Clinical Features of FIP
The effusive form of disease generally is believed to develop in cats with poor cell-mediated immune responses, and the non-effusive form develops in cats with partial cell-mediated immunity. The effusive form of disease is an immune complex vasculitis characterized by leakage of protein-rich fluid into the pleural space, the peritoneal cavity, the pericardial space, and the subcapsular space of the kidneys. Vascular permeability factors, including vascular endothelial growth factor produced by infected monocytes and macrophages might increase the vascular permeability in cats with effusive FIP (Takano, 2011). In the non-effusive form yogranulomatous or granulomatous lesions develop in multiple tissues, particularly the eyes, brain, kidneys, omentum, spleen, and liver. Some affected cats have characteristics of both forms of FIP.
Anorexia, weight loss, lethargy and pyrexia are common presenting complaints. Icterus, ocular inflammation, abdominal distention, dyspnea, or CNS abnormalities such as ataxia are occasionally noted by the owner. In cats with effusive disease, abdominal distention is common and pleural effusion can result in dyspnea and a restrictive breathing pattern as well as muffled heart and lung sounds. Male cats sometimes have scrotal swelling. Occasionally masses (pyogranulomas or lymphadenopathy) can be palpated in the abdomen.
Diagnosis
Enteric Coronavirus
Feline Infectious Peritonitis
The diagnosis of FIP can be challenging as routine laboratory testing does not have many specific findings. Complete blood cell count (CBC) usually shows mild, nonregenerative anemia, microcytosis, neutrophilia (with or without toxic changes), lymphopenia and thrombocytopenia or thrombocytosis. Serum biochemical findings often includes hyperproteinemia, hyperglobulinemia, hypoalbuminemia, increased liver enzyme activities, hyperbilirubinemia, and electrolyte imbalances. Low albumin:globulin ratio (A:G) can aid in diagnosis of FIP, with A:G ≤0.4 making FIP likely. In one study an albumin/globulin ratio of 0.5 had a positive predictive
value of 89%, and an albumin/globulin ratio of 1.0 had a negative predictive value of 91% (Hartmann et al, 2003). When hyperglobulinemia is detected, protein electrophoresis can be performed which usually shows polyclonal gammopathy with greatest increases in the gamma (γ)-globulin fractions (Taylor, 2010).
Acute phase proteins, mainly αlpha1-acid glycoprotein, are often increased (≥1500 μg/mL) in cats with FIP but can also be increased with other inflammatory diseases. Measuring FCoV antibodies in cats with FIP is not very helpful due to the high number of seropositive cats after FECV infection and about 10% of cats with FIP have been reported to be seronegative. Ultrasound often confirms pleural or peritoneal effusion in case of effusive FIP and abdominal lymphadenopathy and medullary rim sign can be seen in both effusive and non-effusive FIP. Fluid analysis and cytology in cases of effusive FIP can be beneficial. The effusions are mostly
consistent with modified transudate or exudate and is usually high in protein (≥3.5 g/dL) and of low cellularity (nucleated cells <5000 cells/μL). Mixed inflammatory cell populations of lymphocytes, macrophages, and neutrophils occur most commonly; neutrophils predominate in most cases, but in some cats, macrophages are the primary cell type seen. Measurement of protein concentrations in effusions and calculation of the albumin/globulin ratio can aid in the diagnosis of effusive FIP.
The gold standard for diagnosis of FIP is immunohistochemistry (IHC) which detects FCoV antigen in macrophages by immunofluorescence or immunoperoxidase methods. FCoV RNA can also be detected in fluid, tissue aspirates or biopsies by reverse transcriptase polymerase chain reaction (RT-PCR). The specificity and sensitivity of RT-PCR varies based on the test and
sample used for diagnostics, with highest specificity being on pleural and peritoneal effusion as FCoV is unlikely to be in effusions from other causes. Diagnosis of non-effusive FIP can be even more challenging due to the absence of effusion. In cases of neurological FIP, cerebrospinal fluid should be taken for analysis and RT-PCR. Cats with ocular involvement can undergo aqueocentesis and RT-PCR performed on aqueous humor. Surgical biopsies of lymph nodes and/or other organs can be taken for histopathology and IHC to confirm diagnosis of FIP; however, this is not always possible. In most cases of the non-effusive (and often also effusive) form, a presumptive diagnosis of FIP is usually made based on the combination of clinical and clinicopathologic findings and the exclusion of other causes for the presenting clinical signs.
Treatment with antivirals
In the past, most cats with systemic clinical signs of FIP died or were euthanized within days to months of diagnosis and the disease used to carry a very grave prognosis. In the recent years, an advancement in the treatment of FIP has been made with the research being focused on new antiviral drugs: GS-441524 (an adenosine nucleoside analogue that inhibits the viral RNA polymerase) and GC376 (a viral protease inhibitor) have shown a promise in the treatment of FIP in both experimentally induced and naturally acquired FIP infection (Pedersen, 2018; Pedersen, 2019; Dickinson, 2020). Several countries (eg. United Kingdom and Australia) now have legal formulations of GS-441524 and remdesivir (a prodrug of GS-441524) available to veterinarians (Coggins et al. 2023, Taylor et al. 2023). Remdesivir is an antiviral drug with a broad-spectrum of activity against RNA viruses that was originally developed to treat hepatitis C virus and Ebola virus in humans. Most recently, remdesivir has been used against SARS-CoV-2 in the COVID-19 pandemic. Unlike GS-441524, remdesivir has low oral bioavailability and is given intravenously (IV) in human patients. Currently, the most common route of administration used for GS-441524 and remdesivir in cats is subcutaneous (SC) injections but many cats are now transitioned to oral administration of GS-441524 after few days of initial injections due to the high prevalence of pain and irritation from the injections (Taylor et al. 2023). Many cats still require supportive therapy (eg. SC fluids, anti-emetic and appetite stimulants, analgesia) and cats with more advanced or neurological signs of the disease might require hospitalization for intravenous fluid therapy and nutritional support via feeding tube. Cats presenting with uveitis usually require topical therapy with corticosteroids and cats with neurological form of FIP that present with seizures might need anti-epileptic therapy (eg. levetiracetam 20-30 mg/kg every 8 hours).
Treatment with GS-441524 or remdesivir is generally recommended for a minimum of 12 weeks and the doses differ depending on the form of the disease; summary of recommended doses is shown in Table 1. In cats experiencing relapse of FIP, additional treatment should be at higher doses. Please note that oral doses of GS-441524 are much higher than SQ doses due to the lower
bioavailability of the drug when administered orally. Positive response rates are usually high (75- 90%) with neurological form being the most difficult to treat; however, relapses after discontinuation of the antiviral medication can occur.
While recent studies have reported the use of drugs like the nucleoside analog GS-441524 as successful treatment of FIP, only remdesivir is currently legally available in the US (Murphy et al. 2018, Park et al. 2018, Pedersen et al. 2018, Pedersen et al. 2019). As a result, owners are purchasing black market variations of these drugs that may not contain the exact amount of the active drug, could contain contaminants and lack veterinary supervision (Jones et al. 2021, Kent et al. 2023). As the purity of these products is uncertain, it makes their use in veterinary medicine challenging. In addition, the drug protocols using SC administration can be difficult for clients and associated with side-effects (Pedersen et al. 2019). Recently, a new study on pharmacokinetics data from molnupiravir (EEID-2801) which showed promise for use at 10 mg/kg, PO, once daily (Cook et al.2022). There is also uncontrolled data from client surveys that suggests efficacy of this unlicensed product as rescue treatment following failure of unlicensed
GS-441524 therapy as well as a first line treatment option for cats with FIP (Roy et al. 2022). A new study on 18 cats with FIP suggested that molnupiravir might be an effective and safe treatment for domestic cats with FIP at a dose of 10-20 mg/kg twice daily (Sase 2023). Molnupiravir has currently an emergency FDA approval for humans for treatment of SARS-CoV-2 in the United States (LagevrioTM, Merck, USA).
Monitoring
Monitoring of cats on the antiviral treatment for FIP is important. Most cats experience improvement of clinical signs within the first few days; however, cats with effusion may initially deteriorate in the first 1-2 days after initiation of treatment (this is reported mainly after IV administration) and may require additional therapeutic thoracocentesis or abdominocentesis. The body weight of the atients should be checked regularly, and the doses of medications (mg/kg) adjusted accordingly. Serial bloodwork (complete blood cell count and serum biochemical panel) should be performed during and after discontinuation of the treatment. Hematocrit, total protein (albumin and globulins) and other abnormal parameters should normalize during the treatment. Remdesivir is reported to cause renal and hepatotoxicity in people, but this is rare in cats and mainly associated with higher doses. In the initial study with GS-441524, effusion resolved in the first 1–2 weeks of treatment, while anemia may not resolve until after 6–8 weeks of treatment
(Pedersen et al, 2019). Abnormal serum protein values usually improve progressively and reach normal levels after 8–10 weeks of treatment.
Treatment with immunostimulants
Polyprenyl immunostimulant (PI) is licensed by the FDA for the reduction of the severity of signs of feline herpesvirus and is reported to be safe in cats over 8 weeks of age. It is believed to modify the immune response through its action on toll-like receptors. Cats with FIP have severe depletion of the CD4+ and CD8+ T-lymphocytes necessary for mounting a cell-mediated immunity response and PI enhances cell-mediated immunity through upregulation of Th1 cytokines. The drug is reported to have therapeutic effect with non-effusive FIP (Legendre, 2009; Legendre, 2017). The dosing recommendations for treatment of FIP is shown in Table 1. One study with 58 cats with a presumptive diagnosis of non-effusive FIP being treated with PI reported that 22% of cats were alive for at least 6 months, and about 5% alive for at least a year (Legendre, 2017).
References and Suggested Reading
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Cook S, Wittenburg L, Yan VC, Theil JH, Castillo D, Reagan KL, Williams S, Pham CD, Li C, Muller FL, Murphy BG. An Optimized Bioassay for Screening Combined Anticoronaviral Compounds for Efficacy against Feline Infectious Peritonitis Virus with Pharmacokinetic Analyses of GS-441524, Remdesivir, and Molnupiravir in Cats. Viruses. 2022;14:2429. doi: 10.3390/v14112429. PMID: 36366527; PMCID: PMC9697187.
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Takano, T., Ohyama, T., Kokumoto, A., Satoh, R., & Hohdatsu, T. Vascular endothelial growth factor (VEGF), produced by feline infectious peritonitis (FIP) virus-infected monocytes and macrophages, induces vascular permeability and effusion in cats with FIP. Virus research, 2011; 158(1-2), 161–168.