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Feline infectious peritonitis (FIP) treatment

Diane D. Addie PhD, BVMS, MRCVS

www.catvirus.com

22 Feb 2018

IMPORTANT NOTICE

Prior to even considering treatment for feline infectious peritonitis (FIP) you

absolutely MUST ensure that the cat really does have FIP. At time of writing, FIP

treatment is mainly immunosuppressive and immunosuppression of a cat with an

infection other than FIP will kill the cat.

Do a FCoV antibody test: provided the test is sensitive enough, a negative result will rule out

FIP. Addie et al, 2015

You can find out which FCoV antibody tests are recommended (and which

ones are useless) at www.catvirus.com/FCoVantibody.htm.

A major differential of FIP is toxoplasmosis: run a toxoplasma antibody test in at-risk cats, for

example those with access to outdoors or who are fed butcher meat. However a positive FCoV

antibody test does NOT confirm FIP.

PREVENTION IS BETTER THAN CURE It is my hope that by the time you have listened to this webinar you will have understood the complexity

of the disease that is FIP. In many other diseases, the destruction of the invading pathogen, by antivirals

or antibiotics, results in the cure of the patient, but FIP is a disease involving the very complex immune

response of the cat. If we don’t completely understand the pathogenesis of FIP how can we hope to fix

it? And the disease isn’t a fixed target, it changes, the pathology changes throughout the infection. FIP

is slightly different in every individual so treatment needs to be tailored to that individual patient: it is

not a case of one size fits all. Therefore it is my view that prevention of FCoV infection is preferable to

an attempt to cure, and prevention can be achieved by hygiene and education.

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PATHOGENESIS OF FIP Due to the slowness of my internet connection I am unable to incorporate some of my important videos into the lecture: please do watch them – they can be counted as CPD.

Please watch my animation of FCoV transmission on

http://www.youtube.com/watch?v=rkqUjeQNEQs

Please watch my animation of FIP pathogenesis on http://www.youtube.com/watch?v=6RyI2LI9R9Q&feature=related

In brief, feline infectious peritonitis (FIP) is the result of an excessive inflammatory response to

infection with feline coronavirus (FCoV). FCoV transmission is indirect, from contact with virus in

faeces, usually from a shared litter tray or via fomites on a litter scoop, brush, floor, etc. The virus is

ingested, is believed to replicate first in the epithelial cells of the small intestine, it undergoes a brief

viraemia, Porter et al, 2014

then is shed from the ileum and colon Herrewegh et al, 1997

into the faeces. In around

90% of cats, virus shedding lasts for a few months in type I FCoV infection, Addie & Jarrett, 2001

and

approximately 2 weeks in type II FCoV infection. Stoddart et al, 1988

In a minority of cats the virus is able to

hijack the monocyte and replicate within it. Regardless of the pathogenicity of the coronavirus infecting

it, the monocyte controls the amount of viral replication within it. Dewerchin et al, 2005

The key cell in the pathogenesis of FIP is the monocyte / macrophage. FCoV-infected

monocytes/macrophages release matrix metalloproteinase (MMP) 9; Kipar et al, 2005

tumour necrosis factor

(TNF)-α; Kipar et al, 2005;

Takano et al, 2007a & 2009

interleukin (IL) -1β and IL-6,Goitsuka et al, 1990

. MMP-9 allows

the extravasation of FCoV-infected monocytes. TNF-α is a major contributor to the inflammatory

response and pathogenesis of FIP. TNF-α is very likely the cause of the lymphopenia seen in FIP. Takano

et al, 2007b TNF-α upregulates fAPN (the receptor for type II FCoVs)

Takano et al, 2007a and, along with GM-

CSF and G-CSF which are also produced by FCoV-infected monocytes, is a neutrophil survival factor. Takano et al, 2009

In later infection, TNF-α production shifts from macrophages to lymphocytes. Dean et al, 2003

Chronic over-production of TNF-α results in cachexia.

In early infection, IL-6 stimulates hepatocytes to release acute phase proteins (such as alpha-1 acid

glycoprotein, AGP). Hepcidin is a type 2 acute-phase protein and iron regulatory hormone which

inhibits iron export from the gut and macrophages by binding to ferroportin: hepcidin is produced

mainly by the liver in response to IL-6. IL-6 causes B lymphocytes to proliferate and differentiate into

plasma cells. Takano et al, 2007b

It is likely that high IL-6 levels found in cats with FIP are the cause of

hypergammaglobulinemia. IL-6 can be pro-inflammatory or anti-inflammatory.

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From this brief synopsis, it is apparent that FIP treatments fall into one or more categories:

Treatment strategy Examples

Anti-virals GC376

Feline interferon omega (Virbagen Omega, Virbac)

Human interferon

Cyclosporin A

Support the monocyte /

immune system

Arginine: i.e. real meat daily

Feline interferon omega (Virbagen Omega, Virbac)

Polyprenyl Immunostimulant (Sass and Sass)

Anti-inflammatories and

immunosuppression

Corticosteroids e.g. prednisolone

Meloxicam (Metacam, Boehringer Ingelheim)

Cyclosporin A

Thalidomide

Targeted modification of the

immune response Anti-TNF-α (metronidazole); anti-TNF- α antibodies (e.g.Infliximab)

? Anti-IL-6 antibodies (e.g. Siltuximab)

? Curcuma longa (turmeric)

? anti-MMP-9 (e.g. doxycycline)

Counteract FIP anaemia Erythropoietin

Erythropoietin was added to this list because non-regenerative anaemia is a consequence of FIP: see

notes on anaemia below.

FIRST STEP TO TREAT EFFUSIVE FIP: DRAW OFF THE EFFUSION! Abdomino- or thoraco-centesis will also physically remove virus-infected cells which are a source of

pro-inflammatory cytokines. Drawing off the effusion will immediately make the cat more comfortable,

especially in thoracic effusive FIP where the cat will be able to breathe better. Remember that the cat

has an intact mediastinum, so you will need to draw effusion off from both sides of the thorax. While

you have the needle in place you can administer feline interferon omega directly to the site of the virus

infection. Effusion can often be removed with minimal restraint and without sedation: in fractious cats,

clipnosis can be attempted: put bull clips or clothes pegs onto the scruff of the neck – the cat will often

go limp for some minutes. Pozza et al, 2008

The effusion should be sent for FCoV RT-PCR to confirm the diagnosis of FIP.

TREATMENT PROTOCOLS AND DOSES OF COMMONLY AVAILABLE DRUGS Remember to get clients to sign an informed consent form when using drugs off-label.

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ANTI-VIRALS

INTERFERONS

Interferons work best administered as closely as possible to the site of infection.

Recombinant feline interferon omega (Virbagen Omega,® Virbac, France)

Feline interferon omega is an alpha interferon and can resist stomach acid. Once a vial is reconstituted, it

will keep for up to 3 weeks at 4oC, or up to 6 months in a freezer.

Dose for effusive FIP: 1 MU*1/kg every other day, and then twice a week for however long it takes

until recovery is obtained or until death administered initially into the abdominal or thoracic cavity (i.e.

the site of the effusion) or subcutaneously.

Dose for non-effusive FIP: 100,000 Units of feline interferon omega per day per os

Diluting Virbagen Omega Virbagen Omega (VO) comes in vials of 10 million units. It should be reconstituted with 1ml of diluent.

Using 10 x 1ml insulin syringes withdraw 0.1ml into each of ten 1ml syringes: you now have 1 MU of

VO per syringe. Freeze 9 of the syringes in a baggie (they will last up to 6 months in the freezer).

Put 1 syringe content (0.1ml) of reconstituted VO IFN (which now has 1 million units of VO) into 4.9

mls of saline or water: this gives you 100,000 units per half ml. Give the cat 0.5 mls of the mixture

daily on food, or gently squirted into the side of the mouth at the commissure of the lips, with the head

gently tilted backwards to encourage swallowing. This diluted mixture will last up to 21 days at 4oC.

Human interferon alpha Interferons are species specific which is why it’s better to use feline interferon than human interferon.

However, the human one is all that’s available in some countries.

Dose: Non-effusive feline infectious peritonitis (FIP): 30 i.u./daily or for 7 days at alternate weeks given

by mouth.

In effusive FIP 30 i.u./daily can be used, or larger doses of interferon can be given by intramuscular

injection daily (104 –106 i.u. per day). By 6–7 weeks, if the cat is still alive, interferon will no longer

work at this dose because the cat will make antibodies against it.

To obtain human interferon-alpha write a prescription for your local pharmacist. Obviously, in areas

where feline interferon is available it is preferable as it is likely to have more effect than the human

interferon.

GC376

Some cat guardians want to go beyond what is currently available and seek the newest possible

treatments. At present, this usually manifests as a request for treatment of their pet with GC 376: at time

* MU = Million units

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of writing (February 2018) there are no clinical trials of this drug ongoing. Updates on its progress are

available on www.sockfip.org.

SUPPORT THE MONOCYTE / MACROPHAGE AND THE IMMUNE SYSTEM

FEED REAL MEAT TO GIVE THE CAT ARGININE

Key message: do NOT give L-lysine to a cat with FIP

Arginine is an essential amino acid in the cat: Morris and Rogers, 1978

necessary for effective function of both

the urea cycle and the monocyte / macrophage. Give real meat daily to augment arginine levels: even

just a tablespoonful a day will make a difference. Or regularly use commercially available real meat

based cat foods such as Applaws & Almo Nature (available from the Zooplus website in Europe: use

Zooplus link on the catvirus website links page to obtain a discount).

POLYPRENYL IMMUNOSTIMULANT – FOR TREATING NON-EFFUSIVE FIP ONLY

There has been no placebo-controlled clinical trial of PPI in cats with FIP published, and a major

problem with the recent publication by Prof. Legendre was that FIP was not diagnosed beyond

reasonable doubt in the 60 cases described. Legendre et al, 2017

I am keen to amass independent data on FIP

treatment using PPI and would love to hear from veterinary surgeons using it: my email address is

draddie@catvirus.com.

PPI is a treatment for non-effusive FIP; it is not recommended in effusive (wet) FIP. PPI is used off-

label in FIP treatment.

Survival was better in cats not concurrently treated with systemic corticosteroids, but it is probably safe

to use topical ophthalmic corticosteroid treatment along with PPI in cats with intra-ocular signs of non-

effusive FIP. Legendre et al, 2017

UK veterinary surgeons will need to apply to the VMD for special import permission.

To obtain PPI: email orders@vetimmune.com, or visit www.vetimmune.com.

Dose: 3.0 mg/kg orally of Polyprenyl Immunostimulant three times a week.

ANTI-INFLAMMATORIES AND IMMUNOSUPPRESSION Cats receiving immunosuppressants should also receive antibiotic cover to protect them against

secondary infections (see section below on Antibiotics). Do a toxoplasma antibody test to determine

whether there is a risk of activating toxoplasmosis by immunosuppressing the cat: if so, use clindamycin

for 4 weeks. Warn the cat’s guardian that latent FHV could also recrudesce.

CORTICOSTEROIDS given to both effusive and non-effusive* FIP cases

*unless the cat is being treated with Polyprenyl Immunostimulant (PPI). Systemic corticosteroids are contraindicated in non-effusive FIP cases being treated with PPI, although topical corticosteroids can be used in ophthalmic preparations. Legendre et al, 2017

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Prednisolone Prednisolone is the main anti-inflammatory / immunosuppressant used in feline infectious peritonitis

therapy, though unfortunately it suppresses both the humoral and cell-mediated immune response. It is

possible that we should be using an anti-inflammatory, rather than an immunosuppressive dose,

especially in effusive FIP, whereas in non-effusive FIP the immunosuppressive dose makes more sense.

2 mg/kg/sid is the high end of an anti-inflammatory dose and low end of immunosuppressive dose.

Trepanier, 2015

Prednisolone should never be used in cats with toxoplasmosis, or septic peritonitis or pleurisy, which is

one reason why cytology of the effusion is a very important part of FIP diagnosis, as there will be many

more white blood cells in the effusion of a cat with sepsis, and a good cytologist will detect the bacteria

or fungi. If in doubt, send the effusion for bacterial culture.

Dose: 1-2 mg/kg/ sid given by mouth, halving the dose every 10-14 days, right down to 0.5 mg/kg every

other day or until an optimal dose for that cat is found (this will be the dose at which alpha-1 acid

glycoprotein (AGP) levels have reduced to, and remain at, normal. (See the section below on monitoring

treatment.)

Prednisone is not recommended in cats: it is not as effective as prednisolone. Trepanier, 2015

Dexamethasone / injectable corticosteroids Dexamethasone (or other injectable corticosteroids) can be used to kick start the immunosuppressive

treatment (or for cats which cannot be pilled). It can also be administered directly to the site of

inflammation in effusive FIP cases.

Dose: dexamethasone 1 mg/kg intrathoracic or intraperitoneal injection on one occasion or every 5 days.

MELOXICAM (METACAM, BOEHRINGER INGELHEIM)

Provided kidney function and blood pressure are normal, consider using the non-steroidal anti-

inflammatory meloxicam instead of corticosteroids. Meloxicam was used for 119 days, along with one

month of metronidazole, in one FIP case report in a cat who survived 787 days. Hugo and Reading, 2015

Dose: 0.05 mg/kg BW, PO, q24h

CYCLOSPORIN A

Has anti-FCoV and immunosuppressant activity.

Use only in cats with toxoplasma antibody titres of zero or give concurrent clindamycin treatment.

Warning: if you give CsA to a FCoV-infected healthy, or diarrhoea-only, cat, you WILL induce

FIP. Only use with extreme caution.

Dose: start at 75 mg/cat/day

reduce to 50 mg/cat/day

reduce to 25 mg/cat/day

THALIDOMIDE

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The rationale of using thalidomide instead of corticosteroids in the treatment of feline infectious

peritonitis is to reduce inflammation and the humoral immune response to feline coronavirus while

leaving the cell mediated (anti-viral) immune response intact. Thalidomide is actually a very safe drug.

Be sure to obtain the owner's consent for using a drug not licensed for cats.

Dose: 50-100mg at night. DO NOT USE IN PREGNANT CATS as it is teratogenic.

ANTIBIOTICS Antibiotic cover is essential when immunosuppressing a cat, with either high dose corticosteroids,

cyclosporin A or anti-TNF-alpha antibodies. Your choice of antibiotics will largely depend on what

your major differential diagnoses are, given the presenting clinical signs. For example, if you are

awaiting FIP confirmation from your laboratory and your major differential diagnoses are

toxoplasmosis, or bacterial peritonitis / pleurisy, then clindamycin (Antirobe) will be your antibiotic of

choice because it covers both aerobic and anaerobic infections; if your major differential is infectious

anaemia, then doxycycline or oxytetracycline will be your choice. Sub-antimicrobial doses of

tetracyclines have anti-MMP activity, which means that they might be a good choice in early effusive

FIP treatment. However, doxycycline should not be used in healthy FCoV carrier cats, at least until

further information becomes available, because doxycycline inhibits interferon-beta and was shown to

increase shedding of the pig coronavirus, transmissible gastroenteritis virus, in vitro. Xing et al, 2017

The most commonly used antibiotic in cats in the UK is cefovecin (Convenia, Pfizer) because of

difficulty in administering pills to cats. Singleton et al, 2017

Cefovecin may be a good choice but I have not

found any publications on its effect on the immune system, although there is a record of it having been

used, along with many other drugs, in FIP in one case report. Hugo and Reading, 2015

It has the advantages of

being administered by a veterinary surgeon, so there is no problem with owner compliance/ability to

dose the cat, and there is no risk to the oesophagus.

A few studies reported that amoxicillin/clavulanic acid (Synulox) can decrease IFN gamma, which is

essential for FIP survival, although those studies were based on laboratory experiments. Brooks et al, 2003;

Padovan et al, 1999 A study in healthy human volunteers showed no interference with IFN gamma.

Dufour et al,

2005

Metronidazole is effective against anaerobic organisms, so is a good choice where bacterial pleurisy is a

differential diagnosis. It inhibits TNF-alpha—i.e. is anti-inflammatory—and was used for one month,

along with meloxicam, in one FIP case who survived 787 days. Hugo and Reading, 2015

However, it is

horrible to taste and can be difficult to administer to cats.

Where antibiotics are used, probiotics should also be given to replenish the microbiome and avoid

overgrowth by pathogenic gut bacteria: my choice is Swanson's Lactococcus rhamnosus - one capsule

per day mixed into food or drink. We have cultured capsules of these in our laboratory at Glasgow and

verified that they contain what is claimed. The Protexin from Australia is also very good but

unfortunately not very palatable:

www.pets-megastore.com.au/protexinprobioticpowder250gms-p-1733.html

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ERYTHROPOIETIN When a cat with FIP has a decreasing rbc count with no evidence of regeneration, then use

erythropoietin, preferably while the Hct is still in the twenties: when it gets lower than 20, it may be too

late.

Dose: A 0.2 ml darbepoetin s.c. injection (0.5 micrograms/kg) given twice weekly to be gradually

reduced, depending on PCV.

This is based on Chalhoub's paper quoting a weekly dose of 1 microgram/kg/week. Chalhoub et al, 2012

FIP PROGNOSIS Cats with effusive FIP usually die more quickly than those with non-effusive FIP: the median survival

time for 33 cats with effusive FIP was 21 days (± 20 days) in one study, Tsai et al, 2011

and 9 days in another

study of 36 cats. Ritz et al, 2007

The cats in the latter study were subjected to biopsy and the additional stress

may have adversely affected their survival time. Ritz et al, 2007

They also received amoxycillin/clavulanic

acid which was reported to decrease interferon-gamma: a key cytokine in FCoV/FIP survival. In

addition the authors of that study surmised that their failure to taper the immunosuppressive doses of

corticosteroids predisposed to secondary infections which led to the deaths of 5 cats. Ritz et al, 2007

Concurrent systemic corticosteroid administration was also noticed to decrease the survival of cats in a

PPI study. Legendre et al, 2017

Cats with thoracic effusion seem to fare better than cats with an abdominal effusion. Cats treated with

Virbagen Omega have been documented as surviving 18 months or more. Ishida et al, 2004; Gunn-Moore & McCann,

2004

In a recent therapeutic study of 60 cats with a presumptive diagnosis of non-effusive FIP, 20%

survived over 200 days: survival varied with sub-type of disease, the most severe being neurological

signs, where mean survival was 38.8 days. Legendre et al, 2017

The manifestation of non-effusive FIP with

the best prognosis appears to be mesenteric lymph node adenopathy as the key clinical finding.

Staging for effusive FIP prognosis to help you to assess whether treatment has a chance of helping or not In this staging system shown in the table below the severity of effusive FIP can be worked out, which

will give you an idea of whether or not it is worth obtaining special drugs to treat, or whether it is

worthwhile continuing treating a case. Look at the parameter in the left hand column, then look at

where the result of your case falls in the range, then put the score for that parameter into the next free

column in the grey shaded cells. Finally work out the total score for your case. An excel file of this table

can be downloaded at http://www.catvirus.com/downloads.html: the total score will automatically fill in

the cell at the bottom. A video of using this table can be found at https://youtu.be/F6FXcWgEZxU.

Interpreting the total score for your case:

0-4: survival time more than 2 weeks

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5-11: survival time less than 2 weeks

over 12: survival time less than 3 days

While this isn’t an absolutely exact predictor, it does give a ballpark indicator of prognosis.

Remember that even giving the cat a few more days can help the cat’s guardian come to terms with the

imminent demise of their pet: corticosteroids don’t cost much and will help ease those last days. Draw

off the effusion to make the pet more comfortable. FIP doesn’t seem to be a painful condition.

Parameter Range Score Your

case date

Your

case date

Your

case date

PCV

(%)

>26

20 – 26

<20

0

2

4

AST

(U/L)

<150

150 – 300

>300

0

2

4

Total bilirubin

(mg/dl)

[umol/L]

(< 0.5) [<8.5]

(0.6 – 2.2) [ 9 – 38 ]

(> 2.2) [ >38 ]

0

2

4

Potassium

(mmol/L)

4.0 – 5.8

3.0 – 3.9

< 3.0

0

2

4

Sodium

(mmol/L)

156 – 165

150 – 155

<150

0

2

4

Total

This table is adapted from that of Tsai et al, 2011. It can be downloaded from the catvirus.com Downloads page and I hope to have a video of using it in the FIP treatment page of the website and it can be seen here:

https://youtu.be/F6FXcWgEZxU.

FIP AND ANAEMIA For FIP treatment to be effective, the causes of the anaemia associated with FIP need to be elucidated

and treated. Commonly two types of anaemia are observed in FIP cases: non-regenerative anaemia,

assumed to be that of chronic disease, and acute haemolytic anaemia: the latter causing the death of

many cats with FIP. Riemer et al 2016

documented anaemia (defined as a packed cell volume less than

30%) in 106 of 200 cats with FIP, with 21 having a Hct of 20% or less. Tanaka et al 2015

cited anaemia

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as the cause of death in 2 of 3 cats treated with Cyclosporin A. Tsai et al 2011

noted that a fall in Hct

heralded the imminent demise of the patient. Anaemia has been reported as a side effect of interferon

treatment in humans, but Tsai et al 2011

found that anaemia occurred equally in groups of cats treated and

not treated with interferon.

Non-regenerative anaemia of chronic inflammation I believe that FCoV/FIP could be one of the unrecognised and under-diagnosed causes of severe non-

regenerative anaemia and haemolytic anaemia in FeLV-negative cats. In a retrospective study of 180

cats with anaemia, FIP was diagnosed in only 17 Korman et al, 2013

but likely was not tested for in most cases

(S. Tasker, personal communication). The reason that the anaemia of FIP has not been given more than

a passing comment previously might be because feline red blood cells circulate for approximately 73

days, White & Reine, 2009

which is longer than most cats with effusive FIP survive. Few reported cases

survive beyond the two-month time-point and the reason for this could be that cats with FIP simply run

out of erythrocytes as a consequence of FIP-induced erythroid bone marrow suppression. The survival

of many cats with FIP might be increased if the bone marrow suppression could be reversed. Tanaka et

al 2015

described one case, treated with Cyclosporin A, where a single treatment with erythropoietin at

around day 60 post-diagnosis reversed the trend of declining Hct and the cat survived another 200 days,

by which time she was 15 years old.

In many cases of FIP there are many pyogranulomata in the kidney cortex, thus another mechanism

which may be involved in the anaemia of FIP could be lack of erythropoietin causing erythroid

hypoplasia/aplasia. Chalhoub et al 2012

treated a cat by kidney transplant and darbopoietin: the cat

survived another year, although it was unclear whether FIP was the cause of the kidney failure or if it

developed due to the immunosuppression following transplant.

The simple inability to synthesise red blood cells does not seem to fully explain FIP-associated anaemia.

White and Reine 2009

stated “Cats tend to develop anaemia of inflammatory disease within two to three

days of the onset of the inflammatory process, and the haematocrit drops by an average of 8%.” The

feline erythrocyte lasts around 73 days, so with non-regenerative anaemia one would expect Hct to fall

by approximately 10% in a week: if it falls more than that in a FIP case, check a blood smear for signs

of immune-mediated haemolytic anaemia: acanthocytes and schistocytes which suggest a degree of

mechanical trauma to red cells. Check for rising bilirubin levels although normal bilirubin levels have

been reported in cats with immune-mediated haemolytic anaemia. Swann et al, 2016

Macrophages are widely distributed in peripheral tissues where they play a crucial role in the defence

against pathogens. This is achieved, at least partially, through the control of intracellular iron

availability, which limits pathogen growth. Gan et al, 2017

Macrophages also play a key role in body iron

homeostasis by recovering iron from effete red blood cells and returning it to the circulation. Gan et al ,2017

M1 polarised macrophages, deal directly with microbes at sites of infection and are pro-inflammatory,

releasing high levels of tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Retention of iron

in M1 macrophages reduces circulating iron levels and thus the availability of this essential nutrient for

extracellular microbes. This also limits the amount of iron available for erythropoiesis, a mechanism

involved in anaemia of inflammatory disease. Gene expression analysis of M1 macrophages showed a

high level of ferritin, associated with iron storage, and a low level of ferroportin, associated with iron

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export. Compared to unstimulated macrophages, transcriptional changes were also noted in hepcidin and

transferrin receptors, both iron regulators which favour iron sequestration in the reticuloendothelial

system. Gan et al ,2017

In contrast to M1 cells, M2 polarised macrophages are anti-inflammatory and have

an iron-release phenotype mediated through an elevated expression of ferroportin. Kramyl, 2017

Microcytosis, which occurs in iron deficiency, was noted in 35% of 188 cats with FIP, of which many

were not yet anaemic. Riemer et al, 2016

Macrophages loaded with iron lose their ability to kill intracellular

pathogens such as Salmonella, Mycobacterium, Chlamydia, and Legionella by IFN- -mediated

pathways . Gan et al ,2017

Presumably, their ability to deal with intra-cellular coronaviruses is similarly

inhibited, thus sequestration of iron in macrophages is doubly hazardous for the cat with FIP, both

leading to anaemia and reducing the macrophage’s ability to destroy the virus.

Immune-mediated haemolytic anaemia The second type of anaemia seen in FIP, acute haemolytic anaemia, is less common but more acutely

fatal. Norris et al 2005

reported 2 of 42 cats with FIP dying of acute haemolytic anaemia and an acute

anaemic crisis leading to euthanasia 7 weeks post-diagnosis has been encountered previously in a FIP

case treated with adipose stem cell therapy (Andy Armitage, personal communication) and in a non-

effusive FIP cat within 4 weeks of onset of clinical signs. Three (2.8%) of 107 cats with immune-

mediated haemolytic anaemia (IMHA) had FIP, 35 of 107 cases had secondary IMHA Swann et al, 2016

and

3 of those cats had FIP, thus 8.6% of secondary IMHA was due to FIP (J. Swann, personal

communication). Tsai et al 2011

noted that all of 51 cats with FIP were moderately to severely anaemic

prior to death. Falling Hct, rising bilirubin and AST were found to be adverse prognostic signs, all being

parameters indicative of intravascular haemolysis. However, Riemer et al 2016

found that only 38 of 109

cats (35%) with hyperbilirubinaemia, but without raised liver enzymes, were anaemic. Raised bilirubin

occurred in 91 of 134 (68 %) of cats with effusion and 15/35 (43 %) of cats with non-effusive FIP. The

authors explained this phenomenon as indicative of increased erythrocyte fragility in FIP.

Erythrophagocytosis was seen in 17 of 28 FIP effusions. Felten et al, 2017

Haemolytic anaemia has been reported in other viral infections such as African Swine Fever, Karalyan et al,

2016 Epstein-Barr virus,

Ontanilla-Clavijo et al, 2017 Human Influenza virus,

Shizuma, 2014 and Parvovirus B19.

Iidaet al, 2016 In contrast, in cats haemolytic anaemia is most frequently associated with infection with

feline leukaemia virus or the haemotropic mycoplasma bacterium. Swann et al, 2016; Tasker et al, 2009

The

pathogenesis of immune-mediated haemolytic anaemia is difficult to explain, and may be different in

each infection. One possible explanation for the haemolytic anaemia of FIP might be that IL-6 causes

the activation of auto-reactive plasma cells. Ironically, bilirubin inhibits the expression of TNF-α

related endothelial adhesion molecules E-selectin and VCAM-1 Mazzone et al, 2009

which contribute to the

pathogenesis of FIP phlebitis by enabling monocyte attachment and extravasation. Acar et al, 2016

MONITORING TREATMENT AND THE CAT’S PROGRESS In my experience, the most efficient measure of a treatment working is when AGP level reduces,

especially if it reduces to normal levels (up to 500 μg/ml). Haematocrit (Hct) should be monitored

continuously to assess anaemia.

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WHEN TO ANNOUNCE RECOVERY AND DISCONTINUE TREATMENT When a cat is eating well, regained normal weight and temperature, and AGP, globulin levels,

Hct and lymphocyte count have all returned to normal, the question will arise whether or not it is

safe to discontinue treatment. Cessation of virus shedding in faeces does not always indicate

that the virus has been eliminated from the entire body.

To be absolutely certain that the cat has recovered, as opposed to being in remission, the FCoV

antibody titre should have reduced to zero using a sensitive FCoV antibody test.

WHEN TO STOP TREATMENT AND EUTHANASE 1. If the cat develops neurological signs.

2. If the cat develops non-regenerative anaemia, haematocrit below 20%, with no response

to erythropoietin.

3. If the cat develops immune-mediated haemolytic anaemia: don’t try a transfusion, it is

unlikely to work.

TARGETED MODIFICATION OF THE IMMUNE RESPONSE: POSSIBLE FUTURE

THERAPIES If you do go down the route of using a drug off-label, make sure that your practice has a well-drafted

consent form which absolves you of any legal liability, and ensure that the client signs it. Take time to

explain any possible risks of side effects to your client.

CURCUMIN

Curcumin is the principal curcuminoid chemical of turmeric (Curcuma longa) rhizomes which are

increasingly available in organic, health food, and Asian shops. This chemical has been shown to

possess anti-inflammatory, Allijn et al, 2016

anti-viral von Rhein et al, 2016; Zhu et al, 2015

and antioxidant properties Leray et al, 2011

and is available as a herbal supplement. Compared with prednisolone, curcumin had

superior activity in suppressing two key pro-inflammatory cytokines implicated in FIP development,

TNF-α and IL-6. Allijn et al, 2016

Curcumin has previously been used in cats resulting in a reduction in the

level of the acute phase protein AGP. Leray, et al, 2016

Curcuma longa rhizomes are not associated with

some of the drawbacks of turmeric powder, which often contains unknown preservatives and fillers and

the cat is exquisitely sensitive to many chemicals. However, in one case of FIP treated with curcumin in

which we have monitored AGP, neither prednisolone nor curcumin were able to reverse the adverse

effects of IL-6, since AGP remained elevated throughout.

Dose: instruct the cat’s guardian to liquidise a 1cm long piece of fresh C. longa rhizome in omega-3 rich

oil every 3 days, store the mixture at 4oC and administer 0.5mL daily. Alternatively, use ¼ teaspoon of

ground organic turmeric, but be aware that turmeric powder is often mixed with other substances, which

may be toxic to cats.

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ANTI-TNF-ALPHA ANTIBODIES (E.G. INFLIXIMAB)

Dr Ishida and I postulated the use of anti-TNF-α antibodies as a possible treatment for FIP in 2008.

Doki et al, 2016b

used anti-feline TNF-α antibodies synthesised in their own laboratory to prevent FIP

development in 2 of 3 cats experimentally infected with a strain of FCoV known for its virulence.

Infliximab is a monoclonal antibody that binds human TNF-α and is used to treat autoimmune diseases

in humans. As TNF-α is highly conserved at a protein level amongst mammalian species Soller et al, 2017

infliximab it is likely to also bind feline TNF-α. I have experience of using it in only one cat and

unfortunately he developed iritis and we lost him to immune-mediated haemolytic anaemia.

TNF-α is essential for an effective immune response against bacteria and suppressing it in a bacterial

peritonitis or pleurisy would be catastrophic.

Dose: one administration of 4mg/kg given in a 0.9% saline infusion over a four-hour period.

ANTI-IL-6 ANTIBODIES (SILTUXIMAB)

Antibody against IL-6 siltuximab (Sylvant) has not yet been tried in any FIP case. IL-6 can be pro-

inflammatory or anti-inflammatory so that the effect of inhibiting its action is not known. However, in a

cat who is going to die of immune-mediated haemolytic anaemia, it might be worth trying.

ADIPOSE STEM CELL THERAPY

We have attempted treatment of two cats with FIP with adipose stem cell therapy: unfortunately both

cats died. The UK expert on Adipose Stem Cell Therapy is Dr Andy Armitage of Greenside Veterinary

Practice. www.greensidevetpractice.co.uk.

PLASMAPHERESIS

Antibodies have a key role in the development of FIP so plasmapheresis to remove them might help cats

with FIP.

PREVENTION IS BETTER THAN CURE By now you will have realised the enormous complexity of unravelling the immune reaction which is at

the heart of the development of FIP. Furthermore, you would have to work out precisely what was

happening in each individual cat before you would know whether it is best to use antivirals, or to inhibit

MMP-9, or TNF-alpha, or IL-6. How could you shift M1 macrophages to M2 macrophages and would

you heal or kill the cat by doing so? How will you reverse the anaemia which the case likely has?

Preventing FIP is more feasible than curing it, and will be the subject of the next webinar in this series.

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SURVIVAL OF CATS IN RECENT STUDIES WHICH TREATED NATURALLY OCCURRING FIP (AND

TWO EXPERIMENTAL INFECTIONS)

Definitions of survivors by authors

Survival Number of cats

FIP type Treatment Antivirals are in

blue, anti-

inflammatories are

underlined.

Reference

Remission 11.2 months post treatment

6 or 7 of 20

6 effusive 1 non-effusive

GC376: a 3C like protease inhibitor

Pedersen et al, 2017

Recovery up to 8 months 6 of 8 effusive (experimental infections)

GC376: a 3C like protease inhibitor

Kim et al

Remission > 2 years 4 of 12 effusive fIFN omega Ishida et al

Partial remission

2-5 months 4 of 12 effusive fIFN omega Ishida et al

Very short term

< 7 days 8 of 21 effusive fIFN omega and prednisolone

Ritz et al

Short term 7-21 days 10 of 21 effusive fIFN omega and prednisolone

Ritz et al

Medium term 21 days to 3 months

2 of 21 effusive fIFN omega and prednisolone

Ritz et al

Long term > 3 months

(180 days)

1 of 21 effusive fIFN omega and prednisolone

Ritz et al / Hartmann & Ritz

Remission 264 days 1 of 1 effusive Cyclosporin A, IFN alpha, erythropoietin

Tanaka et al

Remission 14 months 1 of 3 non-effusive PPI Legendre et al 2009

Remission? over 2 years 2 of 3 non-effusive PPI Legendre et al 2009

Survival <100 days

>100 days

>200 days

>300 days

>900 days

1,829 days

29/60

16/60

8

4

2

1

non-effusive FIP presumed

PPI Legendre et al 2017

Very short term

< 7 days 8 of 16 effusive prednisolone only Ritz et al

Short term 7-21 days 4 of16 effusive prednisolone only Ritz et al

Medium term 21 days to 3 months

4 of 16 effusive prednisolone only Ritz et al

Long term > 3 months 0 of 16 effusive prednisolone only Ritz et al

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Survived 65 days 2 of 3 effusive anti-TNF-alpha MAb Doki et al

Remission 12 months 1 of 1 non-effusive FIP suspected

Darbepoietin, immunosuppressants and kidney transplant

Chalhoub et al

Prolonged survival

787 days 1 of 1 effusive / MLN FIP confirmed

meloxicam, metronidazole, cefovecin, amoxicillin-clavulanic acid, tramadol hydrochloride

Hugo and Reading 2015

IFN = interferon PPI = polyprenyl immunostimulant

FURTHER INFORMATION WEBSITES FIP website by D. Addie: www.catvirus.com. You will find more extensive notes there, plus the FIP

prognosis excel file.

YouTube channel: www.youtube.com/user/DrDianeDAddie

Webinarvet previous FIP webinars: www.thewebinarvet.com/speaker/diane-addie

University of Glasgow Veterinary Diagnostic Laboratory: www.gla.ac.uk/schools/vet/cad/

The book for cat guardians, veterinary nurses and students, FIP and Coronavirus by Diane D. Addie, is

available from Amazon.

To contact me: email draddie@catvirus.com. Please consider becoming a veterinary subscriber to

catvirus.com to be kept informed of my latest research.

ACKNOWLEDGEMENTS I am eternally grateful to the guardians of cats with FIP and with FCoV infection: these grief-stricken

souls have been beyond generous in allowing me to use their stories and photographs and many have

gone on to financially support my work. I also profoundly thank the veterinary surgeons of these cats,

who have gone beyond the call of duty in sharing information. My work wzxould not have been

possible without these people, since I refused to use laboratory cats for my research. I sincerely thank

donors to my research, and the catvirus.com subscribers who support me personally.

I thank the staff of the Veterinary Diagnostic Laboratory Laboratory (VDS) of the University of

Glasgow, without whom my work would not be possible. I am grateful to scientific and veterinary

colleagues worldwide and in the European Advisory Board of Cat Disease for useful discussions and

advice. Last but not least, many thanks to Anthony Chadwick and the staff of Webinarvet for allowing

me such an extensive series on FIP.

DECLARATION OF LACK OF VESTED INTERESTS Apart from a fee from Webinarvet and occasional locum employment at VDS, I have no vested interests

in any of the products mentioned in this webinar: I hold no shares or directorships of any companies and

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no other kind of benefit will come to me as a result of mentioning any specific products: I am

completely independent.

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