VN August 2022

Vetnuus | August 2022 8 Feline Infectious Peritonitis(FIP) has been one of the most prolonged, worst enemies of every cat-lover. It arises via a perfect storm of events: a cat must be infected with the normal feline Corona Virus, which must then undergo multiple mutations to allow a change in tropism from enteric cells to macrophages and an alteration in virulence, and then the host immune response must fail (Pedersen, 2014). It must be noted that not every cat with feline coronavirus will develop the mutations and that not every cat that develops the mutations will develop FIP. Stress and superinfections can increase the risk of FIP development (Tekes &Thiel, n.d.) It is thought that much of the pathology and manifestations of FIP are associated with how the macrophages and the immune system respond to infection. Cats that do not develop clinical FIP despite mutations in the virus are thought to mount a vigorous cell-based immune response (Kennedy, 2020). Antibodies are considered to be counterproductive in a FIP infection by enhancing viral uptake and replication by macrophages (Pedersen, 2014). Antibodies are also thought to contribute to type III hypersensitivity vasculitis (Pedersen, 2009). Within these assumptions, it is believed that the effusive formofFIPisduetoafailuretomountaT-cellresponseinthefaceofavigorous B-cell response(Kennedy, 2020). The dry form of the disease represents an intermediate state – the cellular response is effective at confining the virus in macrophages in focal sites (Kennedy, 2020). The different forms, however, can be somewhat interchangeable: in experimental infection, the dry form usually follows a brief bout of effusive disease, and in the terminal stages of the disease, immunity may completely collapse, and a dry form of FIP can become somewhat effusive (Kennedy, 2020). Diagnosis of the disease remains challenging and is based mainly on a compatible history, signalment, and clinical signs, supported by clinical assays. FIP is typically seen in young cats, often from multi-cat backgrounds (shelters, breeders) (Felten & Hartmann, 2019). CBC findings often include non-regenerative anaemia, total leukocytosis and possibly lymphopaenia. Interestingly, although lymphopaenia is a variable finding, flow cytometry shows a selective decrease in T-lymphocytes, even in cats with normal lymphocyte counts (Kennedy, 2020). Pederson et al. (2015) found that the degree and timing of onset of lymphopenia can be associated with the severity and rapidity of disease progression. Biochemical changes often (but not always) include a changed albumin-to- globulinratio,withanincreaseingamma-globulins(Felten&Hartmann,2019). It may be accompanied by a monoclonal gammopathy demonstrated on serumelectrophoresis. Most cases also showbilirubinaemia and bilirubinuria due to haemolysis. No biochemical changes are specific for a diagnosis of FIP, but the finding of a high A:G ratio has a high negative predictive value when the prevalence in a population is low (Felten & Hartmann, 2019). Azotaemia and increased liver enzymes are also possible. Acute phase proteins can be analysed but cannot distinguish between FIP and other inflammatory conditions (Felten & Hartmann, 2019). Although unable to provide any specificity, diagnostic imaging can increase suspicion of FIP. On abdominal ultrasound, enlarged lymph nodes and pyogranulomatous lesions on kidneys, intestines and liver (Felten & Hartmann, 2019). Granulomas can also be seen on thoracic radiographs. Effusion analysis is instrumental. Effusions contain high levels of protein (>35g/l) and relatively low cellularity, consisting of mainly non-degenerate neutrophils and macrophages (Felten & Hartmann, 2019). Rivalta’s test on effusion simply discriminates between a transudate and exudate – it is not specific for FIP, with other possible diagnose being septic peritonitis and lymphoma (Felten & Hartmann, 2019). The effusion can also be used for immunohistochemical staining of viral particles within macrophages or RT- PCR (Felten & Hartmann, 2019). PCR is another often used diagnostic method. It was previously assumed that only cats with FIP would have detectable levels of FCoV in their blood or tissue – this has proven to be false. Up to 80-90%of FCoV-infected cats will have positive RT-PCR results (Felten & Hartmann, 2019; Pedersen et al., 2015). An assay to detect FCoV mRNA was also not a guaranteed diagnosis, with up to 52% of non-FIP cats having positive results (Felten & Hartmann, 2019). RT-PCR run on effusion samples tended to have a much higher specificity, although FCoV RNA has still been detected in effusions from cats without FIP (Felten&Hartmann, 2019). Fewer studies are available on PCR analysis on CSF and aqueous humour, although results seem to be more promising (Felten & Hartmann, 2019). An assay is also available for real-time RT-PCR to detect S-gene mutation, but this has not proven any significant advantage over other PCR assays (Barker et al., 2017). Coronavirus titres are often high in FIP cases, but surprisingly, low titres and even negative titres have been documented (Meli et al., 2013). It is thought to be due to antibody binding to massive amounts of the virus or immune exhaustion(Kennedy,2020).Additionally,healthycatsmayhaveexceptionally high titres. A positive titre, whether high or low, only indicates exposure to FCoV. Until very recently, no treatment for FIP has been available. In 2018, the first in-vitro assessment of the efficacy of GS441-524was published (Murphy et al., 2018), followed by the first clinical trial in 2019 (Pedersen et al., 2019).This trial showed remarkable results, with 25 of 31 cats surviving long-term follow-up (themost extended follow-up so far is five years). GS-441524 is themetabolite of Remdesivir and is itselfmetabolised intracellularly toanactive triphosphate metabolite (Murphy et al., 2018). This molecule acts as a nucleotide analogue and, when incorporated into RNA, triggers the termination of RNA replicase, halting viral replication (Murphy et al., 2018). Due to the patent being held by Gilead, all research on GS-441524 in cats (and its parent compound, Remdesivir) was halted. However, a roaring black- market trade sprung up, with many “brands” of GS-441524 products being produced and exported. Thousands of cats were treated successfully via this black market trade, with large amounts of anecdotal data collected. Over time, the doses used have been titrated upwards to reduce the chances of relapse. As COVID swept the world, Gilead seized the opportunity and registered Remdesivir for use in COVID patients. It has opened the door for legal use of Remdesivir across most of the world and the production of GS-441524 by compoundingpharmacies,includingSouthAfrica.GS-441524isadministered as a single subcutaneous injection, once daily, for a minimum of 84 days. Different starting doses are reported, depending on what barriers the virus has crossed, i.e. breaching the blood-brain-barrier or blood-eye-barrier. Side- effects areminimal, with themain side-effect being pain on injection and the possibility of fibrosis and skin lesions forming. Increases in hepatic enzymes have been reported, but with no apparent liver toxicity, as well as mild, non- progressive renal toxicity (also not associated with renal failure) (Pederson, n.d.). Case Studies in Feline Infectious Peritonitis Dr RowenaWatson Leading Article