May 24, 2017
By: Phyllis DeGioia
For The VIN News Service
Filled with fluid, this kitten's abdomen presents the classic sign of wet feline infectious peritonitis, the most common of two types of FIP. Both syndromes — effusive (wet) and non-effusive (dry) — are fatal and incurable. Veterinary researchers are hoping to change that.
Half a century since scientists began trying to unlock the mysteries of feline infectious peritonitis, a fatal disease that affects mostly young cats, momentum seems to be building toward a treatment, with research underway at numerous institutions.
"To me, it looks like FIP research in all areas is really ramping up, and we are making bigger strides than we have in the past," observed Dr. Vicki Thayer, executive director of the Winn Feline Foundation, a nonprofit that funds medical studies to improve feline health. "We know a lot more about the virus and what it does."
Winn has granted $675,000 over 25 years to the cause. Another charitable organization, Morris Animal Foundation, pledged $1.2 million in 2015 to fund research to advance knowledge of FIP and find a treatment.
FIP, a devastating condition triggered by infection with a feline coronavirus, is difficult to diagnose. No single test exists; diagnosis is made by taking the sum of numerous findings. Experts at the University of Tennessee's veterinary college estimate that FIP affects as many as 5 percent of cats in shelters and catteries, as well as some smaller proportion of household felines.
Thayer said she's particularly excited about research on reversing the progression of FIP. The work is a collaborative effort between Dr. Niels Pedersen, a veterinary researcher at the University of California Davis, Drs. Yunjeong Kim and Kyeong-Ok Chang of Kansas State University and William Groutas, a medicinal chemist and professor at Wichita State University.
Their study, published in March 2016 in the journal PLOS Pathogens, identifies a promising new compound called 3CL protease inhibitor GC376 that appears to prevent the FIP virus from replicating. It does this by inhibiting protease, an enzyme the virus needs to infect more cells. Stopping viral replication gives the body a chance to recover.The researchers reported, "We found that antiviral treatment led to full recovery of cats when treatment was started at a stage of disease that would be otherwise fatal if left untreated." That study was done with infected laboratory cats. Pedersen and colleagues have since completed testing of GC376 in cats with naturally occurring FIP. He said the results are promising, and the research team aims to publish those findings in a peer-reviewed journal. The research is continuing with clinical trials involving 70 cats.
In addition to GC376, Pedersen's team is screening other prospective drugs for their ability to inhibit FIP. Field trials on a second antiviral compound are slated to begin soon and likely will involve a small number of cats whose owners understand the trial as a research endeavor rather than a treatment. "If things go well, there will hopefully be more drugs to test down the line," Pedersen said.
In other labs, research focuses not on drug development but on the biology that underlies FIP. The virus that causes FIP is the product of mutations in a common feline enteric coronavirus (FECV) which, according to a review paper by Pedersen, is ubiquitous in cats throughout the world and not itself an important pathogen. The Pedersen paper explains: "FECV is shed in the feces of most apparently healthy cats in large multi-cat environments, and transmission results from direct ingestion of feces or contaminated litter and other fomites. Kittens usually become infected at around 9 weeks of age. Mutants of FECV capable of causing FIP are probably generated in large numbers during this initial infection, when levels of FECV replication are extremely high." The laboratory of Gary Whittaker, a professor of virology at Cornell University, is working to identify the mutations responsible for FIP pathogenesis. Whittaker last year received more than $30,000 from Winn and $64,000 from Morris to further his research.
In a video highlighting his work, Whittaker explains that "the conventional approach to this problem is essentially a genetic approach, which means analyzing a lot of samples of cats from a genetic point of view to sequence information of the virus. We kind of twisted that around a little bit and refocused our efforts more from a biochemical point of view, which means looking at the function of the virus first."
Whittaker's ultimate goal is to develop an effective vaccine. One vaccine for FIP is on the market but how well it works is in question. (See "controversial vaccine" below.)
Can vaccines, selective breeding phase out FIP?Making a vaccine against FIP is an ambitious undertaking because of the virus's genetic makeup. Some viruses are deoxyribonucleic acid (DNA) viruses. They either enter a cell or inject their DNA into a cell, then hijack the cell's reproductive machinery to produce more viruses, which go on to infect more cells. The virus that causes chicken pox, as well as those that cause the common cold, are examples of DNA viruses.
By comparison, feline coronavirus, the virus that triggers FIP, is an RNA virus. Examples of RNA viruses are those that cause Ebola, influenza, hepatitis C, AIDS, polio and measles. While RNA and DNA viruses have similar mechanisms for replicating in host cells, RNA viruses are more prone to mutation. That constant mutation can challenge a vaccine's efficacy and make vaccine development difficult."People must understand that it is not possible to easily make vaccines for every infectious agent that we are faced with," Pedersen said. "An example is HIV-1, which has defied every vaccine approach that has been tested. In fact, the early research was so targeted towards vaccines that antiviral drug therapies were put largely aside. It is fortunate that those researchers dedicated to antiviral drugs stuck to their guns, because this is currently the only viable approach against the HIV-related diseases. Hepatitis C is another disease where antiviral drugs have produced the greatest advances, and in the case of this virus, and FIP virus as well, it appears that if you can inhibit virus replication long enough that a proportion of patients will also be aided in recovery by their own immune responses."
Another approach to countering the disease is by exploiting cats' natural immunity. According to Pedersen's review paper, only a small proportion of cats exposed to the FIP virus will develop the disease. He writes: "Resistance to FIP is complicated and involves genetic susceptibility, age at the time of exposure and a number of stressors that occur at the same time as infection and have a negative impact on the ability of the infected cat to eliminate the virus." Pedersen says he's considered exploring ways to breed cats that are immune to FIP infection, but discovered the genetics of susceptibility to be far too complex. He found that mating two FIP-immune cats will not produce kittens that are immune — rather, those kittens are more susceptible. That's the nature of complex genetic traits, he said: Resistance comes from maximum genetic diversity. Breeding closely related resistant cats reduces genetic diversity. For this reason, inbred pedigreed cats have a higher risk for FIP.
Felocell FIP is the only vaccine licensed by the U.S. Food and Drug Administration to aid in preventing feline infectious peritonitis. It contains a temperature-sensitive modified-live mutant strain of coronavirus for intranasal administration in felines older than 16 weeks. Developed by Pfizer (now Zoetis), it has been commercially available since 1991.
Some veterinarians question the vaccine's efficacy. A panel of experts with the American Association of Feline Practitioners declined to recommend the vaccine because of insufficient evidence that it induces clinically relevant protection.
The panel conveyed its finding in a 2013 report, explaining:
"Controversy exists concerning the ability of this vaccine to protect from feline coronavirus infection or to prevent development of disease; little is known about onset and duration of immunity. The vaccine is licensed for annual revaccination, but the maximum duration of immunity has not been determined. Some studies demonstrate protection from disease, while others show little or no benefit from vaccination.
"Most kittens born and reared in environments in which feline coronavirus infection is endemic are infected prior to 16 weeks of age. This may be one reason for the lack of vaccine efficiency in the field."
Most kittens born and reared in environments in which feline coronavirus infection is endemic are infected prior to 16 weeks of age. This may be one reason for the lack of vaccine efficiency in the field.
Plaguing cats for decades
First seen in the 1950s, FIP became the subject of research in the 1970s. The condition was first described at the Angell Animal Medical Center in Boston. Veterinarians around the world subsequently started to recognize cases. The worldwide incidence of FIP among all cats is around 0.3 percent, but the incidence is several times higher in high-density cat populations where there are kittens. The highest incidence is therefore in kitten foster/rescue services, shelters and catteries housing pedigreed felines.
FIP is a syndrome resulting from widespread infiltration of the organs with a type of inflammatory tissue called pyogranuloma; the resulting global inflammation causes failure of infiltrated organs, and fevers unresponsive to antibiotics. FIP comes in "wet" and "dry" forms. The wet form involves fluid buildup: Proteins and plasma leak through blood-vessel walls into the chest or abdominal cavity, causing the patient to appear pot-bellied. In the dry form, pyogranulomatous lesions cause organ damage. Symptoms include fever and poor appetite, as well as inflammation of the eyes and nervous system.
The wet and dry forms of the disease are not mutually exclusive. Some patients progress from the dry to the wet form. With either form, life expectancy after diagnosis can be as short as one week, although some cats survive for months or, rarely, for years. Pedersen noted that while it's commonly thought that cats die quickly from FIP once clinical signs develop, the major cause of death for cats with FIP actually is euthanasia. Further, cats with wet FIP usually are much sicker than cats with dry FIP, so they often are euthanized earlier, he said.
General information about disease prognosis doesn't necessarily apply to any given patient. "I have seen cats go from wet to dry FIP and live for months, and I have even seen an occasional cat with wet FIP and a huge abdomen that is still relatively healthy after a year or more," Pedersen said.
He added: "That is why I object to studies with various therapies that make claims about prolonging the lives of cats with FIP. These studies will often pull longevity studies out of the air that support their claim that a treatment is prolonging life. Owners that are committed to such treatments will naturally treat their cats for a much longer period of time before deciding that it is time to euthanize them or allow them to die a natural death."
With no cure for FIP, the best way for those who raise cats to cope with the disease is by preventing or minimizing its development through good husbandry, Pedersen said. He encourages rescue organizations, breeders and owners to keep catteries small, and to avoid mating cats that have produced kittens that have died of FIP.
While researchers are approaching the disease from multiple directions, Pedersen's bet is on antiviral drugs. Moreover, he maintains that if veterinary researchers hope to cure FIP, they should align themselves with major pharmaceutical manufacturers that are developing drugs for human use. "Veterinary viruses have the same gene targets as their human counterparts, so why not take advantage of the hundreds of millions of dollars that pharmaceutical companies invest in developing antiviral drugs for human diseases?" he argues. "It would be extremely costly if done in isolation by veterinary institutions. We must partner with human companies, and apply their technology and drugs to veterinary purposes." Yunjeong Kim, Pedersen's research collaborator, said antiviral drugs are an undeveloped area in veterinary medicine. "We don't yet have even one antiviral drug specifically licensed for use for animal viral diseases, although animals are afflicted by viral infections just like humans," Kim said. "Hopefully it may change in the near future ... "
Pedersen and colleagues are seeking a pharmaceutical company willing to take GC376 through the costly U.S. Food and Drug Administration approval process to market it for use by clinical veterinarians. Pedersen estimates the process could take a year or more; Thayer envisions a longer wait of 5 to 10 years before commercial availability.
Researcher treats FIP using off-label drug
Yet another approach is applying existing therapeutics to the disease. Dr. Alfred Legendre, a professor in the Department of Small Animal Clinical Sciences at the University of Tennessee College of Veterinary Medicine, has treated the dry form of FIP with polyprenyl immunostimulant (PPI), a biologic approved for feline rhinotracheitis (herpes) virus infection.
Legendre reported in 2009 that PPI appeared to provide effective treatment in three FIP patients. One cat that was treated for 4.5 months survived for 14 months. The other two cats received ongoing treatment and were "alive and well" two years after diagnosis.
Winn provided a grant to Legendre in 2010 to continue the studies. According to a summary by the foundation, 58 cats identified with FIP dry form were treated with PPI and followed for at least a year after diagnosis. Twenty-two percent of the cats lived six months or later; 5 percent were alive one year later. “Cats that responded to treatment had improvement in appetite and general well-being within two to three weeks after starting treatment,” Winn reported. “Dr. Legendre believes PPI treatment increase survival time and quality of life.”
The finding comes with an important caveat, however: “[N]o placebo control group was part of this study on ethical grounds, since FIP is 100 percent fatal,” Winn reported. “Unfortunately, clear benefit with PPI treatment cannot be made. Further studies to be considered would be a combination of an antiviral approach with an immunostimulant like PPI.”
Pedersen envisions a day when most FIP-infected cats can be treated effectively, but the work he and others have put into the effort shows it's not a cinch.
Finding drugs that can fight the virus, drugs that can get into the brain, and getting these drugs marketed is not an easy process.—Pedersen
Jennifer Fiala contributed to this report.
Reprinted from VIN News Service