Vet. J.1996, 37, 681–682. [Google Scholar]
Stranieri, A .; Probo, M .; Pisu, MC; Fioletti, A .; Meazzi, S .; Gelain, ME; Bonsembiante, F .; Lauzi, S .; Paltrinieri, S. Preliminary investigation on feline coronavirus presence in the reproductive tract of the tom cat as a potential route of viral transmission. J. Feline Med. Surg.2020, 22, 178–185. [Google Scholar] [CrossRef]
Evermann, JF; Baumgartener, L .; Ott, RL; Davis, EV; McKeirnan, AJ Characterization of a feline infectious peritonitis virus isolate. Vet. Pathol.1981, 18, 256–265. [Google Scholar] [CrossRef]
Yang, M .; Chen, S .; Huang, B .; Zhong, JM; Su, H.; Chen, YJ; Cao, Q .; He had.; He, J .; Li, XF; et al. Pathological Findings in the Testes of COVID-19 Patients: Clinical Implications. Eur. Urol. Focus2020, 6, 1124–1129. [Google Scholar] [CrossRef]
Ma, X .; Guan, C .; Chen, R .; Wang, Y .; Feng, S .; Wang, R .; Qu, G .; Zhao, S .; Wang, F .; Wang, X .; et al. Pathological and molecular examinations of postmortem testis biopsies reveal SARS-CoV-2 infection in the testis and spermatogenesis damage in COVID-19 patients. Cell Mol. Immunol.2021, 18, 487–489. [Google Scholar] [CrossRef]
Li, D .; Jin, M .; Bao, P .; Zhao, W .; Zhang, S. Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease 2019. JAMA Netw. Open2020, 3, e208292. [Google Scholar] [CrossRef] [PubMed]
Sharun, K .; Tiwari, R .; Dhama, K. SARS-CoV-2 in semen: Potential for sexual transmission in COVID-19. Int. J. Surg.2020, 84, 156–158. [Google Scholar] [CrossRef] [PubMed]
Jing, Y .; Run-Qian, L .; Hao-Ran, W .; Hao-Ran, C .; Ya-Bin, L .; Yang, G .; Fei, C. Potential influence of COVID-19 / ACE2 on the female reproductive system. Mol. Hum. Reprod.2020, 26, 367–373. [Google Scholar] [CrossRef]
Goad, J .; Rudolph, J .; Rajkovic, A. Female reproductive tract has low concentration of SARS-CoV2 receptors. PLoS ONE2020, 15, e0243959. [Google Scholar] [CrossRef] [PubMed]
Cui, P .; Chen, Z .; Wang, T .; Dai, J .; Zhang, J .; Ding, T .; Jiang, J .; Liu, J .; Zhang, C .; Shan, W .; et al. Severe acute respiratory syndrome coronavirus 2 detection in the female lower genital tract. Am. J. Obstet. Gynecol.2020, 223, 131–134. [Google Scholar] [CrossRef]
Scorzolini, L .; Corpolongo, A .; Castilletti, C .; Lalle, E .; Mariano, A .; Nicastri, E. Comment on the Potential Risks of Sexual and Vertical Transmission of COVID-19. Clin. Infect. Dis.2020, 71, 2298. [Google Scholar] [CrossRef] [PubMed]
Petersen, NC; Boyle, JF Immunologic phenomena in the effusive form of feline infectious peritonitis. Am. J. Vet. Res.1980, 41, 868–876. [Google Scholar]
Kipar, A .; May, H .; Menger, S .; Weber, M .; Leukert, W .; Reinacher, M. Morphologic features and development of granulomatous vasculitis in feline infectious peritonitis. Vet. Pathol.2005, 42, 321–330. [Google Scholar] [CrossRef]
McGonagle, D .; Bridgewood, C .; Ramanan, AV; Meaney, JFM; Watad, A. COVID-19 vasculitis and novel vasculitis mimics. Rheumatol Lancet.2021, 3, e224 – e233. [Google Scholar] [CrossRef]
Roncati, L .; Ligabue, G .; Fabbiani, L .; Malagoli, C .; Gallo, G .; Lusenti, B .; Nasillo, V .; Manenti, A .; Maiorana, A. Type 3 hypersensitivity in COVID-19 vasculitis. Clin. Immunol.2020, 217, 108487. [Google Scholar] [CrossRef]
Chen, J .; Lau, YF; Lamirande, EW; Paddock, CD; Bartlett, JH; Zaki, SR; Subbarao, K. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB / c mice: CD4 + T cells are important in controlling of SARS-CoV infection. J. Virol.2010, 84, 1289–1301. [Google Scholar] [CrossRef] [PubMed]
Yasui, F .; Kohara, M .; Kitabatake, M .; Nishiwaki, T .; Fujii, H .; Tateno, C .; Yoneda, M .; Morita, K .; Matsushima, K .; Koyasu, S .; et al. Phagocytic cells contribute to the antibody-mediated elimination of pulmonary-infected SARS coronavirus. Virology2014, 454–455, 157–168. [Google Scholar] [CrossRef] [PubMed]
Chen, G .; Wu, D .; Guo, W .; Cao, Y .; Huang, D .; Wang, H .; Wang, T .; Zhang, X .; Chen, H .; Yu, H.; et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Investig.2020, 130, 2620–2629. [Google Scholar] [CrossRef] [PubMed]
de Groot-Mijnes, JD; van Dun, JM; van der Most, RG; de Groot, RJ Natural history of a recurrent feline coronavirus infection and the role of cellular immunity in survival and disease. J. Virol.2005, 79, 1036–1044. [Google Scholar] [CrossRef] [PubMed]
Haagmans, BL; Egberink, HF; Horzinek, MC Apoptosis and T-cell depletion during feline infectious peritonitis. J. Virol.1996, 70, 8977–8983. [Google Scholar] [CrossRef]
Vermeulen, BL; Devriendt, B .; Olyslaegers, DA; Dedeurwaerder, A .; Desmarets, LM; Favoreel, HW; Dewerchin, HL; Nauwynck, HJ Suppression of NK cells and regulatory T lymphocytes in cats naturally infected with feline infectious peritonitis virus. Vet. Microbiol.2013, 164, 46–59. [Google Scholar] [CrossRef]
Aziz, M .; Fatima, R .; Assaly, R. Elevated interleukin-6 and severe COVID-19: A meta-analysis. J. Med. Virol.2020, 92, 2283–2285. [Google Scholar] [CrossRef]
Merad, M .; Martin, JC Author Correction: Pathological inflammation in patients with COVID-19: A key role for monocytes and macrophages. Nat. Rev. Immunol.2020, 20, 448. [Google Scholar] [CrossRef]
Kai, K .; Yukimune, M .; Murata, T .; Uzuka, Y .; Canoe, M .; Matsumoto, H. Humoral immune responses of cats to feline infectious peritonitis virus infection. J. Vet. Med. Sci.1992, 54, 501–507. [Google Scholar] [CrossRef]
Ni, L .; Ye, F .; Cheng, ML; Feng, Y .; Deng, YQ; Zhao, H .; Wei, P .; Ge, J .; Gou, M .; Li, X .; et al. Detection of SARS-CoV-2-Specific Humoral and Cellular Immunity in COVID-19 Convalescent Individuals. Immunity2020, 52, 971–977. [Google Scholar] [CrossRef]
Kong, Y .; Cai, C .; Ling, L .; Zeng, L .; Wu, M .; Wu, Y .; Zhang, W .; Liu, Z. Successful treatment of a centenarian with coronavirus disease 2019 (COVID-19) using convalescent plasma. Transfus. Apher. Sci.2020, 59, 102820. [Google Scholar] [CrossRef]
Olsen, CW; Corapi, WV; Ngichabe, CK; Baines, JD; Scott, FW Monoclonal antibodies to the spike protein of feline infectious peritonitis virus mediate antibody-dependent enhancement of infection of feline macrophages. J. Virol.1992, 66, 956–965. [Google Scholar] [CrossRef]
Takano, T .; Kawakami, C .; Yamada, S .; Satoh, R .; Hohdatsu, T. Antibody-dependent enhancement occurs upon re-infection with the identical serotype virus in feline infectious peritonitis virus infection. J. Vet. Med. Sci.2008, 70, 1315–1321. [Google Scholar] [CrossRef]
Maemura, T .; Kuroda, M .; Armbrust, T .; Yamayoshi, S .; Halfmann, PJ; Kawaoka, Y. Antibody-Dependent Enhancement of SARS-CoV-2 Infection Is Mediated by the IgG Receptors FcgammaRIIA and FcgammaRIIIA but Does Not Contribute to Aberrant Cytokine Production by Macrophages. mBio2021, 12, e0198721. [Google Scholar] [CrossRef]
Ricke, DO Two Different Antibody-Dependent Enhancement (ADE) Risks for SARS-CoV-2 Antibodies. Front. Immunol.2021, 12, 640093. [Google Scholar] [CrossRef] [PubMed]
Hui, KPY; Cheung, MC; Perera, R .; Ng, KC; Bui, CHT; Ho, JCW; Ng, MMT; Kuok, DIT; Shih, KC; Tsao, SW; et al. Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: An analysis in ex-vivo and in-vitro cultures. Lancet Respir. Med.2020, 8, 687–695. [Google Scholar] [CrossRef]
Li, F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu. Rev. Virol.2016, 3, 237–261. [Google Scholar] [CrossRef] [PubMed]
Clausen, TM; Sandoval, DR; Spliid, CB; Pihl, J .; Perrett, HR; Painter, CD; Narayanan, A .; Majowicz, SA; Kwong, EM; McVicar, RN; et al. SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. Cell2020, 183, 1043–1057. [Google Scholar] [CrossRef] [PubMed]
Cantuti-Castelvetri, L .; Ojha, R .; Pedro, LD; Djannatian, M .; Franz, J .; Kuivanen, S .; van der Meer, F .; Kallio, K .; Kaya, T .; Anastasina, M .; et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science2020, 370, 856–860. [Google Scholar] [CrossRef] [PubMed]
Lan, J .; Ge, J .; Yu, J .; Shan, S .; Zhou, H .; Fan, S .; Zhang, Q .; Shi, X .; Wang, Q .; Zhang, L .; et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature2020, 581, 215–220. [Google Scholar] [CrossRef] [PubMed]
Hoffmann, M .; Kleine-Weber, H .; Pohlmann, S. A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells. Mol. Cell2020, 78, 779–784. [Google Scholar] [CrossRef] [PubMed]
Whittaker, GR SARS-CoV-2 spike and its adaptable furin cleavage site. Lancet Microbe2021, 2, e488 – e489. [Google Scholar] [CrossRef]
Wrobel, AG; Benton, DJ; Xu, P .; Roustan, C .; Martin, SR; Rosenthal, PB; Skehel, JJ; Gamblin, SJ SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects. Nat. Struct. Mol. Biol.2020, 27, 763–767. [Google Scholar] [CrossRef] [PubMed]
Licitra, BN; Millet, JK; Regan, AD; Hamilton, BS; Rinaldi, VD; Duhamel, GE; Whittaker, GR Mutation in spike protein cleavage site and pathogenesis of feline coronavirus. Emerg. Infect. Dis.2013, 19, 1066–1073. [Google Scholar] [CrossRef]
Andre, NM; Miller, AD; Whittaker, GR Feline infectious peritonitis virus-associated rhinitis in a cat. JFMS Open Rep.2020, 6, 2055116920930582. [Google Scholar] [CrossRef]
Jaimes, JA; Millet, JK; Whittaker, GR Proteolytic Cleavage of the SARS-CoV-2 Spike Protein and the Role of the Novel S1 / S2 Site. iScience2020, 23, 101212. [Google Scholar] [CrossRef]
Tang, T .; Jaimes, JA; Bidon, MK; Straus, MR; Daniel, S .; Whittaker, GR Proteolytic Activation of SARS-CoV-2 Spike at the S1 / S2 Boundary: Potential Role of Proteases beyond Furin. ACS Infect. Dis.2021, 7, 264–272. [Google Scholar] [CrossRef]
Peacock, TP; Goldhill, DH; Zhou, J .; Baillon, L .; Frize, R .; Swann, OC; Kugathasan, R .; Penn, R .; Brown, JC; Sanchez-David, RY; et al. The furin cleavage site of SARS-CoV-2 spike protein is a key determinant for transmission due to enhanced replication in airway cells. bioRxiv2020. [Google Scholar] [CrossRef]
Matrajt, L .; Leung, T. Evaluating the Effectiveness of Social Distancing Interventions to Delay or Flatten the Epidemic Curve of Coronavirus Disease. Emerg Infect. Dis.2020, 26, 1740–1748. [Google Scholar] [CrossRef]
Fazio, RH; Ruisch, BC; Moore, CA; Granados Samayoa, JA; Boggs, ST; Ladanyi, JT Social distancing decreases an individual's likelihood of contracting COVID-19. Proc. Natl. Acad. Sci. USA2021, 118, e2023131118. [Google Scholar] [CrossRef] [PubMed]
Gostin, LO; Wiley, LF Governmental Public Health Powers During the COVID-19 Pandemic: Stay-at-home Orders, Business Closures, and Travel Restrictions. JAMA2020, 323, 2137–2138. [Google Scholar] [CrossRef]
Drechsler, Y .; Alcaraz, A .; Bossong, FJ; Collisson, EW; Diniz, PP Feline coronavirus in multicat environments. Vet. Clin. U.S. Small Anim. Pract.2011, 41, 1133–1169. [Google Scholar] [CrossRef]
Ryan, J .; Mazingisa, AV; Wiysonge, CS Cochrane corner: Effectiveness of quarantine in reducing the spread of COVID-19. Mr. Afr. Med. J.2020, 35, 18. [Google Scholar] [CrossRef] [PubMed]
Brooks, SK; Webster, RK; Smith, LE; Woodland, L .; Wessely, S .; Greenberg, N .; Rubin, GJ The psychological impact of quarantine and how to reduce it: Rapid review of the evidence. Lancet2020, 395, 912–920. [Google Scholar] [CrossRef]
Scott, FW Evaluation of risks and benefits associated with vaccination against coronavirus infections in cats. Adv. Vet. Med.1999, 41, 347–358. [Google Scholar] [CrossRef] [PubMed]
Fehr, D .; Holznagel, E .; Bolla, S .; Hauser, B .; Herrewegh, AA; Horzinek, MC; Lutz, H. Placebo-controlled evaluation of a modified life virus vaccine against feline infectious peritonitis: Safety and efficacy under field conditions. Vaccine1997, 15, 1101–1109. [Google Scholar] [CrossRef]
Balint, A .; Farsang, A .; Szeredi, L .; Zadori, Z .; Belak, S. Recombinant feline coronaviruses as vaccine candidates confer protection in SPF but not in conventional cats. Vet. Microbiol.2014, 169, 154–162. [Google Scholar] [CrossRef]
Vennema, H .; de Groot, RJ; Harbor, DA; Dalderup, M .; Gruffydd-Jones, T .; Horzinek, MC; Spaan, WJ Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization. J. Virol.1990, 64, 1407–1409. [Google Scholar] [CrossRef] [PubMed]
Polack, FP; Thomas, SJ; Kitchin, N .; Absalon, J .; Gurtman, A .; Lockhart, S .; Perez, JL; Perez Marc, G .; Moreira, ED; Zerbini, C .; et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N. Engl. J. Med.2020, 383, 2603–2615. [Google Scholar] [CrossRef] [PubMed]
Baden, LR; El Sahly, HM; Essink, B .; Kotloff, K .; Frey, S .; Novak, R .; Diemert, D .; Spector, SA; Rouphael, N .; Creech, CB; et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N. Engl. J. Med.2021, 384, 403–416. [Google Scholar] [CrossRef] [PubMed]
Sadoff, J .; Gray, G .; Vandebosch, A .; Cardenas, V .; Shukarev, G .; Grinsztejn, B .; Goepfert, PA; Truyers, C .; Fennema, H .; Spiessens, B .; et al. Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N. Engl. J. Med.2021, 384, 2187–2201. [Google Scholar] [CrossRef] [PubMed]
Voysey, M .; Clemens, SAC; Madhi, SA; Weckx, LY; Folegatti, PM; Aley, PK; Angus, B .; Baillie, VL; Barnabas, SL; Bhorat, QE; et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: An interim analysis of four randomized controlled trials in Brazil, South Africa, and the UK. Lancet2021, 397, 99–111. [Google Scholar] [CrossRef]
Tanriover, MD; Doganay, HL; Akova, M .; Guner, HR; Azap, A .; Akhan, S .; Kose, S .; Erdinc, FS; Akalin, EH; Tobacco, OF; et al. Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): Interim results of a double-blind, randomized, placebo-controlled, phase 3 trial in Turkey. Lancet2021, 398, 213–222. [Google Scholar] [CrossRef]
Ella, R .; Vadrevu, KM; Jogdand, H .; Prasad, S .; Reddy, S .; Sarangi, V .; Ganneru, B .; Sapkal, G .; Yadav, P .; Abraham, P .; et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: A double-blind, randomized, phase 1 trial. Lancet Infect. Dis.2021, 21, 637–646. [Google Scholar] [CrossRef]
Ali Waggiallah, H. Thrombosis Formation after COVID-19 Vaccination Immunological Aspects: Review Article. Saudi J. Biol. Sci.2021, 29, 1073–1078. [Google Scholar] [CrossRef]
Schultz, NH; Sorvoll, IH; Michelsen, AE; Munthe, LA; Lund-Johansen, F .; Ahlen, MT; Wiedmann, M .; Aamodt, AH; Skattor, TH; Tjonnfjord, GE; et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N. Engl. J. Med.2021, 384, 2124–2130. [Google Scholar] [CrossRef]
See, I .; Lale, A .; Marquez, P .; Streiff, MB; Wheeler, AP; Tepper, NK; Woo, EJ; Broder, KR; Edwards, KM; Gallego, R .; et al. Case Series of Thrombosis with Thrombocytopenia Syndrome after COVID-19 Vaccination-United States, December 2020 to August 2021. Ann. Intern. Med.2022. [Google Scholar] [CrossRef]
Dagan, N .; Barda, N .; Kepten, E .; Miron, O .; Perchik, S .; Katz, MA; Hernan, MA; Lipsitch, M .; Reis, B .; Balicer, RD BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N. Engl. J. Med.2021, 384, 1412–1423. [Google Scholar] [CrossRef] [PubMed]
Hall, VJ; Foulkes, S .; Saei, A .; Andrews, N .; Oguti, B .; Charlett, A .; Wellington, E .; Stowe, J .; Gillson, N .; Atti, A .; et al. COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): A prospective, multicenter, cohort study. Lancet2021, 397, 1725–1735. [Google Scholar] [CrossRef]
Pawlowski, C .; Lenehan, P .; Puranik, A .; Agarwal, V .; Venkatakrishnan, AJ; Niesen, MJM; O'Horo, JC; Virk, A .; Swift, MD; Badley, AD; et al. FDA-authorized mRNA COVID-19 vaccines are effective for real-world evidence synthesized across a multi-state health system. Med2021, 2, 979–992. [Google Scholar] [CrossRef] [PubMed]
Levine-Tiefenbrun, M .; Yelin, I .; Katz, R .; Herzel, E .; Golan, Z .; Schreiber, L .; Wolf, T .; Nadler, V .; Ben-Tov, A .; Kuint, J .; et al. Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine. Nat. Med.2021, 27, 790–792. [Google Scholar] [CrossRef] [PubMed]
Holzworth, J. Infectious diseases of cats. Cornell Vet.1963, 53, 131–143. [Google Scholar]
Weiss, RC; Oostrom-Ram, T. Inhibitory effects of ribavirin alone or combined with human alpha interferon on feline infectious peritonitis virus replication in vitro. Vet. Microbiol.1989, 20, 255–265. [Google Scholar] [CrossRef]
Weiss, RC; Cox, NR; Martinez, ML Evaluation of free or liposome-encapsulated ribavirin for antiviral therapy of experimentally induced feline infectious peritonitis. Res. Vet. Sci.1993, 55, 162–172. [Google Scholar] [CrossRef]
Khalili, JS; Zhu, H.; Mak, NSA; Yan, Y .; Zhu, Y. Novel coronavirus treatment with ribavirin: Groundwork for an evaluation concerning COVID-19. J. Med. Virol.2020, 92, 740–746. [Google Scholar] [CrossRef]
Zeng, YM; Xu, XL; He, XQ; Tang, SQ; Li, Y .; Huang, YQ; Harypursat, V .; Chen, YK Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir / ritonavir plus interferon-alpha, and ribavirin plus lopinavir / ritonavir plus interferon-alpha in patients with mild to moderate novel coronavirus disease 2019: Study protocol. Chin. Med. J.2020, 133, 1132–1134. [Google Scholar] [CrossRef]
Dickinson, PJ; Bannasch, M .; Thomasy, SM; Murthy, VD; Vernau, KM; Liepnieks, M .; Montgomery, E .; Knickelbein, KE; Murphy, B .; Pedersen, NC Antiviral treatment using the adenosine nucleoside analogue GS-441524 in cats with clinically diagnosed neurological feline infectious peritonitis. J. Vet. Intern. Med.2020, 34, 1587–1593. [Google Scholar] [CrossRef]
Pedersen, NC; Perron, M .; Bannasch, M .; Montgomery, E .; Murakami, E .; Liepnieks, M .; Liu, H. Efficacy and safety of the nucleoside analog GS-441524 for the treatment of cats with naturally occurring feline infectious peritonitis. J. Feline Med. Surg.2019, 21, 271–281. [Google Scholar] [CrossRef]
Pedersen, NC; Kim, Y .; Liu, H .; Galasiti Kankanamalage, AC; Eckstrand, C .; Groutas, WC; Bannasch, M .; Meadows, JM; Chang, KO Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. J. Feline Med. Surg.2018, 20, 378–392. [Google Scholar] [CrossRef]
Krentz, D .; Zenger, K .; Alberer, M .; Felten, S .; Bergmann, M .; Dorsch, R .; Matiasek, K .; Kolberg, L .; Hofmann-Lehmann, R .; Meli, ML; et al. Curing Cats with Feline Infectious Peritonitis with an Oral Multi-Component Drug Containing GS-441524. Viruses2021, 13, 2228. [Google Scholar] [CrossRef] [PubMed]
Hartmann, K .; Ritz, S. Treatment of cats with feline infectious peritonitis. Vet. Immunol. Immunopathol.2008, 123, 172–175. [Google Scholar] [CrossRef]
Veronese, N .; Demurtas, J .; Yang, L .; Tonelli, R .; Barbagallo, M .; Lopalco, P .; Lagolio, E .; Celotto, S .; Pizzol, D .; Zou, L .; et al. Use of Corticosteroids in Coronavirus Disease 2019 Pneumonia: A Systematic Review of the Literature. Front. Med.2020, 7, 170. [Google Scholar] [CrossRef] [PubMed]
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA2020, 324, 1330–1341. [Google Scholar] [CrossRef]
Group, RC; Horby, P .; Lim, WS; Emberson, JR .; Mafham, M .; Bell, JL; Linsell, L .; Staplin, N .; Brightling, C .; Ustianowski, A .; et al. Dexamethasone in Hospitalized Patients with Covid-19. N. Engl. J. Med.2021, 384, 693–704. [Google Scholar] [CrossRef]
Tanaka, Y .; Sato, Y .; Osawa, S .; Inoue, M .; Tanaka, S .; Sasaki, T. Suppression of feline coronavirus replication in vitro by cyclosporin A. Vet. Res.2012, 43, 41. [Google Scholar] [CrossRef]
Tanaka, Y .; Sato, Y .; Takahashi, D .; Matsumoto, H .; Sasaki, T. Treatment of a case of feline infectious peritonitis with cyclosporin A. Vet. Re. Case Rep.2015, 3, e000134. [Google Scholar] [CrossRef]
Cour, M .; Ovize, M .; Argaud, L. Cyclosporine A: A valid candidate to treat COVID-19 patients with acute respiratory failure? Crit. Care2020, 24, 276. [Google Scholar] [CrossRef]
Rudnicka, L .; Glowacka, P .; Goldust, M .; Sikora, M .; Sar-Pomian, M .; Rakowska, A .; Samochocki, Z .; Olszewska, M. Cyclosporine therapy during the COVID-19 pandemic. J. Am. Acad. Dermatol.2020, 83, e151 – e152. [Google Scholar] [CrossRef]
Sanchez-Pernaute, O .; Romero-Bueno, FI; Selva-O'Callaghan, A. Why choose cyclosporin A as first-line therapy in COVID-19 pneumonia. Rheumatol. Clin.2021, 17, 555–557. [Google Scholar] [CrossRef] [PubMed]
Softic, L .; Brillet, R .; Berry, F .; Ahnou, N .; Nevers, Q .; Morin-Dewaele, M .; Hamadat, S .; Bruscella, P .; Fourati, S .; Pawlotsky, JM; et al. Inhibition of SARS-CoV-2 Infection by the Cyclophilin Inhibitor Alisporivir (Debio 025). Antimicrob. Agents Chemother.2020, 64, e00876-20. [Google Scholar] [CrossRef] [PubMed]
Carbajo-Lozoya, J .; Ma-Lauer, Y .; Malesevic, M .; Theuerkorn, M .; Kahlert, V .; Prell, E .; von Brunn, B .; Muth, D .; Baumert, TF; Drosten, C .; et al. Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine A-derivatives including Alisporivir. Virus Res.2014, 184, 44–53. [Google Scholar] [CrossRef]
Hugo, TB; Heading, KL Prolonged survival of a cat diagnosed with feline infectious peritonitis by immunohistochemistry. Can. Vet. J.2015, 56, 53–58. [Google Scholar] [PubMed]
Conforti, C .; Giuffrida, R .; Zalaudek, I .; Di Meo, N. Doxycycline, a widely used antibiotic in dermatology with a possible anti-inflammatory action against IL-6 in COVID-19 outbreak. Dermatol. Ther.2020, 33, e13437. [Google Scholar] [CrossRef] [PubMed]
Izes, AM; Yu, J .; Norris, JM; Govendir, M. Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats. Vet. Q.2020, 40, 322–330. [Google Scholar] [CrossRef] [PubMed]
Hung, IF; Lung, KC; Tso, EY; Liu, R .; Chung, TW; Chu, MY; Ng, YY; Lo, J .; Chan, J .; Tam, AR; et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: An open-label, randomized, phase 2 trial. Lancet2020, 395, 1695–1704. [Google Scholar] [CrossRef]
Doki, T .; Takano, T .; Kawagoe, K .; Kito, A .; Hohdatsu, T. Therapeutic effect of anti-feline TNF-alpha monoclonal antibody for feline infectious peritonitis. Res. Vet. Sci.2016, 104, 17–23. [Google Scholar] [CrossRef] [PubMed]
Luo, P .; Liu, Y .; Qiu, L .; Liu, X .; Liu, D .; Li, J. Tocilizumab treatment in COVID-19: A single center experience. J. Med. Virol.2020, 92, 814–818. [Google Scholar] [CrossRef]
Capra, R .; De Rossi, N .; Mattioli, F .; Romanelli, G .; Scarpazza, C .; Sormani, MP; Cossi, S. Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia. Eur. J. Intern. Med.2020, 76, 31–35. [Google Scholar] [CrossRef]
Radbel, J .; Narayanan, N .; Bhatt, PJ Use of Tocilizumab for COVID-19-Induced Cytokine Release Syndrome: A Cautionary Case Report. Chest2020, 158, e15 – e19. [Google Scholar] [CrossRef] [PubMed]
Pediatric Intensive Care Society Statement: Increased Number of Reported Cases of Novel Presentation of Multisystem Inflammatory Disease; Pediatric Intensive Care Society: London, UK, 2020.
Dufort, EM; Koumans, EH; Chow, EJ; Rosenthal, EM; Muse, A .; Rowlands, J .; Barranco, MA; Maxted, AM; Rosenberg, ES; Easton, D .; et al. Multisystem Inflammatory Syndrome in Children in New York State. N. Engl. J. Med.2020, 383, 347–358. [Google Scholar] [CrossRef] [PubMed]
Feldstein, LR; Tenforde, MW; Friedman, KG; Newhams, M .; Rose, EB; Dapul, H .; Soma, VL; Maddux, AB; Mourani, PM; Bowens, C .; et al. Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19. JAMA2021, 325, 1074–1087. [Google Scholar] [CrossRef]
Tullie, L .; Ford, K .; Bisharat, M .; Watson, T .; Thakkar, H .; Mullassery, D .; Giuliani, S .; Blackburn, S .; Cross, K .; De Coppi, P .; et al. Gastrointestinal features in children with COVID-19: An observation of varied presentation in eight children. Lancet Child Adolesc. Health2020, 4, e19 – e20. [Google Scholar] [CrossRef]
LaRovere, KL; Riggs, BJ; Poussaint, TY; Young, CC; Newhams, MM; Maamari, M .; Walker, TC; Singh, AR; Dapul, H .; Hobbs, CV; et al. Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome. JAMA Neurol.2021, 78, 536–547. [Google Scholar] [CrossRef] [PubMed]
Feldstein, LR; Rose, EB; Horwitz, SM; Collins, JP; Newhams, MM; Son, MBF; Newburger, JW; Kleinman, LC; Heidemann, SM; Martin, AA; et al. Multisystem Inflammatory Syndrome in US Children and Adolescents. N. Engl. J. Med.2020, 383, 334–346. [Google Scholar] [CrossRef]
Blumfield, E .; Levin, TL; Kurian, J .; Lee, EY; Liszewski, MC Imaging Findings in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease (COVID-19). AJR Am. J. Roentgenol.2021, 216, 507–517. [Google Scholar] [CrossRef] [PubMed]
Alberer, M .; von Both, U. Cats and kids: How a feline disease may help us unravel COVID-19 associated paediatric hyperinflammatory syndrome. Infection2021, 49, 191–193. [Google Scholar] [CrossRef]
Sharma, C .; Ganigara, M .; Galeotti, C .; Burns, J .; Berganza, FM; Hayes, DA; Singh-Grewal, D .; Bharath, S .; Sajjan, S .; Bayry, J. Multisystem inflammatory syndrome in children and Kawasaki disease: A critical comparison. Nat. Rev. Rheumatol.2021, 17, 731–748. [Google Scholar] [CrossRef]
Groff, D .; Sun, A .; Ssentongo, AE; Ba, DM; Parsons, N .; Poudel, GR; Lekoubou, A .; Oh, JS; Ericson, JE; Ssentongo, P .; et al. Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection: A Systematic Review. JAMA Netw. Open2021, 4, e2128568. [Google Scholar] [CrossRef] [PubMed]
McAloose, D .; Laverack, M .; Wang, L .; Killian, ML; Caserta, LC; Yuan, F .; Mitchell, PK; Queen, K .; Mauldin, MR; Cronk, BD; et al. From People to Panthera: Natural SARS-CoV-2 Infection in Tigers and Lions at the Bronx Zoo. mBio2020, 11, e02220-20. [Google Scholar] [CrossRef] [PubMed]
Gaudreault, NN; Trujillo, JD; Carossino, M .; Meekins, DA; Morozov, I .; Madden, DW; Indran, SV; Bold, D .; Balaraman, V .; Kwon, T .; et al. SARS-CoV-2 infection, disease and transmission in domestic cats. Emerg Microbes Infect2020, 9, 2322–2332. [Google Scholar] [CrossRef] [PubMed]
Miro, G .; Regidor-Cerrillo, J .; Czech Republic, R .; Diezma-Diaz, C .; Montoya, A .; Garcia-Cantalejo, J .; Botias, P .; Arroyo, J .; Ortega-Mora, LM SARS-CoV-2 Infection in One Cat and Three Dogs Living in COVID-19-Positive Households in Madrid, Spain. Front. Vet. Sci.2021, 8, 779341. [Google Scholar] [CrossRef] [PubMed]
Giraldo-Ramirez, S .; Rendon-Marin, S .; Jaimes, JA; Martinez-Gutierrez, M .; Ruiz-Saenz, J. SARS-CoV-2 Clinical Outcome in Domestic and Wild Cats: A Systematic Review. Animals2021, 11, 2056. [Google Scholar] [CrossRef] [PubMed]
Ferasin, L .; Fritz, M .; Ferasin, H .; Becquart, P .; Corbet, S .; Ar Gouilh, M .; Legros, V .; Leroy, EM Infection with SARS-CoV-2 variant B.1.1.7 detected in a group of dogs and cats with suspected myocarditis. Vet. Rec.2021, 189, e944. [Google Scholar] [CrossRef] [PubMed]
Chiba, S .; Halfmann, PJ; Hatta, M .; Maemura, T .; Fan, S .; Armbrust, T .; Swartley, OM; Crawford, LK; Kawaoka, Y. Protective Immunity and Persistent Lung Sequelae in Domestic Cats after SARS-CoV-2 Infection. Emerg. Infect. Dis.2021, 27, 660–663. [Google Scholar] [CrossRef]
Several issues often arise during FIP treatment. Before addressing these issues, it is important to mention the FIP treatment itself. Only antivirals that target specific viral proteins and inhibit FIP replication have been shown to have therapeutic effects. Currently, these include nucleoside analogs and RNA replication inhibitors GS-441524 (and a related prodrug Remdesivir), Molnupiravir (EIDD-2801) and the viral protease inhibitor GC376. Proper administration of these drugs has resulted in the cure of all forms of FIP in more than 90 % with minimal side effects. Most treatments are completed without complications. However, certain issues that are the subject of this article often arise.
I pointed out the problems associated with unwanted sexual behavior in intact females and males treated with specific antivirals. The questions often come from countries where castration is either postponed or not common practice. They fear that the stress of castration and vaccines may affect the outcome of antiviral treatment. I believe that such concerns are exaggerated. If a cat is in treatment and in remission or is considered cured, it is okay to sterilize or neuter it, but preferably in the least stressful way possible. Cats can be neutered and sterilized quickly and efficiently and returned to their homes on the same day (castration) or within one day (sterilization) with minimal preoperative, operative and postoperative drug treatment and restrictions (eg cages, E-collars). Such operations will be less stressful for cats (and owners, which will then be reflected in their cats) than their sexual behavior.
I am also not in favor of hormonal treatment to prevent unwanted sexual behavior in males or females, and I feel that effective castration and sterilization will be less stressful in the long run than such preventive measures. Therefore, if it is necessary to permanently change this behavior, surgical castration is more appropriate than chemical.
Some owners seem to want to keep cured cats intact so that they can be used for breeding later. We know that FIP has both genetic and environmental components, which has led to the recommendation that purebred cats that breed FIP kittens should not be used for breeding. This should be even more true for cats that have been cured of the FIP.
As far as vaccines are concerned, many already know that I am not a big fan of adult vaccines and the first annual booster vaccines because I feel that immunity is long-lasting. I also think that rabies vaccines cannot be used routinely in cats, whether in terms of public health or cats. Nevertheless, I accept that these views are not generally accepted and that the laws in several states require rabies to be vaccinated against rabbits, in some vaccination is not required and in others it is recommended but not required. I have not noticed the consequences of routine vaccinations in any of our cured cats. However, it is not something I would recommend for cats undergoing treatment. The immune system of these cats is responsible for other things than responding to vaccines.
What are the indications for drugs other than specific antivirals for the treatment of FIP? During the initial illness, supportive (symptomatic) treatment may be required to keep the cats alive long enough for the antivirals to take effect. Drugs often used in this early stage usually include antibiotics (doxycycline / clindamycin), analgesics (opioids, gabapentin), anti-inflammatory drugs (corticosteroids, NSAIDS), immunostimulants (interferons, non-specific immunostimulants), and drugs. I have tried to avoid excessive use of these drugs except for temporary use and only if it is strongly justified, especially in severely ill cats during the first days. The most important goal of FIP treatment is to stop the replication of the virus in macrophages, which immediately stops the production of the numerous inflammatory and immunosuppressive cytokines that cause the symptoms of FIP. Although some drugs, such as corticosteroids (prednisolone) or NSAIDs (meloxicam), may inhibit inflammatory cytokines and cause clinical improvement, they are not curative. They can also mask the beneficial effects of GS treatment, which are often monitored to assess the effect and course of treatment. The response to antiviral treatment is also used for diagnostic purposes. The only drugs that completely suppress these harmful cytokines and cure FIP are antivirals such as GS-441524, molnupiravir or GC376, and related compounds. These antivirals cause a dramatic improvement in fever, activity, appetite, etc. within 24-48 hours. This improvement will be much greater than any improvement made with other drugs. Therefore, if the use of other drugs is not warranted, they should be discontinued as soon as the symptoms of FIP have steadily improved.
I also do not believe in many supplements that are said to treat or prevent problems with the liver, kidneys, immune system or other organs. These supplements are expensive and have not been shown to be effective in what they claim. B12 injections only treat B12 deficiency, which is rare, and not anemia in FIP. The same goes for other vitamins. This also applies to a wide range of nutritional supplements and special diets for cats of many types. There is no essential ingredient in any of these supplements that could be provided by well-tested commercial cat food brands. There is also a possibility that some supplements interfere with the absorption of oral antivirals.
How should cats be monitored after treatment and during the post-treatment observation period? From a technical point of view, no further blood tests are needed, especially if routine health assessments such as weight, appetite and temperature are continued during this period. Blood tests during this period do not change the outcome and can only increase the cost of treatment and increase the owner's stress. However, it is common for successfully treated cats to routinely test for blood during a 12-week post-treatment observation, usually every 4 weeks, but sometimes more frequently. In some cases, routine blood testing is continued for 12 weeks after treatment, even out of fear of possible relapse or recurrence. Relapses or new infections after a 12-week observation period are rare and are preceded by external signs of the disease, such as weight loss, lethargy, anorexia, poor coat and fever, which would be the best indicators for a blood test. Blood test panels also contain many values, and it is not uncommon for one or more values to be abnormal in healthy cats. Care must be taken not to over-interpret such abnormalities and to lead to excessive concern or additional testing in order to determine their significance. For example, a mild to moderate increase in one in three liver enzymes in a healthy cat is much less important than in another cat with symptoms of the disease. Read "Various issues common during FIP antiviral treatment and aftercare"
This article discusses the development of knowledge about feline infectious peritonitis (FIP) from its recognition in 1963 to the present and has been prepared to inform veterinarians, cat rescuers and carers, shelter staff and cat lovers. The causative agent of the feline coronavirus and its relationship to the ubiquitous and minimally pathogenic feline intestinal coronavirus, epizootology, pathogenesis, pathology, clinical signs and diagnostics are briefly mentioned. The main emphasis is placed on the risk factors influencing the incidence of FIP and the role of modern antivirals in successful treatment.
Feline infectious peritonitis (FIP) was described as a specific disease in 1963 by veterinarians at Angell Memorial Animal Hospital in Boston (Holzworth 1963) (Fig. 1). Pathology records from this institution and Ohio State University failed to identify earlier cases (Wolfe and Griesemer 1966), although identical cases were soon recognized worldwide. The initial pathological descriptions were of diffuse inflammation of the tissues lining the abdominal cavity and abdominal organs with extensive effusion of inflammatory fluid, after which the disease was eventually named (Wolfe and Griesemer 1966, 1971) (Figs. 2, 3). A second and less common clinical form of FIP, which presents with less diffuse and more widespread granulomatous lesions involving organ parenchyma, was first described in 1972 (Montali and Strandberg 1972) (Figs. 3,4). The presence of inflammatory effusions in the body cavity in the common form and the absence of effusions in the less common form led to the names wet (effusion, non-parenchymatous) and dry (non-effusion, parenchymatous) FIP.
The prevalence of FIP appears to have increased during the panzootic disease caused by feline leukemia virus (FeLV) in the 1960s–1980s, when many cases of FIP were found to be associated with FeLV (Cotter et al., 1973; Pedersen 1976a). Subsequent management of FeLV infection in owned cats through rapid testing and vaccination resulted in an increase in FIP cases. However, recent interest in breeding/rescue along with effective treatment has led to increased awareness of the disease and its diagnosis.
The first attempts did not allow identifying the causative agent of FIP, but confirmed its infectious nature (Wolfe and Griesemer 1966). A viral etiology was established in 1968 using ultrafiltrates of infectious material (Zook et al., 1968). The causative virus was subsequently identified as a coronavirus (Ward 1970), which is closely related to enteric coronaviruses of dogs and pigs (Pedersen et al., 1978).
Confusion arose when feline enteric coronavirus (FECV) was isolated from the feces of healthy cats and proved to be indistinguishable from feline infectious peritonitis virus (FIPV) (Pedersen et al., 1981). Unlike FIPV, which readily induced FIP in laboratory cats, experimental infections with FECV were largely asymptomatic. The relationship between the two viruses became clear when FIPVs were found to be FECV mutants that arise in the body of every cat with FIP (Vennema et al., 1995; Poland et al., 1996).
FECV is ubiquitous in feline populations worldwide and is first shed in faeces from approximately 9–10 weeks of age, coinciding with the loss of maternal immunity (Pedersen et al., 2008 ;). The infection takes place via the faecal-oral route and targets the intestinal epithelium, and the primary signs of enteritis are mild or inconspicuous (Pedersen et al., 2008; Vogel et al., 2010). Subsequent faecal excretion occurs from the colon and usually stops after several weeks or months (Herrewegh et al., 1997; Pedersen et al., 2008; Vogel et al., 2010). Immunity is short-lived and repeated infections are common (Pedersen et al., 2008; Pearson et al., 2016). Over time, stronger immunity eventually develops and cats older than 3 years are less likely to shed the infection in their faeces (Addie et al., 2003). FECV is constantly subject to genetic drift into locally and regionally identifiable clades (Herrewegh et al., 1997; Pedersen et al., 2009).
FECV and FIPV are classified as biotypes of the feline coronavirus (FCoV) subspecies. The genomes of FECV and FIPV biotypes are related at >98 %, but with unique host cell tropism and pathogenicity (Chang et al., 2012; Pedersen et al., 2009). FECVs infect the mature intestinal epithelium, whereas FIPVs lose intestinal tropism and acquire the ability to replicate in monocytes/macrophages. The published names FECV or FIPV will be used here when discussing aspects of the disease specific to each biotype, while the term FCoV will be used when discussing features common to both biotypes.
Three types of mutations are involved in the biotype change of FECV to FIPV. The first type, which is unique to each cat with FIP (Poland et al., 1996), consists of an accumulation of missense and nonsense mutations in the c-terminus of the auxiliary 3c gene, often resulting in truncated 3c gene products (Pedersen et al., 2012 ; Vennema et al., 1995). The second type of mutation consists of two specific single nucleotide polymorphisms in the fusion peptide of the S gene, one or the other form being common to >95 % FIPV and absent in FECV (Chang et al., 2012). A third type of mutation, unique to each FIPV isolate and not found in FECV, occurs in and around the furin cleavage motif between the receptor binding domain (S1) and the fusion domain (S2) of the spike gene (S) (Licitra et al., 2013). These mutations have different effects on furin cleavage activity. Together and in an as yet undetermined manner, they are responsible for the shift of the tropism of the host cell from the enterocyte to the macrophage and for the profound change in the form of the disease.
FCoV, and therefore FECV and FIPV, exist in two serotypes identified by antibodies against the viral neutralizing epitope on the S gene (Herrewegh et al., 1998; Terada et al., 2014). Serotype I FCoVs are identified in cat sera and are prevalent in most countries. Serotype II FCoVs result from recombination with the S part of the canine coronavirus gene (Herrewegh et al., 1998; Terada et al., 2014) and are identified by canine coronavirus antibodies. Serotype II FIPVs are easily cultured in tissue culture, whereas serotype I FIPVs are difficult to adapt to growth in vitro. Serotype I and II FECVs were not grown in conventional cell cultures (Tekes et al., 2020).
FIPVs are found exclusively in activated monocytes and macrophages in affected tissues and effusions and are not secreted into the environment. Therefore, cat-to-cat (horizontal) transmission of FIPV is not the main mode of spread. Rather, FIP follows the pattern of an underlying enzootic FECV infection, with sporadic cases and occasional small outbreaks of disease (Foley et al., 1997). These clusters of cases can be mistaken for epizootics. The only report of an epizootic occurrence of FIP was associated with a single serotype II virus that appeared to develop in a shelter housing both dogs and cats (Wang et al., 2013). Horizontal transmission in this case followed an epizootic rather than an enzootic disease model, with infection spreading rapidly to cats of all ages and in close contact with the index case (Wang et al., 2013).
The low incidence of FIP cases in the population suggests that FIPV mutations arise infrequently. However, studies involving FECV infection in immunocompromised cats infected with FIV and FeLV suggest that FIP mutants may be common but only cause disease under certain circumstances. Nineteen cats infected with feline immunodeficiency virus (FIV) for 6 years and a control group of 20 littermates not infected with FIV were orally challenged with FECV (Poland et al., 1996). Cats in both groups remained asymptomatic for two months when two cats in the FIV-infected group developed FIP. In a second study, 26 young cats with enzootic FECV infection from a breeding colony with no history of FIP were contact-exposed to FeLV carriers (Pedersen et al., 1977). Two kittens in the group subsequently developed FIP 2–10 weeks after becoming FeLV viremic. The question remains, how long can FIPV viruses survive in the body before they are eliminated? According to one of the theories, they persist in the body for a certain time and become pathological only if immunity against them is impaired (Healey et al., 2022). This theory is supported by the way immunity to FeLV develops. Most cats resist FeLV by kitten age and develop robust and permanent immunity, but this occurs within a few weeks, during which the virus persists in a subclinical or latent state (Pedersen et al., 1982; Rojko et al., 1982). . Methylprednisolone given during this period, but not after, will abolish developing immunity and lead to a state of persistent viremia.
Epizootiology is the study of the occurrence, spread and possible control of animal diseases and the influence of environmental, host and agent factors. FIP is considered one of the most important infectious causes of death in cats, although there are no precise data on prevalence. It is estimated that 0.3–1.4 % deaths of cats presented to veterinary institutions are related to FIP (Rohrbach et al., 2001; Pesteanu-Somogyi et al., 2006; Riemer et al., 2016) and in some shelters and breeding stations up to 3.6–7.8 % (Cave et al., 2002). FIP is also described as an environmental disease with a higher incidence of multiple cats. Three-quarters of the FIP cases in the currently ongoing treatment study came from the field through foster carers/rescues and cat shelters, 14 % from kennels, and only 11 % from households.1
Studies based on cases observed in academic institutions have demonstrated the influence of age and gender on the incidence of FIP (Rohrbach et al., 2001; Pesteanu-Somogyi et al., 2006; Pedersen 1976a; Worthing et al., 2012; Riemer et al., 2016) . Three-quarters of the cases in these cohorts occurred in cats younger than 3 years of age, and few cases occurred after 7 years of age. This was also confirmed by a current and ongoing field study from the Czech Republic and Slovakia, in which it was found that more than 80 % cases of FIP occurred in cats under 3 years of age and only 5 % in cats older than 7 years (Fig. 6) .1 Earlier institutional studies differed on the effect of sex, but indications were that male cats were slightly more susceptible to FIP than female cats. This was also confirmed by current data from the field, which show a ratio of males to females of 1.3:1.1. It is unclear whether castration affects the incidence of FIP, with some reports suggesting that it may increase susceptibility (Riemer et al., 2016), while others do not report such a clear effect.1
Other environmental and viral risk factors have been implicated in the increased incidence of FIP, but their significance requires knowledge of disease occurrence in their absence. A possible baseline may have been provided by a study of enzootic FECV infection, which had been unrecognized for many years in a well-managed specific pathogen-free breeding colony (Hickman et al., 1995). This colony was kept in strict quarantine free of other infections and the standard of nutrition and husbandry was high. This colony produced hundreds of kittens each year before the first case of FIP was diagnosed. Such observations suggest that FIP may be a rare phenomenon in the absence of risk factors.
The importance of moving to a new home as a risk factor for FIP is only now being appreciated. Breeders, many of whom have not experienced any cases of FIP in their litters, are most concerned about the announcement that one of their kittens has developed FIP shortly after going to a new home. A recent study found that more than half of cats with FIP had experienced a change in environment, shelter or capture in the weeks before the illness.1 Cats are known to hide outward signs of stress, even when suffering from serious internal disease consequences. Even simple procedures such as changing the cage suppress immunity and reactivate latent herpes virus shedding and disease symptoms in cats (Gaskell and Povey, 1977). Stressful situations, even those that seem minor, can cause a decrease in lymphocyte levels and “sickness behavior” (Stella et al., 2013).
Differences in the genetic make-up of enzootic FCoV strains may also contribute to the prevalence of FIP in the population. Serotype II FIPVs are thought to be more virulent than serotype I and more likely to be transmitted from cat to cat (Lin et al., 2009; Wang et al., 2013). It is also possible that certain FECV clades are more susceptible to mutation to FIPV, which should be studied. The author also observed a disproportionately high proportion of cats with neurologic FIP in some regions, suggesting that genetic determinants in certain FCoV strains may be more neurotropic.
Immunodeficiencies associated with retroviruses are associated with susceptibility to FIP. Up to half of FIP cases during the peak of FeLV panzootic disease were persistently infected with FeLV (Cotter et al., 1973; Pedersen 1976a; Hardy 1981). FeLV infection causes suppression of T-cell immunity, which may inhibit the protective immune response to FIP. The importance of FeLV infection for the incidence of FIP has declined significantly since the 1980s, when carrier elimination and vaccination pushed FeLV back into the wild, where exposures are less severe and immunity is the usual outcome. Chronic feline immunodeficiency virus (FIV) infection has also been shown to be a risk factor for FIP in FECV-infected cats under experimental conditions (Poland et al., 1996). In one recent field study, FeLV infection was recognized in 2 % and FIV in 1 % cats treated for FIP.1
The incidence of FIP in purebred cats is reported to be higher than in random breeding cats, with some breeds appearing to be more susceptible than others (Pesteanu-Somogyi et al., 2006; Worthing et al., Genetic predisposition to FIP has been investigated in several Persian cat breeds and is estimated to account for half the risk of the disease (Foley et al., 1997). Some breeds, such as the Birman, are more susceptible to developing dry than wet FIP (Golovko et al., 2013). Attempts to identify specific genes associated with susceptibility for FIP in Burmese cats included several immune-related genes, but none reached the desired significance (Golovko et al., 2013).The largest study of genetic susceptibility to FIP showed that it is extremely polymorphic and reported consanguinity as a major risk factor. breeding (Pedersen et al., 2016).Specific polymorphisms in several genes have also been associated with high levels of FECV shedding among several breeding cat breeds (Bubeniko and et al., 2020).
In females, FIP, usually the wet form, may develop during pregnancy or in the perinatal period. This phenomenon resembles the suppression of immunity in pregnant women and the predisposition to certain infections (Mor and Cardenas 2010). It is not clear whether subclinical FIP is activated by pregnancy or by increased susceptibility to new infection. Maternal infection early in pregnancy results in fetal death and resorption, while later infections often result in abortion (Fig. 7). Kittens can be born healthy, but develop disease in the perinatal period and die. Some babies are born uninfected thanks to the effectiveness of the placental barrier between mother and fetus or thanks to the help of antiviral treatment (Fig. 8).
A possible increase in the number of cases of FIP was observed in cats older than 10 years in studies conducted 50 years ago (Pedersen 1976a). Slightly more than 3 % cases of FIP in a recent study occurred in cats 10 years of age and older and 1.5 % in cats 12 years of age and older (Fig. 6).1 The occurrence of FIP in the elderly often involves two different scenarios. The first scenario also involves exposure to FECV faecal excretion, but in a unique way. It is common for old cats to mate as kittens and live together in relative isolation unexposed to FECV for many years. One cat in the pair dies, is left alone, and a much younger companion obtained from a rescue organization, shelter, or kennel is brought into the household that has a high probability of excreting FECV. Older cats are also susceptible to the same FIP risk factors as younger cats, as well as other factors associated with aging. The first of these is the impact of aging on the immune system, with the most consequential being the deterioration of cellular immune function (Day 2010). Other risk factors associated with old cats include the debilitating and potentially immunosuppressive effects of diseases such as cancer and chronic diseases of the kidneys, liver, oral cavity and intestines. Some diseases in old cats can be mistaken for FIP or complicate the treatment of FIP if they are present at the same time.
Other risk factors that need further investigation include loss of maternal systemic immunity by separation at birth, early weaning and loss of lactogenic immunity, malnutrition, common kitten infectious diseases, early neutering, vaccination, congenital heart defects, and even a shelter fire (Drechsler et al.), 2011; Healey et al., 2022; Pedersen 2009, Pedersen et al. 2019).1 However, the most important positive risk factor remains the presence of FECV in the population (Addie et al., 1995). The prevalence of FIP in several Persian cat breeds was also related in one study to the proportion of cats that shed FECV at a given time and to the proportion of these cats that are chronic shedders (Foley et al., 1997). The importance of exposure to FECV supports the need to find ways to either prevent infection or reduce its severity. One of the first steps is a better understanding of FECV immunity (Pearson et al., 2019).
The first interface between FECV and the immune system is the lymphatic tissues of the intestine (Malbon et al., 2019, 2020). Although the downstream events leading to FIP are not fully understood, it is possible to speculate based on what is already known about FECV and FIPV infections, other macrophage-tropic infections, and viral immunity in general. During intestinal infection, FECV particles and proteins reach the local lymphatic tissues and are processed by phagocytic cells first into peptides and finally into amino acids. Some of these peptides will be recognized as foreign when arrayed on the cell surface, triggering innate (innate or non-specific) and adaptive (acquired or specific) immune responses (Pearson et al., 2016). FECVs also mutate to FIPV at the same time and in the same cell type. Some of these mutations will allow the virus to replicate in these or closely related cells of a specific monocyte/macrophage lineage.
The host cell for FIPV appears to be a specific class of activated monocytes found around venules on the surface of intestinal and thoracic organs, mesentery, omentum, uveal tract, meninges, choroid and ependyma of the brain and spinal cord, and freely in effusions. These cells belong to the activated (M1) class (Watanabe et al., 2018) and resemble a subpopulation of small peritoneal macrophages described in mice (Cassado et al., 2015). This type of cell arises from circulating bone marrow-derived monocytes that are rapidly mobilized from the blood in response to infectious or inflammatory stimuli. A similar-looking population of activated monocytes has been described around blood vessels in the retina affected by FIP (Ziolkowska et al., 2017). These cells stained for calprotectin, indicating their blood origin. Although FIPV infection occurs initially in smaller activated monocytes, viral replication is most intense in large, vacuolated, terminally differentiated macrophages (Watanabe et al., 2018). The virus released from these cells rapidly infects activated monocytes produced in the bone marrow and drawn to the site from the bloodstream.
The cellular receptor used by FECVs to infect intestinal epithelial cells has not yet been determined. The cellular receptor that FIPVs use to infect activated monocytes is also unknown. RNAs for conventional coronavirus receptors such as aminopeptidase N (APN), angiotensin converting enzyme 2 (ACE2) and CD209L (L-SIGN) were not upregulated in infected peritoneal cells of cats with experimental FIP, and CD209 (DC-SIGN) was significantly underexpressed (Watanabe et al., 2018). An alternative route of infection of activated monocytes may involve immune complexation of the virus and entry into cells by phagocytosis (Dewerchin et al., 2008, 2014; Van Hamme et al., 2008). Activated monocytes in lesions stain strongly positive for FIPV antigen, IgG and complement (Pedersen, 2009) and mRNA for FcγRIIIA (CD16A/ADCC receptor) is markedly increased in infected cells (Watanabe et al., 2018), supporting infection through immune complexation and alternative receptors related to phagocytosis.
Macrophage pathogens are intracellular and elimination of infected cells occurs through lymphocyte-mediated killing. The first line of defense is non-specific lymphocytes, and if they fail, an adaptive immune response to FIPV follows through specific T-lymphocytes. If infected activated monocytes and macrophages fail to be contained and eliminated, they may disseminate locally in the abdominal cavity, possibly from lymph nodes in the lower intestinal region and the site of FECV replication. Spread locally and to distant sites via the bloodstream is by infected monocyte cells (Kipar et al., 2005).
FIP occurs in two basic forms, wet (effusive, nonparenchymatous) (Figures 2 and 3) or dry (noneffusive, parenchymatous) (Figures 4 and 5), with wet FIP accounting for 80 % cases.1 The term "wet" refers to a characteristic fluid discharge in the abdomen or chest (Wolfe and Griesemer 1966, 1971). Wet FIP lesions are dominated by inflammation reminiscent of immediate or Arthus-type hypersensitivity (Pedersen and Boyle, 1980), whereas dry FIP lesions resemble delayed-type hypersensitivity reactions (Montali and Strandberg 1972; Pedersen 2009). The wet and dry forms of FIP therefore reflect competing influences of antibody and cell-mediated immunity and associated cytokine pathways (Malbon et al., 2020, Pedersen 2009). Immunity to FIPV-infected cells, which is the norm, is thought to involve strong cell-mediated responses (Kamal et al. 2019). Dry FIP is thought to occur when cell-mediated immunity is partially effective in suppressing infection, and wet FIP when cellular immunity is ineffective and humoral immune responses predominate.
FIP is considered unique among macrophage infections because it is viral, but the dry form shares many clinical and pathogenic features with feline diseases caused by systemic mycobacterial (Gunn-Moore et al., 2012) and fungal infections (Lloret et al., 2013). . Similarities in pathogenesis also exist between wet FIP and antibody-enhanced viral infections such as dengue fever and dengue hemorrhagic shock syndrome (Pedersen and Boyle 1980; Rothman et al., 1999; Weiss and Scott 1981).
Host responses are thought to solely determine the outcome of FIPV infection and the resulting forms of disease. However, macrophage-tropic pathogens have evolved their own unique defense mechanisms against the host (Leseigneur et al., 2020). One of the mechanisms is the delay of programmed cell death (apoptosis). Delayed apoptosis allows sustained microbial replication and eventual release of more infectious agents, as has also been described in FIPV-infected macrophages (Watanabe et al., 2018). FIPV can also control the recognition and killing of infected activated monocytes by specific or non-specific T-cells. The cell surface targets for T-cells that kill infected cells are likely FIPV proteins (antigens) expressed on major histocompatibility complex class I (MHC-I) receptors. However, surface expression of viral antigens by MHC-I receptors was not detected on FIPV-positive cells collected from FIP tissues or effusions (Cornelissen et al., 2007). DC-Sign has been proposed as a receptor for FIPV (Regan and Whitaker, 2008), but RNA for DC-Sign is markedly underexpressed by infected peritoneal cells, whereas RNA for Fc (MHC-II) receptors is markedly overexpressed and RNA for MHC -I is reduced (Watanabe et al., 2018). This suggests that the normal mode of infection of host cells may be altered by FIPV to favor infection by phagocytosis instead of binding to specific viral receptors on the cell surface, fusion with the cell membrane, and internalization.
Detailed descriptions of the gross and microscopic lesions in the wet form of FIP were first described by Wolfe and Griesemer (1966, 1971). The disease is characterized by vasculitis involving venules in the tissues lining the abdominal or thoracic cavity, organ surfaces, and supporting tissues such as the mesentery, omentum, and mediastinum. The inflammatory process leads to effusions in the abdominal or chest cavity up to a volume of one liter or more (Fig. 2, 3). The underlying lesion is a pyogranuloma, which consists of a focal accumulation of activated monocytic cells in various stages of differentiation, interspersed with non-degenerate neutrophils and sparse numbers of lymphocytes. Pyogranulomas are superficially oriented and appear grossly and microscopically as single and coalescent plaques (Fig. 2).
FIPV antigen is immunohistochemically (IHC) observed only in activated monocytes in lesions and effusions (Litster et al., 2013). Large vacuolated terminally differentiated macrophages are particularly rich in virus (Watanabe et al., 2018), reminiscent of the lepromatous form of leprosy (deSousa et al., 2017). Lymph nodes located near the sites of inflammation are hyperplastic and enlarged.
The relationship between dry and wet FIP was first described in 1972 in a report of cases of unknown etiology with similar pathology (Montali and Strandberg 1972). As the authors state, "this pathological syndrome was characterized by granulomatous inflammation in various organs, but mainly affected the kidneys, visceral lymph nodes, lungs, liver, eyes and leptomeninges". Tissue extracts of these lesions induced wet FIP in laboratory cats, confirming that wet and dry FIP are caused by the same agent.
The gross and microscopic pathology of dry FIP resembles that of other macrophage-tropic infections such as feline systemic blastomycosis, histoplasmosis, coccidioidomycosis (Lloret et al., 2013), tuberculosis and leprosy (Gunn-Moore et al., 2012). Lesions of dry FIP mainly involve the abdominal organs (Figs. 5, 6) and are rare in the thoracic cavity (Montali and Strandberg 1972; Pedersen 2009). Lesions are less widespread and focal than in wet FIP, with a tendency to extend from the serous surfaces into the parenchyma of the underlying organs (Figs. 5, 6). The target of the host immune response are small aggregates of infected monocytic cells associated with venules, similar to pyogranulomas in wet FIP, but surrounded by dense accumulations of lymphocytes and plasma cells and variable fibrosis. The florid hyperemia, edema, and microhemorrhage associated with wet FIP are mostly absent, therefore significant effusions in the body cavities are absent. The host response to foci of infection gives the lesions a gross tumor-like appearance (Figs. 5, 6). Infected activated monocytes in the central focus of infection are less dense and contain lower levels of virus than in the wet form (Pedersen 2009;), a feature of the tuberculoid form of leprosy (de Sousa et al., 2017). Lesions in some places, for example on the wall of the large intestine, can cause a dense surrounding zone of fibrosis, which resembles classic tuberculosis granulomas. Transitional forms also exist between wet and dry forms in a small number of cases and are mostly recognizable at autopsy (Fig. 3).
Ocular and neurological FIP are classified as forms of dry FIP (Montali and Strandberg 1972). However, pathology in the uveal tract and retina and in the ependyma and meninges of the brain and spinal cord is intermediate between wet and dry FIP (Fankhauser and Fatzer 1977; Peiffer and Wilcock 1991). This can be explained by the effect of the blood-ocular and blood-brain barrier in protecting these areas from systemic immune reactions.
Clinical characteristics of FIP
The five most common symptoms in cats with FIP, regardless of clinical form and frequency of occurrence, are lethargy, loss of appetite, enlarged abdominal lymph nodes, weight loss, fever, and deteriorating coat.1 These symptoms can appear quickly, within a week, or they can exist for many weeks or even months before a diagnosis is made. The course of the disease tends to be more rapid in cats with wet FIP than with dry FIP, and growth retardation is common in young cats, especially those with more chronic disease. 20 % cats with fever as the main symptom are eventually diagnosed with FIP (Spencer et al., 2017).
The wet form of FIP occurs in approximately 80 % cases, more often in younger cats, and tends to be more severe and more rapidly progressive than the dry form. Abdominal effusion (ascites) is four times more common than pleural effusion, with abdominal distension (Fig. 9) and dyspnea being common symptoms. Pyrexia and jaundice are more common symptoms in cats with wet than dry FIP (Tasker, 2018).
Most cats with dry FIP present with disease symptoms limited to the abdomen and/or chest. The most common clinical signs of dry FIP are palpable or ultrasound-identifiable masses in the kidney (Fig. 4), cecum, colon, liver, and associated lymph nodes (Fig. 5). Lesions of dry FIP usually spare the thoracic cavity and rarely occur in the skin, nasal passages, pericardium, and testes as part of a wider systemic disease.
Neurological and ocular disease are the sole or secondary features of 10 % of all FIP cases and are 10 times more often associated with dry than wet FIP (Pedersen 2009). The neurological and ocular forms of FIP have been classified as forms of dry FIP, but it may be more appropriate to classify them as distinct forms of FIP resulting from the modifying effects of the blood-ocular and blood-brain barriers behind which they occur. These barriers have a strong impact on the nature of eye and central nervous system (CNS) disease and response to antiviral therapy.
Clinical signs of neurologic FIP involve both the brain and spinal cord and include posterior weakness and ataxia, generalized incoordination, seizures, mental dullness, anisocoria, and varying degrees of fecal and/or urinary incontinence (Foley et al., 1998; Dickinson et al., 2020) ( Fig. 10). Extreme intracranial pressure can lead to sudden herniation of the cerebellum and brainstem into the spinal canal and spinal shock syndrome. Prodromal symptoms include compulsive wall or floor licking, litter eating, involuntary muscle twitching, and reluctance or inability to jump to high places. Eye involvement may precede or accompany neurological disease. Neurological FIP is a common phenomenon with antiviral therapy, either occurring during treatment of non-CNS forms of FIP or as a manifestation of disease relapse after treatment cessation (Pedersen et al., 2018, 2019; Dickinson et al., 2020).
Eye involvement is usually obvious and is confirmed by ophthalmoscopic examination of the anterior and posterior chambers. Ocular FIP affects the iris, ciliary bodies, retina, and optic disc to varying degrees (Peiffer and Wilcock, 1991; Ziółkowska et al., 2017; Andrew, 2000). The earliest symptom is often a unilateral change in the color of the iris (Fig. 11). The anterior chamber may appear cloudy and may show high protein levels and water turbidity on refraction. Inflammatory products in the form of activated macrophages, red blood cells, fibrin markers and small blood clots are washed into the anterior chamber. This material often adheres to the back of the cornea as keratic precipitates (Fig. 12). The disease can also affect the retina in tapetal and non-tapetal areas and lead to retinal detachment. Intraocular pressure is usually low, except in cases complicated by involvement of the ciliary body and glaucoma (Fig. 12, 13).
Signaling, environmental history, clinical signs, and physical examination findings often point to FIP (Tasker, 2018). A thorough physical examination should include body weight and temperature, coat and body condition, manual palpation of the abdomen and abdominal organs, gross assessment of cardiac and pulmonary function, and a cursory examination of the eyes and neurological system. Strong suspicion of an effusion in the abdominal or thoracic cavity may warrant confirmatory aspiration and even in-house fluid analysis as part of the initial examination.
Abnormalities in the complete blood count (CBC) and basic serum biochemical panel are important factors in the diagnosis of FIP (Tasker, 2018; Felten and Hartmann, 2019) and monitoring of antiviral therapy (Pedersen et al., 2018, 2019; Jones et al., 2021). ; Krentz et al., 2021) (Fig. 14). Total leukocyte counts are most likely high in cats with wet FIP, but low counts can occur with severe inflammation. A high leukocyte count is often associated with neutrophilia, lymphopenia, and eosinopenia. Mild to moderate non-regenerative anemia is also frequently seen in both wet and dry FIP. Total protein is usually elevated due to elevated globulin levels, while albumin values tend to be low (Fig. 14). This results in an A:G ratio that is often lower than 0.5-0.6 and is considered one of the most consistent indicators of FIP. However, a low A:G ratio can occur in situations where both albumin and globulin are within the reference range or in other diseases. Therefore, the A:G ratio should not be the only FIP indicator and should always be evaluated in the context of other FIP indicators (Tasker, 2018; Felten and Hartmann, 2019). Serum protein values obtained from most serum chemistry panels are usually adequate. Serum protein electrophoresis can provide additional information, especially if protein values from serum chemistry are questionable (Stranieri et al., 2017).
Overreliance on CBC and serum biochemistry abnormalities can lead to diagnostic uncertainty when absent, despite the fact that no test value is consistently abnormal in all cases of FIP (Tasker, 2018)1. The biggest differences are between the clinical form of the disease, with leukocytosis and lymphopenia being more common in cats with wet than with dry FIP (Riemer et al., 2016). Hyperbilirubinemia is common in cats with FIP, but especially in cats with wet FIP (Tasker, 2018). The author also found that many cats with primary neurological FIP show minor or no blood abnormalities. Blood test values for FIP also vary from study to study (Tasker, 2018).
A complete analysis of the effusion is important to diagnose wet FIP and to rule out other potential causes of fluid accumulation (Dempsey and Ewing, 2011). It includes color (clear or yellow), viscosity (thin or viscous), presence of precipitates, ability to form a partial clot on standing, protein content, leukocyte count, and differential. The nature of the fluid may vary depending on the duration of the disease and its severity. Effusions in cats with more severe disease usually have protein values close to serum values, are more viscous, contain more leukocytes, are more yellow in color, and have a greater ability to form partial clots on standing. Chronic effusions tend to be less inflammatory in nature, with lower protein and leukocyte counts, less viscous and clearer. These values can be determined on the spot in most clinics. The clotting factor is determined by comparing the fluid collected in the serum and in the anticoagulant tubes after standing. Color and viscosity can be approximated and protein levels can be estimated using a handheld refractometer to determine total solids. Cells are pelleted from the fluid and analyzed on a fast-stained slide using light microscopy, and the leukocyte count and differential are estimated. Cells include nonseptic neutrophils, small and medium-sized mononuclear cells, and large vacuolated macrophages (Fig. 15). It is important to note that effusions can occur in a variety of conditions, such as heart failure, cancer, hypoproteinemia, and bacterial infections. Effusions in these other diseases usually have different identifying features.
A positive Rivalt test on abdominal or chest fluid is often used to diagnose FIP as a cause of effusion, and a negative test tends to rule it out (Fischer et al., 2010) (Fig. 16). However, the test may be positive in inflammatory effusions of another cause and negative in some cats with FIP. Therefore, Rivalt's test is most helpful in combination with other clinical findings of FIP and should not replace a thorough fluid analysis (Felten and Hartmann, 2019).
Serum total and direct bilirubin levels are often elevated, especially in cats with wet FIP (Fig. 14), and may be associated with jaundice and bilirubinuria. Hyperbilirubinemia in FIP is not caused by liver disease (Tasker, 2018), but rather by vasculitis, microhemorrhage, hemolysis, and destruction of damaged red blood cells by macrophages locally and in the liver. The released hemoglobin is finally metabolized to bilirubin, which is then conjugated in the hepatocytes and excreted in the urine. Glucuronidation is essential for bilirubin excretion, and genetic disorders affecting glucuronidation in humans prevent its excretion (Kalakonda et al., 2021). Cats as a species are deficient in the enzymes required for glucuronidation, making it difficult to excrete substances such as bilirubin (Court and Greenblatt 2000).
Although FIP can affect the kidneys and liver, it is not severe enough to cause significant loss of kidney or liver function. However, serum tests for blood urea nitrogen (BUN) and creatinine as indicators of kidney disease and alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma glutamyltransferase (GGT) as indicators of liver disease are often mildly elevated in cats with FIP, especially with a more acute and serious disease (Fig. 14). Therefore, slightly abnormal test values should not be interpreted excessively if other clinical signs of liver or kidney disease are not present, while their significant increase should point to the possibility of concurrent and possibly predisposing diseases of these organs.
Serum can also be tested for other markers of systemic inflammation, such as increased levels of alpha-1-acid glycoprotein (AGP) (Paltrinieri et al., 2007) and feline serum amyloid A (fSAA) (Yuki et al., 2020). They may also prove useful in monitoring response to antiviral therapy (Krentz et al., 2021).
Radiography can be helpful in identifying chest and abdominal effusions. Abdominal ultrasound can reveal a smaller amount of effusion, identify enlarged mesenteric and ileo-cecal-colic lymph nodes, thickening of the colonic wall and lesions in organs such as the kidneys, liver and spleen (Lewis and O'Brien 2010). It may also be useful in examining the chest for lesions and assisting with needle aspiration or biopsy.
Antibody titers against FCoV have decreased since the first report nearly 50 years ago (Pedersen 1976b). The reference antibody test uses indirect fluorescent antibody staining (IFA) IFA titers ≥ 1:3200 in FIP cats are higher than most FECV-exposed cats (1:25–1:400). Newer tests often use ELISA procedures for rapid in-house or laboratory testing, but are qualitative rather than quantitative. IFA antibody titers decrease during successful antiviral treatment in many cats, but remain high in others (Dickinson et al., 2020; Krentz et al., 2021). Sequential titers can show a gradual increase in titers during the development of FIP (Pedersen et al., 1977), but previous serum samples are rarely available for comparison. Like most tests, FCoV antibody levels should not be used as the sole criterion to diagnose or rule out FIP (Felten and Hartmann, 2019) or to assess treatment success (Krentz et al., 2021).
Reverse transcriptase polymerase chain reaction (RT-PCR) is the primary means of identifying FCoV RNA in inflammatory effusions, fluids, or affected tissues (Felten and Hartmann, 2019). Accessory gene 7b RNA is present at the highest levels in tissues, fluids or exudates infected with FECV or FIPV, making it the most sensitive target for detecting low levels of virus (Gut et al., 1999). RT-PCR for FIPV S gene mutations is often used in samples that are positive for 7b RNA to be specific for FIPV (Felten et al., 2017). Other studies suggest that RT-PCR assays for FIPV-specific S gene mutations have similar specificity for FIP, but at the cost of a significant loss of sensitivity (Barker et al., 2017). A decrease in sensitivity is associated with an increase in the number of false negative results. False-negative RT-PCR tests also occur in samples that do not contain sufficient numbers of infected macrophages or in cats with very low levels of virus. False-negative results are especially common when testing whole blood.
Immunohistochemistry (IHC) detects feline coronavirus nucleocapsid protein in formalin-fixed tissues with high sensitivity and specificity, but is not as popular as RT-PCR (Litster et al., 2013; Ziółkowska et al., 2019). Specimens for IHC must contain intact infected macrophages (Fig. 17), which requires careful separation of cells from effusions and mounting them on slides, or formalin-fixed, paraffin-embedded diseased tissues that show lesions compatible with FIP. The coronavirus antigen in macrophages within a typical FIP lesion or fluid is seen only in FIP, giving IHC a high level of specificity.
A thorough ophthalmological examination is necessary to diagnose the characteristic changes of FIP (Pfeiffer and Wilcock 1991; Andrew, 2000). A sample of aqueous humor from the anterior chamber of an inflamed eye may also be useful for cytology, PCR and IHC.
Neurological FIP is often diagnosed using contrast-enhanced magnetic resonance imaging (MRI) and is often associated with cerebrospinal fluid (CSF) analysis (Crawford et al., 2017; Tasker, 2018; Dickinson et al., 2020). However, these are expensive procedures that are not always available and carry a certain risk for the cat. MRI lesions include obstructive hydrocephalus, syringomyelia, and herniation of the foramen magnum with contrast enhancement of the meninges of the brain and spinal cord and ependyma of the third ventricle, mesencephalic aqueduct, and brainstem. CSF shows an increased number of proteins and cells (neutrophils, lymphocytes, monocytes/macrophages) and, if present, can be reliable material for PCR or IHC examination.
Neurologic and/or ocular forms of FIP are often confused with systemic feline toxoplasmosis, and many cats with FIP are empirically treated for toxoplasmosis before a diagnosis of FIP is made. Fortunately, the availability of effective treatment for FIP has curtailed this practice. Systemic toxoplasmosis is much less prevalent than FIP, and fewer than 1 % cats with FIP were serologically positive in one field study.1 Therefore, testing or treatment for toxoplasmosis should only be considered once FIP has been adequately diagnosed.
Antiviral treatment as a diagnostic tool
Situations commonly occur where clinical findings point to FIP but doubts remain. Then there is a choice of performing several diagnostic tests, which may not lead to a more definitive diagnosis. An alternative diagnostic approach is treatment with a suitable antiviral for 1-2 weeks in the correct dose for the suspected form of FIP.2 Treatment often produces clinical improvement in as little as 24-48 hours and this rapidly progresses over the next 2 weeks and the total duration of treatment (Fig. 18). No response to test treatment and/or deterioration in health would indicate the need for further investigation of the cause(s) of ill health.
Before 2017, there was no cure for FIP, and treatment was mainly aimed at alleviating the symptoms of the disease (Izes et al., 2020). Such supportive treatment was aimed at maintaining good nutrition, controlling inflammation (corticosteroids), changing immune responses (interferons, cyclophosphamide, chlorambucil) and inhibiting key cytokine responses (pentoxifylline and other TNF-alpha inhibitors). Nutritional supplements that were supposed to help specific organ functions were also commonly used, such as one (Polyprenyl Immunostimulant) that was supposed to improve immunity and prolong survival in cats with dry but not wet FIP (Legendre et al., 2017). The effect of good supportive care on survival could not be determined because most cats were euthanized after diagnosis or within days or weeks. The survival rate for even the mildest forms of dry FIP and the most permanent treatment in one study was only 13 % at 200 days and 6 % at 300 days (Legendre et al., 2017).
Many commercially available drugs and compounds inhibit FIPV infection or replication in vitro, some of which are drugs known to inhibit specific HIV or hepatitis C proteins, while others work by inhibiting normal cellular processes that the virus usurps for its own life cycle (Hsieh et al., 2010; Izes et al., 2020; Delaplace et al., 2021). These various drugs and agents include cyclosporine and related immunophilins, several nucleoside and protease inhibitors, vioporin inhibitors, pyridine N-oxide derivatives, chloroquine and related compounds, ivermectin, several plant lectins, ubiquitin inhibitors, itraconazole, and several antibiotics. However, the concentrations required to inhibit viral replication in vitro often approach toxic values for cells. It has also been difficult to transfer favorable in vitro conclusions to animals, and studies in sick cats have rarely followed. Ribavarin inhibits FIPV replication in vitro, but was not effective as a treatment for experimental FIP (Weiss et al., 1993). The efficacy of chloroquine was tested in laboratory cats infected with FIPV, but clinical outcomes in treated cats were only slightly better than untreated ones and hepatotoxicity was demonstrated (Takano et al., 2013). A 3-month-old kitten with chest wet FIP treated with itraconazole and prednisolone developed neurological FIP and was euthanized after 38 days of treatment (Kameshima et al., 2020). Mefloquine also inhibited FIPV replication at low concentrations in cultured feline cells without cytotoxic effects, and preliminary pharmacokinetic studies in cats appeared favorable (Yu et al., 2020), but evidence of its safety and efficacy in clinical trials in cats with FIP has yet to be established. published.
A breakthrough in the treatment of FIP occurred in 2016-2019 when antiviral drugs were reported that target specific FIPV proteins essential for replication. The first of these drugs was GC376, a major protease inhibitor (Mpro ) FIPV (Kim et al., 2016; Pedersen et al., 2018). Protease inhibitors prevent the formation of individual viral proteins by inhibiting their cleavage from polyprotein precursors. GC376 was able to cure all experimentally infected cats and 7 of 21 cats with naturally occurring wet and dry FIP, but was less effective for cats with ocular or neurological signs (Pedersen et al., 2018). The second of these drugs was GS-441514, the active part of the prodrug remdesivir (Gilead Sciences; Murphy et al., 2018; Pedersen et al., 2019). GS-441524 is an adenosine nucleoside analog that blocks FIPV replication by inserting a nonsense adenosine into the developing viral RNA. GS-441524 was also able to cure all experimentally infected cats (Murphy et al., 2018) and 25/31 cats with naturally occurring wet and dry FIP (Pedersen et al., 2019). It has also been shown to be effective at higher doses in several cats with ocular and neurological FIP (Pedersen et al., 2019) and is now the drug of first choice for cats with neurological FIP (Dickinson et al., 2020). GS-441524 has cured thousands of FIP cats from around the world over the past three years, with an overall cure rate of just over 90 % (Jones et al., 2021).1
Although the ability of GC376 and GS-441524 to treat cats has been known for several years, neither is currently legally available in most countries. The rights to GC376 have been purchased by Anivive, but it has not yet been launched.3 Potential conflicts with the development of remdesivir for the treatment of COVID-19 in humans led Gilead Sciences to withhold rights to GS-441524 for animal use, prompting the creation of an unapproved source for GS-441524 from China (Jones et al, 2021).1,2,4 Remdesivir is rapidly metabolized in the body to GS-441524 and has been approved for the treatment of FIP in some countries.2 GS-441524 can also be administered orally in higher doses and is currently commonly used in practice (Krentz et al., 2021).1
The efficacy of drugs such as GC376 and GS-441524 on FIP cats, the use of which preceded the COVID-19 pandemic, has been recognized by researchers investigating related SARS-CoV 2 inhibitors (Yan et al., 2020; Vuong et al., 2021). Remdesivir, an injectable drug called glaucoma (Gilead), has been used worldwide to reduce mortality from COVID-19 (Beigel et al., 2020). GC373, the active form of the prodrug GC376, has undergone simple modifications to increase efficacy and oral bioavailability (Vuong et al., 2021). The GC373-related drug, nirmatrelvir, has been successfully tested against early COVID-19 infections and has been approved for the treatment of early COVID-19 and marketed as paxlovid (Pfizer). Paxlovid consists of two medicines, nirmatrevir and the HIV protease inhibitor ritonavir. Ritonavir is not a significant inhibitor of SARS-CoV 2, but is reported to prolong the half-life of Mprowhen used in combination (Vuong et al., 2020). Nirmatrelvir and paxlovid have not been tested in cats with FIP at present, but based on experience with the closely related drug GC376, oral treatment of some forms of FIP may be important in the future.
Two other nucleoside analogs, EIDD-1931 and EIDD-2801 (Painter et al., 2021), have been investigated for the treatment of multiple RNA virus infections in humans and animals. EIDD-1931 is the experimental designation for beta-D-N4-hydroxycytidine, a compound widely studied since the 1970's. Beta-D-N4-hydroxycytidine is metabolized to a ribonucleoside analog, which is incorporated into RNA instead of cytidine and leads to fatal mutations in the viral RNA strand. The compound is an inhibitor of a wide variety of human and animal RNA viruses, including all known coronaviruses. EIDD-1931 was modified to increase oral absorption and was termed EIDD-2801 (molnupiravir) (Painter et al., 2021). Molnupiravir is deesterified in the body to its active ingredient, beta-D-N4-hydroxycytidine. Therefore, EIDD-1931 and molnupiravir are analogous to GS-441524 and remdesivir. Molnupiravir is marketed for the home treatment of primary COVID-19 under the names Lagevrio (Merck, USA) or Molnulup (Lupine, India).
Both EIDD-1931 and EIDD-2801 have been shown to be effective in inhibiting FIPV in tissue culture (Cook et al., 2021), and EIDD-2801 is currently used to treat some cases of FIP in the field.5,7 The effective concentration of 50 % (EC50) for EIDD-1931 against FIPV is 0.09 µM, EIDD-2801 0.4 µM and GS-441524 0.66 µM (Cook et al., 2021). The percentage cytotoxicity at 100 μM for these compounds is 2.8, 3.8 and 0.0. Thus, EIDD-1931 and -2801 are slightly more inhibitory to viruses, but more cytotoxic than GS-441524. Resistance to GS-441524 has been reported in some cases of FIP (Pedersen et al., 2019) and to remdesivir in patients with COVID-19 (Painter et al., 2021), but these isolates remain sensitive to molnupiravir (Sheahan et al., 2020). This may prove useful in combating resistance to GS-441524 in cats and humans and in developing multidrug therapy to prevent the development of resistance.
What will full approval of medicines like molnupiravir and paxlovid mean for cats? Full human approval should allow veterinarians in most countries to legally procure medicinal products authorized for human consumption for direct use in animals, provided that the guidelines for use in non-food producing animals are followed.6 This requires a reformulation of a medicine made for humans and purchased at a price for humans. Hopefully, antivirals similar or identical to those approved for humans will be licensed exclusively for animals and sold at a much lower price, but this is likely to take years.
Commercial and policy issues that limit the current use of antivirals such as GS-441524 in animal diseases such as FIP are for current cat owners and feline support groups who have already bypassed the current drug approval system and its emphasis on overriding human needs, irrelevant (Jones et al., 2021; Krentz et al., 2021). Advocates of FIP treatment are currently found around the world and often associate under the expanded FIP Warrior brand. Members of these groups often act as intermediaries between owners, veterinarians and antiviral suppliers and often provide advice to those who are unable to obtain veterinary treatment assistance. Some of these groups, such as FIP Warriors Czech Republic / Slovakia7, have placed their experience with FIP treatment on the Internet, where they provide much-needed information about current antiviral treatment.
Current situation of FIP treatment
The current drug of choice for the treatment of FIP is the adenosine nucleoside analog GS-441524, which was first published in the scientific literature under experimental conditions (Murphy et al., 2018) and later against naturally occurring disease (Pedersen et al., 2019). Although initial experimental and field studies of GS-441524 were conducted in collaboration between researchers at Gilead Sciences and the University of California, Davis, the relationship between Remdesivir and GS-441524 and the onset of the COVID-19 pandemic in 2019 led Gilead Sciences to eventually did not grant rights to use GS-441524 to animals on the grounds that it could interfere with the development of Remdesivir for human use.4 Objections to this decision have been raised directly by the company and in several internet forums.4 Subsequent pressure from cat owners, cat rescue groups and cat lovers, along with opportunistic Chinese drug manufacturers, quickly created an alternative unapproved source of GS-441524, its market and treatment network.4 This network has largely bypassed veterinarians, most of whom have decided to wait for the drug to be legalized (Jones et al., 2021). The result of this relationship was an almost seamless transition of FIP treatment with GS-441524 from the laboratory to a rapidly expanding worldwide network of groups, under the umbrella of FIP Warriors (Jones et al., 2021).4,7
The sale and use of GS-441524 in practice for the treatment of FIP began almost immediately with the first publication of the results of field trials (Pedersen et al., 2019) (Fig. 19).
The fact that GS-441524 is not legally approved for use in animals has prevented many veterinarians from recognizing or participating in this treatment. Only 25 % cats in the CZ / SK treated group received veterinary support during treatment (Fig. 20), although more veterinarians may have been involved in the diagnosis of the disease. Interestingly, this number was higher than the 8.7 % treated cats in the United States that received veterinary care (Jones et al., 2021). However, participants in CZ / SK studies and similar groups around the world are not without medical experience, as many of them are engaged in temporary care / rescue and have had considerable direct and indirect veterinary experience with cat diseases and their treatment and castration programs.
From the first laboratory studies and research of Chinese manufacturers, it was known that GS-441524 can be absorbed orally, although with less efficiency (Kim et al. 2016).9 The first sellers of GS-441524 further investigated this fact and found that effective blood levels could be achieved by increasing the amount administered orally compared to injection.8 Supplements have often been added to GS-441524 oral capsules or tablets, claiming that they increase absorption or have additive therapeutic benefits (Krentz et al., 2011). Most major retailers of GS-441524 now offer oral versions, and oral therapy is becoming increasingly popular either as a single treatment or in combination with GS-441524 (Figure 21). The success of GS-441524 oral therapy did not differ significantly from GS-441524 injection therapy (Figure 22).
The recommended dosing schedule for GS-441524 based on published data from field studies (Pedersen et al., 2019) was 4 mg / kg, subcutaneous (SC), daily (q24h), ie 4 mg / kg, SC, q24h. This recommended starting dose for cats with wet or dry FIP without ocular or neurological symptoms tended to increase to 6 mg / kg SC q24h over time (Fig. 23). 8 mg / kg SC q24h is the current recommended dose for cats with ocular symptoms and 10 or 12 mg / kg SC q24h for cats with neurological symptoms.
The optimal duration of treatment, as determined in the initial clinical study, is 84 days (Pedersen et al., 2019). In some cases of acute wet FIP in younger cats, healing has been achieved in 6-8 weeks, but some cats need more than 84 days. As shown in Figure 24.72 % cats were treated for 81-90 days, 19 % longer and only 9 % were treated shorter. Unfortunately, there is no simple and accurate test to determine the moment of cure, and the decision to stop treatment is based on a complete return to health and normal blood test values. Cats treated for much longer than 100 days were usually those requiring a GS dose higher than 12 mg / kg per day by injection or equivalent oral dose, cats that relapsed during the 12-week post-treatment observation period, cats with neurological disease or cats that have become resistant to GS-441524.
The treatment success rate for all forms of FIP in cats from the Czech Republic and Slovakia is 88.1 % in the first treatment, but when cats that relapsed after the first treatment and recovered after the second treatment (3.1 %) were included, the overall success rate was more as 91 % (Fig. 25). This cure rate is identical to the cure rate of other groups of FIP fighters (Jones et al., 2021). Treatment success did not differ between cats with wet or dry FIP and without ocular or neurological impairment (Fig. 26). However, the cure rate in cats with ocular and neurological impairments was lower, at 80 % compared to 92 % in all other forms of FIP (Fig. 26).
Cats that have been successfully treated for FIP have been followed for 4 to 5 years, including cases reported in the first field studies. There have been no recurrences or recurrent cases of FIP in this group of first field trials. Data on annual survival are available from a much larger population of the CZ / SK study, which shows that 90.5 % cats are still healthy one year after the end of treatment (Fig. 27). Only 1.3 % of these cats died from causes other than FIP and 8.2 % cohort is currently in an unknown medical condition. The low proportion of cats that died of unknown causes within a year of treatment and their positive response to treatment suggest that FIP has been diagnosed correctly.
EIDD-2801 (molnupiravir) is currently being used in the field for the main treatment and for the treatment of GS-441524-resistant cats.5,7,9 EIDD-1931, the active form of EIDD-2081, needs to be further researched because it is no longer covered by patent protection and is thus easily approved for use in animals if it is found to be truly safe and effective.5 Nirmatrelvir, an oral form of GC373 and a closely related GC376, still needs to be studied for the treatment of FIP.
I am indebted to Ladislav Mihok and his collaborator from "FIP Warriors Czech Republic / Slovakia" for allowing me to share data from their website. This website contains the most important, comprehensive and organized collection of data on FIP antiviral treatment today. The website also contains useful information and advice on starting, conducting and monitoring current treatment. The collection of cats and their data is continuously and regularly updated and at the time of writing this article included more than 600 cats with FIP.
Addie DD, Toth S, Murray GD, Jarrett O, 1995. Risk of feline infectious peritonitis in cats naturally infected with feline coronavirus. American Journal of Veterinary Research, 56, 429-34.
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.
Andrew SE, 2000. Feline infectious peritonitis. Veterinary Clinics of North America and Small Animal Practice 30, 987-1000.
Barker EN, Stranieri A, Helps CR, Porter EL, Davison AD, Day MJ, Knowles T, Kipar A, Tasker S, 2017. Limitations of using feline coronavirus spike protein gene mutations to diagnose feline infectious peritonitis. Veterinary Research 48, 60.
Beigel JH, Tomashek KM, Dodd LE, Mehta EK, Zingman BS, et al., 2020. Remdesivir for the Treatment of Covid-19 - Final Report. New England Journal of Medicine, 383, 1813-1826,
Bubenikova J, Vrabelova J, Stejskalova K, Futas J, Plasil M, Cerna P, Oppelt J, Lobova D, Molinkova D, Horin P, 2020. Candidate gene markers associated with fecal shedding of the feline enteric coronavirus (FECV). Pathogens 9, 958.
Cassado Ados A, D'Império Lima, Bortoluci KR., 2015. Revisiting mouse peritoneal macrophages: heterogeneity, development, and function. Frontiers in Immunology 6, 225.
Cave TA, Thompson H, Reid SW, Hodgson DR, Addie DD, 2002. Kitten mortality in the United Kingdom: a retrospective analysis of 274 histopathological examinations (1986 to 2000). Veterinary Record 151, 497–501.
Cook SE, Vogel H, Castillo D, Olsen M, Pedersen N, Murphy BG, 2021. Investigation of monotherapy and combined anticoronaviral therapies against feline coronavirus serotype II in vitro. Journal of Feline Medicine and Surgery. doi: 10.1177 / 1098612X211048647. Epub ahead of print. PMID: 34676775.
Cornelissen E, Dewerchin HL, Van Hamme E, Nauwynck HJ, 2007. Absence of surface expression of feline infectious peritonitis virus (FIPV) antigens on infected cells isolated from cats with FIP. Veterinary Microbiology. 121, 131-137,
Cotter SM, Gilmore CE, Rollins C. 1973, Multiple cases of feline leukemia and feline infectious peritonitis in a household. Journal of the American Veterinary Medical Association 162, 1054–1058.
Court MH., Greenblatt DJ. 2000, Molecular genetic basis for deficient acetaminophen glucuronidation by cats: UGT1A6 is a pseudogene, and evidence for reduced diversity of expressed hepatic UGT1A isoforms Pharmacogenetics, 10, 355-369
Crawford AH, Stoll AL, Sanchez-Masian D, Shea A, Michaels J, Fraser AR, Beltran E, 2017. clinicopathologic features and magnetic resonance imaging findings in 24 cats with histopathologically confirmed neurologic feline infectious peritonitis. Journal of Veterinary Internal Medicine 31, 1477–1486.
Day MJ, 2010. Aging, immunosenescence and inflammageing in the dog and cat. Journal of Comparative Pathology 142 Suppl 1, S60-69.
Delaplace M, Huet H, Gambino A, Le Poder S, 2021. Feline coronavirus antivirals: A review. Pathogens 10, 1150. doi: 10.3390 / pathogens10091150.
Dempsey SM, Ewing PJ, 2011. A Review of the Pathophysiology, Classification, and Analysis of Canine and Feline Cavitary Effusions. Journal of the American Animal Hospital Association 47, 1–11.
de Sousa JR, Sotto MN, Simões Quaresma JA, 2017. Leprosy as a complex infection: Breakdown of the Th1 and Th2 immune paradigm in the immunopathogenesis of the disease. Frontiers in Immunology 8,1635.
Dewerchin HL, Cornelissen E, Van Hamme E, Smits K, Verhasselt B, Nauwynck HJ, 2008. Surface-expressed viral proteins in feline infectious peritonitis virus-infected monocytes are internalized through a clathrin- and caveolae-independent pathway. Journal of General Virology 89, 2731–2740
Dewerchin HL, Desmarets LM, Noppe Y, Nauwynck HJ, 2014. Myosins 1 and 6, myosin light chain kinase, actin and microtubules cooperate during antibody-mediated internalization and trafficking of membrane-expressed viral antigens in feline infectious peritonitis virus infected monocytes. Veterinary Research 45, 17.
Dickinson PJ, Bannasch M, Thomasy SM, Murthy VD, Vernau KM, Liepnieks M, Montgomery E, Knickelbein KE, Murphy B, Pedersen NC, 2020. Antiviral treatment using the adenosine nucleoside analogue GS ‐ 441524 in cats with clinically diagnosed neurological feline infectious peritonitis. Journal of Veterinary Internal Medicine 34, 1587–1593.
Drechsler Y, Alcaraz A, Bossong FJ, Collisson EW, Diniz PP, 2011. Feline coronavirus in multicat environments. Veterinary Clinics North America and Small Animal Practice41, 1133-1169.
Fankauser R, Fatzer R, 1997. Meningitis and chorioependymitis granulomatosa der Katze. Possible conditions for infectious peritonitis (FIP). Client Practice 22, 19–22.
Felten S, Leutenegger CM, Balzer HJ, Pantchev N, Matiasek K, Wess G, Egberink H, Hartmann K, 2017. Sensitivity and specificity of a real-time reverse transcriptase polymerase chain reaction detecting feline coronavirus mutations in effusion and serum / plasma of cats to diagnose feline infectious peritonitis. BMC Veterinary Research 13, 228.
Felten S, Hartmann K, 2019. Diagnosis of Feline Infectious Peritonitis: A Review of the Current Literature. Viruses 11, 1068.
Fischer Y, Sauter-Louis C, Hartmann K, 2012. Diagnostic accuracy of the Rivalta test for feline infectious peritonitis. Veterinary Clinical Pathology 41, 558–67.
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. Journal of the American Veterinary Medicine Association 210, 1313-1318.
Foley JE, Lapointe JM, Koblik P, Poland A, Pedersen NC, 1998. Diagnostic features of clinical neurologic feline infectious peritonitis. Journal of Veterinary Internal 12, 415–423.
Gaskell RM, Povey RC, 1977. Experimental induction of feline viral rhinotracheitis virus re-excretion in FVR-recovered cats. Veterinary Record 100, 128–133.
Golovko L, Lyons LA, Liu H, Sørensen A, Wehnert S, Pedersen NC, 2013. Genetic susceptibility to feline infectious peritonitis in Birman cats. Virus Research 175, 58–63.
Gunn-Moore DA, Gaunt C, Shaw DJ, 2012. Incidence of mycobacterial infections in cats in great britain: estimate from feline tissue samples submitted to diagnostic laboratories. Transboundary and Emerging Diseases. 60, 338-344.
Gut, M, Leutenegger, CM, Huder, JB, Pedersen NC, H, 1999. One-tube fluorogenic reverse transcription-polymerase chain reaction for the quantitation of feline coronaviruses. Journal of Virological Methods 77, 37–46.
Hardy WD Jr., 1981. Feline leukemia virus non-neoplastic diseases. Journal of the American Animal Hospital Association 17, 941-949.
Healey EA, Andre NM, Miller AD, Whitaker GR, Berliner EA, 2022. Outbreak of feline infectious peritonitis (FIP) in shelter-housed cats: Molecular analysis of the feline coronavirus S1 / S2 cleavage site consistent with a 'circulating virulent-avirulent theory 'of FIP pathogenesis. Journal of Feline Medicine and Surgery Open Reports 8, 20551169221074226.
Herrewegh AAPM, Mähler 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.
Herrewegh AA, Smeenk I, Horzinek MC, Rottier PJ, de Groot RJ, 1998. Feline coronavirus type II strains 79-1683 and 79-1146 originate from a double recombination between feline coronavirus type I and canine coronavirus. Journal of Virology 72, 4508–4514.
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.
Hsieh LE, Lin CN, Su BL, Jan TR, Chen CM, Wang CH, Lin DS, Lin CT, Chueh LL. 2010. Synergistic antiviral effect of Galanthus nivalis agglutinin and nelfinavir against feline coronavirus. Antiviral Research 88, 25–30.
Holzworth J, 1963. Some important disorders of cats. Cornell Veterinarian 53, 157–160.
Izes AM, Yu J, Norris JM, Govendir M, 2020. Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats. Veterinary Quarterly 40, 322–330.
Jones S, Novicoff W, Nadeau J, Evans S, 2021. Unlicensed GS-441524-like antiviral therapy can be effective for at-home treatment of feline infectious peritonitis. Animals 11, 2257.
Mustaffa-Kamal F, Liu H, Pedersen NC, Sparger EE, 2019. Characterization of antiviral T cell responses during primary and secondary challenge of laboratory cats with feline infectious peritonitis virus (FIPV). BMC Veterinary Research 15,165.
Kameshima S, Kimura Y, Doki T, Takano T, Park CH, Itoh N, 2020. Clinical efficacy of combination therapy of itraconazole and prednisolone for treating effusive feline infectious peritonitis. Journal of Veterinary Medical Science 82, 1492–1496.
Kim Y, Liu H, Galasiti Kankanamalage AC, Weerasekara S, Hua DH, Groutas WC, Chang KO, Pedersen NC, 2016. Reversal of the progression of fatal coronavirus Infection in cats by a broad-spectrum coronavirus protease inhibitor. PLoS Pathogens 12: e1005531.
Kipar A, May H, Menger S, Weber M, Leukert W, Reinacher M, 2005. Morphologic features, and development of granulomatous vasculitis in feline infectious peritonitis. Veterinary Pathology 42, 321–330.
Krentz D., Zenger K., Alberer M., Felten S., Bergmann M, Dorsch R., Matiasek, K., Kolberg, L., Hofmann-Lehmann, R., Meli, ML, et al., 2021. Curing cats with feline infectious peritonitis with an oral multi-component drug containing GS-441524. Viruses 13, 2228.
Legendre AM, Kuritz T, Galyon G, Baylor VM, Heidel RE, 2017. Polyprenyl immunostimulant treatment of cats with presumptive non-effusive feline infectious peritonitis in a field study. Frontiers in Veterinary Science 4, 7.
Teacher C, Lê-Bury P, Pizarro-Cerdá J, Dussurget O, 2020. Emerging Evasion Mechanisms of Macrophage Defenses by Pathogenic Bacteria. Frontiers in Cellular and Infection Microbiology, 10, 538.
Lewis KM, O'Brien RT, 2010. Abdominal ultrasonographic findings associated with feline infectious peritonitis: a retrospective review of 16 cases. Journal of the American Animal Hospital Association. 46, 152-60.
Licitra BN, Millet JK, Regan AD, Hamilton BS, Rinaldi VD, Duhamel GE, Whittaker GR, 2013. Mutation in spike protein cleavage site and pathogenesis of feline coronavirus. Emerging Infectious Diseases 19, 1066–1073.
Lin CN, Su BL, Wang CH, Hsieh MW, Chueh TJ, Chueh LL, 2009. Genetic diversity and correlation with feline infectious peritonitis of feline coronavirus type I and II: A 5-year study in Taiwan. Veterinary Microbiology 136, 233–239.
Litster AL. Pogranichniy R, Lin TL, 2013. Diagnostic utility of a direct immunofluorescence test to detect feline coronavirus antigen in macrophages in effusive feline infectious peritonitis. Veterinary Journal 198, 362–366.
Lloret A, Hartmann K, Pennisi MG, Ferrer L, Addie D, Belák S, Boucraut-Baralon C, Egberink H, Frymus T, Gruffydd-Jones T, et al., 2013. Rare systemic mycoses in cats: blastomycosis, histoplasmosis and coccidioidomycosis: ABCD guidelines on prevention and management. Journal of Feline Medicine and Surgery 15, 624–627.
Longstaff L, Porter E, Crossley VJ, Hayhow SE, Helps CR, Tasker S, 2017. Feline coronavirus quantitative reverse transcriptase polymerase chain reaction on effusion samples in cats with and without feline infectious peritonitis. Journal of Feline Medicine and Surgery 19, 240–245.
Mahase E. 2021. Covid-19: Molnupiravir reduces risk of hospital admission or death by 50% in patients at risk, MSD reports. BMJ 375, n2422.
Malbon AJ, Meli ML, Barker EN, Davidson AD, Tasker S, Kipar A, 2019. inflammatory mediators in the mesenteric lymph nodes, site of a possible intermediate phase in the immune response to feline coronavirus and the pathogenesis of feline infectious peritonitis? Journal of Comparative Pathology 166, 69–86.
Malbon AJ, Russo G, Burgener C, Barker EN, Meli ML, Tasker S, Kipar A, 2020. the effect of natural feline coronavirus infection on the host immune response: A whole-transcriptome analysis of the mesenteric lymph nodes in cats with and without feline infectious peritonitis. Pathogens 7, 524.
Mor G, Cardenas I, 2010. The immune system in pregnancy: A unique complexity. American Journal of Reproductive Immunology 63, 425–433.
Murphy BG, Perron M, Murakami E, Bauer K, Park Y, Eckstrand C, Liepnieks M, Pedersen NC, 2018. The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Veterinary Microbiology 219, 226–233.
Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, Morin MJ, Szewczyk LJ, Painter GR, 2021. Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent with activity against SARS-CoV-2. Antimicrobial Agents and Chemotherapeutics 65: e02428-20.
Paltrinieri S, Giordano A, Tranquillo V, Guazzetti S, 2007. Critical assessment of the diagnostic value of feline α1-acid glycoprotein for feline infectious peritonitis using the likelihood ratios approach. Journal of Veterinary Diagnostic Investigation. 19, 266-272.
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, 1976b. Serologic Studies of Naturally Occurring Feline Infectious
peritonitis. American Journal of Veterinary Research 37, 1447–1453.
Pedersen NC, 2009. A review of feline infectious peritonitis virus infection: 1963-2008. Journal of Feline Medicine and Surgery 11, 225–258.
Pedersen NC, Boyle J, 1980. Immunologic Phenomena in the Effusive Form of Feline Infectious Peritonitis. American Journal of Veterinary Research 41: 868–876.
Pedersen NC, Ward J, Mengeling WL, 1978. Antigenic relationship of the feline infectious peritonitis virus to coronaviruses of other species. Archives of Virology58, 45–53.
Pedersen NC, Allen CE, Lyons LA, 2008. Pathogenesis of feline enteric coronavirus infection. Journal of Feline Medicine and Surgery 10, 529–541.
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, Meric SM, Hoe E, Johnson L. Plucker S, Theilen GH, 1982. The clinical significance of latent feline leukemia virus infection. Feline Practice 14, 32–48.
Pedersen NC, Black JW, Boyle JF, Evermann JF, McKeirnan AJ, Ott RL, 1984. Pathogenic differences between various feline coronavirus isolates. Advances in Experimental Medicine and Biology 173, 365–380.
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. Viruses1, 166-184.
Pedersen NC, Liu H, Durden M, Lyons LA, 2016. Natural resistance to experimental feline infectious peritonitis virus infection is decreased rather than increased by positive genetic selection. Veterinary Immunology and Immunopathology 171, 17–20.
Pedersen NC, Liu H, Scarlett J, Leutenegger CM, Golovko L, Kennedy H, Kamal FM, 2012. Feline infectious peritonitis: role of the feline coronavirus 3c gene in intestinal tropism and pathogenicity based upon isolates from resident and adopted shelter cats. Virus Research 165,17-28
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, Perron M, Bannasch M, Montgomery E, Murakami E, Liepnieks M, Liu H, 2019. Efficacy and safety of the nucleoside analog GS-441524 for the treatment of cats with naturally occurring feline infectious peritonitis. Journal of Feline Medicine and Surgery 21, 271–281.
Peiffer RL Jr, Wilcock BP, 1991. Histopathologic study of uveitis in cats: 139 cases (1978-1988). Journal of the American Veterinary Medical Association 198, 135–138.
Pesteanu-Somogyi LD, Radzai C, Pressler BM, 2006. Prevalence of feline infectious peritonitis in specific cat breeds. Journal of Feline Medicine and Surgery 8, 1–5.
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.
Regan A, Whitaker G, 2008. Utilization of DC-SIGN for entry of feline coronaviruses into host cells. Journal of Virology 82, 11992-11996.
Riemer F, Kuehner KA, Ritz S, Sauter-Louis C, Hartmann K, 2016. Clinical and laboratory features of cats with feline infectious peritonitis – a retrospective study of 231 confirmed cases (2000-2010). Journal of Feline Medicine and Surgery 18, 348–356.
Rohrbach BW, Legendre AM, Baldwin CA, Lein DH, Reed WM, Wilson RB, 2001. Epidemiology of feline infectious peritonitis among cats examined at veterinary medical teaching hospitals. Journal of the American Veterinary Medical Association 218, 1111–1115.
Rojko J, Hoover E, Quackenbush, S. Olsen RG, 1982. Reactivation of latent feline leukemia virus infection. Nature 298, 385–388.
Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Aostini, ML, Leist, SR, Schäfer, A, Dinnon, KH 3rd., Stevens, LJ et al., 2020. An orally bioavailable broad-spectrum antiviral inhibitions SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Science Translational Medicine. 12, eabb5883.
Spencer, SE, Knowles, T, Ramsey, IK. 2017. Pyrexia in cats. retrospective analysis of signalment, clinical investigations, diagnosis and influence of prior treatment in 106 referred cases. Journal of Feline Medicine and Surgery 19, 1123–1130.
Stella J, Croney C, Buffington T, 2013. Effects of stressors on the behavior and physiology of domestic cats. Applied Animal Behavior Science 143, 157-163.
Stranieri A, Giordano A, Bo S, Braghiroli C, Paltrnieri S, 2017. Frequency of electrophoretic changes consistent with feline infectious peritonitis in two different time periods (2004–2009 vs 2013–2014). Journal of Feline Medicine and Surgery 19, 880–887.
Takano T, Katoh Y, Doki T, Hohdatsu T, 2013. Effect of chloroquine on feline infectious peritonitis virus infection in vitro and in vivo. Antiviral Research. 99, 100–107.
Tasker S, 2018. Diagnosis of feline infectious peritonitis: Update on evidence supporting available tests. Journal of Feline Medicine and Surgery 20, 228–243.
Tekes G, Ehmann R, Boulant S, Stanifer ML, 2020. Development of feline ileum- and colon-derived organoids and their potential use to support feline coronavirus infection. Cells 9, 2085.
Terada Y, Matsui N, Noguchi K, Kuwata R, Shimoda H, Soma T, Mochizuki M, Maeda K, 2014. Emergence of pathogenic coronaviruses in cats by homologous recombination between feline and canine coronaviruses. PLoS One 9, e106534.
Van Hamme E, Dewerchin HL, Cornelissen E, Verhasselt B, Nauwynck HJ, 2008. Clathrin- and caveolae-independent entry of feline infectious peritonitis virus in monocytes depends on dynamin. Journal of General Virology 89, 2147–2156.
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.
Vuong, W, Fischer C, Khan MB, van Belkum MJ, Lamer T, Willoughby, KD, Lu, J, Arutyenova, E, Joyce, MA, Saffran, HA et al., 2021. Improved SARS-CoV-2 Mpro inhibitors based on feline antiviral drug GC376: Structural enhancements, increased solubility, and micellar studies. European Journal of Medicinal Chemistry, 222, 113584.
Wang YT, Su BL, Hsieh LE, Chueh LL, 2013. An outbreak of feline infectious peritonitis in a Taiwanese shelter: Epidemiologic and molecular evidence for horizontal transmission of a novel type II feline coronavirus. Veterinary Research, 44, 57.
Ward JM, 1970. Morphogenesis of a virus in cats with experimental feline infectious peritonitis. Virology 41, 191–194.
Watanabe R, Eckstrand C, Liu H, Pedersen NC, 2018. Characterization of peritoneal cells from cats with experimentally-induced feline infectious peritonitis (FIP) using RNA-seq. Veterinary Research 49, 81.
Weiss RC, Scott FW, 1981. Antibody-mediated enhancement of disease in feline infectious peritonitis: comparisons with dengue hemorrhagic fever. Comparative Immunology, Microbiology and Infectious Diseases 4, 175-189.
Weiss RC, Cox NR, Martinez ML, 1993. Evaluation of free or liposome-encapsulated ribavirin for antiviral therapy of experimentally induced feline infectious peritonitis. Research in Veterinary Science 55, 162e72.
Wolfe, LG, Griesemer, RA, 1971. Feline infectious peritonitis: a review of gross and histopathologic lesions. Journal of the American Veterinary Medical Association 158, 987–993.
Worthing KA, Wigney DI, Dhand NK, Fawcett A, McDonagh P, Malik R, Norris JM, 2012. Risk factors for feline infectious peritonitis in Australian cats. Journal of Feline Medicine and Surgery 14, 405–412.
Yan VC, Muller FL, 2020. Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment. ACS Medicinal Chemistry Letters 11, 1361–1366
Yu J, Kimble B, Norris JM, Govendir M, 2020. Pharmacokinetic profile of oral administration of mefloquine to clinically normal cats: A preliminary in-vivo study of a potential treatment for feline infectious peritonitis (FIP). Animals 10, 1000.
Yuki M, Aoyama R, Nakagawa M, Hirano T, Naitoh E, Kainuma D, 2020. A Clinical Investigation on serum amyloid A concentration in client-owned healthy and diseased cats in a primary care animal hospital. Veterinary Sciences, 7, 45.
Ziółkowska N, Paździor-Czapula K, Lewczuk B, Mikulska-Skupień E, Przybylska-Gornowicz B, Kwiecińska K, Ziółkowski H, 2017. Feline infectious peritonitis: immunohistochemical features of ocular inflammation and the distribution of viral antigens in the structures of the eye. Veterinary Pathology, 54, 933-940.
Zook BC, King NW, Robinson RL, McCombs HL, 1968. Ultrastructural evidence for the viral etiology of feline infectious peritonitis. Veterinary Pathology 5, 91–95.
Hughes D, Howard G, Malik R, 2021. Treatment of FIP in cats with Remdesivir. Clinical review, 2021. The Veterinarian. https://www.turramurravet.com.au/wp-content/uploads/2021/07/FIP-Article_The-Veterinarian.pdf (Accessed 5 March 2022).
Anonymous. Thanks to Cats, One Promising Coronavirus Treatment is Already in Development-The GC376 story. 2021, https://anivive.com/coronavirus (Accessed 4 April 2022)
Abstract: Feline infectious peritonitis, or simply FIP, is a coronavirus viral disease in cats, usually less than three years old. It is manifested by an extreme inflammatory reaction in the tissues in the abdomen, kidneys and brain. This review article discusses the various diagnostic tests and their benefits in diagnosing cases of suspected FIP for definitive diagnosis. This review can help compare different diagnostic parameters and also raise awareness of their advantages and disadvantages.
Feline infectious peritonitis (FIP) is a well-known and widespread coronavirus (CoV) -induced systemic disease in cats, characterized by fibrinous-granulomatous serositis with protein-rich exudates in the body cavities, granulomatosis-announcing phlebitis in the gallbladder and periphels Scott 1981; Kipar et al. 2005). Feline CoV (FCoV) spreads via the faecal-oral route and is primarily infected with enterocytes (Pedersen 1995), but subsequently spreads systemically via monocyte viremia (Meli et al 2004; Kipar et al 2005). The increased ability of the virus to replicate has been shown to be a key feature in the development of FIP, and FIP is also thought to be caused by mutations in common feline enteric coronavirus (FECV), which occurs in cats worldwide and is not a serious infection (Pedersen et al 2009; Healey et al 2022). Approximately 10 % infected cats have mutations that result in feline infectious peritonitis. In large multi-cat situations, FECV is excreted in the faeces of most seemingly healthy cats and the transmission occurs through direct contact with faeces or contaminated litter and other fomits (Pedersen et al 2004). Kittens become infected at approximately 9 weeks of age (Pedersen et al. 2008). The time between the onset of clinical signs and death also varies, but younger cats and cats with effusive disease have a shorter course of disease than older cats and cats with non-effusive disease (Pedersen 2014). Even with severe FIP, some cats can live for months. in multi-feline situations, feline enteric coronavirus (FECV) is extremely common and highly contagious. Almost all cats that come into contact with FECV from secreting cats become ill, but on the other hand, the infection is usually asymptomatic or causes only mild temporary diarrhea (Pedersen et al. 2008; Vogel et al. 2010; Ermakov et al. 2021). On the other hand, feline infectious peritonitis virus (FIPV) is not transmitted via the faecal-oral route, but originates from avirulent FECV in a small percentage of infected cats and causes feline infectious peritonitis (FIP) (Pedersen et al 1981; Vennema et al. 1998). Anorexia, lethargy, weight loss, pyrexia, ocular and neurological symptoms such as gait abnormalities or inappropriate mentoring are non-specific (Giori et al 2011; Kipar et al 2014). The infection takes two forms: "wet" and "dry". The dry form causes inflammatory changes around the vessels, seizures, ataxia and excessive thirst, while the wet form leads to enlargement of the abdomen due to excessive accumulation of fluid in the abdominal cavity. Specificity is always the most important diagnostic value to consider in order to avoid misdiagnosis of FIP in unaffected cats.
2. Diagnostic tests for feline infectious peritonitis
The diagnosis takes into account the age, origin, clinical signs and physical examination of the cat. Abdominal distension with ascites, dyspnoea with pleural effusion, jaundice, hyperbilirubinuria, marked masses of the kidneys and / or mesenteric lymph nodes, uveitis and various neurological symptoms are common in cats with effusive (wet) or non-fusive (dry) forms of FIP. and / or spinal cord. Ocular changes often occur in cats with FIP, with the most common ocular disorders being retinal changes. Retinal cuff cuffs may occur, which appear as blurred gray lines on either side of the vessels. Occasionally, granulomatous changes in the retina occur. FIPV infection has been found to be associated with T-cell depletion by apoptosis, although the virus cannot infect CD4 + and CD8 + T-cells (Haagmans et al. 1996; De Groot et al. 2005). Due to the high mortality rate, many veterinarians and pet owners are cautious about a diagnosis based on "reasonable assurance". The challenge is to decide whether the test increases the likelihood that clinical symptoms are caused by FIP (indirect tests) or offers a definitive diagnosis (direct tests). It is important to note that the sensitivity and specificity of any indirect test will vary depending on the likelihood that the cat is infected due to other factors. This means that a positive predictive value of the test, such as complete blood count (CBC) or albumin: globulin (A: G) ratio, to predict FIP will be much higher in cats with FIP-like signaling than in cats with non-FIP signaling. It should be noted that the results of other indirect tests are only estimates and the results of additional indirect tests have the potential to confuse and support the diagnostic process.
3. Diagnostic tests
The problem with FIP diagnostics is that non-invasive tests are not reliable enough. In general, effusion tests have a significantly higher predictive value than blood tests (Stranieri et al. 2018; Hartmann et al. 2003). As a result, the identification of FIP ante mortem in cats without significant effusion is particularly difficult. The most useful ante-mortem indicators are positive anti-Corona (IgG) antibody titers in cerebrospinal fluid (CSF), high total serum protein, and MRI changes such as periventricular contrast enhancement, ventricular dilatation, and hydrocephalus. However, monoclonal antibodies from affected tissues and coronavirus-specific polymerase chain reaction (PCR) are valuable in post mortem evaluations (Foley et al. 1998). As a clear diagnosis cannot be made on the basis of symptoms, medical history and clinical and laboratory indicators alone, these factors should always be considered as a whole, sometimes in combination with other factors such as molecular or even more invasive diagnostic procedures.
3.1. Analysis of effusion samples
If FIP with effusion is suspected, the effusion sample can be incredibly helpful in making a diagnosis and then in hematological findings, so obtaining effusion samples should always be a top priority. In the case of ascites, the sample can be obtained by ultrasound-guided thin-needle aspiration or the "flying cat" technique. To identify small amounts of fluid in the chest and abdomen, ultrasonography provides useful assistance in locating effusion bags in the abdomen, while evidence of pericardial effusions can be obtained through suppressed cardiac echoes and electrocardiographic changes. Ultrasonography should be used repeatedly to identify any small volume effluents, and ultrasonography may also be used to guide the sampling of small bags of fluid. In cats with pericardial effusions, auscultation of the heart detects muffled sounds and the ECG reveals typical changes. FIP effusions are often clear, viscous / sticky, straw yellow and rich in protein (cytology often describes a dense eosinophilic protein background) with a total protein concentration> 35 g / l (> 50 % globulins). Chlootic effusions are rarely described. FIP effusions are often pyogranulomatous in nature with macrophages, non-degenerate neutrophils and a relatively small number of lymphocytes. As a result, effusions are often referred to as modified transudates based on cell number (<5 × 109 cells / L), but exudates based on protein concentration (greater than 35 g / L). Typical FIP effusions have a low A: G ratio (see above) and an increased AGP content, which is similar to the serum content. A recent study (Hazuchova et al. 2017) found that AGP concentrations in effusions (> 1.55 mg / ml) are more useful (sensitivity and specificity 93 %) in distinguishing FIP cases from cases without FIP than serum AGP levels or other APPs. The rival test is a simple test that can be used to distinguish transudate from exudate in a effusion sample (Barker and Tasker 2020). Positive results simply suggest that the effluent is exudate and not specific to FIP; positive transudate results have been documented in situations other than FIP (eg, bacterial / septic peritonitis and lymphoma) (Fischer et al. 2012).
3.2. Serum biochemistry
Although the changes in blood biochemistry observed in FIP cases are variable and often non-specific, there are several key anomalies that need to be addressed in order to confirm the diagnosis of FIP.
3.2.1. Acute phase proteins
Many inflammatory and non-inflammatory diseases produce acute phase proteins (APPs) in the liver in response to cytokines released by macrophages and monocytes (particularly interleukins 1 and 6 and tumor necrosis factor α). AGP is an abbreviation for α1-acid glycoprotein and its examination may help in the diagnosis of FIP. Although the increase in AGP levels (> 0.48 mg / ml) is not specific for FIP, patients with FIP often have significantly high AGP levels (> 1.5 mg / ml). As a result, the magnitude of the increase may be valuable in helping to diagnose FIP, with higher levels more effectively increasing the suspicion index (Giori et al 2011; Hazuchova et al 2017).
In 89% cases, hyperglobulinemia is present; often in association with hypoalbuminemia or low-normal serum albumin levels (observed in 64.5 % cases) (Riemer et al. 2016). Hyperproteinemia may not always occur due to the existence of hypoalbuminemia. The albumin: globulin (A: G) ratio is low in hyperglobulinemia and hypoalbuminemia (low-normal albumin concentration) and this parameter can be used to assess the likelihood of FIP in a particular case.
Hyperbilirubinemia occurs in 21-63 % cases of FIP and is more common in effusive FIP, where alanine aminotransferase (ALT), alkaline phosphatase (ALP) and γ-glutamyltransferase enzymes are commonly high (although these may be slightly increased in FIP cases). FIP is rarely associated with hyperbilirubinemia due to immune-mediated hemolytic anemia (IMHA) (Norris et al. 2012) and cats are often not severely anemic. In the absence of high liver enzyme activity or severe anemia, the presence of hyperbilirubinaemia should suggest FIP (note that sepsis and pancreatitis may cause hyperbilirubinaemia without increased liver enzyme activity). Based on a stepwise evaluation of cats with FIP, it was documented that hyperbilirubinemia was more typically recognized in cats just before death or euthanasia than in the first presentation (Harvey et al. 1996). In addition, higher bilirubin levels were observed in cats just before death or euthanasia than in the first presentation.
In FIP, hematological changes are non-specific; however, there are several abnormalities that need to be checked to confirm the diagnosis. Lymphopenia is the most common change (55 - 77%) in cases, with a recent study (Riemer et al. 2016) revealing lymphopenia in only 49.5 % cases of FIP, with neutrophilia (39 - 57 %), left-sided and mild to severe normocytic, normochromic anemia (37-54 %) (Riemer et al. 2016; Norris et al. 2012). Recently, an association between FIP and microcytosis (with or without anemia) has been discovered. FIP can cause severe IMHA with concomitant regenerative anemia; however, this is an unusual phenomenon.
ELISAs, indirect immunofluorescence antibody assays, and rapid immunocompromination assays are the most common assays for anti-FCoV antibodies in serum (Addie et al. 2015). In most studies, cells infected with CoV pigs or cats are used as substrate and titers are measured in multiples of serum dilutions. A positive anti-FCoV antibody test means that the cat has been infected with FCoV and has seroconverted (which lasts 2-3 weeks after infection). The tests are therefore of limited clinical importance. Breed-dependent differences in anti-FCoV antibody titers were found, which could indicate differences in the breed's response to FCoV infection (Meli et al. 2013). Although cats with FIP had higher anti-FCoV antibody titers than cats without FIP, no difference was found between the median anti-FCoV antibody titers in healthy cats and cats with suspected FIP. As a result, the titer in one animal is only marginally useful in identifying cats with FIP (Bell et al. 2006). Many clinically healthy cats (especially those in multi-cat households) have positive and often very high anti-FCoV antibody titers, while 10 % cats with FIP are seronegative, which could be due to virus binding to the antibody and its inaccessibility for serological testing. which also points to problems with interpretation (Meli et al 2013). A negative FCoV antibody test if dry FIP is suspected may be more effective at excluding FIP (Addie et al. 2009). Nevertheless, negative results have been observed in neurological FIP situations (Negrin et al 2007). As a result, doctors disagree on whether to perform a serological test in suspected cases, even though a positive result almost always means FCoV exposure.
3.5. Current trends in diagnostics
The use of anti-coronavirus antibody testing in cerebrospinal fluid (CSF) for diagnosis in cases involving the central nervous system is another breakthrough in which IgG is detected in the CSF. However, in most cases, the antibody was detected only in cats with high serum IgG titers (Boettcher et al. 2007) An important difference between feline coronavirus and FIP infection is the behavior of the NSP3c gene. The infected tissue isolates from the second case were found to have a disrupted gene 3c, while in the first case the gene was intact. Mutation of the S1 / S2 locus and modulation of the furin recognition site, which is normally present in the S-gene of the enteric coronavirus (Levy and Hutsell 2019), is also a crucial contributing factor. The diagnostic utility of cerebrospinal fluid immunocytochemistry is also used to diagnose FIP manifested by severe central nervous system involvement. Immunocytochemical staining (ICC) of feline coronavirus antibodies in cerebrospinal fluid macrophages is a highly sensitive test, especially for the diagnosis of ante mortem with a sensitivity of 85 % and a specificity of 83.3 % (Gruendl et al 2017).
In cats with suspected FIP, anamnesis, clinical signs and clinicopathological examinations should be correlated. The dry form is more difficult to diagnose than the wet form. In the wet form, laboratory analysis of the fluid can be performed, such as the Rivalt's test. If the test is negative, the probability of FIP is small, but if the test is positive, additional diagnostic tests should follow to confirm FIP. In FIP, the A: G ratio is low because hyperglobulinemia and hypoalbuminemia (low normal albumin concentration) are present, and this parameter can be used to assess the likelihood of FIP in a particular case. Patients with FIP often have significantly high levels of AGP (α1-acid glycoprotein). When distinguishing FIP cases from non-FIP cases, AGP concentrations in effusions (> 1.55 mg / ml) have a sensitivity and specificity of 93 %.
Conflict of interests
The authors declare that they do not have a conflict of interest.
No financial support was provided from any institute or other source.
Addie D, Belak S, Boucraut-Baralon C (2009) Feline infectious peritonitis. ABCD guidelines on prevention and management. J Feline Med Surg 11: 594–604.
Addie D, Belák S, Boucraut-Baralon C, Egberink H, Frymus T, Gruffydd-Jones T, Hartmann K, Hosie MJ, Lloret A, Lutz H (2009) Feline infectious peritonitis. ABCD guidelines on prevention and management. Journal of Feline Medicine and Surgery 11: 594–604.
Addie DD, le Poder S, Burr, P (2015) Utility of feline coronavirus antibody tests. J Feline Med Surg 17: 152–162.
Barker E, Tasker S (2020) Update on feline infectious peritonitis. In Practice 42: 372–383.
Bell ET, Malik R, Norris JM (2006) The relationship between the feline coronavirus antibody titre and the age, breed, gender and health status of Australian cats. Aust Vet J 84: 2–7.
Bell ET, Toribio JA, White JD (2006) Seroprevalence study of feline coronavirus in owned and feral cats in Sydney, Australia. Aust Vet J 84: 74–81.
Boettcher IC, Steinberg T, Matiasek CEG, Hartmann K, Fischer A (2007) Use of anti-corona virus antibody testing of cerebrospinal fluid for diagnosis of feline infectious peritonitis involving the central nervous system. J Am Vet Med Assoc 230: 199-205.
De Groot-Mijnes JD, Van Dun JM, Van der Most RG, de Groot RJ (2005) Natural history of a recurrent feline coronavirus infection and the role of cellular immunity in survival and disease, Journal of Virology 79: 1036–1044
Fischer Y, Sauter-Louis C, Hartmann K (2012) Diagnostic accuracy of the Rivalta test for feline infectious peritonitis. Vet Clin Pathol 41: 558–567.
Foley JE, Lapointe JM, Koblik P, Poland A, Pedersen NC (1998) Diagnostic features of clinical neurologic feline infectious peritonitis. J Vet Intern Med 12: 415423.
Giori L, Giordano A, Giudice C (2011) Performances of different diagnostic tests for feline infectious peritonitis in challenging clinical cases. J Small Anim Pract 52: 152–157.
Gruendl S, Matasek K, Matiasek L, Fischer A, Felten S, Jurina K, Hartmann K (2017) Diagnostic utility of cerebrospinal fluid immunocytochemistry for diagnosis of feline infectious peritonitis manifesting in central nervous system. J Feline Med Surg 19: 576–585.
Haagmans BL, Egberink HF, Horzinek MC (1996) Apoptosis and T-cell depletion during feline infectious peritonitis. J Virol 70: 8977–8983
Hartmann K, Binder C, Hirschberger J, Cole D, Reinacher M, Schroo S, Frost J, Egberink H, Lutz H, Hermanns W (2003) Comparison of different tests to diagnose feline infectious peritonitis. J. Vet. Intern. Med.17: 781–790.
Harvey CJ, Lopez JW, Hendrick MJ (1996) An uncommon intestinal manifestation of feline infectious peritonitis: 26 cases (1986-1993). J Am Vet Med Assoc 209: 1117–1120.
Hazuchova K, Held S, Neiger R (2017) Usefulness of acute phase proteins in differentiating between feline infectious peritonitis and other diseases in cats with body cavity effusions. J Feline Med Surg 19: 809–816.
Healey EA, Andre NM, Miller AD, Whitaker GR, Berliner EA (2022). Outbreak of feline infectious peritonitis (FIP) in shelter-housed cats: molecular analysis of the feline coronavirus S1 / S2 cleavage site consistent with a 'circulating virulent – avirulent theory'of FIP pathogenesis. Journal of Feline Medicine and Surgery Open Reports 8: 20551169221074226.
Kipar A, May H, Menger S, Weber M, Leukert W, Reinacher M (2005) Morphological features and development of granulomatous vasculitis in feline infectious peritonitis, Veterinary Pathology 42: 321–330
Kipar A, Meli ML (2014) Feline infectious peritonitis: Still an enigma? Vet. Pathol. 51: 505–526.
Levy JK, Hutsell S (2019) MSD veterinary manual: Feline infectoius peritonitis (FIP). USA: Merck Sharp and Dohme Corp.
Meli M, Kipar A, Müller C, Jenal K, Gönczi EE, Borel N, Gunn-Moore D, Chalmers S, Lin F, Reinacher M, Lutz H (2004) High viral loads despite absence of clinical and pathological findings in experimental cats infected with feline coronavirus (FCoV) type I and in naturally FCoV-infected cats, Journal of Feline Medicine and Surgery 6: 69–81.
Meli ML, Burr P, Decaro N (2013) Samples with high virus load cause a trend toward lower signal in feline coronavirus antibody tests. J Feline Med Surg 15: 295– 299.
Negrin A, Lamb CR, Cappello R (2007) Results of magnetic resonance imaging in 14 cats with meningoencephalitis. J Feline Med Surg 9: 109–116.
Norris JM, Bosward KL, White JD (2012) Clinico-pathological findings associated with feline infectious peritonitis in Sydney, Australia: 42 cases (1990-2002). Aust Vet J 83: 666–673.
Pedersen NC (2014) An update on feline infectious peritonitis: diagnostics and therapeutics. The veterinary journal 201: 133-141.
Pedersen NC (2009) A review of feline infectious peritonitis virus infection: 1963–2008. J. Feline Med. Surg.11: 225–258.
Pedersen NC (1995) An overview of feline enteric coronavirus and infectious peritonitis virus infections. Feline Practice 23: 7–20.
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, Sato R, Foley JE, Poland AM (2004) Common virus infections in cats, before and after being placed in shelters, with emphasis on feline enteric coronavirus. Journal of Feline Medicine and Surgery 6: 83–88.
Pedersen NC, Boyle JF, Floyd K (1981) Infection studies in kittens, using feline infectious peritonitis virus propagated in cell culture. Am. J. Vet. Res.42: 363– 367.
Riemer F, Kuehner KA, Ritz S (2016) Clinical and laboratory features of cats with feline infectious peritonitis - a retrospective study of 231 confirmed cases (2000-2010). J Feline Med Surg 18: 348–356.
Stranieri A, Giordano A, Paltrinieri, S Giudice C, Cannito V, Lauzi S (2018) Comparison of the performance of laboratory tests in the diagnosis of feline infectious peritonitis. J. Vet. Diagn. Investig. 30: 459–463.
Vennema H, Poland A, Foley J, Pedersen NC (1998) Feline infectious peritonitis viruses arise by mutation from endemic feline enteric coronaviruses. Virology 243: 150–157.
Vogel L, Van der Lubben M, teLintelo EG, Bekker, CP Geerts T, Schuijff LS, Grinwis GC, Egberink HF, Rottier PJ (2010) Pathogenic characteristics of persistent feline enteric coronavirus infection in cats. Vet. Res. 41: 71–82.
Weiss RC, Scott FW (1981) Pathogenesis of feline infectious peritonitis: nature and development of viraemia, American Journal of Veterinary Research 4: 382– 390. Read “FIP Diagnostics Overview”
Those who have followed my career know that I have many interests in addition to infectious diseases of cats. However, I am best known for feline medicine and diseases that plague multi-cat environments. This interest in infectious diseases started in 1965 as a second-year veterinary student but evolved after I joined the faculty of the UC Davis School of Veterinary Medicine in 1972. My first appointment was to help win President Nixon’s war on cancer. This war emphasized potential viral causes of cancer, in particular retroviruses and human leukemias. This was my entry back into the world of feline leukemia virus (FeLV). Of course, my interest was more on FeLV infection as it applied to cats than any application to human cancers. It became rapidly apparent that FeLV infection was a serious panzootic (pandemic) of cats that had unknowingly spread from feral to pet cats in the preceding decades and would account for one-third of mortality in cats in the 1960s and 70s. Cat lovers quickly mobilized once the virus was discovered and started raising money to support FeLV research. The original SOCK was created by a group of amazing cat lovers led by Vince, Connie and Dorothy Campanile and friends. SOCK it to leukemia became the rallying cry of the group and I was privileged to join forces with them from their beginning to end. Thereafter, donations from cat lovers and not federal research funds provided the bulk of our research into FeLV infection at UC Davis. This research led to an understanding of how FeLV became a pandemic of pet cats, how it caused a wide range of diseases, and how it could be controlled. FeLV infection of pet cats was brought under control in the 1970’s and 1980’s through rapid diagnostic tests and vaccination. The conquest of FeLV infection was one of the highlights of veterinary research of the period, and perhaps one of the most important contributions of modern feline medicine in the 20th century. SOCK it to leukemia had ultimately worked itself out of existence with over $1M dollars raised towards the ultimate conquest of FeLV infection. FeLV infection still exists in nature, where it remains a problem for a small number of younger cats coming into foster/rescues and shelters from the field.
During this same period, another highly fatal disease was rearing its head. Feline infectious peritonitis (FIP) was first reported in 1963 by veterinarians from the Angell Memorial Animal Hospital in Boston. It was later found to be closely linked to FeLV infection and the hope was that it would largely disappear with control of FeLV. This did not prove true and FIP soon replaced FeLV as a major infectious cause of deaths in cats up to this time. As a result, the torch was passed from SOCK it to leukemia to SOCK it to FIP. This was also a natural progression for my research. FIP was my first “love” from the time I helped research the first cases of FIP at UC Davis as a veterinary student in 1965. My interest in FIP only took second stage for a brief period in the 1980s with my work on HIV/AIDS and subsequent discovery of feline immunodeficiency virus (FIV). FIP has been my major research interest for the last three decades.
I am pleased to have had the support of SOCK FIP over these later years. One of our greatest discoveries at UC Davis was how an innocuous and ubiquitous feline enteric coronavirus (FECV) ends up causing such a highly fatal disease as FIP. Our theory that the virus of FIP arose as an internal mutation of FECV was first met with great skepticism but is now universally accepted. The internal mutation theory has led to a much better understanding of the conditions under which FIP occurs and how the FIP virus causes disease. Unfortunately, no one, including us, was able to find a successful vaccine for FIP. This failure led to my interest in curing rather than preventing FIP using modern antiviral drugs, which I became familiar with during the HIV/AIDS pandemic. The capstone of my almost 50-year experience with FIP was the discovery of two antiviral drugs that could cure FIP. Thousands of cats from round the world have been cured of FIP with antiviral drugs researched at UC Davis over the last 3 years. Our discoveries at UC Davis could have been impossible without the significant long-term financial and moral support of SOCK FIP and cat owners who have donated money.
The discovery of a cure for FIP has once again brought SOCK FIP to a logical ending, just as the conquest of FeLV infection ended the need for the original SOCK. Although I am retired, I continue to work with cat owners and caregivers on how to use antiviral drugs to treat FIP and will maintain my relationship with SOCK FIP as a consultant on FIP treatment and a lifelong member. Admittedly, there is still research to be done with FIP, mainly in the areas of disease prevention. Hopefully, others will take up this and other areas of FIP research. The question now is how SOCK can best improve the health of our cats and kittens. SOCK FIP is in the process of evaluating a broader mission than just FIP. This mission may or may not involve fund raising for research and could be more informational. We welcome suggestions on how the long history of SOCK’s can be used to improve the health of our cats and kittens. Read "Four Decades Save Our Cats and Kittens and What's Next"
Department of Microbiology and Immunology E-mail: email@example.com Sponsor: Cornell Feline Health Center Research Grants Program Title: Two Vaccine Platforms to Prevent Feline Coronavirus Disease Project Amount: $69,920 Project Period: July 2021 to June 2022
DESCRIPTION (provided by applicant):
While most cats infected with Feline Coronavirus (FCoV) develop mild to inapparent diarrheal disease, a subset of them develop the devastating and deadly feline infectious peritonitis (FIP). FCoV can spread via fecal-oral or respiratory routes, particularly in cat shelter environments. Coronaviruses have three envelope glycoproteins, S, E, and M, but the surface protein (S) is in charge of viral entry. S binds the cell surface receptor and then merges the viral membrane to the cell plasma or endosomal membranes, causing viral entry. S also causes cell-cell fusion (syncytia) post-infection. The S protein of most coronaviruses is also highly immunogenic. The devastating FIP disease begs the development of protective vaccines. We identified a small molecule, XM-01, that embeds within viral membranes and inhibits membrane fusion. Importantly, this novel method of inhibition renders virions noninfectious, while maintaining the native conformations of the surface glycoproteins, ideal for eliciting effective immune responses against such viral glycoproteins. Remarkably, vaccination with XM-01-treated influenza virions yielded an increase in neutralizing antibodies and survival rate, and a decrease in morbidity and mortality upon viral challenge in a mouse model, as compared to the traditional formalin-inactivated influenza vaccine. Thus, our Aim 1 will be to determine whether XM-01 can be used to develop a FeCoV inactivated vaccine. Importantly our recent preliminary data includes already determined conditions for complete FCoV inactivation. We will optimize XM-01 inactivation of FCoV in preparation to determine whether this vaccine can yield a robust immune response against this virus. Additionally, our lab has successfully used replication-incompetent vesicular stomatitis virus (VSV)-based pseudotyped virions to vaccinate and protect hamsters against Nipah, Hendra, and Ebola virus diseases with 100% safety and 100% efficacy (manuscript in final revision for Nature Publishing Journals Vaccines). Our Aim 2 will use the replication-incompetent VSV system to develop a vaccine against FCoV. We will optimize incorporation of FCoV-S into VSV virions in preparation to determine whether this vaccine can yield a robust immune response against this virus. As both inactivated and replication-incompetent virions vaccine platforms have been successfully used to prevent other viral diseases, the completion of our Aims will allow our vaccine platforms to readily advance to vaccination clinical trials/licensing. Read "Two vaccination platforms to prevent feline coronavirus disease"
Infectious feline peritonitis (FIP) is a fatal disease caused by feline coronavirus (FCoV) infection. FCoV can be divided into serotypes I and II. The virus that causes FIP (FIPV) is said to occur sporadically and does not often spread from one cat to another. An outbreak in one animal shelter in Taiwan was recently confirmed. FCoV from all cats in this shelter was analyzed to determine the epidemiology of this outbreak. Thirteen of the 46 (28,2%) cats with typical FIP symptoms were identified. Of these, FIP was confirmed in seven cats by necropsy or histopathological examination. Despite the fact that in this environment with more cats, more than one FCoV was identified, eight cats with symptoms of FIP were reliably found to be infected with FCoV type II. Sequence analysis revealed that FIPV type II, found from feline faeces, body effusions and granulomatous tissue homogenate from cats that underwent FIP, contained identical recombination in all cases. WITH gene. Two cats that succumbed to FIP were found to have an identical nonsense mutation in 3c gene. The excretion of this type II virus in faeces of the effusive form of FIP can be detected up to six days before the animal dies. In general, our data demonstrate that horizontal transmission of FIPV is possible and that FIP cats may pose a potential risk to other cats living in the same environment.
Infectious feline peritonitis (FIP) is a fatal disease of cats caused by feline coronavirus (FCoV) infection. FCoV is an enveloped RNA virus that belongs to the species Alphacoronavirus, family Coronaviridae and in order Nidovirales. The size of the FCoV genome is approximately 28.9 kb, including the nonstructural replication gene; four structural genes that encode spike (S), envelope, membrane, and nucleocapsid proteins; and five helper / nonstructural genes 3abca 7ab.
Feline coronaviruses cause mild, invisible, and transient bowel infections and are ubiquitous among cat populations worldwide . They occur in two serotypes, I and II [man]3]. Type I FCoV predominates here, while type II virus represents only 2-30% infections [4–8]. Following the accumulation of genetic evidence, it is apparent that FCoV type II was formed by two homologous recombinations between FCoV type I and canine coronavirus CoV (CCoV) [9,10]. Both serotypes can mutate in the host, lead to macrophage tropism and a systemic disease called infectious feline peritonitis [cat]2,11,12]. Due to poor virus shedding in FIP studies in cats, mutant FIP viruses (FIP-inducing FCoV, FIPV) appear to be contained only in diseased tissues and are not naturally transmitted in cat-to-cat contact [2,11,13,14].
In this article, we report an epizootic FIP in a shelter in Taiwan that was caused by a new Type II FCoV. Epidemiological and molecular examination of isolates from various healthy and sick cats from this shelter strongly suggests that the virus was introduced by moving kittens from another shelter with subsequent horizontal spread to adult cats with which the new kittens shared the shelter.
Materials and methods
Animals and sampling
A total of 46 cats from a private shelter were included in this study, which ran from September 2011 to August 2012. This shelter houses adult cats and from time to time a few kittens. All the cats were either strayed or rescued, and some of them were obtained from the homes of various private rescue stations where the rescued cats were temporarily housed. Before the onset of the disease, all cats lived together in an indoor environment without cages, sharing food, drink and toilets. Some cats were siblings, others were not related to them (Table 1).
Table 1 Information on all cats from this shelter in which FIP was suspected and in which the disease was confirmed
Ascites, jaundice, granulomatous lesions in the kidney, fibrinous peritonitis
July 11, 2011
December 14, 2011
Granulomatous changes in the kidneys, liver, lungs, brain and eyes
December 28, 2011
Ascites, pleural effusion and pericardial effusion, granulomatous changes in the kidneys, liver and intestine.
Effusive / non - fusive
July 11, 2011
November 5, 2011
Granulomatous changes in the kidneys, liver and omentum
February 14, 2012
Ascites and pleural effusion, jaundice, fibrinous peritonitis, granulomatous changes in the kidneys, liver, lungs and spleen.
Effusive / non - fusive
March 19, 2012
Jaundice, fibrinous peritonitis, granulomatous changes in the thoracic and abdominal walls, kidneys, liver, lungs, spleen omenta and eyes.
Effusive / non - fusive
April 13, 2012
Jaundice, enlargement of the liver and mesenteric lymph nodes, granulomatous changes in the kidneys and lungs.
1 Age of cats at the time of clinical signs of FIP. 2 Not available. a, b, c : siblings.
Faeces or rectal samples were taken from all asymptomatic cats at least once to monitor for FCoV. Body swabs, blood samples, swab specimens, including rectal, nasal, oral and conjunctival specimens, were taken as standard from cats that already showed signs of the disease or were suspected of having FIP. In addition to supportive care, cats with suspected FIP were treated with prednisolone (Prelon®, YF Chemical Corp., New Taipei City, Taiwan), benazepril (Cibacen®, Novartis, Barbera del Valles, Spain) and recombinant human interferon alpha (Roferon®-A). , Roche, Basel, Switzerland). Cats that succumbed to the disease were necropsied for pathological confirmation. During necropsy, body exudates were first removed with a needle and syringe, followed by swabs, blood, urine and granulomatous lesions on the internal organs. All samples were frozen at -20 ° C until use. All samples were tested for FCoV nested reverse transcription polymerase chain reaction (RT-nPCR) [man]15]. Samples with positive results were subsequently subjected to further analysis.
Sample preparation and reverse transcription
Swab samples were suspended in 1 ml of water treated with 0.1% diethyl pyrocarbonate (DEPC). Stool samples were suspended with 9x treated water 0.1% DEPC by vortexing. The suspension was centrifuged and the supernatant was transferred to a new tube. About 0.5 g of tissue was frozen and then crushed with a mortar and pestle in the presence of 2 ml of Trizol . Total RNA was extracted from 300 μl of swab suspension, whole blood, faeces suspension, tissue homogenate and body effusion using Trizol. Twenty-one microliters of isolated RNA was reverse transcribed with specific primer N1 (5′-gctacaattgtatcctcaac-3 ′) or P211  with Moloney mouse leukemia reverse transcription (Invitrogen, CA, USA). The reaction was incubated at 37 ° C for 60 min, at 72 ° C for 15 min and finally at 94 ° C for 5 min.
FCoV type determination by nested PCR
Nested PCR was performed for FCoV typing according to the procedures of Addie et al.  with a slight modification. After reverse transcription, 5 μl of complementary DNA was added to 25 μl of PCR mix (Invitrogen, CA, USA) according to the manufacturer's instructions for the following primer sets: S1 and Iffs to determine FCoV type I and S1 and Icfs to determine FCoV type II. Nested PCR was performed on 2 μl of the first PCR product using nested primers. The expected size of the second PCR achieved for type I and type II FCoV was 360 and 218 bp. RT-nPCR products were electrophoresed and then the target DNA fragments were purified (Geneaid Biotech, Ltd, Taipei) and sequenced (Mission Biotech, Taipei, Taiwan) - from both orientations.
Gene amplification, sequencing and analysis 3a and 3c from FCoV type II
For amplification 3a of the FCoV type II gene from FIP cats, a set of specific primers was designed that is able to amplify from WITH type II gene to gen 3a. Complementary DNA, amplified with a primer set, targeted the 3 'end WITH FCoV type II gene (Icfs) and 5 ′ end 3a FCoVe gene (3aR2: 5′-caccaaaacctatacacacaag-3 ′). The temperature cycle was as follows: 5 minutes preheating at 94 ° C; 35 cycles of denaturation at 94 ° C for 20 s, annealing at 50 ° C for 20 s and extension at 72 ° C for 30 s; and final extension at 72 ° C for 5 minutes. This was followed by a second series of amplification using primers nIcfs and 3aR2; the expected product size was about 600 bp. Amplicons were electrophoresed, purified, and sequenced from both orientations to confirm nucleotide sequences.
For amplification 3c of the FCoV type II gene from FIP cats, a set of specific primers was designed that is able to amplify from WITH type II gene to gen 3c. Complementary DNA was amplified with forward primer (Icfs) and reverse primer (E68R: 5′-aatatcaatataattatctgctgga-3 ′ and N21R: 5′-gttcatctccccagttgacg-3 ′, respectively). The temperature cycle was as follows: 5 minutes preheating at 94 ° C; 40 cycles of denaturation at 94 ° C for 30 s, annealing at 46 ° C for 30 s and extension at 72 ° C for 90 s; and final extension at 72 ° C for 7 minutes. Following a second series of amplification using primers nIcfs and E68R, the products were electrophoresed, purified and sequenced from both orientations to confirm nucleotide sequences.
Phylogenetic analysis and recombinant analysis of FCoV type II
Several sequence alignments were performed using ClustalW 2.0 with manual editing in EditSeq (DNASTAR, Madison, USA). Phylogenetic analyzes were performed using MegAlign, version 7.2.1 (DNASTAR, Madison, USA). Bootscan and similar graphs were compiled using SimPlot 3.5.1 software (SCRoftware, Baltimore, USA).
Confirmation of the FIP outbreak in the cat shelter
The shelter has been operating for three and a half years. Prior to August 2011, there were no records of FIP. The kittens (cats 1, 3, 4, 8 and 10) were moved to this shelter between June and July 2011. After arrival, these kittens played together and lived together with adult cats that lived here before. Prior to the outbreak, the kittens were individually taken to a veterinarian for vaccination and adoption visits. Fever was first detected in four kittens (cats 1, 3, 4, 5) within a few days (from 15 to 18 August) (Table 1). Clinical symptoms, e.g. fever, anorexia, neurological symptoms, shortness of breath and enlargement of the abdomen were observed over the next two months and the kittens gradually died between 1 September and 22 October (Table 1). Shelters from the shelter asked for our help on September 27. All cats housed in the shelter for a long time were immediately examined for FCoV using the RT-nPCR method. All FCoV-positive cats were isolated and kept separately. Nevertheless, starting in September, adult cats with FIP (cats 7-13) showed clinical signs similar to kittens, and all of these cats later died.
Six kittens (cats 1-6) with body effusions or neurological symptoms that succumbed in the first two months were not confirmed for necropsy (Table 1). Cat 1 was once brought to our teaching hospital and ascites (free fluid in the abdominal cavity) was taken from her. In cats 7-13, typical symptoms were found, namely ascites or pleural effusions in the body cavity (effusive FIP) and granulomatous lesions in some organs, especially in the kidneys, nuclei, lungs, omentum (forecourt) and eyes (non-effusive FIP). In cats 9, 11 and 12, necropsy showed a mixed form of the disease (Table 2) 1).
A total of 13 of the 46 cats (28.3%) died between September 2011 and April 2012 at FIP. At this time, 33 cats (71.7%) appeared to be clinically healthy and 26 of these asymptomatic cats (78.7%) were positive at least once for FCoV - detected from faeces using the RT-nPCR method. The other seven of these asymptomatic cats were negative for FCoV (Table 2) 2).
Table 2 Detection of the occurrence and type of FCoV from faeces samples in healthy cats from the same shelter
++: FCoV detected in the first round of PCR. +: FCoV detected only in nested PCR.
FIPV type II was found in all cats that succumbed to FIP
In order to further investigate the relationship between these seven histopathologically confirmed FIP cats, the amplified DNA was typed, sequenced and analyzed. FIPV type II was detected in all eight animals that succumbed to FIP, from swabs, faeces, urine, body effusions, cerebrospinal fluid, and tissue homogenates (Table 3). Type II viruses that cause FIP have been found not only in diseased tissue but also in faeces samples (cats 7, 11, 12 and 13), nasal / oral / conjunctival swab samples (cats 7, 8, 9, 11 and 12). ) and in urine collected by cystocentesis (cat 11) (Table 3). Although no necropsy was performed, ascites from cat 1 - the first cat to die in the shelter at FIP - were available for analysis. This cat was confirmed to be infected with type II virus. In healthy animals, only type I or FCoV was detected from faeces samples without type determination (Table 2) 2). Cats 8, 9 and 13 were infected with both types of FCoV (Table 2) 3). Although it has been found that in this environment with many cats there is more than one type of FCoV, ie. type I, II or non-typed viruses, FCoV type II infection was found in all eight FIP cats, whereas this was not the case in healthy animals (Tables 2 and33).
Table 3 Characteristics 3c FCoV genes obtained from different samples of FIP cats
WITH instead of gene crossing
Integrity 3c geneb
R / F
A / P
R / F
A / P
I / II
NIGHT, nose / mouth / conjunctival swabs; R / F, rectal swabs or stool samples; A / P, ascites or pleural effusion; CSF, cerebrospinal fluid; Li, liver; Lu, lungs; Ki, kidney; Br, brain; Sp, spleen; Int, gut. +: FCoV positive, but virus type cannot be determined. -: FCoV negative. a: FCoV / NTU2 / R / 2003; GenBank: DQ160294. b: E47 *, G210 * and Q218 *: truncated 3c proteins with premature stop codons at amino acids 47, 210 and 218 were found.
FIPV type II of the same origin was found in cats that succumbed to FIP
Recombination at the 3 ′ end WITH of the putative recombination site at nucleotide 4250 was determined in all FCoV type II animals obtained from body effusions and tissue homogenates in cats 1, 7, 9, 10, 11, 12 and 13 (Additional set 1) (Table 3). Sequences above this site show greater similarity to CCoV, whereas sequences beyond this site were more similar to type I FCoV (Fig. 1). 1). Indeed, these findings suggest that FCoV type II, found in all FIP cats, has a common origin.
Identical nonsensical mutation on 3c The gene was found in two cats that succumbed to FIP
In order to further analyze the relationship of these FIPVs, they were 3c genes, a proposed virulence-associated FIP, are amplified from the disease-causing FCoV type II. Mutated 3c genes with identical premature stop codon at nucleotides 628-630 (amino acids 210, G210 *) were found in two FIP cats, cat 9 (ascites, spleen and brain) and 12 (ascites and rectal swabs from the day the cat died and four days previously) (Fig. 2A). It is worth noting that FIPV, obtained from cat 12, showed the same nonsense mutation as the virus in its ascites. Intact 3c the genes were discovered in cats 1, 7 and 10, which had previously succumbed to FIP. Two other clear / different nonsense mutations were found in cats 11 (E47 *) and 13 (Q218 *) (Fig. 1). 2AB, Table 3).
FIPV type II excretion can be detected in the terminal phase in FIP cats
The occurrence of FCoV was continuously analyzed to elucidate a possible route of FIPV secretion and transmission. Disease-associated FCoV type II was found to be excreted by the nasal / oral / conjunctival route and faeces (Table 4). Faecal and nasal / oral / conjunctival type II shedding can be detected from day 6 (cat 11) and from day 4 (cat 12) before death. Viremia can be detected during the terminal stage in cats suffering from FIP up to 18 days before death, and concomitant faecal excretion was detected in one cat (cat 12) (Table 4).
Table 4 Excretion and serotypes of feline coronavirus detected in FIP cats in a cat shelter
Days before death
+: FCoV positive; -: FCoV negative. I, II: FCoV type I or type II. *: Samples were taken immediately before euthanasia, except for cat 12, which were sampled after death.
The possibility of horizontal transmission is generally questioned in FIP because (i) the occurrence of FIP is sporadic and it is common for only one of them to develop FIP in an environment with a large number of cats ; (ii) internal mutation theory, which describes that FIPV is a mutant generated from enteric FCoV in one cat [12,17]; (iii) there is insufficient evidence that the mutant FIPV is eliminated from FIP cats; and (iv) mutations 3c gene is unique for every FIP cat [man]11,13,18]. The current belief is that cats that have succumbed to FIP do not excrete and pass FIPV to other cats [11,13,14,18–20]. Our data indicate that this outbreak of FIP was caused by viruses of the same origin. First, all cats that died of FIP had a type II infection, and recombination of these seven type II viruses was located at the same site. Recombination of type II viruses currently available in the genetic bank, i.e. FIPV 79-1146, FCoV 79-1683 and FCoV NTU156, were all unique, specific and occurred independently [9,10]. Second, FIPV, found in three kittens that died within the first two months after the onset of fever, had an intact 3c gene, whereas viruses from cats that survived longer (died four to eight months later) all contained a nonsensical mutation, i. G210 * (cats 9 and 12), E47 * (cat 11) and Q218 * (cat 13). Because the three nonsense mutations found in FIPV in these animals were all located at different sites, the viruses that originally infected these cats should be intact. 3c gene - similar to the virus found in kittens that died earlier. Following infection, local mutations occurred during virus replication in individual cats, resulting in FIPV with 3c a gene that carries meaningless mutations in different places. The finding that viruses, which were identified not only in tissues but also in faecal samples in two cats (cats 9 and 12), had an identical mutation in 3c gene, further confirmed that there was a horizontal transfer (Table 2) 3). Taken together, all of these findings demonstrated that highly virulent FIPV spread horizontally from one animal to another.
This is the first report of an FIPV type II outbreak with evidence of horizontal disease-causing FCoV transmission. The FIP broke out after five kittens (cats 1, 3, 4, 8 and 10) entered this shelter between June and July 2011. Because causative type II viruses with a specific genetic marker in the S gene have been confirmed as feline and canine coronavirus recombination, and some of the kittens that died earlier were found to have lived together or next to dogs between rescue and transport to the shelter. of these kittens may have been the source of this type II virus. Dogs and especially young dogs often shed large amounts of canine coronavirus in their faeces in shelters, and recombination between feline-canine and canine-feline coronavirus is already well documented [man]21–23]. In addition, type II causative viruses have been detected in a number of excreta and secretions in cats that have died of FIP (Table 3), demonstrating that it is possible to spread between cats.
Although immediately after the first examination of all animals from this FCoV shelter, FCoV-secreting cats were housed in separate cages and transmission subsequently ceased, mortality at the onset of the disease was high (28%, 13/46). The results of three studies that looked at the outbreak of FIP have been reported earlier. The results of a four-year study conducted at a nearby cat kennel showed an average mortality of 17.3% ; the mortality rate from a ten-year study conducted at a nearby kennel was 29.4% (5/17) . Another epidemic study conducted in seven kennels / shelters revealed >10% mortality . The high incidence of FIP in these closed breeding stations could be influenced by genetically predisposed breeding animals. In our study, only a few FIP cats in this shelter were siblings and the other cats were not genetically related. Our study shows that even without the influence of genetic predisposing factors, FIP mortality can be high in a confined environment with a large number of cats if the spread of FCoV, which causes the disease, remains undetected.
In this environment with a large number of cats, three FIP cats were infected not only with FCoV type II, but also co-infected with FCoV type I (Table 3). Type I FCoV was found only in faecal samples, while type II FCoV was found in various samples, including body effusions, granulomatous tissue homogenates, and cerebrospinal fluid. This finding indicates that FCoV type II was a major cause of FIP in these doubly infected animals. This finding is consistent with our previous finding that FCoV type II infection is significantly associated with FIP .
The presence of FCoV in whole blood in the terminal phase has been identified previously [26,27]; however, to our knowledge, the presence of FIPV in faeces prior to the final stage of the disease was not published anywhere until our study. The excretion of this type II virus in faeces and by the nasal / oral / conjunctival route can be detected in the effusive form of FIP up to six days before the death of the animal. Another experimental study of the infection showed that inoculated viruses could not be detected until about two weeks after inoculation, before clinical signs of the disease developed . In summary, FIPV transmission could occur at the beginning, before the manifestations of the disease and in the terminal phase. When the disease broke out in our case, all the cats were initially placed together in an open room. After seven cats gradually succumbed to the disease, all FCoV-positive cats were housed separately in cages and kept separately. Isolation probably inhibited disease transmission. This outbreak of disease, which killed 13 cats, allowed us to make it clear that FIPV can be transmitted horizontally and to show that the isolation of sick cats should be taken into account in an environment where more cats are present.
The authors claim that they have no competitive interests.
Contributions and contributions of authors
YTW performed sampling and preparation, FCoV detection, type determination, amplification 3c gene and other analyzes and compiled a manuscript. The BLS supervised the sampling and treatment of all FIP animals and contributed to the compilation of the manuscript. LEH participated in the amplification 3c gene, genetic analysis and manuscript preparation. The LLC devised the study, participated in the design of the study, coordinated and participated in the preparation of the manuscript. All authors read and approved the final version of the manuscript.
Additional file 1:
The authors would like to thank the caregivers in the mentioned cat shelter, without whose help this study would not have been possible.
Lai MMC, Perlman S, Anderson LJ. In: Fields virology. Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE, editor. Philadelphia: Lippincott Wiilliams & Wikins; 2007. Coronaviridae; pp. 1305–1335.
Pedersen NC. A review of feline infectious peritonitis virus infection: 1963-2008. J Feline Med Surg. 2009; 44: 225–258. doi: 10.1016 / j.jfms.2008.09.008. [PubMed] [Cross Ref]
Pedersen NC, Black JW, Boyle JF, Evermann JF, McKeirnan AJ, Ott RL. Pathogenic differences between various feline coronavirus isolates. Adv Exp Med Biol. 1984; 44: 365-380. doi: 10.1007 / 978-1-4615-9373-7_36. [PubMed] [Cross Ref]
Lin CN, Su BL, Wang CH, Hsieh MW, Chueh TJ, Chueh LL. Genetic diversity and correlation with feline infectious peritonitis of feline coronavirus type I and II: a 5-year study in Taiwan. Vet Microbiol. 2009; 44: 233–239. doi: 10.1016 / j.vetmic.2008.11.010. [PubMed] [Cross Ref]
Addie DD, Schaap IA, Nicolson L, Jarrett O. Persistence and transmission of natural type I feline coronavirus infection. J Gen Virol. 2003; 44: 2735–2744. doi: 10.1099 / vir.0.19129-0. [PubMed] [Cross Ref]
Benetka V, Kubber-Heiss A, Kolodziejek J, Nowotny N, Hofmann-Parisot M, Mostl K. Prevalence of feline coronavirus types I and II in cats with histopathologically verified feline infectious peritonitis. Vet Microbiol. 2004; 44: 31–42. doi: 10.1016 / j.vetmic.2003.07.010. [PubMed] [Cross Ref]
Hohdatsu T, Okada S, Ishizuka Y, Yamada H, Koyama H. The prevalence of types I and II feline coronavirus infections in cats. J Vet Med Sci. 1992; 44: 557–562. doi: 10.1292 / jvms.54.557. [PubMed] [Cross Ref]
Kummrow M, Meli ML, Haessig M, Goenczi E, Poland A, Pedersen NC, Hofmann-Lehmann R, Lutz H. Feline coronavirus serotypes 1 and 2: seroprevalence and association with disease in Switzerland. Clin Diagn Lab Immunol. 2005; 44: 1209–1215. [PMC free article] [PubMed]
Lin CN, Chang RY, Su BL, Chueh LL. Full genome analysis of a novel type II feline coronavirus NTU156. Virus Genes. 2013; 44: 316–322. doi: 10.1007 / s11262-012-0864-0. [PubMed] [Cross Ref]
Herrewegh AA, Smeenk I, Horzinek MC, Rottier PJ, de Groot RJ. Feline coronavirus type II strains 79-1683 and 79-1146 originate from a double recombination between feline coronavirus type I and canine coronavirus. J Virol. 1998; 44: 4508–4514. [PMC free article] [PubMed]
Rottier PJ, Nakamura K, Schellen P, Volders H, Haijema BJ. Acquisition of macrophage tropism during the pathogenesis of feline infectious peritonitis is determined by mutations in the feline coronavirus spike protein. J Virol. 2005; 44: 14122–14130. doi: 10.1128 / JVI.79.22.14122-14130.2005. [PMC free article] [PubMed] [Cross Ref]
Chang HW, de Groot RJ, Egberink HF, Rottier PJ. Feline infectious peritonitis: insights into feline coronavirus pathobiogenesis and epidemiology based on genetic analysis of the viral 3c gene. J Gen Virol. 2010; 44: 415–420. doi: 10.1099 / vir.0.016485-0. [PubMed] [Cross Ref]
Stoddart ME, Gaskell RM, Harbor DA, Gaskell CJ. Virus shedding and immune responses in cats inoculated with cell culture-adapted feline infectious peritonitis virus. Vet Microbiol. 1988; 44: 145-158. doi: 10.1016 / 0378-1135 (88) 90039-9. [PubMed] [Cross Ref]
Herrewegh AA, de Groot RJ, Cepica A, Egberink HF, Horzinek MC, Rottier PJ. Detection of feline coronavirus RNA in feces, tissues, and body fluids of naturally infected cats by reverse transcriptase PCR. J Clin Microbiol. 1995; 44: 684–689. [PMC free article] [PubMed]
Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987; 44: 156–159. [PubMed]
Poland AM, Vennema H, Foley JE, Pedersen NC. Two related strains of feline infectious peritonitis virus isolated from immunocompromised cats infected with a feline enteric coronavirus. J Clin Microbiol. 1996; 44: 3180–3184. [PMC free article] [PubMed]
Pedersen NC, Liu H, Scarlett J, Leutenegger CM, Golovko L, Kennedy H, Kamal FM. Feline infectious peritonitis: role of the feline coronavirus 3c gene in intestinal tropism and pathogenicity based upon isolates from resident and adopted shelter cats. Virus Res. 2012; 44: 17–28. doi: 10.1016 / j.virusres.2011.12.020. [PubMed] [Cross Ref]
Foley JE, Poland A, Carlson J, Pedersen NC. Patterns of feline coronavirus infection and fecal shedding from cats in multiple-cat environments. J Am Vet Med Assoc. 1997; 44: 1307–1312. [PubMed]
Foley JE, Poland A, Carlson J, Pedersen NC. Risk factors for feline infectious peritonitis among cats in multiple-cat environments with endemic feline enteric coronavirus. J Am Vet Med Assoc. 1997; 44: 1313–1318. [PubMed]
Stavisky J, Pinchbeck G, Gaskell RM, Dawson S, German AJ, Radford AD. Cross sectional and longitudinal surveys of canine enteric coronavirus infection in kennelled dogs: a molecular marker for biosecurity. Infect Genet Evol. 2012; 44: 1419–1426. doi: 10.1016 / j.meegid.2012.04.010. [PubMed] [Cross Ref]
Decaro N, Mari V, Elia G, Addie DD, Camero M, Lucente MS, Martella V, Buonavoglia C. Recombinant canine coronaviruses in dogs, Europe. Emerg Infect Dis. 2010; 44: 41–47. doi: 10.3201 / eid1601.090726. [PMC free article] [PubMed] [Cross Ref]
Decaro N, Buonavoglia C. An update on canine coronaviruses: viral evolution and pathobiology. Vet Microbiol. 2008; 44: 221–234. doi: 10.1016 / j.vetmic.2008.06.007. [PubMed] [Cross Ref]
Watt NJ, MacIntyre NJ, McOrist S. An extended outbreak of infectious peritonitis in a closed colony of European wildcats (Felis silvestris) J Comp Pathol. 1993; 44: 73–79. doi: 10.1016 / S0021-9975 (08) 80229-0. [PubMed] [Cross Ref]
de Groot-Mijnes JD, van Dun JM, van der Most RG, de Groot RJ. Natural history of a recurrent feline coronavirus infection and the role of cellular immunity in survival and disease. J Virol. 2005; 44: 1036–1044. doi: 10.1128 / JVI.79.2.1036-1044.2005. [PMC free article] [PubMed] [Cross Ref]
Tsai HY, Chueh LL, Lin CN, Su BL. Clinicopathological findings and disease staging of feline infectious peritonitis: 51 cases from 2003 to 2009 in Taiwan. J Feline Med Surg. 2011; 44: 74–80. doi: 10.1016 / j.jfms.2010.09.014. [PubMed] [Cross Ref]
Origin of FIP exudates. Sweat in wet FIP comes from small vessels (venules) that line the surface of the abdominal and thoracic organs (visceral) and walls (parietal), mesentery / mediastinum, and omentum. The spaces around these vessels contain a specific type of macrophages that come from monocyte progenitors that constantly recirculate between the bloodstream, the interstitial spaces around the venules, the afferent lymph, the regional lymph nodes, and back into the bloodstream. Other sites of this recirculation are located in the meninges, brain ependyma, and uveal eye tract. A small proportion of these monocytes develop into immature macrophages (monocyte / macrophage) and eventually into resident macrophages. Macrophages are constantly looking for infections.
FIPV is caused by a mutation in feline enteric coronavirus (FECV) present in lymphoid tissues and lymph nodes in the lower intestine. The mutation changes FECV cell tropism from enterocytes to peritoneal-type macrophages. Monocytes / macrophages appear to be the first cell type to be infected. This infection causes more monocytes to leave the bloodstream and begin to turn into macrophages, which continue the cycle of infection. . Monocytes / macrophages do not undergo programmed cell death as usually expected, but continue to mature into large virus-loaded macrophages. These large macrophages eventually undergo programmed cell death (apoptosis) and release large amounts of virus, which then infects new monocytes / macrophages. . Infected monocytes / macrophages and macrophages produce several substances (cytokines) that mediate the intensity of inflammation (disease) and immunity (resistance). [1,2].
Inflammation associated with FIP leads to three types of changes in the venules. The first is loss of vascular wall integrity, micro-bleeding, and leakage of plasma protein rich in activated complement clotting and activation factors and other inflammatory proteins. The second type of damage involves thrombosis and blocking blood flow. The third injury occurs in more chronic cases and involves fibrosis (scarring) around the blood vessels. Variations in these three events determine the amount and composition of exudates according to the four Starling forces that determine the movement of fluids between the bloodstream and interstitial spaces. .
The classic effusion in wet FIP is mainly due to acute damage to the vessel walls and leakage of plasma into the interstitial spaces and finally into the body cavities. Protein that escapes into the interstitial spaces attracts additional fluids, which can be exacerbated by blocking venous blood flow and increasing capillary pressure. This type of effusion, known as exudate, also contains high levels of protein, which is involved in inflammation, immune responses and blood clotting.
This fluid also contains a large number of neutrophils, macrophages / monocytes, macrophages, eosinophils and a lower number of lymphocytes and red blood cells. This classic type of fluid has the consistency of egg white and forms weak clots containing a high amount of bilirubin. Bilirubin does not originate from liver disease, but rather from the destruction of red blood cells that escape into interstitial tissue cells and are taken up by monocytes / macrophages and macrophages. Red blood cells break down and hemoglobin is broken down into heme and globin. Globin is further metabolized to biliverdin (greenish color) and finally to bilirubin (yellowish color), which is then excreted by the liver. However, cats lack the enzymes used for conjugation and are therefore ineffective in removing bilirubin from the body. . This leads to the accumulation of bilirubin in the bloodstream and gives the effusion a yellow tinge. The darker the yellow tint, the more bilirubin is in the effusion, the more severe the initiating inflammatory response and the more severe the resulting bilirubinemia, bilirubinuria and jaundice.
The opposite extreme of the classic and more acute effusion in FIP are effusions arising mainly from chronic infections and blockage of venous blood flow and consequent increase in capillary pressure. High capillary pressure results in effusion that is more distant to interstitial fluid than plasma, has a lower protein content, is watery rather than sticky, clear or slightly yellow in color, is not prone to clotting, and has a lower number of acute inflammatory cells such as neutrophils. There are also FIP effusions that are among these extremes, depending on the relative degree of acute inflammation and chronic fibrosis. These transient types of fluids are commonly referred to in the veterinary literature as modified transudate, but this is a misnomer. The modified transudate begins as a transudate and changes as it persists and causes mild inflammation. Low protein and cell effusions in FIP arise as exudates and not as transudates and do not conform to this description. The more correct term is "modified exudate" or "variant exudate outflow".
How long do sweats usually last in cats treated with GS-441524 or GC376? The presence of abdominal effusions often leads to a large dilation of the abdomen and is confirmed by palpation, hollow needle aspiration, X-ray or ultrasound. Cats with thoracic effusions are most often presented with severe shortness of breath and are confirmed by radiological examination and aspiration. Chest effusions are almost always removed to relieve shortness of breath and recur slowly compared to abdominal effusions. Therefore, abdominal effusions are usually not removed unless they are massive and do not interfere with respiration, as they are quickly replaced. Repeated drainage of abdominal effusions can also deplete proteins and cause harmful changes in fluid and electrolyte balance in severely ill cats.
Chest effusions disappear faster with GS-441524 treatment, with improved breathing within 24-72 hours and usually disappearing in less than 7 days. Abdominal effusions usually decrease significantly within 7-14 days and disappear within 21-28 days. The detection of exudates that persist after this time depends on their amount and method of detection. Small amounts of persistent fluid can only be detected by ultrasound.
Persistence of exudates during or after antiviral treatment. There are three basic reasons for the persistence of exudates. The first is the persistence of the infection and the resulting inflammation at a certain level, which can be caused by inappropriate treatment, poor medication or drug resistance. Inadequate treatment may be the result of incorrect dosing of the wrong drug or the acquisition of virus resistance to the drug. The second reason for fluid persistence is chronic venous damage and increased capillary pressure. This may be due to a low-grade infection or residual fibrosis from an infection that has been removed. The third reason for persistence is the existence of other diseases, which can also manifest as exudates. These include congenital heart disease, in particular cardiomyopathy, chronic liver disease (acquired or congenital), hypoproteinemia (acquired or congenital) and cancer. Congenital diseases causing effusions are more common in young cats, while acquired causes and cancer are more commonly diagnosed in older cats.
Diagnosis and treatment of persistent effusions. A thorough examination of the fluid, as described above, is a prerequisite for diagnosis and treatment. If the fluid is inflammatory or semi-inflammatory and the cell pellet is positive by PCR or IHC, the reason for the persistence of the infection must be determined. Was the antiviral treatment performed correctly, was the antiviral drug active and its concentration correct, was there evidence of acquired drug resistance? If the fluid is inflammatory and PCR and IHC are negative, what other diseases are possible? Low protein and non-inflammatory fluids that are negative for PCR and IHC indicate a diagnosis of residual small vessel fibrosis and / or other contributing causes such as heart disease, chronic liver disease, hypoproteinemia (bowel disease or kidneys). Some of the disorders causing this type of effusion may require an exploratory laparotomy with a thorough examination of the abdominal organs and a selective biopsy to determine the origin of the fluid. The treatment of persistent effusions will vary greatly depending on the end cause. Persistent effusions caused by residual small vessel fibrosis in cats cured of the infection often resolve after many weeks or months. Persistent discharges caused in whole or in part by other diseases require treatment for these diseases.
Identification and characteristics of persistent effusions. The presence of fluid after 4 weeks of GS treatment is unpleasant and is usually detected in several ways depending on the amount of fluid and its location. Large amounts of fluid are usually determined by the degree of abdominal dilation, palpation, X-ray and abdominal aspiration, while smaller amounts of fluid are best detected by ultrasound. Persistent pleural effusion is usually detected by X-rays or ultrasound. Overall, ultrasound is the most accurate means of detecting and semiquantitatively determining thoracic and abdominal effusions. Ultrasound can also be used in combination with thin needle aspiration to collect small and localized amounts of fluid.
The second step in examining persistent effusions is to analyze them based on color, protein content, white and red blood cell counts, and the types of white blood cells present. Fluids generated primarily by inflammation will have protein levels close to or equal to plasma and a large number of white blood cells (neutrophils, lymphocytes, monocytes / macrophages and large vacuolated macrophages). Fluids produced by increased capillary pressure are more similar to interstitial fluid with proteins closer to 2.0 g / dl and cell counts <200. The Rivalt test is often used to diagnose FIP-related effusions. However, this is not a specific test for FIP, but rather for inflammatory effusions. It is usually positive for FIP effusions that are high in protein and cells, but is often negative for very low protein and cell effusions. The effluents that are between these two types of effusions will be tested either positively or negatively, depending on where they are in the spectrum.
The third step is the analysis of exudates for the presence of FIP virus. This usually requires 5 to 25 ml or more of fluid. For fluids with a higher protein and cell count, a smaller amount may suffice, while for fluids with a low protein and cell count, a larger amount is required. The freshly collected sample should be centrifuged and the cell pellet analyzed for the presence of viral RNA by PCR or cytocentrifuged for immunohistochemistry (IHC). The PCR test should be for FIPV 7b RNA and not for specific FIPV mutations, as the mutation test does not have sufficient sensitivity and does not provide any diagnostic benefits . Samples that are positive by PCR or IHC provide definitive evidence of FIP. However, up to 30 % samples from known cases of FIP may have a false negative test either due to an inappropriate sample and its preparation, or because the RNA level of the FIP virus is below the level of detection. It is also true that the less inflammatory the fluid, the lower the virus levels. Therefore, effusions with lower protein and white blood cell levels are more likely to be tested negative because viral RNA is below the detection limit of the test.
 Watanabe R, Eckstrand C, Liu H, Pedersen NC. Characterization of peritoneal cells from cats with experimentally-induced feline infectious peritonitis (FIP) using RNA-seq. Vet Res. 2018 49 (1): 81. doi: 10.1186 / s13567-018-0578-y.
. Kipar A, Meli ML, Failing K, Euler T, Gomes-Keller MA, Schwartz D, Lutz H, Reinacher M. Natural feline coronavirus infection: differences in cytokine patterns in association with the outcome of infection. Vet Immunol Immunopathol. 2006 Aug 15; 112 (3-4): 141-55. doi: 10.1016 / j.vetimm.2006.02.004. Epub
. Court MH. Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms. Vet Clin North Am Small Anim Pract. 2013; 43 (5): 10391054. doi: 10.1016 / j.cvsm.2013.05.002