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The 3 F’s Rachel Dean BVMS DSAM(fel) MRCVS, Recognised RCVS specialist in feline medicine Associate professor in Feline Medicine, Director of the Centre of Evidence Based Veterinary Medicine, School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus. Loughborough LE12 5RD Tel: 0115 951 6575 Email: [email protected] These notes are a comprehensive review of Feline infectious peritonitis, feline immunodeficiency virus and feline leukaemia virus. The lecture will cover some of the interesting aspects of these infections but will not cover everything in these notes! Feline infectious peritonitis: A diagnostic dilemma Feline infectious peritonitis is a fatal condition of predominantly young cats. There is only limited understanding of the pathogenesis of this complex disease. The clinical presentation of affected cats can vary significantly and reaching a diagnosis is not straightforward. There is no single diagnostic test for FIP. Treatment of this disease is supportive at best and it is invariably fatal. The virus FIP is caused by feline coronavirus (FCoV). Feline coronaviruses is one of the RNA viruses which are very prone to mutation when they replicate hence multiple ‘strains’ exist. It is difficult to culture FCoVs in vitro, but there are two serotypes FCoV type I which is feline only and FCoV type II which is genetically more similar to the canine coronaviruses. Most strains of FCoV will cause no clinical signs in infected cats, though mild transient diarrhoea is sometimes seen. The diarrhoea may be more apparent if other enteric pathogens are present Two biotypes of FCoV are often referred to in the veterinary literature: 1 1. Feline Enteric Coronavirus (FECV): the biotype that can’t leave the gut and causes only a mild diarrhoea, and 2. Feline Infectious Peritonitis Virus (FIPV): a biotype that can leave the gut and cause FIP. However strains of FECV have been detected in the blood and it is now thought that any strain of FCoV has the potential to cause FIP. This means wherever FCoV infection exists so does the potential to develop FIP. Transmission and Epidemiology Infection with FCoV is endemic within the feline population as it is a highly contagious virus. The prevalence of FCoV is thought to be approximately 40% in the general cat population but this can rise to over 80% in pedigree and multicat households. However the prevalence of FIP itself is still low, but accurate measures of incidence are not available. It is thought by some that the prevalence of FIP may be increasing due to alterations in cat husbandry leading to more indoor only, multicat households. Spread of infection is primarily through ingestion of the virus via indirect transmission from contact with faeces from infected cats. Direct transmission is possible via mutual grooming, sharing of food bowls etc. The virus doesn’t persist well in environment but can survive for up to 7 weeks in dried faeces. Following initial infection with FCoV there is a definite primary stage where faecal shedding of virus is high. Cats will then vary with shedding patterns and can a) Stop shedding after a period of time, or b) Become intermittent shedders at a low level, or c) Persistently shed virus at a low level Re-infection will FCoV mirrors primary infection with marked viral shedding after the cat is infected. This variation in viral shedding is probably due to cat (immunological factors), viral factors and environmental factors. Pathogenesis 2 The true pathogenesis of FIP remains unclear and involves a complex interaction of the virus with cats’ the immune system. It is an immune-mediated disease involving the virus, antibody and complement. The development of FIP depends on: 1) Viral factors – viral load, mutation 2) Cat factors – immune status, genetic predisposition 3) Environmental factors – the level of contamination of the environment with virus, overcrowding etc 4) Both cell mediated immunity and humoral immunity are involved in the protection from FIP and clearance of FCoV infection. A cat can be immunocompromised due to i) Illness ii) Age – very young or very old iii) Stress – multicat households, recent rehoming or surgery etc iv) Genetic predisposition This is potentially why almost 50% of FIP cases are seen in cats under the age of 2, and why we see more FIP cases in multicat, pedigree and rescue environments. To cause FIP, a multi-systemic disease, the FCoV has to leave the gut and become systemic. The development of disease may be caused by 1) The virus infecting macrophages/monocytes, which then attach and cause damage to blood vessels allowing the virus to enter tissues 2) The formation of immune complexes leading to the development of pyogranulomas and organ damage. The clinical signs and pathology of the disease are attributed to: i) To the vasculitis and subsequent leakage of protein rich fluid from the damaged vessels, and, ii) Damage to organs due to vascular damage and pyogranuloma formation This means multiple organs can be involved leading to the multitude of clinical signs. Feline infectious peritonitis is therefore a misnomer and often leads to confusion for cat owners. Feline infectious vasculitis would be a far more appropriate name. 3 A case of FIP is most frequently an isolated event and this is because the development of FIP occurs within the host. However sometimes ‘outbreaks’ of FIP are reported. Genetic sequencing of the viruses involved in these ‘outbreaks’ show that different strains are responsible for each case but they may originate from a ‘parent’ virus. These outbreaks are more likely due to the cats being of similar genetic background and exposure to common environmental factors which pre-dispose the cat to developing FIP. The problem with FIP: Making an ante-mortem diagnosis of FIP is difficult. However there are ‘clues’ in the signalment, clinical signs and diagnostic tests that can point you in the right direction. Signalment There are clues in the history that may make the clinician suspicious of FIP, these include: Waxing and waning non-specific clinical signs Young cat (peak incidence 2years old, smaller peak for cats over 13 years old) Pedigree cat Multicat household Rescue cat at rehoming facility Recent ‘stress’ – rehoming, neutering, vaccination, weaning Clinical Signs There is no clinical sign that is pathogonomic for FIP. The clinical signs of FIP are often differentiated into effusive (‘wet’) and non-effusive (‘dry’) FIP. In the authors opinion these presentation are just two extremes of the same condition. If a patient with ‘dry’ FIP is monitored carefully and investigated fully, an effusion is frequently identified. There is no doubt that cats with ‘wet’ FIP have pyogranulomatous damage to organs as well as significant vasculitis leading to an effusion. Cats with FIP can present with various combinations of the following clinical signs: Pyrexia, lethargy inappetance – the classic ‘sick’ cat!! 4 pyrexia Abdominal effusion – this can be excessive and may cause vomiting, diarrhoea and tachypnoea due to the size of the effusion Dyspnoea, tachypnoea, muffled heart sounds –this is most commonly due to a thoracic effusion, but pyogranulomas are frequently found throughout the lung parenchyma. Jaundice (see below) Neurological signs – these can vary significantly, though signs of cerebellar dysfunction are common in the author’s experience Ocular is signs – photophobia, ocular pain, uveitis, iritis, keratic precipitates, perivascular cuffing of the retinal vessels A few tips: Some cats with a marked abdominal effusion can initially be very bright and have a good appetite. A cat with neurological or ocular manifestations of FIP can vary significantly in severity over time despite advancing disease and increased severity of pathology. This may be erroneously attributed as a response to treatment Diagnosis At this point in time there is no single diagnostic test for FIP. Naming a diagnostic test an FIP test is incorrect and misleading! Therefore it is imperative to be methodical and thorough when investigating a cat for FIP – be vigilant for the ‘clues’! Signalment A good thorough case history is vital for obtaining some of the ‘clues’ associated with FIP (see above) Clinical examination: The clinical signs of FIP can be varied and vague; hence a complete physical examination is required. Some of the ocular and neurological manifestations can be subtle. Repeat clinical examination is vital to monitor to progression of exiting clinical signs or the development of further new clinical signs I always include: 5 Routine physical examination – HR, PR, RR, BT, lymph node palpation etc Complete ocular examination – including examination of the retina Complete neurological examination – put the cat on the floor and watch it walk, the signs of cerebellar dysfunction can be subtle Careful abdominal palpation – a small abdominal effusion may give an abdomen a stodgy feel. Some cats present with an abdominal mass, this may be enlarged abdominal lymph nodes, some cats present with a thickened ileocaecocolic junction (biopsy will demonstrate a pyogranulomatous enteritis). Performing blood tests as part of an investigation of an FIP case is important, no abnormality/ finding should be considered in isolation. Haematology The ‘clues’ include: Lymphopenia Non regenerative anaemia Neutrophilia with left shift Blood biochemistry The ‘clues’ include Hyperglobulinaemia –. This can be significant leading to albumen: globulin of 0.4. If serum protein electrophoresis is performed this can be demonstrated as a polyclonal gammopathy. Hyper bilirubinaemia – this is often in the absence of raised liver enzymes. The author has also found increased fasting bile acids in a number of cases. α1 alpha glycoprotein may be increased – this is an anti-inflammatory and immunomodulatory agent in the body. This will also increase in other inflammatory and neoplastic conditions Imaging 6 Both ultrasound and radiography can be helpful in identifying abdominal and thoracic effusions and lymphadenopathies. Occasionally, using ultrasound, lesions can be identified in the liver and kidneys but these are no specific for FIP. Effusion analysis The presence of an effusion will increase the suspicion of FIP, but again this is not pathogonomic. Where possible it is important to try and obtain a sample of the fluid for analysis – biochemistry, specific gravity and examination of the cells present in the effusion should be performed. Differential diagnose such as heart disease, liver disease and neoplasia should be considered. The effusions caused by FIP can vary in appearance and in consistency. It may appear chylous or haemorrhagic, and could be a modified transudate or an exudate The classic effusion is: straw coloured and clear sticky – this is due to the protein content with globulins >35g/l and A:G <0.4 low cellularity – cells present will be mostly neutrophils and macrophages The Rivalta test (put a drop of fluid into 98% ascetic acid – and watch for precipitation due to high protein content) is easily performed. A negative test result would make FIP unlikely. Immunofluorescence can be performed on the fluid to try and identify FCoV in the macrophages. A positive result is conclusive of FIP; however a negative result does not rule it out. This test is further hampered by the low cellularity and therefore low levels of macrophages often found in the effusions. Serology The presence of antibodies to FCoV IS NOT DIAGNOSTIC OF FIP. A positive FCoV titre indicates that the cat has been exposed to FCoV. The majority of cats with FCoV titres will NOT develop FIP, because the virus is so contagious most cats that are not 100% indoors will encounter the virus. Make sure that you send all your samples to a good diagnostic laboratory with expertise in feline infectious diseases. 7 CSF analysis In cats with neurological signs, obtaining CSF can be useful in supporting a diagnosis of FIP. In general the CSF will have increased levels of protein and will show marked pleocytosis. It is also worth testing for FCoV antibodies in the CSF as a positive result in the presence of other findings will increase the suspicion of FIP. Histopathology This is considered to be the only definitive test for FIP as the pyogranulomas are very characteristic. Unfortunately histopathology is often undertaken at post-mortem, but biopsies taken ante-mortem should be considered. Immunofluorescence can be performed on biopsy tissue to confirm FIP. Treatment Supportive and symptomatic treatment are both very important in cases of FIP. For example raining large effusion, or administering fluids and NSAIDs can give cats’ transient relief. More specific treatment with prednisolone and recombinant feline interferon ω have been suggested as more specific therapy, but in the authors experience the positive effects of these treatments are short lived. Prevention and Control Feline coronavirus is highly contagious and endemic in the UK cat population. This means preventing infection is fraught with difficulty. Simple hygiene procedures in multicat households and rescue facilities will significantly reduce environmental contamination. For example: reduce cat numbers – fewer cats, less virus clean litter trays as soon as they are used keep litter trays away from food bowls Establishing a coronavirus free environment is difficult but has been tried in some breeding households. A coronavirus-free cat is antibody negative and FCoV negative on 8 faeces using PCR. To attempt to maintain a coronavirus free household the following steps would have to be taken: Initially blood test and faeces test all cats. Separate positives and negatives and mange as two separate groups Don’t mix cats until they have been faeces PCR negative for at least 3months Early wean (age 5-6weeks) all kittens and maintain in isolation until 12-16weeks Maintain a closed household There is currently no FCoV vaccine available in the UK. Feline Immunodeficiency Virus (FIV) The virus The feline immunodeficiency virus belongs to the lentivrius family, and is an RNA virus. This means it requires an enzyme called reverse transcriptase (RT) to replicate. RT facilitates the formation of proviral DNA which can be replicated so new virus can be formed. Proviral DNA can also integrate with host DNA which can be permanent. Various different subtypes (or clades) of FIV, that differ in their genetic make-up have been identified. The different subtypes (A, B, C, D and E) have differing geographical distribution between and within countries. Multiple subtypes have been isolated from naturally infected FIV positive cats. The significance of the different subtypes should be remembered when considering diagnosis and vaccination (see later). FIV is similar to HIV, but it is though that FIV has existed in the population much longer than HIV has in the human population. The similarities between HIV and FIV have meant that FIV has been used experimentally in research aimed at developing HIV treatments and an HIV vaccine. This has led to significant increases in the understanding of the transmission, pathogenesis, treatment and prevention of FIV infection. Epidemiology and transmission. 9 FIV is common worldwide and there is a significant prevalence in the UK. The prevalence varies depending on which cat population is being tested. There is no current data on the prevalence of infection in the UK. It is thought that 3-4% of healthy cats will be FIV positive, but this can increase in the sick cat population. The prevalence may be as high as 20% in feral cats. FIV does not survive well in the environment and readily killed by disinfectants, so spread of infection is through direct cat to cat transmission. High levels of FIV are found in both blood and saliva. Biting and fighting is thought to be the most common route of transmission, hence there is a higher prevalence of FIV in entire male cats. FIV negative cats that live in close contact with FIV positive cats tend not to become infected if there is no fighting. It is unclear what the risk is for the negative cats in a multicat household such as this. Some but not all of the kittens born to an FIV positive queen will acquire infection in utero or via the milk post-partum. Proviral DNA has been found in the tissues of neonates in the absence of FIV antibodies in the blood, the significance of this is unclear. FIV has also been isolated from semen and therefore, whilst rare, sexual transmission can also occur. Pathogenesis The consequences of infection with FIV will depend on The age of the cat at infection The FIV isolate involved The amount of virus The route of infection Whether the infection is with free virus or cell associated virus Following infection, the virus is taken up by macrophages and lymphocytes, and distributed to the lymphoid organs where it replicates. Virus is also distributed to organs such as the kidney, central nervous system, bone marrow, lung and intestines. Viraemia peaks a few weeks after infection and then falls as the body mounts an immune response. Many antibodies to FIV are produced but these are ultimately ineffective at clearing infection, but viral replication slows down and viraemia decreases. After the initial phase 10 of infection there is a very gradual decline in immune function which is demonstrated by a decrease in CD4+ lymphocytes. These are helper lymphocytes that are vital for effective cell mediated and humoral immunity. The consequential immunosuppression leads to chronic infection, chronic inflammatory conditions and neoplasia. Clinical signs Cats with FIV are presented at many different stages of infection. They are occasionally presented during the early stages of infection and marked viraemia, and may have the following non-specific signs: Lymphadenopathy Pyrexia Lethargy Inappetance. Occasionally acute gastroenteritis, conjunctivitis, stomatitis and respiratory tract disease is seen. Frequently FIV infection is not suspected at this stage and often goes un-noticed by owners. Following initial infection cats will often be asymptomatic for years and will not be presented for veterinary attention until the more chronic stages of infection. The clinical signs are attributed to a chronic progressive immunosuppression and are due to: Chronic opportunist infections – e.g. Demodex, Cryptosporidia, Toxoplasmosis, Haemoplasma, Calicivirus, multiple fungi/bacteria Chronic inflammatory conditions – e.g. stomatitis, rhinitis, uveitis conjunctivitis, nephritis Neoplasia (Cats with FIV are 5-10 times more likely to get neoplasia than FIV negative cats) Primary viral effects – e.g. pyrexia, lymphadeopathy, weight loss The signs are chronic and recurrent. Diagnosis of FIV Most diagnostic tests are based around indentifying antibodies (as opposed to antigen in FeLV testing) in the blood of persistently infected cats. Patient-side diagnostic tests and 11 the screening tests used at commercial laboratories use enzyme linked immunosorbant assays (ELISA) or rapid immunomigration (RIM) technology to detect antibodies to the transmembrane envelope protein gp40, the core protein p24 or both. Prior to performing a test for FIV it is important to establish How likely is FIV infection? How reliable is the test that you select? (sensitivity and specificity) Are you using the test properly? It is important to ensure that: o The test is performed at the correct temperature o That plasma/serum rather than whole blood is used (as specified in many test kits) o The test is read at the correct time This will reduce the number of tests that need to be repeated!! A positive antibody result will be obtained when: 1. A persistently infected cat is tested 2. A kitten born to an FIV positive queen is tested, due to the transfer of maternally derived antibodies. These antibodies can persist for up to 16 weeks, often longer – so re-testing of kittens is advised at 6 months of age, or a text for antigen should be used in young kittens. 3. It is a false positive! 4. (If the cat has received an FIV vaccine.) A negative antibody result will be obtained when 1. A cat is not infected with FIV 2. In FIV infected cats where either the anti-FIV antibodies produced are not detected by the test used or where no anti-FIV antibodies have been produced. If it is in the very early stages of infection antibodies may not have been produced yet, though up to 15% of FIV-infected cats never seroconvert, remaining seronegative 3. It is a false negative! 12 In most situations when a positive result is obtained this should be confirmed by a further test. Commercial laboratories offer a range of tests which can be used to confirm a positive including: o Immunofluorescence o Western blotting o PCR o Virus isolation (this can take up to 3 weeks!) Always chose a laboratory that has expertise in feline infectious diseases and contact them if an unusual result is obtained. Note: Some laboratories offer PCR technology to confirm the presence of FIV infection. Due to the genetic differences between clades (see notes above), some PCRs will not identify all strains so false negatives can arise. PCRs are being developed to identify more than one clade at a time in a single sample – this technique should overcome these concerns Management of FIV-infected cats Chronically infected FIV cats can live for long periods of time with good symptomatic and supportive therapy. Ideally an FIV positive cat should be assessed by a veterinary surgeon at least once every 6 months to monitor for infections, neoplasia Monitoring should include: Complete clinical examination, including ocular examination, and neuro examination where appropriate Haematology – monitor for bone marrow suppression Biochemistry - monitor organ function, notably kidney function Urinalysis (including culture) Faecal analysis if clinical signs (including weight loss) attributable to the intestinal tract are noted. FeLV antigen testing is also recommended as this can have a significant effect on the prognosis and management of the case. 13 Preventative medicine in the asymptomatic FIV-infected cat (1) Vaccination - ideally with killed vaccines (2) Routine flea and worm prevention (3) High quality diet (avoiding raw milk or meat, and therefore the risk of opportunist infection with Mycobacteria bovis and Toxoplasma gondii) (4) Dental care and oral hygiene is recommended as many FIV-infected cats suffer from chronic gingivostomatitis. (5) Keep the cat indoors: to reduce spread of the disease and minimise exposure of the immunocompromised patient to other infectious agents. (6) Neuter any entire FIV positive cats (7) Reduce stress where possible It is important to emphasise to owners the role that they play in caring for an FIV positive cat. Without a dedicated owner successful management will be limited. In an ideal world if the owner of an FIV positive cat has more than one cat, the cats should be housed separately or rehomed. If there is no conflict in the house the risk of spread of infection is low but not zero! If the owner is reluctant to separate the cats then the use separate feeding bowls to minimise the risk of transmission of virus via saliva is recommended. If an FIV positive cat becomes sick it is important to emphasise to the owner that they must seek veterinary treatment very promptly. It is thought that 80% of clinical signs in FIV-infected cats are related to immunosuppression and resultant secondary infection. Many of the conditions can be overcome if treated promptly and aggressively, for example: Anaemia due to Mycoplasma haemofelis can be successfully treated with antibiotics Gingivitis is a common finding in FIV infected (and non-FIV infected!) cats. Regular dental check-ups and treatment accompanied by oral hygiene will potentially reduce the severity and frequency of the recurrence. 14 Pyrexic, leucopenic cats should be treated with broad spectrum antibiotics as soon as possible. Neoplasia in FIV positive cats can still be treated and it is thought that they can respond as well as an FIV negative cat initially, though the long term prognosis is poor. Chronic anaemia is often seen in the latter stages of FIV, erythropoietin will help alleviate some of the associated clinical signs. Prolonged usage will lead to the development of antibodies to the EPO so the treatment will be rendered ineffective Specific antiviral treatment Many drugs have been used against FIV in vitro with a view to treating HIV in man, hence many of them are either toxic to cats, not formulated in a practical ‘cat’ size or are prohibitively expensive!. There is very little evidence in the veterinary literature regarding the use of anti-virals in naturally infected cats. Hence we are still limited with FIV specific therapy. AZT is the most commonly used specific anti-viral drug used in FIV positive cats. It is a reverse transcriptase inhibitor that works because they are nucleoside analogues which compete with cellular nucleotides that are the building blocks for proviral DNA – hence these drugs inhibit viral replication. This drug has been shown to improve the clinical signs and laboratory parameters in some FIV cats. It is often recommended for FIV cats with chronic gingivostomatitis that has been unresponsive to all other therapy. AZT can be used orally or subcutaneously at a dose of 5mg/kg 2-3 times daily. Anaemia can be seen as a side-effect of AZT so should not be used in cats that already have low red blood cell counts. The anaemia is usually reversible and only seen at doses of up to 15mg/kg/day. Haematology should therefore be regularly assessed throughout therapy. Eventually the virus would become resistant to RT inhibitors, this combined with the potential side-effects means these drugs are often only used as a ‘last resort’. Recombinant feline omega interferon (virbagen omega) is now licensed for use in FIV (and FeLV) positive cats during the non-terminal stages of infection. The effects and application of this drug in retrovirus positive cats has not been fully assessed. 15 Evening primrose oil, has been suggested to have beneficial effects such as increased body weight, haematocrit and neutrophil count have been reported. The recommended dose rate of one 550mg capsule daily Prevention Fort Dodge have developed an FIV vaccine – Fel-O-Vax FIV, which is licensed in the USA and Japan. As the vaccine effectively induces a protective antibody response, general use in the cat population would make it impossible to interpret antibody test results. A vaccinated cat would give the same result as an infected cat. Not all clades are included in the vaccine, so accurate information about the prevalence of clades in the UK and many parts of Europe and evidence demonstrating cross-protection is required. 16 Feline Leukaemia Virus (FeLV) Infection The virus Feline leukaemia virus, like FIV is a single-stranded RNA virus belonging to the retrovirus family. To divide retroviruses require the enzyme reverse transcriptase (RT) that enables genomic RNA to be transcribed to proviral DNA. This proviral DNA is then incorporated into the host DNA of the infected cell, which means that all subsequent daughter cells will also be ‘infected’ with proviral DNA. Endogenous retrovirus DNA is found within the feline genome. This DNA material will not produce viral particles, but becomes important when a cat meets an exogenous retrovirus (see below). FeLV is divided into 3 subgroups based on differences in the envelope protein gp70: 1. Subgroup FeLV-A. This is the form of the virus which is infectious from cat to cat, it is low pathogenicity but highly contagious. 2. Subgroup FeLV-B. This subgroup arises within an individual cat from combinations of FeLV-A and endogenous retrovirus DNA. FeLV-A is also required to facilitate replication of FeLV-B. FeLV-B is not contagious. It is found with FeLV-A in approximately 50% of cats who have neoplasia due to FeLV. 3. Subgroup FeLV-C. This subgroup is also non-contagious and arises within the cat after genomic and FeLV-A DNA combine. It is much rarer than the other subgroups and is associated with non-regenerative anaemias. Epidemiology and transmission The true prevalence of FeLV in the UK is unknown. However it is widely agreed that the prevalence of infection has decreased since the introduction of FeLV vaccination and active ‘test and remove’ programmes. It is thought that the prevalence may be 1% in health cats and up to 12% in sick cats. Some studies have shown a much higher prevalence (up to 20%) in sick cats. In contrast to FIV, FeLV is of higher prevalence in ‘friendly’ or ‘social’ cats as prolonged contact is needed for transmission (see below). Hence FeLV is seen equally in males and females, and is more common in younger cats. FeLV is transmitted via close cat to cat contact, mostly through saliva and nasal secretions. In viraemic cats the level of virus in saliva is many times higher than in blood. 17 The level of virus shedding through saliva is the same whether the cat is sick or healthy. Infection is spread through social activities such as mutual grooming and sharing food bowls. The virus does not survive well in the environment and is easily killed by disinfectant. FeLV infected pregnant queens can vertically transmit infection to their offspring through grooming, in utero and through milk. Most FeLV positive queens are infertile, and if any kittens are born they are highly likely to be permanently infected. Kittens are more susceptible to infection with FeLV than adult cats, and the majority of cats with FeLV related illness will be less than 6 years of age. However older cats can still become permanently infected with FeLV and succumb to FeLV related diseases Pathogenesis Following infection via the oronasal route, the virus replicates in the lymphoid tissue of the oropharynx. There are 4 main outcomes to infection: 1. Recovery: In many cats an effective immune response is mounted and infection never becomes systemic. These cats will often have anti-FeLV antibodies and will have good protection from infection for a number of years 2. Transient viraemia: If an adequate immune response is not mounted, then FeLV will spread systemically via lymphocytes and monocytes. If this period of viraemia is short-lived and is stopped before the bone marrow is infected, then the cat will recover and be protected from further infection. This transient viraemia and viral shedding lasts approximately 3-6 weeks (maximum 16weeks), cats will be positive for viral antigen during this viraemic period. If the viraemia persists and the bone marrow is infected, whilst a small proportion of cats can still clear infection, the majority go on to be either persistently or latently infected. 3. Latent infection: Cats that are latently infected have FeLV DNA in the cells of the bone marrow but will not be viraemic so will be negative on routine antigen testing. The latency can be reactivated (spontaneously or in times of stress e.g. lactation) and the cat becomes viraemic and sheds virus once more (and becomes positive on antigen testing). Cats with a latent infection may intermittently 18 relapse, recover or eventually develop a persistent viraemia and die due to FeLV related disease. 4. Persistent viraemia: Following transient viraemia or latent infection FeLV cats can become persistently viraemic and shed high levels of virus. Within 3 years 80% of these cats will develop FeLV related disease and die. Clinical signs The majority of cats present with clinical signs of FeLV due to: Anaemia Immunosuppression, or Neoplasia Anaemia The anaemia associated with FeLV can be regenerative or non-regenerative Regenerative anaemia can be a consequence of: Immune mediate haemolytic anaemia Thrombocytopenia Haemoplasma infection Non-regenerative anaemia can be a consequence of Pancytopenia – due to direct viral effects on all cell lines in the bone marrow Pure red cell aplasia – due to direct viral effects selective for red cell precursors in the bone marrow Anaemia of chronic disease- e.g. neoplasia, chronic inflammatory conditions Leukaemia – Myeloid or lymphoid Myelopthesis/myelofibrosis Lymphoma of the bone marrow Immunosuppression FeLV has a more debilitating effect on the immune system than FIV. The mechanisms by which FeLV causes immunosuppression are poorly understood, but the virus has profound effects on both cell mediated and humoral immunity. The consequences are chronic, debilitating bacterial, fungal and viral infections 19 Neoplasia Various different tumours have been attributed to FeLV infection, and the presence of FeLV markedly increases a cat’s risk of neoplastic disease. The most common are: o Lymphoma – Mediastinal, alimentary, multicentric, extranodal (e.g. renal, spinal, ocular) o Leukaemia – Lymphoid or myeloid o Other solid tumours – fibrosarcomas, osteochondromas The clinical signs associated with FeLV infection are therefore varied and numerous. The presenting clinical signs will depend on the organ systems affected, and commonly include: Lymphadenopathy – reactive or neoplastic Gastrointestinal – vomiting, diarrhoea, weight loss Respiratory – altered respiratory rate and pattern due to mediastinal, pleural, parenchymal and upper respiratory tract infection or neoplasia Ocular – uveitis/conjunctivitis due to secondary infection, chronic inflammation, or neoplasia Neurological – signs referable to the central and peripheral nervous system can be present due to infectious, inflammatory or neoplastic conditions Urinary – e.g. enomegaly (most commonly due to lymphoma), neurological dysfunction of the lower urinary tract Reproductive failure Diagnosis of FeLV infection There are patient side tests available to aid the diagnosis of FeLV. These identify the viral antigen p27 most commonly by ELISA or RIM methods. The majority of these test have high sensitivity (nearly 100%) so false negatives are rare. However as the prevalence of infection is very low in healthy cats and specificity is around 98%, A positive patient side test should ALWAYS be confirmed by a second test. 20 The positive predictive value is much more reliable in sick cats where the prevalence of infection is higher. When testing for FeLV remember, 1. FeLV vaccines do not interfere with testing as we are looking for antigen not antibody (many vaccinated cats will not have antibodies either but are protected) 2. A positive test result does not tell you if a cat is permanently or transiently infected. Re-testing 12 weeks later or delaying testing until 12 weeks after known exposure will help differentiate the two. 3. Any cat that is viraemic is potentially shedding virus and can infect other cats 4. If a cat has a non-regenerative anaemia or a tumour that we commonly encounter in FeLV infection but is antigen negative, then confirmatory tests are recommended. 5. A cat with latent infection can still be antigen negative yet harbour infection, and may be viraemic at a later date. (see discordant results) (It is important to ensure that the patient side tests are carried out in line with the manufacturer’s instructions to improve accuracy – see FIV notes) Confirmatory tests Virus Isolation – this is currently the most commonly employed confirmatory test for FeLV infection in the UK. Immunofluorescence – this is commonly used in the USA and identifies virus within white blood cells Polymerase Chain Reaction – PCRs have now been developed to detect exogenous FeLV infection, and are very sensitive (see below). They are not yet commonly used in diagnostic laboratories Discordant results There are a number of cats that will test positive on routine screening tests (ELISA and RIM) but will be negative on virus isolation or Immunofluorescence. A discordant result means circulating antigen is detectable but virus isn’t. Approximately 10% of all positive results are discordant, though in some studies this reached 40%! 21 Variations in test sensitivity, latent and localised infections may account for some of the discordant results – but not all of them. The concerns are: Are cats with discordant results infectious? Are they likely to succumb to FeLV related disease? These questions largely remain unanswered, but it is thought most persistently discordant cats should be considered false positives. Interestingly some cats that are antigen positive by are negative on confirmatory tests are proviral DNA positive on PCR. In fact some cats that are negative on all other tests can be positive on PCR – the significance of these results is unclear. It has been suggested that all cats that meet FeLV may incorporate proviral DNA, but they will not necessarily be viraemic or infectious. Further work needs to be done to clarify this situation and follow cats that are PCR positive but not antigenaemic or viramic.. Haematology in FeLV infected cats. Various abnormalities of all cell lines can be found in FeLV positive cats. The author advises sending the sample away to a reputable commercial laboratory for analysis and blood smear examination by an experienced veterinary haematologist FeLV testing is recommended in any ‘at risk’ cat with severe or multiple abnormalities on blood smear examination. FeLV positive anaemic cats can demonstrate macrocyctosis, even when the anaemia is non–regenerative. Immature forms (e.g. erythroblasts, lymphoblasts) of all cells lines can be found in circulation in cats with FeLV infections of the bone marrow Treatment All FeLV positive cats should be separated from FeLV negative cats (a) Healthy FeLV-infected cats A positive result in a healthy cat should mean that a confirmatory test is performed and the cat re-tested in 12 weeks. The majority of cats will only be transiently infected. The true healthy FeLV positive cat will succumb to disease at some point. Regular health 22 screening as suggested for FIV cats is recommended for FeLV positive cats. A very poor prognosis should be given (b) Sick cats infected with FeLV Cats with disease due to FeLV have a very guarded prognosis. Aggressive rapid treatment of opportunist infections and chronic inflammatory conditions is recommended (see FIV notes). Lymphoma due to FeLV infection will still respond to chemotherapy and other treatment modalities but the long term prognosis is poor. Control FeLV does not survive well outside the cat; therefore fomites and environmental contamination do not pose a threat to a naive cat. If a FeLV positive cat is housed in isolation with no missing of food bowls, grooming equipment etc, spread of infection is unlikely. Endemic infection in catteries and breeding establishments is thankfully much less common than it used to be. The ‘test and remove’ management scheme of a problem household, where all positive cats are removed, isolated and re-tested 12 weeks later will successfully eliminate infection from a multicat household There are many FeLV vaccines currently on the market that almost all demonstrate good protection from persistent infection. FeLV vaccines do not prevent transient viraemia but are important in the control of FeLV in cat populations. 23