Published by: Ingrid King. Last Updated on: May 4, 2023 by Crystal Uys

young-kitten-FIP

Written by Ingrid R. Niesman, MS PhD

Sometimes it’s hard to know which part of me should come out first, the observant and curious scientist, or the deeply passionate cat lover. I registered for the Winn Feline Foundation FIP (Feline Infectious Peritonitis) Symposium based on the opportunity to dive more deeply into the feline medicine scientific world. I never experienced FIP in my cats or had an understanding of feline enteric coronavirus (FECV) or the mutated FIP culprit. I was unprepared to understand the depth of passion surrounding this disease, and the lengths scientists and owners have gone to achieve the breakthroughs in treatment and prevention presented in this two-day symposium.

A brief history of FIP

FIP is a direct predecessor of an original FECV infection. Coronaviruses are, in general, ubiquitous among species, but have a propensity to jump from original to novel hosts, something that is termed a zoonotic exchange.

FIP was not a concern until the middle of the last century, coinciding with the rapid rise of pet ownership worldwide. Whether FECV was endemic in feral populations or originated from a precursor virus in overcrowded antiquated animal shelters or backyard catteries is a question for another day. Today, very few kittens or cats can escape exposure to non-virulent FECV. Most clear the infection easily, but many may still harbor and shed virion particles (the infectious virus) for many months. Transmission is through an oral route. Litter tracking, grooming and even handing by humans spreads this virus throughout a population. The insidious part of an FECV infection rarely occurs, less than 15% of the time. Within this subset, only a small percentage of that group is unlucky enough to develop the full blown pathogenic virulent mutated form, the previously fatal FIP infection.

how-fip-develops

How FIP develops

FECV is one of the largest single stranded RNA genomes known to date, approximately four times larger than HIV, a similar RNA virus. RNA viruses have rapid mutational changes that can be driven by anti-viral therapies, environmental conditions or any other number of host factors that impact viral propagation. FECV is no exception. During one of the Symposium sessions, Dr. Niels Pedersen, a leading feline virologist at UC-Davis, outlined his lab’s findings on specific mutations in FECV that allow the virus infecting intestinal cells to gaining access to the immune system of host cats.

This is where I sat up and took notice. The virulent infection takes hold in cells that are usually part of the surveillance system – the macrophage. Whereas, FECV barely causes the immune system to yawn, FIPV causes the opposite effect. FIPV infections ramp up the immune system and generate an inflammatory storm of biblical proportions. Inflammation-inducing proteins are regulatory signals that control responses to infections by screaming to hosts that danger lurks and must be dealt with quickly. Levels of these proteins rise rapidly and then quickly decrease as host immune systems take control of the situation. FIPV appears to short-circuit this delicate cycle, leading to full blown FIP.

Understanding clinical pathology from a science perspective: time is of the essence

I learned in the first Roundtable Discussion that perhaps the greatest challenge for clinicians is a lack of tools for a definitive diagnosis. When dealing with a potential FIP case, time is of the essence. Yet, diagnosing an FIP case is involved and based on exclusion of other possible causes. This takes valuable time, additional money and invasive procedures, considerations that are particularly detrimental to the young cats stricken with this disease.

Looking for antibodies to the original FECV virus is one method to demonstrate infection. One protein of FECV can cause a host to produce antibodies. However, these antibodies are likely to cross-react with other coronaviruses, raising the specter of inaccurate results. It was reported in the Discussion Session that antibody detection could be applied to just macrophages instead of whole blood, but reported studies returned high levels of false-positives and require an invasive procedure to obtain the macrophages.

If antibody testing is problematic, is there a molecular approach that could detect the virus? Assays for viral RNA show promise but miss many cases. The current commercially available qPCR test does not appear to detect blood virus levels at all, rendering it useless unless lesions from potentially infected cats are tested. Using tissue markers appears to provide some robust results, but of course this is at the expense of an invasive biopsy of an affected kitty and a lengthy period of time needed to prepare the sample.

What are we missing?

So, where does this leave your local vet? The clinical characteristics, fever, loss of appetite, lethargy, and diarrhea, mimic many typical, treatable conditions.  No vet wants to tell an owner that they have either missed the disease or misdiagnosed the condition.

Looking at the fundamental differences between FECV and FIPV may yield a definitive marker, one capable of distinguishing an active case of FIPV. From my scientific perspective, more research into the actual cell biology of FIPV infections could find additional markers useful for clinical assay development. Research equals money, which is lacking for feline medicine discovery. Therefore, the best current recommendation is to use the guidelines laid out by one of many published diagnosis trees to exclude other conditions rather than confirm FIPV. Sadly, this is far from satisfactory when a young kitten’s life hangs in the balance.

From my brief survey of the literature, this is where the field stood a decade ago, stymied by a lack of funding, a dearth of feline specific molecular tools, and a disease that defeats immune regulation. This is the point where my scientific side yields to the empathetic human side.

A personal story of FIP

Judith (not her real name) was a symposium attendee, one of the many audience members who had experienced the consequences of an FIPV infection firsthand. She had rescued her neutered male as a day-old singleton from a shelter, and bottle raised him to a healthy, active kitten.

Late last spring, she noticed him lying down in awkward poses. He had slowed down. He had lost weight despite eating normally. After an initial vet visit, where blood was drawn and potential dental issues explored, an ultrasound revealed a large pocket of abdominal fluid, which was hampering his ability to lay down comfortably. The drained fluid was dark and ominous. Further PCR analysis (a test to detect the genetic material of a virus) was inconclusive. The kitten tested positive for FECV (feline enteric corona virus,) but FIPV resulted in mixed results.

One vet suggested that this was clearly FIP and recommended euthanasia.  Determined not to give up on her beloved friend, Judith reached out to another vet, who suggested she begin researching options on social media, which led her to UC-Davis and Kansas State University.

Treatment options for FIP

The Saturday afternoon session at the Winn Feline Symposium was dedicated to possible treatment options for client cats.

This disease grows slowly in the acute phase, as occurred with Judith’s cat, with symptoms that are easily dismissed. As the immune system switches into hyperdrive in one sense, it shuts down another part. A cat’s ability to fight invaders is actually suppressed when the white blood cells that are supposed to kill infected macrophages are told to ignore their instructions, allowing unfettered propagation of the virus. Thus, immune-system stimulants like Polyprenyl ImmunostimulantTM (PI) have effectiveness in cats with the “dry” form of FIP. Feline interferon-omega, a suggested treatment, seems ineffective. The yet-to-be-field-tested properties of the FDA-approved antifungal drug itraconazole are a shot in the dark, but shows promising results in the lab.

With most cats succumbing to this disease in a matter of days or weeks, the race for a truly effective antiviral or combination of antivirals cannot be a marathon.

Promising drugs caught in regulatory quicksand

The two most-promising compounds are mired in FDA regulatory quicksand. This is where the story becomes personal.

Having worked in and around drug development, I fully appreciate the efforts of teams of biologists, chemists and clinicians to bring new drugs to life. It’s a long and expensive road with no guarantees at the end. Pharmaceutical companies prioritize profit when making decisions about future therapeutic areas and therefore devote far more resources to human than animal disease. While that approach is understandable as a business decision, it may be discounting the growing attitude among pet parents that they will pay whatever is necessary to treat their pets.

Of the new drugs, GC376 has a difficult regulatory path towards FDA approval. Originally discovered to fight FIPV, it was developed by veterinary scientists for veterinary use. But the original 2018 small-scale field study was less than encouraging; out of an initial 20 FIPV-positive cats, only seven remained disease free for up to 14 months, a dismal 30 percent “cure” rate.

A more promising candidate is GS-441524, a synthetic intermediary in the chemical manufacturing of another antiviral being developed to fight Ebola. GS-441524 is highly effective in treating FIP. Out of 31 cats recruited for an initial study, four were immediately euthanized and one died early on. However, after 12 weeks of treatment, 18 cats were essentially disease-free. Relapses were treated at higher doses. By the study’s end, 25 cats had survived. These are remarkable numbers, which offer hope for afflicted animals and their humans.

But there is an obstacle to approval, and it involves the FDA and people with Ebola. The FDA has separate tracks for approvals of human and animal medicines. But, in rare instances, they allow intersection of the two when adverse events crop up, equating human and cats metabolically. This is why GS-441524 is stopped. One cat outlier could derail or lengthen the approval process for a related human drug. Delays mean money is lost, even if the final outcome is approval. So, the drug is not currently in the approval process for felines.

Desperate humans turn to the black market

Which brings us back to Judith. Increasingly desperate, she eventually turned to the black market. While GS-441524 is patented in the US, its chemical synthesis and structure are widely available, which has made the drug attractive to medical chemists who can illicitly manufacture it. And that is where we are today – with a thriving underground in black-market kitty drugs.

Judith was reluctant to trust the black-market drugs at first. “The vial was unlabeled,” she told me, “with no dosage included and no directions. Was I giving my guy something to save him or kill him?” But she purchased a 12-week supply. Within the first two daily injections, the once-lethargic cat was diving under a nightstand to retrieve a favorite toy. “I think it’s shameful that they are hesitant to allow this drug to be developed for cats,” Judith says now.

FIP-survival-cat
Left: Day of diagnosis
Right: 84 days after last dose

Getting the drug approved for felines will be challenging. Only a few segments of the government recognize that humans and animals share common health concerns and the FDA is not one of them. Meanwhile, people like Judith and the audience at the Winn Feline Foundation Symposium are moving outside of the regulated-drug realm to seek cures.

Judith’s experience raises pressing questions about whether the primary mission of the National Institute of Health should be expanded to include companion animals. We share not only our lives with our pets, after all, but also our health issues. Alternatively, a separate institute could be funded for animal-drug discovery, or animal-drug discovery could conveniently be folded into funding for the National Center for Advancing Translational Sciences. That center’s acronym, after all, is NCATS.

The proof is in the box

The major point source for infection is the shared litter box. In a multiple cat household, cats share the facilities. Some are avid diggers, others prefer a plop and sniff method. The next guy in the queue is exposed to whatever has been left behind. Virus is shed into feces and can stick to whatever type of litter is filling the box, allowing the virus to stick to paws and get tracked throughout a house.

Short of isolating each cat to a separate box by microchipped doors, there are limited ways to prevent cross contamination between household buddies. So, perhaps a change in the properties of litter can reduce the chance that virus will stick to pieces or better yet, litters could have intrinsic viricidal capabilities.  Dr. Diane Addie, PhD, BVMS, MRCVS at www.catvirus.com has recently published an extensive study of the properties of specific kitty litter composition and the infectivity of FECV in multi-cat environments.

Her team used two methods to look at the different brands and composition. First, they looked at how much virus stuck to the litter and could still infect cells, a noninvasive approach. From this screen, they determined four kitty litters that stopped the virus from killing cells in culture. To see if these particular formulations could block or lessen viral shedding in realistic multi-cat settings, they used DNA amplification, PCR, to detect infections in cats by collecting swabs. In the end, no litter completely inactivated FECV but litters based on Fuller’s earth (clay litters) proved advantageous in reducing viral shedding over time.

What’s next?

Surely in the future, this study can be the foundation for development of a true anti-viral litter that is safe and cost effective for multi-cat households and shelters, helping to break the cycle of transmission. But until that day arrives, only two other controls can reduce virus transmission. One, development of an effective vaccine and two, find other environmental designs to reduce or eliminate exposure.

 Vaccination as a method to stop transmission

Very little time was devoted to discussing where the science sits in terms of vaccine development during the two day symposium. This is understandable since the audience would be befuddled by a foreign jargon related to antigenicity, molecular structure and binding constants; all principles that are necessary to grasp the complexity of vaccine immunity. With limited incentives to develop an FIPV vaccine, most coronavirus vaccine development is focused on SARS and MERS, but feline medicine can build on the groundwork established by this research. In both cases, vaccines against the conserved Spike protein – the pointy crowns on the outside of the viral particle – have some efficacy, more so with SARS and less so with MERS. As more data emerges from studies of proteins expressed in either the FECV or FIPV phases of disease, more possible immunogens can arise.

The physical state of the vaccine also plays into its effectiveness. Introduction of the promoter of immunity – the antigen – by another virus, usually an adenovirus, is a commonly used method, along with tethering the protein to nanoparticles. Zoetis Inc. markets a modified live virus vaccine against FIPV. Unfortunately, this vaccine is only shown effective in non-infected healthy cats. Ironically, healthy single cat households rarely harbor FECV, so even though these cats may be vaccinated, they are not the major route of cyclic infection.

Taking action to stop this disease from infecting another kitten

Which leaves us with the human touch to help prevent the virus from spreading. Two very unique concepts were introduced in the waning sessions of the symposium.

Twice the size to reduce the stress

The first practical control was presented by Dr. Kate Hurley, DVM, the Director of the UC Davis Koret Shelter Medicine Program. Designed to control feline respiratory infections in crowded shelters, the Low Stress Cat Housing (developed by Hurley’s colleague Dr. Denae Wagner) is also effectively reducing the spread of many feline viruses, including FECV. By separating living rooms from the litter boxes and providing quiet spaces for caged cats, her housing provides a more stress-free space, with enhanced size (8 ft²) over standard 4 ft² cages.

kate-hurley-cat-portals

The low stress design includes a sliding portal between the litter and living space, so during cleaning, the cats can be effectively isolated. Therefore, the animals are left untouched by the caretaker, preventing incidental transmission to the next cage. In a study of nine shelters cited by Dr. Hurley, there was a 50-fold reduction in herpes transmission once these units were in place. “We can’t completely eliminate FECV, it’s a roll of the dice. It’s very readily transmitted,” explains Dr. Hurley. “But if feline herpes can be considered a canary in a coal mine, we are off to a good start.”

Cage-free kittenhood

No one really likes to think about cats in cages. What if we prevent kittens from ever being in cages or crowded conditions from the start? Kittens have some protective immunity for FECV early in life from nursing. When people find young litters of kittens, they bring them to shelters out of kindness, which unfortunately then exposes them to the harsh multi-cat environment without the benefits of a mother’s protection.

Our second concept relies on community involvement and action to keep young kittens safe and free from FIPV worries later. The Placer County Animal Shelter has a model program that should spread nationwide. As Katie Ingram, the Animal Services Manager, discussed during the symposium, the shelter contracts with a local fostering group, Kitten Central, to immediately come and take the kittens before they enter the shelter. The County provides all kitten care supplies, medicines and vaccinations to support the foster families. However, they retain “ownership”, relieving the group from adoption worries. At 2lbs, when they are still cutely adoptable, the kittens are returned.

Programs that take vulnerable kittens to sanctuaries rather than cages are the keys for prevention until we can vaccinate, diagnose and treat this dreadful disease. Virus-free means FIP free.

The end of this journey

I have taken you full circle, from infection, diagnosis and treatment to prevention of this fatal disease.

I want to thank the Winn Feline Foundation for hosting this informative meeting.  Seldom does the scientific community get to interact with the constituents most influenced by their solitary work. Although I am not working in this field, I personally gained significant understanding of the biology of the virus, the clinical ramifications and most importantly, the politics of animal medicine.

I have long believed that our investment in animal health is woefully dismal given the meteoric rise of pet ownership and the close bonds we are forming with many different companion animals. If you agree with me, contact your representatives about funding more animal health research through The National Institutes for Health (NIH), United States Department of Agriculture (USDA) or National Science Foundation (NSF).

Ingrid R. Nie

Ingrid R. Niesman MS PhD is the Director of the SDSU Electron Microscope Imaging Facility at San Diego State University.

About the author