Ending FIP, Is There Hope? A Summary of Dr. Niels Pedersen’s Presentation at the Winn Feline Foundation Symposium

Original article: Ending FIP, Is There Hope? A Summary of Dr. Niels Pedersen's Presentation at the Winn Feline Foundation Symposium (29.6.2017)

Summary: Carol Johnson DVM, PhD. A Heather Lorimer Ph.D.
For clarification, additional information from literature articles by Dr. Pedersena.

Feline Infectios Peritonitis (FIP) is one of the most complex infectious diseases and is undoubtedly one of the worst diseases imaginable. It is caused by an RNA virus from the coronavirus family Nidovirales. Other RNA viruses that the reader may be familiar with include the Ebola virus, influenza virus, AIDS, and rhinoviruses. Coronaviruses are named after protrusions that look like a crown (or corona) when viewed under an electron microscope. Coronaviruses can cause disease in almost every animal species, but as such, coronaviruses are species-specific: feline coronaviruses do not infect humans, dogs, or other animals.

Feline enteric coronavirus (FECV, also referred to in the literature as FCoV) usually remains in the intestinal tract and infects the upper layer of cells lining the small intestine before settling in the large intestine. FECV can cause mild diarrhea and vomiting, but is not considered a serious pathogen in the intestinal tract.

An FECV-infected cat can shed the virus in large quantities and excretion can continue for months. Cats are obligatory carnivores and, as a result, have a very short digestive tract. This may play a role in high virus shedding. Immunity to FECV is usually temporary and previously immune animals may be reinfected. This is one of the reasons why vaccination prevention is difficult, if not impossible.

FECV specific mutations they allow him to leave the intestinal tract, where he infects cells of the immune system called macrophages, which usually help fight infection. This mutated version of FECV is called FIPV (feline infectious peritonitis virus). Infected macrophages spread the disease in the cat's body in a similar way as tuberculosis (TB) bacteria spread in humans or animals. FIPV-associated mutations occur in three parts of the FECV genome, but a particular mutation may be unique to each cat. As many as 20% FECV infections can lead to subclinical macrophage infection, but relatively few cats develop FIP. Similarly, up to 40% of the world's human population is infected with tuberculosis bacteria, but few people have developed complete tuberculosis. Unlike TB, FIPV is not transmitted to other cats; the transmission takes place via an unmutated FECV.

FIP is a population-related disease high-density cats, where kittens are part of the equation. Kittens are most susceptible to developing FIP and are usually infected with FECV at about 9 weeks of age. In general, FIP can also occur in a dense urban or rural population of free-range cats. In the United States, FIP is more common in cats and kittens from conventional, high-density shelters and feline shelters or rescue stations where kittens may be exposed to large viral loads. Another source of FIP are kennels. Not only are a number of cats concentrated in farms, but there may also be genetic predispositions that may also play a role (up to 50% in some cases). Although the genetic risk is clear, genetic analysis shows that susceptibility to FIP is likely to involve a large number of genes. As a result, inbreeding is associated with susceptibility to FIP, but genetic testing for this susceptibility is not currently possible. Overall, FIP occurs in about 0.3% cats, but can occur in up to 1-5% (or more) cats in high-density sites, such as kennels or rescue stations.

The FIP is on the rise probably due to the increasing number of rescued cats in which kittens can be fed from bottles, weaned prematurely and exposed to large amounts of FECV.

There is a dry and wet form of FIP, but there may be combined forms and it is possible to change from one form to another. In general, the moist form, characterized by effusion, which leads to enlargement of the abdomen or fluid in the lungs, along with other symptoms, has a rapid course and can kill the cat very quickly (in this case, it is often death due to euthanasia). The dry form can last for months to about a year, sometimes longer.

Risk factors for FIP development they include the prevalence of cats that shed FECV, the intensity of virus shedding, the number of cats aged 4 to 29 months (most sensitive) and genetic predisposition (in bred cats). FIP often occurs in young cats after a stressful event, such as castration or sterilization. In these cases, the cat may already have FIPV-infected macrophages in the lymph nodes, and stress allows FIP to break out.

FIP can also develop in older cats. It typically happens that one (or more) cats in a multi-cat household die due to old age and the owner feels that the remaining cat needs a new friend, so he gets the kitten out of the shelter. The older cat has long since lost immunity to FECV and is now susceptible to infection. Due to older age, an older cat may have a worse immune response than a younger animal and is more likely to develop FIP.

Dr. Pedersen is of the opinion that FIP can usually be diagnosed relatively easily. Kittens or young cats with a viscous, slimy, yellow-colored fluid in the abdomen or thoracic cavity are likely to have FIP. The dry form of FIP may be more difficult to diagnose, but in young cats it is usually a combination of symptoms associated with chronic ill health, including weight loss, cyclic fever, characteristic blood count (anemia, decreased albumin, increased globulin, low albumin to globulin ratio, increase in absolute neutrophil count, decrease in absolute lymphocyte count, increase in bilirubin, etc.) and coronavirus titre ≥ 1: 3200, which helps to guide the diagnosis of FIP. Dry FIP may present with neurological symptoms such as convulsions or ocular lesions. Autopsy of most cases confirms characteristic lesions and leads to characteristic histological findings. Tissue or histological specimens can be further tested by various techniques, such as polymerase chain reaction (PCR), immunofluorescence (IFA) (frozen tissue only) or immunohistochemistry (IHC) (formalin-fixed tissue), but Dr. Pedersen considers these tests to be confirmatory. He believes that in almost all cases it is possible to diagnose FIP by routine examination. Some diagnostic tools lead to false negative results. For example, PCR, a commonly used diagnostic test, has about 30% false negative results.

Traditional treatment does not work. Immunosuppressants such as corticosteroids may make the cat feel better, but the course of the disease will not change. Biological agents do not work. Vaccines do not work because the kitten is usually infected with FECV before vaccination and because the immunity is only temporary. The most common cause of death in cats with FIP is euthanasia due to loss of quality of life as the disease progresses relentlessly. Although the wet form of FIP is often very fast, some cats may live longer with supportive care than one might think (weeks or months). Pulmonary fluid should be aspirated, but abdominal fluid should generally not be aspirated. Dry cats can stay alive for months or more. Spontaneous remissions may occur, but usually all cats eventually succumb to FIP.

Hope comes in the form of new antivirals. RNA viruses share many of the same types of genes and therefore present similar goals in drug development. This means that drugs designed to block one type of RNA virus may prove useful in the treatment of another type. Two potential drugs that may be effective in the treatment of FIP are protease inhibitors and nucleoside analogs (NUCs), which specifically target viral enzymes. RNA viruses often form one very large protein, which is cleaved by very specific proteases into the individual viral proteins needed to assemble new viruses. Drugs that inhibit specific proteases have been developed as antiviral drugs for various viruses. NUCs used to prevent HIV genome replication (reverse transcriptase inhibitors) in AIDS patients may also block RNA-dependent RNA polymerases that replicate the coronavirus genome. Cats, like all mammals, do not have an RNA-dependent RNA polymerase, so it is an enzyme specific for a given virus. Protease inhibitors act in the late phase of cell infection, while NUCs act in the early phase.

GC376, a protease inhibitor, was the first drug of its kind to be studied in cats. Dr. Pedersen worked with a team of veterinarians and chemists at Kansas and Wichita State Universities to treat cats experimentally infected with FIP, and later naturally infected cats. The treatment included 20 naturally infected symptomatic cats with FIP. Thirteen eventually died, some relapsing after remission and death due to neurological FIP. Seven cats survived and now appear to be free of disease, one to 1 year after treatment. A study in symptomatic, naturally infected cats determined a safe dose of drugs and determined an optimal treatment time of 12 weeks. However, treatment of cats with neurological symptoms was not successful, probably because the drug does not cross the blood-brain barrier. The drugs had few adverse effects; one of the most pronounced was the inhibition of adult tooth formation, which is a known side effect of this group of drugs. The limiting factor in the study was the final amount of drug produced.

EVO984 is a nucleoside analogue - reverse transcriptase inhibitor developed by Gilead Sciences. NUCs may have some advantage over protease inhibitors because they act in the early stages of virus infection of the cell. Gilead has provided several NUCs for which Dr. Pedersen tested their effectiveness against FIPV in vitro, followed by a pharmacokinetic study and finally a study in cats with artificially induced FIP. UC Davis needed to obtain extensive documentation and knowledge before treatment could be done on client pets with naturally developed FIP, and this study is underway right now. The drug appears to be safe, has been able to reverse the symptoms of FIP, including effusion, and some cats have successfully entered remission. Like GC376, EVO984 is not effective on neurological FIP because it does not cross the blood-brain barrier well. Although this study has only been running for a few months, it looks more promising than GC376. The test has only lasted 12 weeks, but all 24 cats that took part are currently alive.

Translator's note: EVO984 later became known under a new name, which is known to almost everyone who treated a cat with FIP. EVO984 is nothing but GS441524. In addition, GS441524 has been shown to cross the blood-brain barrier at increased doses and thus to treat neurological forms of FIP.

Next steps: Although the studies appear promising, many questions remain unanswered. Dr. Pedersen believes that if his study is successful, it may be necessary for the second group to confirm his results. It was pointed out that additional funding may be needed through the Winn Feline Foundation's Bria Fund, which encouraged everyone to contribute to future FIP research. Gilead is excited about the preliminary results, but the company develops medicines for human use and does not have an animal health division. Gilead suggested Dr. Pedersen that if the results remain promising, they can continue to do so or look for a partner who specializes in animal health products. However, due to the low prevalence of FIP in the world, the drug may not be attractive enough for large pharmaceutical companies. Dr. However, Pedersen pointed out that there may be a way to find a way out using the FDA's 2004 Minor Use and Minor Species Animal Health Act.

Questions and Answers:

The question was asked why more cats could not be treated in the study. The drugs are experimental and have limited supplies. Dr. Pedersen feels that he only needs about 20 cats to draw conclusions, as this is usually a deadly disease. He also said that the desperate owners sometimes offered him a large amount of money so that their cat could be included in the study. He said it was very sad, but strict criteria had to be followed to be included in the study and it was not possible to meet everyone.

Asked about the genetic predisposition and whether it is possible to select purebred cats resistant to FIP, Dr. Pedersen shared his experience with randomly selected breeding cats experimentally infected with the highly lethal FIPV laboratory strain. Despite infection, about 20% cats did not develop FIP. When these cats were housed together, their kittens did not develop FIP in only about 10%. When the second generation of surviving cats were bred together, FIP developed in all their offspring. Dr. Pedersen believes that these results support the concept that the most resistant cats are crossbred cats, where many immune system genes are heterozygous (having two different versions of each gene), so that a cat's immune system can respond and attack a wider range of pathogenic targets. He believes that when cats are bred, the cat's immune system becomes more homozygous (they have two copies of the same version of each gene), which reduces the variety of targets to which the immune system can respond. Because mutations that change FECV to FIPV vary, cats with a broader ability to respond to small viral changes are likely to be better protected. Breeders should minimize the use of males that have fathered kittens that have died of FIP. Why males? Because individual breeding males generally produce more offspring than breeding females, they therefore have a greater impact on the next generation of cats.

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