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Journal of Feline Medicine and Surgery (2018) 20, 228–243

CLINICAL review

Diagnosis of feline
infectious peritonitis
Update on evidence
supporting available tests
Séverine Tasker

Practical relevance: Feline coronavirus(FCoV) infection is very common in cats,
usually causing only mild intestinal signs
such as diarrhoea. Up to 10% of FCoV
infections, however, result in the fatal
disease feline infectious peritonitis (FIP).
Clinical challenges: Obtaining a definitive
diagnosis of FIP based on non-invasive approaches
is difficult. Confirmation of the disease relies onfinding appropriate cytological or histopathologicalchanges in association with positive immunostaining
for FCoV antigen. In FIP cases with effusions,cytology and immunostaining on effusion samples
can be relatively easy to perform; otherwise
obtaining diagnostic samples is more challenging
and collection of biopsies from tissues with grosslesions is necessary. In the absence of a definitive
diagnosis, a high index of suspicion of FIP may
be obtained from the cat’s signalment and history,
combined with findings on clinical examination andlaboratory test results. If largely consistent with FIP,
these can be used as a basis for discussion withthe owner about whether additional, more invasive,
diagnostic tests are warranted. In some cases it
may be that euthanasia is discussed as analternative to pursuing a definitive diagnosis antemortem, especially if financial limitations exist or
where there are concerns over a cat’s ability totolerate invasive diagnostic procedures. Ideally,
the diagnosis should be confirmed in such patientsfrom samples taken at post-mortem examination.
Global importance: FIP occurs wherever FCoV
infection is present in cats, which equates to mostparts of the world.
Evidence base: This review provides acomprehensive overview of how to approach thediagnosis of FIP, focusing on the tests available tothe veterinary practitioner and recently publishedevidence supporting their use.

What are coronaviruses?
Coronaviruses are large, enveloped, positive-sense, single-stranded RNA
viruses with non-segmented genomes of around 30,000 nucleotides inlength.1 Feline coronavirus (FCoV) is a subspecies of the alphacoronavirus
1 species, along with canine coronavirus (CCoV). Coronaviruses exhibit
a high rate of mutation during RNA replication and therefore exist as
clusters of genetically diverse populations, known as quasispecies.2,3This genetic diversity, along with a readiness to recombine with othercoronavirus strains, is associated with their pathogenicity and crossspecies transmission. FCoVs appear to have emerged in the 1950s, possibly
due to cross-species transmission, and cats worldwide have now beenfound to be infected with FCoV, with the exception of those residing
in a few areas, such as the Galápagos Islands4 and Falkland Islands,5
likely due to the isolation afforded by their remote island habitat.

FCoV serotypes
Two so-called serotypes of FCoV are recognised: type 1, which represents
the vast majority of field strains found in naturally infected cats, althoughgeographical variation exists;6,7 and type 2, which arose following recombination events between type 1 FCoV and CCoV.8 The two FCoV serotypes are
distinguished primarily by the genetic and serological differences in theirtransmembrane spike (S) gene and protein, respectively. The S protein(Figure 1) is important as it is the part of the FCoV that binds to the host (feline)
receptor, mediating host cell entry.9 The S protein of type 2 FCoVs resembles
that of CCoV and, like CCoV, type 2 FCoVs use aminopeptidase N as their
feline host cell receptor. The receptor for type 1 FCoVs is unknown.10

Figure 1 Schematic
diagram of an FCoV
particle. The spike
protein binds to the feline
receptor, mediating hostcell entry. The feline
receptor is known to beaminopeptidase N for type
2 FCoVs, but is, as yet,unknown for type 1
FCoVs. Modified
with permission fromDr Emi Barker

Séverine Tasker
BSc, BVSc, PhD, DSAM, DipECVIM-CA,
PGCertHE, FHEA, MRCVSThe Feline Centre, Langford Vets,
Bristol Veterinary School,
University of Bristol, Bristol, BS40 5DU, UK
Email: s.tasker@bristol.ac.uk

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doI: 10.1177/1098612X18758592© The Author(s) 2018

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R E V I E W / Diagnosis of FIP

The complex relationshipbetween FCoV and feline
infectious peritonitis
FCoV infection is very common in cats. Around
40% of the domestic cat population has been
infected with FCoV, and this figure increases to
90% in multi-cat households.11,12 Modern trends
in feline husbandry (eg, more cats kept indoors
and in multi-cat households) are likely to have
led to an increase in FCoV-related disease.13
Natural infections with FCoV are transient in~70% of cats, but persistent infections occur in~13% of cats.13 These persistently infected animals are sometimes referred to as ‘carrier’ or‘chronically shedding’ cats. In most cases, FCoV
infection is asymptomatic or results in only mild
gastrointestinal clinical signs (eg, inappetence,
diarrhoea, vomiting), although more severe
gastrointestinal disease is sometimes seen.
Interestingly, around 5–10% of cats are believed
to be resistant to FCoV infection.13 However, in asmall percentage of cases, FCoV infection resultsin feline infectious peritonitis (FIP), a fatal disease that is a common cause of death in young
cats.14,15 occasionally, and possibly with increasing frequency recently, outbreaks of FIP (when alarger percentage of cats are affected) in multicat households or shelters are reported.16,17 No
curative treatments for FIP are currently available, although some novel treatments, including
protease inhibitors, show promise.18–20
Asymptomatic FCoV infection was previously
believed to be confined to the intestinal tract,
but we now know that healthy FCoV-infectedcats can have systemic infection, albeit withlower viral loads than cats with FIP.3,21–23

Factors contributing to
the development of FIP
Viral factors
Viral factors are important in the pathogenesis
of FIP. As described in the box on page 228,
the S protein of FCoV mediates host cell entry.
The S protein contains a putative fusion peptidethat enables fusion of the FCoV envelope withthe host cell membrane.24 Mutations in the
S gene can result in amino acid substitutionsin the transcribed S protein that influence thetropism of FCoV.25 Studies have identified
mutations in the fusion peptide sequence of the
FCoV S gene that were thought to be markersof FIP,26,27 as well as changes in the closely
related furin cleavage site that were also
thought to be correlated with FIP.28 Recently, it
has been found that the fusion peptide mutations are likely to be markers of systemic
FCoV infection, which can occur in both FIP
and non-FIP cats, rather than of FIP per se.29
However, these mutations are still importantas it is probably via these, and/or other muta-

tions, that the FCoV acquires its monocyte/
macrophage tropism that allows it to spreadsystemically, outside of the intestinal tract, andcontribute to the development of FIP.
other viral factors mediating effective andsustained replication in monocytes, and activation of infected monocytes, are also likely to
be important for the subsequent developmentof FIP following systemic FCoV infection.30
Host factors
Host factors are additionally very likely to play
an important part in FIP development. These
include the host immune response (eg, T lymphocyte depletion occurs in cats that developFIP), the ability of monocytes to sustain FCoV
replication, breed and genetics.31–34
Environmental factors
Environmental factors, such as the level ofstress and overcrowding in a household, mayalso play a role. These may act to accelerate therate of viral replication in an individual cat,35
which could increase the generation of viralmutants and support FIP development.

Approaching a diagnosis

Asymptomatic
FCoV infection
was previously
believed to be
confined to theintestinal tract,
but we now
know that
healthy FCoVinfected cats
can havesystemic
infection.

Making a definitive diagnosis
A definitive diagnosis of FIP traditionallyrelies on histopathological examination oftissues, usually with detection of the virus
within lesions by immunohistochemistry (IHC)
for FCoV antigen. Immunostaining of FCoV
antigen in effusion samples is also an option incases with effusions showing biochemical andcytological features consistent with FIP.
Histopathological examination, effusion
analysis and FCoV antigen immunostaining
are discussed in more detail later.
Obtaining a high index of suspicion
In the absence of a definitive diagnosis, a highindex of suspicion of FIP may be obtained frombackground information, clinical signs and routine clinicopathological results. With experience,
this can be used as a basis for discussion with theowner of whether additional, more invasive,
diagnostic tests (eg, surgical biopsy of affected tissues) are warranted. In such cases it may be that
euthanasia is discussed as an alternative to pursuing a definitive diagnosis ante-mortem; thismay be preferable in, for example, shelter cats,
where there are financial limitations, or when cats
are very sick and concerns exist over a patient’s
ability to tolerate further diagnostic procedures.
If euthanasia is performed without a definitive
diagnosis, post-mortem examination is strongly
advised and relatively simple to perform.36 Thispermits both assessment for gross changes
consistent with FIP (Figure 2) and samplingfor histopathological examination. If financial

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R E V I E W / Diagnosis of FIP

Many important differential diagnoses
should be considered in cats suspected of having FIP, such as toxoplasmosis, mycobacterial
infection and lymphocytic cholangitis. These,
and others, are described in Table 1, together
with consideration of features distinguishingthose diseases from FIP.

limitations preclude the latter, it is worth
contacting researchers with an interest in FIP(eg, the University of Bristol Feline Coronavirus
Research Group and Bristol-Zurich FIP
Consortium) to see if samples are beingsought for research studies that could allow
for analysis at a reduced cost or free of charge.

Yellow sticky effusion visible in the abdomen

Granulomas evident on the surface of the kidneys

Fibrinous plaques visible on the surface of thespleenGranulomas visibleon the surface of
the intestines

Figure 2 Typical gross post-mortem findings in cases of FIP. Granulomatous lesions in organs or fibrinous
plaques on the serosa of organs may be visible in the abdominal or thoracic cavity; tissues that are good
to examine for these are the mesenteric lymph nodes, liver, spleen, kidneys and intestinal surfaces, aswell as the peritoneal lining of the abdominal wall and diaphragm. In effusive cases, yellow sticky fluid
can be visible in the pleural and/or peritoneal cavities, but the pericardium can also be checked for fluid

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Fibrinous plaques visible on the omentum,
together with enlargement of the mesentericlymph nodes

Granulomas visible on the surface of the lungs

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R E V I E W / Diagnosis of FIP

Table 1

Diseases to consider in the differential diagnosis of FIP

Disease/condition

Possible distinguishing features from FIP and course of action

Toxoplasmosis

Transmission/epidemiology: Acquired via vertical transmission (in young cats) or by hunting or eating raw meat
Clinical signs: Cats may have hepatic, pulmonary, neurological, muscle and/or pancreatic involvement. Signs can include lethargy,
anorexia, dyspnoea (pneumonia and/or pleural effusions can occur), jaundice, abdominal effusions, uveitis (especially posterior) and/or
neurological signs
Diagnostic testing: Clinical toxoplasmosis is less common than FIP and is not usually associated with the severe hyperglobulinaemia
or reduced albumin:globulin ratio often seen with FIP. Hyperbilirubinaemia may occur. Serology (high IgM titre or rising IgG titre) may be
helpful for diagnosis. Organisms may be found on sampling and microscopic examination of, for example, lung or lymph node. PCR canalso be performed on such samples to demonstrate the presence of Toxoplasma gondii DNA. Cerebrospinal fluid (CSF) PCR can also be
performed in cases with neurological signs
Treatment: If toxoplasmosis is suspected, trial treatment with clindamycin can be instigated to see whether there is a positive response

Lymphocytic
cholangitis (LC)Epidemiology: Persians may be predisposed but more recent studies have failed to show this breed predisposition
Clinical signs: Often associated with jaundice. Some cats with LC have an abdominal (unicavitary) effusion
Diagnostic testing: The nature of the effusion is similar to that seen with FIP in terms of protein concentration (ie, high), although cellcounts in LC are usually higher than those seen with FIP. A marked hyperglobulinaemia can also be seen with LC. Both LC and FIP
cases can be hyperbilirubinaemic. Unlike FIP, LC is also usually associated with marked increases in liver enzymes, especially cholestatic
markers (ie, alkaline phosphatase and gamma-glutamyltransferase), compared with the more mild or modest increases that occur in FIP
cats. Additionally, cats with LC are not usually as sick as those with FIP; for example, they can be polyphagic rather than inappetent

Neoplasia(eg, lymphoma,
abdominal
carcinoma)

Epidemiology: Lymphoma can affect young cats, but is seen in cats of all ages. Other neoplasias tend to be seen in older cats. Focal
FIP lesions in the intestine or (especially mesenteric) lymph nodes can present very similarly to cases with apparently solitary neoplasmsof these organs
Clinical signs: Lymphoma can involve multiple body organs and, like FIP, can result in lymphadenopathy and/or bicavitary effusions.
Cats are often systemically ill
Diagnostic testing: Sampling of affected tissues or effusions followed by cytology may yield a diagnosis of lymphoma rather than themixed inflammatory cells typically seen on cytological sampling of FIP-affected tissues. Other neoplastic lesions (eg, carcinomas) may
be diagnosed on cytology of effusions

Pancreatitis

Clinical signs: Cats may present with anorexia, jaundice and weight loss. Marked pyrexia is not usually a feature, although pyrexia canoccur in acute pancreatitis cases that are associated with severe pain and/or sepsis
Diagnostic testing: Hyperbilirubinaemia may occur. A small amount of abdominal fluid (typically with a high protein concentration andhigh cell count [non-degenerate neutrophils], in contrast to the high protein, low cell count effusions with FIP) is sometimes present inacute cases. Pancreatitis can be diagnosed by ultrasonographic examination of the pancreas and measurement of feline pancreatic
lipase immunoreactivity
Treatment: Trial treatment with antiemetics and analgesics may be warranted

Retroviral
infection

Epidemiology: Feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) infections are both found more commonly in adults
than juveniles, but age-related immunity plays a role in FeLV infection, with younger cats being more prone to infection. Both viruses are
more likely to occur in outdoor cats. FeLV affects both males and females, whereas males are at increased risk of FIV infection
Clinical signs: Both FeLV and FIV infection can be associated with pyrexia, lethargy, lymphadenopathy and/or uveitis
Diagnostic testing: FIV infection can be associated with a marked hyperglobulinaemia. Note that retrovirus-positive status may act
as a risk factor for the development of FIP

Mycobacterial
infection
includingtuberculosis (TB)

Epidemiology: There is geographical variation in prevalence, and infection is usually associated with a history of outdoor access andhunting
Clinical signs: Lymphadenopathy, respiratory signs and/or uveitis may be seen, as well as draining non-healing wounds. Affected cats
may be relatively well despite the disease, and pyrexia and inappetence are not common features although acute presentations of, forexample, dyspnoea can occur. Mycobacterial infections that involve the lungs typically affect the lung parenchyma rather than presenting
with pleural effusions as in FIP
Diagnostic testing: Mycobacterial infection is not usually associated with the severe hyperglobulinaemia or reduced albumin:globulin
ratio seen with FIP. Hypercalcaemia may be present. Cytology of affected lymph nodes or organs shows inflammatory changes(macrophages prominent but inflammation can be similar to FIP with pyogranulomatous changes). Ziehl–Neelsen staining on cytology
or biopsy samples may be positive, and samples can be submitted for culture (although positive culture results can take weeks to obtainwith slower growing organisms, and culture may be impossible with some mycobacterial species). An interferon gamma test, performedon blood samples, is now available to assist in the diagnosis of suspected feline TB cases

Pyothorax

Clinical signs: Can be associated with pyrexia. A pleural effusion is seen
Diagnostic testing: Thoracic effusion analysis reveals very high cell counts due to marked neutrophilic inflammation, with degeneratechanges and possibly intracellular bacteria, although any previous antibiotic treatment may mean that bacteria are not seen. Unicavitaryeffusion

SepsisCan be associated with many conditions; for example, septic peritonitis, pyothorax, pneumonia, pyelonephritis
Clinical signs: Cats may present with pyrexia (although cats can also present with low temperatures), tachycardia or bradycardia,
tachypnoea, and other signs associated with the source of sepsis
Diagnostic testing: Leukocytosis, band neutrophilia and hyperbilirubinaemia (in the absence of raised hepatic enzyme activity) may
be present

Septic peritonitis

Clinical signs: Can be associated with pyrexia. An abdominal effusion is seen
Diagnostic testing: Abdominal effusion analysis reveals very high cell counts due to marked neutrophilic inflammation, with degeneratechanges and possibly intracellular bacteria, although any previous antibiotic treatment may mean that bacteria are not seen. Unicavitaryeffusion. Glucose concentration in the abdominal effusion is lower than that in the blood (by >1.1 mmol/l)Congestive heart
failure (CHF)

Clinical signs: Bicavitary effusions in the pleural and peritoneal spaces are possible, although pleural effusions are far more common
with feline CHF than abdominal effusions, and abdominal effusions alone are very rarely seen with feline CHF. The presence of a gallop
sound, arrhythmia and possibly heart murmur may increase the index of suspicion for CHF. Jugular vein distension may be present withright-sided CHF. Pyrexia is not a feature
Diagnostic testing: The fluid is a modified transudate with little protein, in contrast to the fluid seen with FIP. Echocardiography will
confirm cardiac disease and CHF

RabiesIn countries where rabies is endemic, this must be considered as a differential diagnosis in unvaccinated cats presenting withneurological signs, especially acute behavioural changes and progressive paralysis

Modified from Tasker S and Dowgray N,36 with permission from BSAVA Publications, Gloucester

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Courtesy of Sheila Crispin

Abdominal effusionWet(effusive) FIP
Typical signs of wet (effusive)
FIP form< Abdominal effusion(abdominal distension)< Pleural effusion (dyspnoea,
tachypnoea)< Pericardial effusion< Scrotal swelling

Overlap between wet and dry forms
Typical signs ofboth forms< Lethargy< Pyrexia< Anorexia< Weight loss
< Jaundice< Lymphadenomegaly

Figure 3 Examples of clinical signs
seen in cases of FIP. Clinical signs are
typically assigned to wet or dry FIP
presentations, but there is much overlap
between the two presentations andmany signs are seen in both forms

Signalment and backgroundevidence for FIP
It should be remembered that FIP is mostcommon in young cats (those less than 3 yearsof age, and especially those less than 2 yearsof age)37 but a smaller peak of cases is seen
in cats older than 10 years of age. Male cats
are also at a slightly higher risk.37 Some
breeds in some countries may be predisposed
to FIP,38,39 but this is likely due to the presenceof unknown specific genetic risk factors
in those breeds in those countries, andgeneralised breed predispositions may notexist.37 A recent history of stress (adoption,
being in a shelter, neutering, upper respiratory tract disease, vaccination, etc) may beapparent37 and may play a part in triggering
the development of FIP in an FCoV-infected
cat.
Although living in a multi-cat householdincreases the likelihood of being FCoV
seropositive, a recent large study37 found that

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Posterior uveitis

Most FIP
cases with
effusionsalso have
granulomatous
lesions visibleat postmortem
examination.

Dry (noneffusive) FIP

Typical signs of dry (non-effusive)
FIP form< Neurological signs (eg, ataxia, head tilt,
hyperaesthesia, nystagmus, seizures,
behavioural changes)< Ocular signs (eg, iritis [iris discolouration],
corneal oedema, dyscoria/anisocoria,
loss of vision, hyphaema, hypopyon,
keratic precipitates, aqueous flare,
perivascular cuffing, chorioretinitis,
subretinal fluid accumulation causing
partial retinal detachment)< Less commonly, non-pruritic papules
or nodules in the skin
Courtesy of Animal
Health Trust

Pleural and pericardial effusions

Jaundiced mucous membranes

Anterior uveitis

the majority of cats presented to a university
hospital with FIP were from households
containing a small number of cats at the timeof diagnosis.

Clinical signs
FIP typically manifests as a vasculopathy
resulting in (‘wet’) effusions (up to 80% of FIP
cases have effusions), or granuloma formation
resulting in (‘dry’) mass lesions, or a combination of the two; indeed, most FIP cases with
effusions also have granulomatous lesions
visible at post-mortem examination.
Clinical signs (Figure 3) seen in both
effusive and non-effusive FIP include lethargy, anorexia, weight loss (or failure togain weight/stunted growth in youngercats), a fluctuating pyrexia that is usually
non-responsive to drugs such as antibiotics
or non-steroidal anti-inflammatories, andsometimes jaundice (more common in effusive FIP).

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A recent study40 evaluating referral feline
cases with a history of pyrexia found that
FIP was the most common diagnosis made(20.8%, 22/106 cats), showing the importanceof FIP as a differential diagnosis in pyrexic
cats in this population of referred cats.
Another study, describing FIP cases only,
reported that body temperature exceeded
39.5°C in 81% of cats and 40°C in 39% of cats.37
Pyrexia was far more common in cats with
effusive FIP than those with neurological noneffusive FIP.37
Lymphadenomegaly can also be present inboth the effusive and non-effusive forms of FIP.
Effusive (wet) FIP is associated withabdominal, pleural and/or pericardial effusions (occasionally in the scrotum too of entire
male cats), and is often quite acute in nature,
progressing within a few days or weeks andseverely limiting survival.41 These cats canpresent with dyspnoea, tachypnoea and/or
abdominal distension.
Non-effusive (dry) FIP is typically associatedwith neurological signs (which can be focal,
multifocal or diffuse in nature, often with central vestibular signs, occasionally as a T3–L3
myelopathy)42 and/or ocular signs (anterior
and/or posterior uveitis) and is more chronic,
progressing over a few weeks to months.
dermatological signs (manifesting typically assmall, multiple, non-pruritic papules or nodules)43,44 have also been reported in dry FIP.
Renomegaly may occur in non-effusive
FIP with renal involvement. occasionally adiffuse pyogranulomatous pneumonia isreported.
It is important to remember that clinicalsigns of FIP can change over time, so repeatedclinical examinations are important to detect
newly apparent signs (eg, development of asmall volume of effusion, ocular changes visible on retinal examination).
Focal non-effusive FIP occasionally occurs,presenting typically as a palpable abdominal
mass. It can be particularly challenging todiagnose as the lesions can be hard to initiallydifferentiate from neoplasia and mycobacterial infection. Reports of focal FIP cases
have comprised cats presenting with mesentericlymph node enlargement due to necrogranulomatous lymphadenitis,45 or solitary muralintestinal lesions of the colon or ileocaecocolic
junction with associated regional lymphadenopathy.46 The cats with focal intestinal
FIP had a history of vomiting and diarrhoea.

Clinical signs of FIP can changeover time, so repeated clinicalexaminations are important.

Possible findings from routine
laboratory tests
Haematology
Haematological changes in FIP are non-specificbut there are a number of abnormalities that canbe looked for to support a diagnosis. Lymphopenia is particularly common (55–77% of cases,
although a recent study37 found only 49.5% of
FIP cases to be lymphopenic), with neutrophilia(39–57%), a left shift, and mild to moderatenormocytic, normochromic anaemia (37–54%)
also reported.37,44–49 An association between FIP
and microcytosis (with or without anaemia)
was recently reported.33 Severe immunemediated haemolytic anaemia (IMHA), withan associated regenerative anaemia, can occur
with FIP,49 but is uncommon.
Serum biochemistry
The changes in serum biochemistry in FIP cases
are varied and often non-specific, but there are anumber of important abnormalities that should
be looked for to support a diagnosis of FIP.

Hyperglobulinaemia
Hyperglobulinaemia is reported in 89% of cases,
often with hypoalbuminaemia or low-normal
serum albumin (seen in 64.5% of cases).37 The
presence of hypoalbuminaemia alongside hyperglobulinaemia means that hyperproteinaemia
may not always occur; past reports documented hyperproteinaemia in up to 60% of cases,
especially in dry FIP cases, but lower prevalences of 17.5% have been reported recently.37
The combination of hyperglobulinaemia andhypoalbuminaemia or low-normal albumin concentration also means that the albumin:globulin(A:G) ratio is low, and this parameter can be useful to evaluate how likely FIP is in an individualcase. Reports of useful cut-off values for A:G
ratios in the diagnosis of FIP vary, but it has beensuggested that an A:G ratio of <0.4 makes FIP
very likely, while an A:G ratio of >0.8 makes FIP
very unlikely.47–49 Although these cut-off values
are useful to consider, the author does not use a
specific value but looks at the A:G ratio in conjunction with other diagnostic test results; thelower the value, the bigger the suspicion for FIP
becomes, especially if other findings are consistent with a diagnosis of FIP. Interestingly, a study
in a population of cats with a low prevalence ofFIP (akin to the situation that is usually encountered in veterinary practice) found that an A:G
ratio of >0.6 was useful in ruling out FIP, but thatlower ratios were not helpful in ruling in FIP.50
Additionally, the frequency and extent of
hypoalbuminaemia, hyperglobulinaemia, low
A:G ratio and serum protein electrophoresis(SPE) abnormalities reported in FIP cases havedecreased recently.37,51 With respect to SPEchanges, in one study51 cases diagnosed with

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FCoV serology in FIP

FIP from 2013–2014 tended to have elevatedalpha (α)2-globulins rather than the elevatedgamma (γ)-globulins seen in cases from2004–2009. This is possibly due to veterinarians
diagnosing FIP earlier, meaning that cases havenot progressed to show elevated γ-globulins.
Polyclonal and monoclonal elevated γ-globulins
have been reported with FIP,52 although polyclonal elevations are far more common.

Hyperbilirubinaemia
Hyperbilirubinaemia occurs in 21–63% of FIP
cases, and is especially seen with effusive FIP,
often without marked elevations in alanine
aminotransferase (ALT), alkaline phosphatase(ALP) or γ-glutamyltransferase enzyme activity(although these can be moderately elevated in
FIP cases). Hyperbilirubinaemia due to IMHA is
uncommonly reported with FIP,49 and cats areoften not severely anaemic. Thus the presence ofhyperbilirubinaemia in the absence of elevatedhepatic enzyme activities or severe anaemia
should raise the index of suspicion for FIP (notethat sepsis and pancreatitis can also cause hyperbilirubinaemia in the absence of elevated hepatic
enzyme activities [Table 1]). one study47 found,by sequential assessment of cats with FIP, that
hyperbilirubinaemia was more commonly identified in cats just before their death or euthanasia
than at first presentation. Additionally, thisstudy also found that the bilirubin levels weremore elevated in cats just before their death or
euthanasia compared with at first presentation.

Acute phase proteins
Acute phase proteins (APPs) are made in theliver in response to cytokines released frommacrophages and monocytes (especially interleukins 1 and 6 and tumour necrosis factor α)
in many inflammatory and non-inflammatory
diseases.
α1-acid glycoprotein (AGP) is an APP, and its
measurement can be helpful in the diagnosis of
FIP. Although AGP elevations (>0.48 mg/ml)
per se are not specific for FIP, markedly elevated
AGP levels (>1.5 mg/ml) are often seen in FIP
cases. Therefore, the magnitude of the increase
may be helpful in aiding diagnosis of FIP, withhigher levels being more useful in raising theindex of suspicion.53–56 Indeed, a study foundthat when the pretest probability of FIP was high(ie, history and clinical findings supportive of
FIP), moderate serum AGP levels (1.5–2 mg/ml)
could discriminate cats with FIP from catswithout FIP, but only higher serum AGP levels(>3 mg/ml) could support a diagnosis of FIP incats with a low pretest probability of disease (ie,history and clinical findings not supportive of
FIP).55 However, another, albeit very small, studyof unusual cases of FIP found that modest AGP
concentrations (>1.5 mg/ml) were still able todiscriminate between FIP and non-FIP cases.53

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Analysis ofany effusion
sample in asuspected
case of FIP
is extremely
helpful for
diagnosis,
so obtaining
samples of
effusionsshould always
be a priority.

Figure 4 Typical appearanceof effusion seen in cases of
FIP. Effusions tend to beclear, viscous and strawyellow in colour

Serum antibody tests for FCoV are usually
ELISAs, indirect immunofluorescence antibody tests or rapid immunomigration tests.57
Most use CoV-infected swine or feline cells asa substrate and titres are read in distinct
multiples of serum dilutions. A positive FCoV
antibody test indicates that the cat has been
infected with FCoV and has seroconverted(this takes 2–3 weeks from initial infection).
Breed-related differences in median FCoV
antibody titre have been detected, and may
reflect differences in breed response to FCoV
infection.58,59
Although FIP cats tend to have higher FCoV
antibody titres than non-FIP cats, there is muchoverlap, with no difference between median
FCoV antibody titres in healthy and suspected
FIP cats. Therefore, the titre in an individual
animal is of limited use in distinguishing catswith FIP.59 Many clinically healthy cats (especially those in multi-cat households) have positive,
often very high, FCoV antibody titres, while~10% of cats with FIP are seronegative (thiscould be due to the presence of virus in thesample binding antibody and rendering it
unavailable to the serological test),60 highlighting difficulties in interpretation. It may be thata negative FCoV antibody result in a suspected
dry FIP case is more useful to rule out a diagnosis
of FIP;61 however, negative results have beenreported in cases of neurological FIP.62 As aresult, clinicians vary as to whether they perform
serology in suspected cases, although a positive
result certainly indicates exposure to FCoV.

Analysis of effusion samples
Analysis of any effusion sample in a suspectedcase of FIP is extremely helpful for diagnosis,
so obtaining samples of effusions should
always be a priority. Ultrasonography is
generally regarded as being more sensitive
than radiography for the detection of small
volumes of fluid in the thorax and abdomen,
but this may depend on where pockets of fluid
reside. Repeated ultrasonography to identify
any small volume effusion is recommended
and, similarly, ultrasonography can be used to
guide sampling of small pockets of fluid.
FIP effusions (Figure 4) are usually clear, viscous/sticky, straw-yellow and protein-rich (thickeosinophilic proteinaceous backgrounds areoften described on cytology), with a total protein
concentration of >35 g/l (>50% globulins). Veryoccasionally chylous effusions are described.
Typical FIP effusions have similar low A:G
ratios (see above) and raised AGP concentrations
to those in serum. A recent study found that
AGP concentrations (of >1.55 mg/ml) in effusions were more useful (sensitivity and speci-

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R i va l t a ’s t e s t
To perform the Rivalta’s test, 8 ml of distilled water and
one drop of 98% acetic acid (vinegar can be used) are
mixed in a universal pot, and then one drop of effusion
is carefully placed onto the surface of the liquid.
A positive test is indicated by the drop staying
attached to the surface of the liquid, retaining its
shape with a connection to the surface (Figure 5),or floating slowly to the bottom. A negative test isindicated by the drop disappearing and the solution
remaining clear. Interpretation of results can beproblematic due to subjectivity and difficulties in
deciding whether a result is truly positive or negative.63

ficity of 93%) in differentiating FIP and nonFIP cases than AGP levels in the serum orother APPs;56 however, the ‘diagnosis’ of FIP in
the cats in this study was not always confirmedby histopathology and immunostaining.
FIP effusions are poorly cellular (usually <5 x
109 cells/l), and are typically pyogranulomatousin nature with macrophages, non-degenerate
neutrophils and very few lymphocytes. The effusions are therefore often described as modified
transudates based on cell counts (<5 x 109 cells/l)
but as exudates based on protein concentrations(>35 g/l). Rivalta’s test (see box above) is a crude
point-of-care assay that can be performed on aneffusion sample to allow rapid differentiation oftransudate from exudate. A positive result merely means that the effusion is an exudate and thus
is not specific for FIP; positive results are reported in non-FIP cases (eg, bacterial/septic peritonitis and lymphoma).64 Although cytology
can sometimes be successful in diagnosing bacterial/septic peritonitis and lymphoma, to help
discriminate these from FIP, many vets may
not be confident performing cytology in-house.
Serology for FCoV antibodies can also be
performed on effusion samples, with veryvaried results,60,65 so the author does not
perform this test in suspected cases of FIP.
Immunostaining for FCoV antigen and RTPCR for FCoV RNA on effusion samples canalso be performed (see later).

Figure 5 This is a positive
Rivalta’s test as the drop
has retained its shape witha connection to the surfaceof the liquid. A positive result
indicates that the effusion
being tested is an exudate,but is not specific for FIP

Miscellaneous diagnostic tests

In cases with neurological clinical signs, imaging of the brain by MRI may be useful todemonstrate changes. For example, obstructive hydrocephalus, syringomyelia, foramen
magnum herniation and marked contrast
enhancement of the meninges, third ventricle,
mesencephalic aqueduct and brainstem havebeen reported with FIP.42,66,67
Cerebrospinal fluid (CSF) can be collectedfrom neurological cases, although care should betaken as the risk of brain herniation is significant.
CSF may show elevated protein concentrations(>0.30 g/l cisternal samples, >0.46 g/l lumbar
samples; occasionally FIP cats show marked
elevations of >2 g/l) and an increased cell count(>8 x 106 cells/l lumbar and cisternal samples;
FIP cats can have counts of >1000 x 106 cells/l),
with the cell type being predominantly neutrophilic, mononuclear or mixed.42,68 Someneurological cases of FIP have unremarkable
CSF analysis results. Samples of CSF can also
be submitted for RT-PCR for FCoV RNA andimmunostaining for FCoV antigen (see below).

RT-PCR for FCoV

RT-PCR assays
are available
for thedetection of
FCoV; however,they are notspecific for
FIP-associated
FCoVs.

RT-PCR assays are available for the detectionof FCoV; however, they are not specific for
FIP-associated FCoVs. FCoV RT-PCR assays
amplify both cell-associated subgenomic mRNA(short lengths of transcriptional RNA produced
when the FCoVs replicate), as well as cellassociated or virion-associated genomic RNA,
with the relative abundance of each determinedby the positioning of primers (ie, where along the
FCoV sequence the primers bind during PCR).69
As viral transcription starts at the 3' end of the
FCoV genome (Figure 6) there are more subgenomic mRNAs containing viral 3' sequence thanthose containing viral 5' sequence, hence quantitative assays (ie, RT-qPCR) directed at the 5' endof the genome (eg, viral replicase complex genes)
are less susceptible to viral load overestimation
than those directed at the 3' end of the genome(eg, 7a/b non-structural protein genes).

Figure 6 Schematic diagramof the FCoV genome. FCoV
RT-PCR assays detect FCoVRNA. The section of the genome
amplified by different RT-PCRsvaries depending on the positionof the primers used in theassays. As viral transcription
starts at the 3' end of the FCoV
genome, with the production ofmultiple subgenomic RNAs at
this 3' end, PCR assays withprimers located at the 3' endof the genome (eg, in the M or
N regions) will be susceptible
to viral load overestimation asthese will amplify these subgenomic RNAs, as well as the genomic RNA present in the FCoV. Conversely, PCR assays with primers located at the 5' end of the genome(eg, the RNA polymerase) will amplify primarily genomic RNA and will be less prone to viral load overestimation. Assays directed at the 3' end of the FCoV genome will tend
to be more sensitive in detecting the presence of FCoV, due to their ability to amplify both subgenomic and genomic RNA. Coronaviruses, including FCoV, frequently undergo
mutations and recombinations, meaning that PCRs designed to be specific for particular sequences may not amplify all FCoVs. PCRs can be designed to target conserved
regions of the genome to minimise this, but elimination of FCoV sequence variability as a cause of non-amplification is impossible. Modified with permission from Dr Emi Barker

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Laboratories should be able to report thesensitivity and specificity of the RT-PCRs
they are using to detect FCoV RNA, and thebinding site of the primers they use can givesome indication as to whether the assay will
be prone to viral load overestimation (seeabove). As an RNA virus, FCoV shows ahigh rate of errors during replication and any
viral mutations at the site of primer and/orprobe binding can result in loss of PCR assay
efficiency, and ultimately sensitivity. PCR
conditions may be altered to tolerate suchmutations, but this can result in a loss of
specificity.70
The results of RT-PCR for FCoV RNA can bereported rapidly if the laboratory used has
a fast turnaround time; however, once time
taken to submit the sample to the laboratory
is factored in, reporting of results can still take a
few days. This is usually quicker than immunostaining on tissue samples and may be quicker than immunostaining on effusion samples,but immunostaining can provide a definitive
diagnosis whereas RT-PCR does not. Recently
a rapid molecular technique (loop-mediatedisothermal amplification) for detecting FCoVRNA in-house has been described,71 although
it suffered from poor sensitivity.

Which samples can be tested?
RT-PCR can be used to detect FCoV RNA intissue, effusion, blood, CSF or aqueous humour
samples from suspected cases of FIP (see box
below). Tissue samples should not be formalin
fixed, as formalin degrades the target RNA and
can decrease PCR sensitivity; indeed, RNA isvery sensitive to degradation and samples forresearch purposes are often collected into
RNA preservation fluids. However, the needfor special collection conditions for other samples destined for routine diagnostic purposesby RT-PCR is unproven. The presence (particularly of high levels) of FCoV RNA in blood,
effusion, tissue, CSF and/or aqueous humour
samples can be highly supportive of a diagnosis
of FIP but, in the author’s opinion, cannot be
regarded as delivering a definitive diagnosis.
FCoV RT-PCR can also be performed on faecal
samples, but this is primarily used to identify
cats that are shedding the virus for the management of infection in a multi-cat household.
Faecal FCoV RT-PCR is not used to aid in the
diagnosis of FIP, but interestingly recent studies have found that cats with FIP are more
likely to be shedding FCoV,69 and have higher
amounts of FCoV RNA as determined by RTqPCR,29 in their faeces than cats without FIP.

RT-PCR can be used to detect FCoV RNA
in tissue, effusion, blood, CSF or aqueous humour samples
from suspected cases of FIP.
F C o V R T- P C R : h o w d o d i f f e r e n t s a m p l e s c o m p a r e ?
Tissue samples
Tissue samples from cats with FIP are significantly more
likely to be FCoV RT-PCR positive,69 and have significantly
higher FCoV loads by RT-qPCR,29 than tissue samples from
non-FIP cats, although cats without FIP can still be positive
for FCoV by RT-PCR. For example, in a recent extensive
study,69 90.4% of tissue samples from FIP cats were FCoV RTqPCR positive compared with only 7.8% of tissue samples
from non-FIP cats. Not surprisingly, in FIP cats, FCoV loads
tend to correlate with histopathological findings suggestiveof FIP.68,72 Thus, the presence of high levels of FCoV RNA (ie,low threshold cycle values of around <30 using the PCR
assay from Langford Vets Diagnostic Laboratories*) in tissue

samples appears to be highly supportive of a diagnosis of FIP.
Selection of appropriate tissues to sample can be guided
by clinical signs, imaging results and cytological findings(eg, pyogranulomatous inflammation), but non-invasive
collection of such tissue can be difficult. Often laparotomy,
or even laparoscopy, may be considered too invasive toperform in a sick cat in which the index of suspicion of FIP
is very high. Alternatively, ultrasound-guided needle core(eg, Tru-Cut) biopsies may be collectable relatively noninvasively, and a recent abstract73 suggested that ultrasoundguided fine needle aspirates could be a good alternative totissue samples for FCoV RT-PCR analysis.

Effusion samples
Effusion samples are usually obtainable using relatively easy,minimally invasive techniques, especially if a moderate amountof abdominal or pleural effusion is present. Effusion samples
in FIP cases often contain FCoV RNA.72 Recent publishedstudies have amplified FCoV RNA in most (72–89%) FIP effusion
samples but not in any non-FIP effusion samples,74–76 although

one recent study did amplify FCoV RNA, albeit at a low level,in abdominal fluid from one cat (out of a total of 29 control cats)that did not have FIP.69 Overall, as for tissue samples, thepresence of (high) levels of FCoV RNA in an effusion sample
that also has cytological and biochemical features consistent
with FIP appears to be highly supportive of a diagnosis of FIP.

Continued on page 237

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Molecular techniquescharacterising FCoV S genemutations
What techniques can be used?
Following the detection of FCoV RNA by RTPCR, it may be possible to then characterise
targeted sections of FCoV genomic sequences
present in a sample using molecular techniquessuch as pyrosequencing, Sanger sequencing
or PCR with sequence-specific hydrolysis
probes. Such techniques are not always successful; for example, if only low levels of FCoV arepresent (this can preclude sequence analysis) or
if FCoV sequence variability means that targeted sequencing techniques cannot generatesequence results. Characterisation of FCoV
genomic sequences would be most useful if FIPspecific mutations existed, as the detection ofthese mutations would be diagnostic for FIP.
Is mutation analysis useful?
A 2012 paper has described amino acid differences in the fusion peptide encoded by the
FCoV S gene as being markers of FCoVs associated with FIP,26 raising the possibility that
detection of the underlying S gene mutations
could be used to definitively diagnose FIP.
Similarly, amino acid differences in the furincleavage motif, also encoded by the S gene,
have been correlated with FIP disease.28
However, these S gene markers were identified by comparing the sequences of FCoVs

S genemutationanalysisin FCoVs
does notsubstantially
improve theability todiagnose FIP
as comparedwith detectionof FCoValone.

found in the tissues of FIP cats with thosefound in the faeces of healthy non-FIP cats.
Researchers in the author’s group at Bristol
hypothesised that the fusion peptide
sequence mutations could reflect the cellulartropism of the FCoV (ie, systemic monocyte/macrophage-associated FCoV or intestinal
epithelium-associated FCoV) rather thanbeing specific for FIP, knowing that non-FIP
cats can have systemic FCoV infection. They
compared the S gene sequences, from theregion of the previously described fusion peptide mutations, of FCoV detected in the tissuesof FIP cats with those detected in the tissues ofnon-FIP cats.29 This allowed evaluation of the
S gene sequences of FCoVs associated withsystemic FCoV infection in both non-FIP and
FIP cases. They found that the S gene mutations present in most of the FIP tissues werealso present in most of the tissues of non-FIP
cats that had systemic FCoV infection.
A recent, more extensive, study confirmed
these findings, and calculated that if theidentification of S gene mutated FCoVs was
included as an additional confirmatory step tothe detection of FCoV by RT-PCR, this only
slightly increased specificity for the diagnosis
of FIP in tissue samples (from 92.6 to 94.6%).69
Sensitivity was moderately decreased (from89.8% to 80.9%) as non-mutated FCoVs weresometimes identified and mutation analysis
was not possible in all tissue samples (eg, due to
low FCoV copy numbers or the presence of typeContinued from page 236
Blood samples
When FCoV RT-PCR was performed on plasma or serum samples from FIP and non-FIP cats,74,76 none of the non-FIP casesand very few (9–15.4%) of the FIP cases gave positive resultsfor FCoV RNA. A recent experimental study3 also failed to show
any FCoV RNA in the plasma of three FCoV-infected cats overthe first 12 weeks of infection. In another study,72 FCoV RNA
was rarely detected in the blood of 20 FIP cases. Thus, use of
FCoV RT-PCR on blood, plasma or serum samples is not

helpful in the diagnosis of FIP due to low sensitivity.
Peripheral blood mononuclear cells (PBMCs) may be a bettertarget for PCR than serum, as shown in one study,76 but sensitivity was still very poor at 28.6%. Similarly the experimental
study3 on three FCoV-infected cats only infrequently detected
cell-associated FCoV in the blood over the first 12 weeks
of infection; in this study the cells used to determine cellassociated viraemia were not stipulated as being PBMCs.

CSF samples
A recent paper described the use of FCoV RT-PCR on CSF
samples and found it to have 100% specificity for FIP but asensitivity of only 41.2%.77 A study by the author’s researchgroup69 gave similar results. However, not all cats included inthese studies had neurological signs as CSF was collected at
post-mortem examination independent of presenting signs.
Therefore, the population tested may not reflect those cats

Aqueous humour samples
Robust studies have yet to be performed evaluating FCoV
RT-PCR on aqueous humour samples, although positive
results have been reported in cats with FIP.69

that would have had CSF samples collected for diagnostic
purposes. In the aforementioned recent paper the sensitivityof RT-PCR rose to 85.7% when only cats with neurologicaland ophthalmological signs were considered.77 Thus, FCoV
RT-PCR on CSF appears to be a useful additional test in catswith neurological signs, as a positive result is highly supportive of a diagnosis of FIP.

*Langford Vets Diagnostic Laboratories FCoV information:www.langfordvets.co.uk/diagnostic-laboratories/diagnosticlaboratories/pcr-acarus/feline-coronavirus

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2 FCoVs). These results question the value of
S gene mutation analysis over and above thedetection of FCoV by RT-PCR, particularly inview of the extra financial expense and timerequired to perform this additional analysis.
Analysis for S gene mutations has also been
performed on effusions in recently publishedstudies.74,75 The majority of FCoVs in the effusions of FIP cats do indeed have the mutations
described.26 In one study,75 12/17 FCoV-positive
FIP effusion samples had S gene mutations,while one did not have a mutation and four
could not be sequenced due to the low levelsof FCoV present. In another study,74 32/36
FCoV-positive FIP effusion samples had
S gene mutations, while three did not havemutations and one could not be sequenced.
The recent extensive study by the author’sgroup69 calculated that the identification of
S gene mutated FCoVs as an additional step tothe detection of FCoV alone by RT-PCR did notincrease specificity for the diagnosis of FIP in
fluid samples (primarily effusions but also CSF
and aqueous humour) – specificity stayed at
97.9% – but markedly decreased sensitivity(from 78.4% to 60%), for the same reasons as
described for the tissue samples. In this study69
all FCoV-positive samples from cats with FIP had
S gene mutations in CSF samples, while no nonFIP samples were positive for FCoV. Therefore,
S gene mutation analysis in FCoVs does notsubstantially improve the ability to diagnose
FIP in effusion or fluid samples as comparedwith detection of FCoV RNA alone by RT-PCR.

Histopathological examination
Samples of affected tissues, such as liver,kidney or mesenteric lymph nodes, can becollected ante-mortem by ultrasound-guided
percutaneous needle-core biopsy, laparoscopy
or laparotomy, although the invasive natureof collection may preclude this in sick cats.
Samples are often collected at post-mortem
examination following euthanasia due to ahigh index of suspicion of FIP. Samples areevaluated for characteristic histopathologicalchanges of FIP, which, when present, aregenerally regarded as being reliable fordiagnosis. Immunostaining for FCoV antigen isusually also recommended to confirm thediagnosis. However, a lack of histopathologicallesions is more difficult to interpret, especiallyin cases with a high index of suspicion of FIP,
as absence of gross lesions to guide biopsy
could lead to sampling of non-affected organs
or tissue.78 A small study recently documented
that 5/8 FIP cases did not have histopathology
changes typically consistent with FIP, eventhough large representative biopsies weretaken;53 diagnosis in these cases was based on
positive FCoV antigen immunostaining.

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Immunostaining of FCoV antigen
Immunostaining is performed on formalinfixed tissues using IHC, or on cytological(typically effusion) samples using immunocytochemistry (ICC) or immunofluorescence(IF). These techniques exploit the binding ofantibodies to host cell-associated FCoV antigens, which are subsequently visualised byenzymatic reactions producing a colourchange (ICC) or by fluorescence (IF).
Positive FCoV antigen immunostainingof tissues is said to confirm a diagnosis of
FIP (ie, it is very specific); a negative result,however, does not exclude FIP as a diagnosis
as FCoV antigens may be variably distributed
within lesions78 and thus are not detected
in all histopathological sections preparedfrom lesions from FIP cases.30 This somewhat
contradicts the suggestion by some that
immunostaining is mandatory to confirm/
exclude FIP in doubtful cases,53 though the
problem may be overcome by taking multiple
and/or large samples with confirmed pathology, as well as possibly requesting additional
sections of biopsies with pathology to be cut
and stained.
Immunostaining of effusion samples has
shown variable sensitivity (ranging from
57–100%).79–84 Since this technique relies on
staining FCoV antigen within macrophages
in the effusion, and the effusion is often
cell-poor and/or the FCoV antigen is masked
by FCoV antibodies in the effusion, a false
negative result may be obtained. Immunostaining was thought to be very specific;
however, two (heart failure and cholangiocarcinoma cases) of seven non-FIP effusions
were positive by IF in one study,82 and eight(including two cats with heart failure andtwo cats with neoplasia) of 29 non-FIP
effusions were positive by ICC in another,79
raising questions about the specificity of ICC.
The reported poorer specificity may be
due to the methodology used in one study(ie, double staining for both FCoV antigen
and macrophages [via major histocompatibility complex II staining] was used), and thesuboptimal storage of slides in the other,which could cause non-specific staining andfalse positive results. Some have suggested
that using cell pellets produced from centrifuged effusion samples to prepare formalinfixed, paraffin-embedded samples that canthen be treated like a tissue specimen for IHC,
can improve the reliability of detection of
FCoV antigen,30 although the processing
time required for this would be longer thanfor ICC.
FCoV antigen ICC staining has been reported as being successful in detecting FCoVin the CSF of a cat with neurological FIP.85

Positive FCoV
immunostainingof tissues
is said toconfirm adiagnosis of
FIP, but anegative result
does notexclude FIP.

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A recent study evaluated ICC in the CSF(collected at post-mortem examination) ofcats with and without FIP that presented
with and without neurological signs.86
This study found that 17/20 cats with
FIP gave positive results, as did 3/18 catswithout FIP, limiting the test’s specificity,although methodology may again have been
an issue. These analyses excluded cases
in which cellularity was inadequate for ICC
to be performed. Application of ICC to CSF
samples collected ante-mortem from a larger
number of cats with neurological signs due
to FIP and non-FIP causes would be desirable
to further evaluate the usefulness of thistechnique.
The use of FCoV antigen immunostaining
has recently been described in aqueous
humour samples collected at post-mortem
examination from cats with and without FIP.87
The study evaluated FCoV ICC in aqueous
humour samples from 25 cats with FIP(interestingly the majority were effusive FIP
cases, and did not present with uveitis) and 11
non-FIP cats. A sensitivity of 64% and specificity of 81.8% were demonstrated. Positive
results were obtained in two of the 11 control
cats, one with lymphoma and one withpulmonary adenocarcinoma; neither hadaqueous humour cytological features consis-

KEY points< Look for features that could be suggestive of FIP in the history
and on clinical examination: young cat, originally from a multi-cat
household (including shelters or catteries), fluctuating non-responsive
pyrexia, evidence of an effusion, and ocular or neurological signs.

< Look for a lymphopenia on haematology.

< Look for hyperglobulinaemia, hyperbilirubinaemia (in the absenceof moderate to severe increases in ALT and ALP enzyme activity,
or anaemia), a reduced A:G ratio and elevated AGP(>1.5 mg/ml) on serum biochemistry.

< Prioritise finding and sampling any effusion, whether pleural, peritonealor pericardial in type. Effusions due to FIP are typically clear, viscous,
sticky and straw-yellow, with a total protein concentration of >35
g/l and a low A:G ratio of <0.4. AGP concentrations can also beraised as in the serum. FIP effusions are poorly cellular (usually<5 x 109 cells/l) and typically pyogranulomatous in nature.

< Be aware of the value and limitations of currently available tests

in achieving a definitive diagnosis of FIP. In particular:– Demonstration of FCoV antigen by immunostaining in effusions
or biopsies, in association with typical cytological or histopathologicalfeatures of FIP, provides for a definitive diagnosis of FIP.
– Detection of FCoV RNA by RT-PCR, especially if present at highlevels, in diagnostic samples such as effusions, CSF andbiopsies, is highly supportive of a diagnosis of FIP.
– Detection of FCoV spike gene mutations following
a positive FCoV RT-PCR result does not appear tooffer additional information for the diagnosis of FIP.

tent with FIP (pyogranulomatous inflammation). Being able to use aqueous humour for
reliable diagnostic investigations in cases of
FIP would be especially valuable as it would
be possible to collect this in non-effusive
cases, although the sample collection technique used in this study would need to bemodified (eg, smaller gauge needle) for use
ante-mortem. Further evaluation of ICC on
aqueous humour samples collected antemortem from cats with uveitis due to FIP and
non-FIP causes would be helpful to further
evaluate the usefulness of this technique.
It is possible that fine needle aspirates could
also be used as samples for FCoV antigen
immunostaining, but sensitivity may be poor
due to difficulties in targeting lesions. Further
studies would be necessary to evaluate theirutility in the diagnosis of FIP and no evidence
currently exists to support this.

Acknowledgements
ST would like to acknowledge the many contributions made by the University of Bristol Feline
Coronavirus Research Group and Bristol-Zurich
FIP Consortium to the viewpoints and discussions
described in this review. Special thanks go to
Emi Barker and Samantha Saunders for theirhelpful comments on this manuscript, and to
Jacqui Norris and Anja Kipar for helpful
discussions on FCoV antigen staining. Andrew
davidson, Anja Kipar and Stuart Siddell arealso thanked for their valued contributions topast and current FCoV research. Additional thanks
go to the veterinary practices, cat owners, cat
breeders and rescue centres that helped in theacquisition of samples used in these researchstudies and to colleagues, current and past, at theFeline Centre and Veterinary Pathology Unit,
Langford Vets, University of Bristol, who haveassisted in obtaining samples.

Conflict of interest
ST is a member of the World Forum for Companion
Animal Vector Borne diseases, supported by Bayer
Animal Health, and of the European Advisory
Board on Cat diseases, supported by Boehringer
Ingelheim. She also does work for the Moleculardiagnostic Unit, Langford Vets, University ofBristol.

Funding
ST receives financial support for current infectious
disease research from BSAVA Petsavers, Journal ofComparative Pathology Educational Trust, Langford
Trust, Langford Vets Clinical Research Fund,
Morris Animal Foundation, NERC/BBSRC/MRC,
Petplan Charitable Trust, South West BiosciencesdTP and Zoetis Animal Health.

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Case notes
Hector, a 3-year-old
castrated Ragdoll, presented
with a 4 week history of
progressive lethargy andreduction in appetite,with severe inappetence
and a non-responsive
pyrexia documented
over the past week.

Sampling of abdominal lesions Abdominal
ultrasonography was repeated and attempts were madeto take fine needle aspirates of the abdominal masses.
This was difficult as the masses were highly vascularised –but samples were taken of the lymph node. Cytology revealed
the presence of lymphocytes, neutrophils, plasma cells andmacrophages, although some of these cells could have been
blood derived. Ziehl–Neelsen (ZN) staining of the cytologicalsamples was negative.

Clinical examination Mild dehydration with slight pallor was

SPE This confirmed the hypoalbuminaemia and showed
the presence of a polyclonal elevation in γ-globulins.

noted. Chest auscultation was unremarkable. The cat was
pyrexic at 40oC. A non-painful but large nodular mid-abdominal
mass was palpable; it felt quite mobile. No other abdominal
abnormalities were noted. Peripheral lymph nodes were normal.

SPE

Haematology A mild non-regenerative anaemia,
monocytopenia and eosinopenia were present. The lymphocyte
count was normal.

Serum biochemistry Hypoalbuminaemia (20.4 g/l;
reference interval [RI] 24–35) and hyperglobulinaemia(69.3 g/l; RI 21–51), with a markedly reduced A:G ratioof 0.29, were present. Liver parameters, including bilirubin,were normal. A mild hypokalaemia was recorded.

Imaging Abdominal
ultrasonography
revealed multiple
thickening of, andlesions in, an area ofthe small intestine andassociated lymph nodes.
(left) Thickened small
intestine; (below) enlarged
jejunal lymph node

0

10

(mm)

20

30

AGP Levels were markedly elevated at 2.15 mg/ml (RI ⩽0.48
mg/ml, with FIP cases usually having values >1.5 mg/ml).
Decision making Hector’s signalment, history, serum
biochemistry, SPE and AGP findings were all consistent witha diagnosis of FIP. The cytology of the lymph node was also
supportive. On the day following admission, Hector becamemuch duller and the pyrexia remained. Differential diagnoses
were discussed with the owner who elected euthanasia inview of Hector’s condition and the likely diagnosis of FIP.
Mycobacterial infection was also considered as a differential
diagnosis but Hector was an indoor cat, not a hunter,and the ZN staining had been negative.

Post-mortem examination Post-mortem examination
Slight hepatomegaly
was found, but withnormal hepatic
echogenicity, anda left chronic renal
infarct. Chest
radiography revealed
only mild sternal
lymphadenopathy.

Ophthalmic and neurological examinations These
were normal.

Initial management Systolic blood pressure was low at
95 mmHg on admittance, and this, together with the presenceof dehydration, necessitated administration of intravenous
fluid therapy (IVFT), which corrected the dehydration andnormalised blood pressure. Urinalysis, performed on urine
taken after the start of IVFT, was largely unremarkable.

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revealed a large mass involving the jejunal lymph nodes(centered around major blood vessels) and also the small
intestine. These findings were consistent with focal FIP or
mycobacterial infection. Histopathology of sections of the mass
showed severe necrosis and fibrosis, with a mixed inflammatory
cell infiltrate in the wall of the intestine and areas of mucosal
ulceration and extension
into the serosa. Similarareas of severe necrosis,
fibrosis and inflammation
were evident in thelymph node mass. IHC
for FCoV antigen in thesections was strongly
positive. A diagnosis of
focal dry FIP was made.
Mass visible on
gross post-mortem
examination

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