key: cord-0733644-lx6qrufs authors: Addie, Diane; Belák, Sándor; Boucraut-Baralon, Corine; Egberink, Herman; Frymus, Tadeusz; Gruffydd-Jones, Tim; Hartmann, Katrin; Hosie, Margaret J.; Lloret, Albert; Lutz, Hans; Marsilio, Fulvio; Pennisi, Maria Grazia; Radford, Alan D.; Thiry, Etienne; Truyen, Uwe; Horzinek, Marian C. title: Feline infectious peritonitis. ABCD guidelines on prevention and management date: 2009-07-31 journal: Journal of Feline Medicine & Surgery DOI: 10.1016/j.jfms.2009.05.008 sha: 397e55ca3a30fa1a2ae28d63ff3efc421ad374fd doc_id: 733644 cord_uid: lx6qrufs Overview Feline coronavirus infection is ubiquitous in domestic cats, and is particularly common where conditions are crowded. While most FCoV-infected cats are healthy or display only a mild enteritis, some go on to develop feline infectious peritonitis, a disease that is especially common in young cats and multi-cat environments. Up to 12% of FCoV-infected cats may succumb to FIP, with stress predisposing to the development of disease. Disease signs The ‘wet’ or effusive form, characterised by polyserositis (abdominal and/or thoracic effusion) and vasculitis, and the ‘dry’ or non-effusive form (pyogranulomatous lesions in organs) reflect clinical extremes of a continuum. The clinical picture of FIP is highly variable, depending on the distribution of the vasculitis and pyogranulomatous lesions. Fever refractory to antibiotics, lethargy, anorexia and weight loss are common non-specific signs. Ascites is the most obvious manifestation of the effusive form. Diagnosis The aetiological diagnosis of FIP ante-mortem may be difficult, if not impossible. The background of the cat, its history, the clinical signs, laboratory changes, antibody titres and effusion analysis should all be used to help in decision-making about further diagnostic procedures. At the time of writing, there is no non-invasive confirmatory test available for cats without effusion. Disease management In most cases FIP is fatal. Supportive treatment is aimed at suppressing the inflammatory and detrimental immune response. However, there are no controlled studies to prove any beneficial effect of corticosteroids. Vaccination recommendations At present, only one (intranasal) FIP vaccine is available, which is considered as being non-core. Kittens may profit from vaccination when they have not been exposed to FCoV (eg, in an early-weaning programme), particularly if they enter a FCoV-endemic environment. fatal disease that is most common in multi-cat environments [EBM grade III]. 8, 11 Some breeds (eg, Bengals) and individual lines within breeds are more likely to succumb to FIP. 12 Age is an important risk factor, and 70% of cases are less than 1 year old. 13, 14 However, the disease has been observed in cats 17 years of age; it may also be more likely in entire cats compared with neutered ones. 12 Stress experienced by persistently FCoVinfected cats (eg, surgery, visit to a cattery, moving, co-infection with feline leukaemia virus), predisposes them to develop FIP. 13 Stress management is therefore an important part of control. In breeding catteries, kittens usually become infected at a young age, mostly at 5-6 weeks, when maternally derived antibodies (MDA) have waned; however, infection at 2 weeks of age has also been detected. 15 Faeces are the main source of FCoV, with litter boxes representing the principal source of oral infection in groups of cats. Since virus is rarely found in the saliva of healthy cats, it plays a minor role in groups with close contact or when sharing feeding bowls. 16 Transplacental transmission has been described from a queen that developed the disease during pregnancy, 17 but is very rare. 18 Susceptible cats are most likely to be infected following contact with FCoV in faeces from asymptomatic cats. Although transmission from FIP cases may occur, this usually does not lead to disease under natural conditions; however it has been demonstrated experimentally. After natural infection, cats begin to shed virus in the faeces within 1 week and continue to shed for weeks, months, and a few even for life (also called carriers). 2, 16, 19 Faecal excretion may reach high levels and appears to be continuous. 2, 16, 19 Pathogenesis Most FCoV-infected cats either stay healthy or show only a mild enteritis. Only a proportion of FCoV-infected cats will develop FIP, a pyogranulomatous vasculitis. 5, 28 The pathogenesis of FIP may be explained by an increased number of mutants, stochastically arising during bursts of replication (eg, under immune suppression), some of them growing to high concentrations in monocytes and macrophages. [21] [22] [23] Mutations have been identified in non-structural genes, and more may remain to be identified. These highly virulent FCoV mutants have consistently induced FIP under experimental conditions, but their virulence has not been traced to a molecular source. 24, 25 The viral load and the cat's immune response determine whether FIP will develop. Both viral genetics and host immunity are likely to play a role in the development of FIP. 23, 26, 27 The pathology of FIP has been classified into two forms: an effusive (wet) FIP characterised by polyserositis (eg, thoracic and abdominal effusion) (Fig 1) and vasculitis, and a non-effusive (dry) FIP characterised by granulomatous lesions in organs (Fig 2) . 28 These two forms reflect clinical extremes of a continuum. An uncommon enteric form described in young cats with diarrhoea and vomiting was associated with nodular intestinal pyogranulomatous lesions. 29 Faeces are the main source of FCoV, with litter boxes representing the principal source of oral infection in groups of cats. Susceptible cats are most likely to be infected following contact with FCoV in faeces from asymptomatic cats. Evidence-based medicine (EBM) is a process of clinical decision-making that allows clinicians to find, appraise and integrate the current best evidence with individual clinical expertise, client wishes and patient needs (see Editorial on page 529 of this special issue, doi:10.1016/j.jfms.2009.05.001). This article uses EBM ranking to grade the level of evidence of statements in relevant sections on epidemiology, diagnosis, disease management and control, as well as vaccination. Statements are graded on a scale of I to IV as follows: ✜ EBM grade I This is the best evidence, comprising data obtained from properly designed, randomised controlled clinical trials in the target species (in this context cats); ✜ EBM grade II Data obtained from properly designed, randomised controlled studies in the target species with spontaneous disease in an experimental setting; The form that a cat develops is thought to depend on the strength of the T cell-mediated response, which is probably the only efficient immune response against disease progression. 5, 21 Progression of the infection to FIP may be the consequence of severe immunodepression by T cell depletion. 30 The wet forms are presumed to arise as a consequence of weak cell-mediated immune responses. 5 Attempts to identify a tissue distribution of FCoV that is diagnostic for FIP have been fruitless. In cats with FIP, virus replicates to high titres in monocytes and can be found in many organs. 28, 32 In asymptomatic cats, FCoV is mainly confined to the intestine. However, a low level monocyte-associated viraemia can sometimes also be detected in healthy animals by reversetranscriptase PCR (RT-PCR). 31,75 A significant difference in viral replication in haemolymphatic tissues has been demonstrated between cats that died from FIP and healthy long-term carriers. 32 Monocytes and macrophages remain infected in the presence of high antibody levels. The mechanism of this immune evasion could be an escape from antibody-dependent lysis due to the absence of viral antigens on the surface of infected cells. 22, 33 The direct consequence may be a quiescent infection state and long incubation period. When monocytes and 596 JFMS CLINICAL PRACTICE perivascular macrophages are activated, the typical widespread pyogranulomatous and vasculitis/perivasculitis lesions may develop in the kidneys, mesenteric lymph nodes, lungs, liver, spleen, omentum and brain of cats with FIP. 28 It has been suggested that cats mounting a strong cell-mediated immune response do not develop FIP, whereas cats showing a predominantly humoral response progress to disease. 5 Hypergammaglobulinaemia is common in cats with FIP. 34, 51, 54 Also, a drastic depletion of T cells from blood and lymphoid tissues has been described. 30, 35 Passive immunity Maternally derived antibodies usually provide protection until about 5-6 weeks of age. 8 Levels decline and become undetectable by 6-8 weeks of age. Active immune response ✜ Cell-mediated immunity Cats that stayed healthy after experimental FCoV infection have been shown to display a better cell-mediated immune response than those that progressed to FIP. 30 ✜ Humoral immunity The role of humoral immunity in protecting against FIP is ambiguous. Clearance of natural infections has been associated with antibodies directed against the FCoV S protein. 36 Conversely, antibodies directed against the S protein can be detrimental. In cats with pre-existing antibodies, 'antibodydependent enhancement' has been observed experimentally, resulting in a shortened disease course and earlier death. This enhancement was observed irrespective of whether cats had acquired antibodies through passive or active immunisation. [37] [38] [39] However, pre-existing antibody is not a precondition; in field studies cats developed FIP on first exposure to FCoV. 2, 40 Clinical signs The clinical picture of FIP is highly variable, reflecting the variability in the distribution of the vasculitis and pyogranulomatous lesions. The distinction between effusive and noneffusive (wet and dry) forms of FIP is of some value in recognising the clinical presentations; however, although it may contribute to diagnosis, there is considerable overlap between the two forms. Fever that is refractory to antibiotics, lethargy, anorexia and weight loss are common -specific signs but occasional cases remain bright and retain body condition; lesions compatible with FIP pathology have also been found incidentally in healthy cats undergoing abdominal surgery. Ascites is the most obvious manifestation of the effusive form (Figs 3 and 4). 41 Thoracic and pericardial effusion may occur. In some cats, effusion is restricted to the thorax and these cases usually present with dyspnoea. Serositis can involve the tunica vaginalis of the testes, leading to scrotal enlargement. Non-effusive FIP is often more difficult to diagnose. Fever, anorexia and lethargy may be the only signs, particularly in the early stages of disease. More specific signs will depend on the organs affected by the vasculitis and pyogranulomatous lesions, commonly the abdominal organs. Renal involvement ( Fig 5) may lead to renomegaly, which is detectable on palpation. Mural lesions in the colon or ileocaecocolic junction occasionally occur and may be associated with chronic diarrhoea and vomiting. There may also be palpable enlargement of the mesenteric lymph nodes, which potentially may be misinterpreted as neoplasia. 42 A diffuse pyogranulomatous pneumonia is seen in some cases, leading to severe dyspnoea. 43 Ocular involvement with uveitis is common (Fig 6) , leading to changes in iris colour, dyscoria or anisocoria secondary to iritis, 44 sudden loss of vision and hyphaema (Fig 7) . Keratic precipitates may appear as 'mutton fat' deposits on the ventral corneal endothelium (Fig 8) . The iris may show swelling and a nodular surface, and aqueous flare may be detected. On ophthalmoscopic examination, Neurological signs are reported in at least 10% of cats with FIP. 13, 45 They reflect focal, multifocal or diffuse involvement of the brain, spinal cord and meninges. 46 The most commonly reported signs are ataxia, hyperaesthesia, nystagmus, seizures, behavioural changes and cranial nerve deficits. 45, 47 Cutaneous signs -multiple nodular lesions caused by pyogranulomatous-necrotising dermal phlebitis and skin fragility -have recently been reported. 48 Aetiological diagnosis of FIP ante-mortem may be difficult, if not impossible, because of the invasiveness of taking biopsies from a sick cat. Currently, there is no non-invasive confirmatory test available for cats without effusion. Effusions should first be looked for, because their analysis is very useful and they can be obtained relatively non-invasively. The background of the cat, its history, the clinical signs, laboratory changes and antibody titres should all be used to help in decision-making about further diagnostic procedures. 13 Haematology profiles are often altered in cats with FIP. White blood cell counts can be either decreased or increased. Lymphopenia is common; but lymphopenia in combination with neutrophilia, known as a 'stress leukogram', can occur in many other diseases. However, a normal lymphocyte count makes FIP unlikely. A mild to moderate non-regenerative anaemia is also a common finding, but may occur in almost any chronic disease of the cat. A common laboratory finding is an increase in total serum protein concentration caused mainly by a rise in gamma globulins. 50 Hyperglobulinaemia was found in around 50% of cats with effusion and about 70% of cats without effusion. 51 After experimental infection, an early increase in alpha-2 globulins was seen, while gamma globulins and antibody titres increased just before the onset of clinical signs. 52, 53 Serum total protein levels can reach concentrations of 120 g/l (12 g/dl). The albumin/globulin ratio has a higher diagnostic value than either total serum protein or gamma globulin concentrations, because if the liver is affected, both albumin and globulin will decrease. 13, 54 Although viral antigen has not been found in the glomeruli of cats with FIP, 55 it is hypothesised that low albumin is usually associated with protein loss caused by glomerulopathy secondary to immune complex deposition, or by extravasation of protein-rich fluid during vasculitis. An optimum cut-off value of 0.8 has been determined for the albumin/globulin ratio, above which FIP is extremely unlikely [EBM grade I]. 54, 56 Serum protein electrophoresis may reveal both polyclonal and monoclonal hypergammaglobulinaemia as well as an increase in acute phase proteins. Liver enzymes, urea and creatinine can all be elevated, depending on the degree and site of organ damage, but are generally not useful in establishing a diagnosis. Hyperbilirubinaemia and icterus are frequent and often reflect hepatic necrosis. 54 High bilirubin levels in the absence of haemolysis and elevation of R E V I E W / ABCD guidelines on feline infectious peritonitis 598 JFMS CLINICAL PRACTICE liver enzyme activity should raise the suspicion of FIP. High serum alpha-1 acid glycoprotein (AGP) levels (>1500 μg/ml) may support the diagnosis, 57 but levels are also high in other inflammatory conditions. Additionally, AGP levels may be high in healthy cats infected with FCoV, especially in households where the infection is endemic. 58 If there is effusion, a sample must be obtained, because tests on effusions have a higher diagnostic value than blood tests. However, only about half of cats with effusion suffer from FIP. 59 Although effusions of clear yellow colour and sticky consistency are often called 'typical', their presence alone in body cavities is not diagnostic. Sometimes the fluid has a different appearance and cases with pure chylous effusion have been reported. 60 Usually, the protein content is very high (>35 g/l), consistent with that of an exudate, whereas the cellular content is low (<5000 nucleated cells/ml) and approaches that of a modified or pure transudate. Cytology of the effusion in cats with FIP is variable but usually consists predominantly of macrophages and neutrophils. Electrophoresis is a diagnostic tool with a high positive predictive value if the albumin/globulin ratio is <0.4, and a high negative predictive value if the ratio is >0.8. 56 Major differential diagnoses include inflammatory liver disease, lymphoma, heart failure and bacterial peritonitis or pleuritis. 'Rivalta's test' is a simple, inexpensive method that can be performed in clinical practice to distinguish transudates from exudates. 54 Not only the high protein content, but also high concentrations of fibrinogen and inflammatory mediators, lead to a positive reaction. The test has a positive predictive value of 86%, and a high negative predictive value of 96% for FIP, as determined by a study of cats that presented with effusion (prevalence of FIP, 51%). 54 Positive Rivalta's test results may also be obtained in cats with bacterial peritonitis or lymphoma. However, it is usually easy to differentiate these effusions by macroscopic examination, cytology and/or bacterial culture. To perform the test, a transparent reagent tube (volume 10 ml) is filled with 7-8 ml distilled water, and one drop of acetic acid (98%) is added and mixed thoroughly. One drop of the effusion fluid is carefully layered onto the surface of this solution. If the drop disappears and the solution remains clear, the Rivalta's test is defined as negative. If the drop retains its shape, stays attached to the surface or slowly floats down to the bottom of the tube (drop-or jellyfishlike), the test is defined as positive. Analysis of cerebrospinal fluid (CSF) from cats with neurological signs due to FIP lesions may reveal elevated protein (50-350 mg/dl; normal value <25 mg/dl) and pleocytosis (100-10,000 nucleated cells/ml) with mainly neutrophils, lymphocytes and macrophages. However, this is not diagnostic. 46 In many cats with FIP that have neurological signs, the CSF is normal. Serum antibody titres may contribute diagnostic information, if interpreted with care. A high percentage of healthy cats are FCoV antibody-positive and most of them will never develop FIP. Thus, the presence of antibodies does not indicate FIP and their absence does not exclude FIP. It has been contended that more cats have been killed as a result of false interpretation of FCoV antibody test results than by the disease itself. There is no 'FIP antibody test' -all that can be measured is antibody against FCoV. Methodology (and titres) may vary considerably between laboratories. Low titres do not rule out FIP, and a significant proportion of cats manifesting FIP are seronegative. In cats with fulminant FIP, titres may decrease terminally because the high virus loads in the cat's body bind antibody, forming immune complexes. Very high titres can be of (limited) diagnostic value since they indicate an increased like lihood of FIP. 52, 54 FCoV reverse-transcriptase PCR The RT-PCR to detect FCoV in blood is sometimes used diagnostically. However, the assay cannot diagnose FIP: positive FCoV RT-PCR results have also been obtained in healthy carriers that did not develop FIP for a period of some 70 months [EBM grade I]. 31, 61 In addition, negative FCoV RT-PCR results are not uncommon in cats with FIP. 54 Methods of virus detection include the demonstration of FCoV antigen in macrophages in effusions by immunofluorescence, 54, 62 or in tissue samples by immunohistochemistry. While FCoV may be present systemically in healthy cats, only in FIP cases will there be sufficient viral antigen in macrophages to result in positive staining. Positive staining of intra -cellular FCoV antigen in macrophages in effusions can be 100% predictive of FIP, versus a negative predictive value of 57%; this discrepancy is explained by low numbers of macrophages in effusion smears. 54 Immunohistochemistry has been used to detect FCoV antigen, and it was also 100% predictive of FIP when positive. 63 However, invasive methods (eg, laparotomy or laparoscopy) are usually necessary to obtain the tissue samples. Any cat in a hospital is a potential source of FCoV infection, and routine hygiene measures must be taken. Any FIP case will shed FCoV and precautions to avoid infection of other cats are particularly important. However, in a multi-cat household, the other cats will probably already have been exposed to the FCoV from the patient, so there is no benefit in isolating the patient. In households where a single FIP patient has been euthanased, it is recommended to wait for 2 months before obtaining a new cat, to allow environmental FCoV to die off. If there are other cats in that household, they are likely to carry FCoV. Before introducing a new cat into that environment, the FCoV infection status of both existing and new cats should be established, 26, 73 and the number of cats per floor space, their age, social compatibility and other factors likely to influence their behavioural interactions must be considered. Treatment (or euthanasia) should only be considered after every effort has been made to obtain a definitive diagnosis. Feline infectious peritonitis is fatal in most cases. There have been occasional reports of cats surviving for several months after diagnosis. 64 However, few controlled field studies have been published. In one placebo-controlled study of treatment with feline interferonomega, no benefit was observed [EBM grade I]. 65 The prognosis for cats with FIP is poor: the median survival after diagnosis is around 9 days. 65 Factors that indicate a short survival time are low lymphocyte counts, high bilirubin values, and large volumes of effusion. Cats that do not improve within 3 days are unlikely to show any benefit from treatment and euthanasia should be considered. have been tried (Table 1) , but these studies were not properly controlled. Supportive treatment is aimed at suppressing the inflammatory and detrimental immune response, usually with cortico steroids. However, there are no controlled studies to prove any beneficial effect of cortico steroids, only anecdotal reports [EBM grade III]. a g n o s t i c a p p r o a c h t o F At present there is only one FIP vaccine available, which the ABCD considers as being non-core (see box on page 602). Feline infectious peritonitis is a problem in cats kept in groups, particularly in breeding catteries and rescue situations. Since the virus is transmitted predominantly via the faecal-oral route, hygiene is most important. Feline coronavirus infection is maintained in a household or cattery by continual cycles of infection and re-infection, the source of infection being the litter tray. 2, 46 Rarely is FIP a problem among cats leading an indoor-outdoor lifestyle. Reduction of FCoV contamination and risk of transmission can be achieved by avoiding large numbers of cats in individual households, keeping groups of 3 (well-adapted) cats per room, observing strict hygiene, and providing outdoor access to allow the cats to bury their faeces. Otherwise, sufficient litter trays should be provided, cleaned frequently, and kept in different rooms from the food bowls. TABLE 1 of this approach is controversial. Shedders can be detected using real-time quantitative RT-PCR screening of faeces, but multiple sampling is necessary. Virus shedding occurs over several months and is sometimes lifelong, especially in multi-cat households. 2, 16, 19 Kittens typically develop FIP in the postweaning period. 74 Breeders are often unaware of an endemic FCoV infection, because FIP deaths usually occur when the kittens have left the cattery and are in a new household. Most kittens are protected from FCoV infection by MDA until they are 5-6 weeks of age. Feline coronavirus transmission has been prevented by isolating pregnant queens 2 weeks before birth, moving their kittens to a clean environment when they are 5-6 weeks old, and maintaining them there until they go to a new home. 8, 26 For this method to succeed, the breeder is required to follow strict quarantine hygiene methods, which require special knowledge and facilities. The efficacy of this method has been questioned. 15 Strict hygiene precautions must be enforced at all times to minimise viral spread and virus contamination. Ideally, cats should be kept separately. New catteries should be designed with infectious disease control and stress reduction as priorities. Vaccination may be considered for cats that are unlikely to have experienced FCoV infection before entering a boarding or rescue cattery. Many attempts have been made to develop an FIP vaccine, most of which failed, with antibody-dependent enhancement of infection observed experimentally and resulting in more vaccinated than control cats developing FIP. At present there is only one vaccine, available in the USA and in some European countries. It is administered intranasally and contains a temperature-sensitive mutant of the type II FCoV strain DF2; type I coronaviruses are, however, more prevalent in the field. 2, 16 Results from experimental studies have been inconsistent, with preventable fractions between 0 and 75%. [66] [67] [68] [69] The results of field studies have been equally contradictory. [70] [71] [72] The not unexpected conclusion is that this vaccine might not be effective in seropositive cats that have already been exposed to FCoV. The antibody-dependent enhancement of infection that was a feature of some experimental vaccine trials has not been observed in field studies, suggesting that the vaccine can be considered safe. [70] [71] [72] The ABCD considers the FIP vaccine to be non-core. Kittens may profit from vaccination if they have not been exposed to FCoV (eg, in an early-weaning programme), particularly if they enter an FCoV-endemic environment. If immunisation is considered, a primary vaccination course consisting of two doses 3 weeks apart from the age of 16 weeks onwards should be followed. Vaccination before 16 weeks has been shown not to protect against infection. 15 In breeding catteries, most kittens are already seropositive by the time of vaccination, FCoV infections occurring much earlier than at 16 weeks of age. 8 Where a cat's lifestyle has justified primary vaccination, annual boosters may be con sidered. Although studies on the duration of immunity are lacking, it is thought to be short-lived. The ABCD considers the FIP vaccine as being non-core. ✜ Haematology suggestive of FIP shows lymphopenia, non-regenerative anaemia, increased total serum protein, hyperglobulinaemia, a low albumin/globulin ratio, high alpha-1 acid glycoprotein levels and high FCoV antibody titres. Rivalta's test, has high protein levels and a low albumin/globulin ratio, and contains neutrophils and macrophages. ✜ The prognosis for cats with FIP is poor. The median survival time after diagnosis is around 9 days. ✜ Euthanasia should only be considered after every effort has been made to obtain a definitive diagnosis. ✜ FIP is a problem in group-housed cats (breeding and rescue catteries), and is rarely encountered in cats leading an indoor-outdoor lifestyle. ✜ At present, there is only one (intranasal) vaccine, available in the USA and in some European countries. 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The European Advisory Board on Cat Diseases (ABCD) is indebted to Dr Karin de Lange for her judicious assistance in organising this special issue, her efforts at coordination, and her friendly deadline-keeping. The tireless editorial assistance of Christina Espert-Sanchez is gratefully acknowledged. The groundwork for this series of guidelines would not have been possible without financial support from Merial. The ABCD particularly appreciates the support of Dr Jean-Christophe Thibault, who respected the team's insistence on scientific independence.