What are FIP and feline coronavirus?
About feline infectious peritonitis
Feline infectious peritonitis (FIP) is a fatal infectious inflammatory disease of cats. As the name suggests, an infectious agent, feline coronavirus (FCoV), is involved in the disease. FIP was first described by Holzworth in 19631, although it wasn’t until 1970 that Ward identified a virus similar to known coronaviruses as the pathogen causing the disease2.FIP is a progressive, fatal disease, which is caused by FCoV. FCoV infection is widespread in the feline population. The majority of FCoV infections cause only mild enteritis, the infected cat suffers no long-term disease and eventually eliminates the virus. However, in a small number of cases, the infected cat continues to shed FCoV in faeces for a prolonged period, becoming a virus carrier3. FCoV usually exhibits a strong tropism for enterocytes, in a small fraction of infections the virus develops a tropism for monocytes and macrophages4. These cells of the immune system play a pivotal role in FIP disease development. Infected cells become disseminated through the vascular and lymphatic systems, producing a systemic infection, although recent studies suggest that systemic infection may not always induce FIP5. Cats developing FIP have a poor prognosis and often euthanasia is elected within 2 to 3 weeks of diagnosis. FIP occurs in 5-10% of the FCoV-infected cat population4 and exists in two forms, a ‘wet’ form where an effusion is observed (ascitic, thoracic or pericardial) and a “dry” form where there is no effusion present but acute vasculitis is observed and granulomatous lesions may occur on various organs, leading to additional clinical signs.
Feline coronavirus was discovered by Ward in 19702. The virus is enveloped and contains a single-strand positive-sense RNA. RNA genomes are more frequently mutated than the DNA genomes of humans and other animals because errors occur during viral replication, when the genome is reverse transcribed within the host cells. FCoV belongs to the Coronaviridae family, sub-family Coronavirinae, genus Alphacoronavirus, species alphacoronavirus 1.
The virus may be genetically classified into two genotypes of FCoV, both genotypes have the ability to cause FIP6. The FCoV I genotype has been estimated to be responsible for approximately 80-95% of FCoV infections in the field7. Coronaviruses in general are ubiquitous in the environment. You may recognise the names SARS (Severe Acute Respiratory Syndrome) and MERS (Middle Eastern Respiratory Syndrome), both diseases caused by coronaviruses. Both are believed to have originated from bat coronavirus reservoirs and are thought to have jumped species to humans, possibly via the palm civet as an intermediate host8. Some human coronaviruses cause short-term infections such as the common cold and resolve without any lasting damage. FCoV does not infect humans, commonly coronaviruses are host specific, only infecting closely related species. FCoV is genetically similar to the canine coronavirus and it has been postulated that FCoV II originated from a double recombination event involving FCoV I and canine coronavirus I7.
What are the challenges for FIP research?
FIP diagnosis is notoriously difficult and is often only confirmed post-mortem. The clinical signs associated with disease are non-specific and include pyrexia, lethargy, reduced appetite, mood changes, anorexia and neurological or ocular changes. FIP occurs only after a cat has become infected with FCoV, however, unlike many infectious diseases, FCoV serology alone is insufficient to determine whether an animal has or does not have the disease; many animals are co-incidentally seropositive but do not develop FIP9. A number of new diagnostic tools are in development to improve FIP diagnosis; however, there is currently no gold-standard non-invasive tool available for the diagnosis of dry FIP. Effusive FIP can be confirmed by the demonstration of FCoV RNA in the cavity effusion (typically thoracic or abdominal)10,11. A battery of tests may be used to help diagnose FIP, including FCoV serology, FCoV viral RNA detection, haematology, cytology and biochemistry12,13. A number of the parameters and their related reference ranges were first described decades ago. I am in the fortunate position to have access to a wealth of data collected from previous FIP cases, fifteen years’ worth of data from the Veterinary Diagnostic Services database. It is my intention to use these data to assess and analyse these parameters using mathematical modelling techniques to determine whether diagnostic criteria can be adjusted to improve prediction of disease state, or modelled in unison so that we can more effectively predict the development of disease. In addition, I will survey a sample population of those cats and collect clinical outcome data, including clinical history, survival time from diagnosis (including survival to death/euthanasia). These data will be evaluated and the results will lead to improvements in our diagnostic algorithms, based on mathematical modelling. At present, often by the time a diagnosis of FIP is made, unfortunately an affected cat has very little time left to live; either it dies naturally of the disease or is euthanased due to the progression of the disease and associated suffering.
In an infected individual, FCoV exists as a population of subtly different strains or ‘quasispecies’, like human immunodeficiency virus (HIV). Some of these FCoV viral particles have mutations, which trigger an abnormal immune response in the infected cat, changes in the spike protein are thought to alter the virulence of the virus14,15. Neither the factors driving mutation nor the mechanisms involved in the irregular host immune response are particularly well understood. One challenge with feline coronavirus and FIP is that occurrences of FIP are sporadic; FCoV infection is widespread, but FIP occurs in only 5% of the population4. Epidemics do not occur, small epizootic outbreaks do occur occasionally but infrequently. Mutant virus particles are not thought to be shed in the faeces16,17, although this theory was recently challenged by Wang et al.18 It was previously supposed that FIP causing FCoV was not transmitted horizontally. These factors mean that tracing infections and controlling spread of disease is particularly difficult. The outcome for a cat infected with FCoV infection depends on whether or not highly virulent FCoVs exist within their infecting quasispecies.
Treatment and vaccination
There are no specific treatments for FIP, but some treatments have been trialled, often for disease management in desperate situations; such treatments are usually targeted at controlling clinical signs. Few controlled clinical trials have been performed with drugs to treat FIP. There are several studies currently evaluating antiviral compounds that could potentially lead to development of FIP therapeutics.
There is currently no vaccine available in the UK against FCoV. The vaccine available in other countries around the world is not recommended as a core vaccine, because it causes enhancement of infection in seropositive cats19.
A phenomenon known as antibody dependant enhancement (ADE) was shown in experimental studies to have an adverse effect on naturally infected/exposed animals20. ADE has been described in other diseases, such as Dengue fever: previous exposure to the pathogen actually increases susceptibility to infection. Therefore, if an animal has had previous exposure, even from vaccination, there is the risk of more severe clinical signs following infection.
5. Porter E, Tasker S, Day MJ, et al. Amino acid changes in the spike protein of feline coronavirus correlate with systemic spread of virus from the intestine and not with feline infectious peritonitis. Vet Res 2014; 45: 49–60.
9. Herrewegh AA, de Groot RJ, Cepica A, et al. Detection of feline coronavirus RNA in feces, tissues, and body fluids of naturally infected cats by reverse transcriptase PCR. J Clin Microbiol 1995; 33: 684–9.
10. Doenges SJ, Weber K, Dorsch R, et al. Comparison of real-time reverse transcriptase polymerase chain reaction of peripheral blood mononuclear cells, serum and cell-free body cavity effusion for the diagnosis of feline infectious peritonitis. J Feline Med Surg 2017; 19: 344–350.
11. Longstaff L, Porter E, Crossley VJ, et al. Feline coronavirus quantitative reverse transcriptase polymerase chain reaction on effusion samples in cats with and without feline infectious peritonitis. J Feline Med Surg 2017; 19: 240–245.
12. Rohrer C, Suter PF, Lutz H. The diagnosis of feline infectious peritonitis (FIP): retrospective and prospective investigations. / Die Diagnostik der felinen infektiösen Peritonitis (FIP): Retrospektive und prospektive Untersuchungen. Kleintierpraxis 1993; 38: 379–383.
16. Stoddart ME, Gaskell RM, Harbour DA, et al. Virus Shedding and Immune Responses in Cats Inoculated with Cell Culture-Adapted Feline Infectious Peritonitis Virus. Vet Microbiol Elsevier Sci Publ BV 1988; 16: 145–158.
17. Chang H-W, de Groot RJ, Egberink HF, et al. Feline infectious peritonitis: insights into feline coronavirus pathobiogenesis and epidemiology based on genetic analysis of the viral 3c gene. J Gen Virol 2010; 91: 415–420.
18. Wang Y-T, Su B-L, Hsieh L-E, et al. An outbreak of feline infectious peritonitis in a Taiwanese shelter: epidemiologic and molecular evidence for horizontal transmission of a novel type II feline coronavirus. Vet Res 2013; 44: 57.
20. Hohdatsu T, Yamada M, Tominaga R, et al. Antibody-Dependent Enhancement of Feline Infectious Peritonitis Virus Infection in Feline Alveolar Macrophages and Human Monocyte Cell Line U937 by Serum of Cats Experimentally or Naturally Infected with Feline Coronavirus. J Vet Med Sci 1998; 60: 49–55.