December 15, 2017

 

 A glimmer of hope for a fatal feline disease

Controlling risk factors for feline infectious peritonitis is difficult, while new antiviral drugs show great promise

Posted Nov. 29, 2017

Feline infectious peritonitis is a heartbreaking disease. It usually strikes kittens and is almost always fatal.

According to the Morris Animal Foundation, FIP is a leading cause of death in kittens and young cats and is most common in indoor, multicat environments such as shelters and catteries. In October 2015, Morris made a three-year, $1.2 million commitment to fund research that will advance understanding of feline infectious peritonitis and to dedicate resources to stop the disease.

Winn Feline Foundation has funded FIP research through the years, including 21 projects through the Bria Fund for FIP research. Winn devoted its 2017 symposium, June 29 in Chicago, to FIP prevention and treatment. The speaker was longtime FIP researcher Dr. Niels C. Pedersen, professor emeritus at the University of California-Davis School of Veterinary Medicine.

The American Association of Feline Practi­tioners focused its 2017 conference, Oct. 19-22 in Denver, on feline infectious diseases and pediatrics, starting with FIP. Dr. Pedersen spoke on "Risk Factors Affecting the Incidence of FIP in Dense Multi-Cat Environments" and "Use of Novel Anti-viral Drugs to Treat Cats with Naturally Occurring FIP."

Some of the questions after the first session illustrated the difficulties in preventing and treating the disease. Audience members asked about controlling FIP in a kitten rescue, managing a pair of young cats in a home, and interpreting diagnostic test results. None of the answers was clear-cut.

Dr. Pedersen presented hope in the second session. He has participated in trials on two antiviral drugs that have led to remission in some cats with FIP.

"Antiviral drugs are the answer," he said. "We've opened the door and shown that we can successfully cure a large percentage of these cats." 

Risk factors

Dr. Pedersen started studying the disease in 1964. Back then, FIP went hand in hand with feline leukemia. The incidence of both conditions dropped after release of a vaccine against feline leukemia virus, but now the incidence of FIP is rising."A lot of veterinarians claim they don't see this disease, but I think we're now starting to recognize all of the forms that occur—and especially some of the chronic dry cases," Dr. Pedersen said. "As we start to recognize the full spectrum of the disease, we'll start seeing more of it."

​​Smokey was a participant in a field trial of the protease inhibitor GC376 for treating feline infectious peritonitis. Mona was a participant in a field trial of the nucleoside inhibitor EV0984 for treating FIP.
(Cat photos provided to Dr. Niels C. Pedersen by the cats' owners)
The basic virus is feline enteric coronavirus, an RNA virus that is ubiquitous throughout the world and spread via the fecal-oral route. Up to 60 percent of cats in multicat environments shed the virus at any given time. There are two serotypes, with type 1 being predominant and type 2 accounting for 5 to 20 percent of cases.

Both types can mutate during primary or secondary infection, transitioning to attack macrophages. One study found that mutation occurs in about 20 percent of infections, but the incidence of FIP is 0.3 to 1.3 percent among all cats in studies done in North America and Europe.

"The disease is relatively uncommon compared to the rate of the mutations occurring," Dr. Pedersen said. "Most cats that undergo this mutation in their body have the ability to immunologically respond to it." The question is why some cats fail to mount an effective immune response. 

​Peanuts, GC376 field trial ​Luna, EV0984 field trial
​(Cat photos provided to Dr. Niels C. Pedersen by the cats' owners)

The incidence of FIP in a cat population can be as high as 10 percent or as low as zero—and can fluctuate. At high risk is any dense cat population with kittens as part of the equation. High-risk populations include cats at foster and rescue organizations and dense populations of free-roaming cats.

Risk factors for FIP have to do with the host, environment, and agent. The host factors include early weaning, age at the time of coronavirus infection, genetic susceptibility, stresses at the time of enteric coronavirus exposure, and the occurrence of FIP-causing mutants. Stresses at the time of coronavirus exposure can include weaning, overcrowding, elective surgical procedures, vaccinations, and concurrent infections.

Risk factors

Host

  • Early weaning.
  • Age at time of coronavirus infection.
  • Genetic susceptibility.
  • Stresses at the time of enteric coronavirus exposure.
  • Weaning.
  • Overcrowding.
  • Elective surgical procedures.
  • Vaccinations.
  • Concurrent infections.
  • Occurrence of FIP-causing mutants.

Environment

  • Overcrowding.
  • Mixed ages.
  • Shared litter boxes.
  • Diet.

Agent

  • The severity of the coronavirus exposure.
  • The strain of coronavirus in terms of virulence and mutability.
  • Possibly the serotype of coronavirus.
Source: Dr. Niels Pedersen, 2017 American Association of Feline Practitioners Conference 

Environmental factors include overcrowding, mixed ages, shared litter boxes, and diet. Among the agent factors are the severity of the coronavirus exposure, the strain of coronavirus in terms of virulence and mutability, and possibly the serotype of coronavirus.

"Cats do not transmit FIP virus to each other," Dr. Pedersen said. The macrophage pathogen is present only in diseased tissues and no longer replicates in the gut. The virus that is passed from cat to cat is the ubiquitous and largely nonpathogenic parent enteric coronavirus.

In the announcement about its FIP funding, the Morris Animal Foundation characterized the disease as difficult to diagnose. Nonspecific, early signs of illness include loss of appetite, weight loss, signs of depression, rough hair coat, and fever. Later signs can include fluid accumulation in the abdomen.

Dr. Pedersen believes FIP is not hard to diagnose. He said, "FIP is a death sentence, and death sentences require definitive proof, don't they?" Not so, he said. Veterinarians know what it is when a young cat comes in with fever, a big belly full of fluid, and other signs. Dr. Pedersen said the diagnosis can be made with a high degree of certainty on the basis of signalment, clinical signs, physical findings, and a simple fluid analysis—including cell count and protein concentration.

Supportive care will prolong life, and some cats with FIP can live in a state of chronic disease for weeks, months, or, rarely, a year or more. He said, "Immunostimulants and immunosuppressives have no curative powers. Vaccines are not effective. That leaves us with antiviral agents." ​

Novel drugs

Dr. Pedersen said veterinarians must learn from research on human RNA viruses such as HIV, hepatitis C virus, influenza virus, and Ebola virus. It is possible to make drugs that interfere with specific replication processes of viruses.

"The results of our preliminary field studies with two drugs, a protease inhibitor and a nucleoside inhibitor, are showing great promise in curing certain forms of FIP," Dr. Pedersen summarized after the AAFP conference.

One candidate for treating FIP is the protease inhibitor GC376. Researchers at Kansas State University; Wichita State University in Wichita, Kansas; and UC-Davis studied the drug in eight cats with experimentally induced disease. The results appeared in "Reversal of the progression of fatal coronavirus infection in cats by a broad-spectrum coronavirus protease inhibitor" on March 30 in PLoS Pathogens, an online journal of the Public Library of Science. The study is available at http://jav.ma/FIPtreatment.  

According to the abstract, "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."

 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."

PLoS Pathogens, "Reversal of the progression of fatal coronavirus infection in cats by a broad-spectrum
coronavirus protease inhibitor"

 Researchers at the universities conducting that study plus Washington State University then conducted a field trial of the drug in 20 cats with naturally occurring disease. The results appeared in "Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis" online Sept. 13 ahead of print in the Journal of Feline Medicine and Surgery. The study is available at http://jav.ma/FIPtreatment2.

According to the abstract, "GC376 showed promise in treating cats with certain presentations of FIP and has opened the door to targeted antiviral drug therapy."

At the AAFP conference, Dr. Pedersen explained that all the cats returned to normal health, but 14 cats had fatal relapses not responsive to the drug. Six cats went into remission, with one receiving the nucleoside inhibitor EV0984. The major adverse effect was inhibition of the formation of permanent teeth in young kittens.

Dr. Pedersen also described unpublished research on EV0984, which inhibits nucleoside reverse transcription. Researchers studied the drug against experimental FIP, then went into a field trial with 30 cats. Four cats died within one to two weeks of related and unrelated complications, but 26 cats achieved complete remission of disease signs. Two-thirds of the latter cats are in long-term and hopefully permanent remission after 12 weeks or so of treatment.

One-third of cats had disease relapses after stopping treatment; one failed to respond to re-treatment, while the rest have responded well to re-treatment. The latter cats may require prolonged or indefinite therapy. There were no major adverse effects.At the conference, Dr. Pedersen cautioned that commercialization of drugs is not easy. Afterward, he continued, "We feel that FIP-specific antiviral drugs will become the treatment of choice for FIP, but we are reluctant to make guesses on when they might appear in the hands of veterinarians."

In the book "50 Years of Advancing Feline Medicine" celebrating Winn's upcoming anniversary in 2018, Dr. Pedersen concluded, "The quest for a cure has been slow, but scientists around the world have built a solid base of knowledge of FIP that is finally yielding exciting breakthroughs, especially in the area of anti-viral drug therapy."

Related JAVMA Content

​Researchers find antiviral treatment for feline infectious peritonitis (June 1, 2016)

Morris commits $1.2 million to fight feline infectious peritonitis (Dec. 1, 2015)