Lisa Wogan
Original article: Novel coronavirus strain in FIP-infected cats defies pattern;
5.12.2023
The first signs of problems appeared at the end of last year (2022) in Cyprus, an island state in the eastern Mediterranean, known for its abundance of free-roaming cats. Some veterinarians there have begun to see an increase in cases of Feline Infectious Peritonitis (FIP), a fatal disease of cats.
The cats had a fever, were lethargic, losing weight and did not want to eat. Some had swollen abdomens, others had tumor-like lesions. Some were staggering, uncoordinated. Some had inflamed, cloudy or discolored eyes.
FIP usually occurs in cats as a rare reaction to infection with a common pathogen, feline enteric coronavirus (FECV). The virus is shed in the feces of infected cats, from where it can be spread to other cats. FECV is a subtype of feline coronavirus (FCoV), which is one of hundreds of known coronaviruses and does not infect humans. However, this virus is very common among stray cats and cats that live with several other cats. Cats infected with FECV are generally asymptomatic and remain healthy. However, sometimes the virus mutates and causes FIP.
In Cyprus, thousands of cats were diagnosed in the first months of this year. The disease spread rapidly, contradicting common ideas about how FIP develops.
“It’s just not right,” said Dr. Danielle Gunn-Moore, a professor of feline medicine at the Royal (Dick) School of Veterinary Medicine at the University of Edinburgh, when she found out this summer that the number of diagnoses on the island had increased 40-fold compared to the previous year.
So far unpublished work, which was published on the bioRxiv portal in November before being published in a peer-reviewed journal, offers preliminary answers to the question of why so many cats fell ill in Cyprus. Based on RNA sequencing of samples from dozens of cats with FIP, the authors of the paper argue that a strain of coronavirus that arose from separate feline and canine coronaviruses may have combined, linking the fecal excretion and infectivity of the common FECV virus with the virulence of the mutated FIP virus to one pathogen.
"In normal FIP, the FIP virus is rarely spread," said Gunn-Moore, the author of the paper. "That's a huge difference in the new outbreak. Everything suggests it's directly transmitted."
Veterinary researchers asked by VIN to comment on the paper called the evidence “interesting” and “highly suggestive” but not definitive. They say further research is needed, which the authors say is underway.
Concerns are growing on "Cat Island"
In short
- Thousands of cats on the Mediterranean island of Cyprus have been diagnosed this year with feline infectious peritonitis, a fatal and usually rare feline disease.
- The disease spread quickly among the many free-ranging cats on the island, upsetting the conventional wisdom about how FIP develops.
- The authors of the new paper, which has not yet been peer-reviewed, say the outbreak was caused by a new strain of the pathogen that evolved from separate cat and dog coronaviruses, a recombination that increases its ability to spread.
- Veterinarians in Cyprus are treating many sick cats with antivirals, some of which have been developed to treat humans with Covid-19.
- A cat imported to the UK from Cyprus in August has been confirmed to be infected with the new strain.
Dr. Demetris Epaminondas, vice president of the Pancyprian Veterinary Association (PVA), first learned of the “alarming increase in FIP cases” in December last year from his wife, a practicing veterinarian. He soon began receiving similar reports from other doctors.
The potential rise in the deadly feline disease is of particular concern in an area sometimes called “cat island,” where cats roam, scurry, hunt and sleep everywhere. Large colonies of the cats, revered as holy, live in and around monasteries, where they are cared for by monks. Elsewhere, residents feed and care for neighborhood felines. There is no official estimate of the number of cats on the island.
PVA sent a questionnaire to 150 veterinary clinics in Cyprus to try to find out what was going on. Twenty-four clinics reported a total of approximately 500 cases of FIP in the first three months of 2023, a tenfold increase over the first three months of the previous year. In April, the number of reports peaked at around 2,000 cases.
These numbers only include cats on about half the island, an area of more than 2,000 square miles. Cyprus has been divided since the 1970s: The area to the south and west is under the control of the Republic of Cyprus, which has a Greek Cypriot majority and is a member of the European Union. The area to the north is occupied by Turkish military forces and is not under the effective control of the Cypriot government. There have been no official FIP announcements from the north.
dr. Charalampos Attipa, a veterinary pathologist from Cyprus, noticed the increase in cases in January while reviewing test results for Vet Dia Gnosis Ltd., a veterinary diagnostic laboratory he helped found in 2021.
There is no single test that can diagnose every case of FIP. Therefore, the diagnosis is often made based on a summary of clues from the patient's history, physical examination, and various diagnostic tests, including PCR tests. PCR stands for polymerase chain reaction, a technique that allows users to rapidly amplify a small sample of genetic material for study.
In the diagnosis of FIP, small segments of the genetic material of the coronavirus are identified by PCR in a sample of fluid from the lining of the abdomen (peritoneum) or lungs (pleura) or from the spine, or from a biopsy of tumor-like lesions.
In 2021 and 2022, Vet Dia Gnosis recorded three and four positive PCR tests in cats with FIP in Cyprus. From January to August 2023, 165 positive FIP-related PCR tests were recorded.
"These are just cats whose owners paid to have PCR done," Attipa said. "This is most likely the tip of the iceberg. But we don't really know the size of the iceberg. That's the problem."
Attipa, who started at the University of Edinburgh in April, is the lead author of the preprint paper. He is also a key member of an international collaboration investigating the virology, epidemiology and therapy of the current epidemic.
At the beginning of the year, Attipa, Epaminondas and others focused on raising awareness among veterinarians and the public. The effort led to several missteps, including a report picked up by multiple news outlets that 300,000 cats had died from the disease. Epaminondas said the figure was an unofficial and inaccurate estimate by animal welfare organizations. Additionally, the PVA estimate of 8,000 infected cats by mid-July was incorrectly reported by the Associated Press as 8,000 dead. There is no official estimate of the number of dead.
The number of PCR-confirmed cases began to decline in April, but this may not be cause for celebration just yet.
“Initially, people didn’t know what the disease was, so they took their animals to the vet to get a diagnosis,” Epaminondas said. But as awareness grew, cat owners and caretakers became aware of the rise in FIP and the clinical signs, such as a swollen abdomen, present in one form of the disease. “Because they can find treatment on the black market, they don’t want to spend money to get the disease properly diagnosed,” he said.
In recent years, antiviral compounds have shown remarkable promise in reversing the course of FIP. However, these compounds are not approved for veterinary use in many countries. As a result, a black market for antiviral drugs, mostly made in China, is flourishing, fueled by desperate cat owners who treat their animals on their own. A 2021 study of cats given unlicensed antivirals in the US found a survival rate of 80 % and above.
The number of PCR tests increased again in August, which may be due to the Cypriot government approving the veterinary use of molnupiravir, an antiviral drug used to treat Covid-19 in humans. Cats must be PCR positive for their owners or caretakers to receive a prescription.
According to Epaminondas, caseload data for most of the second half of the year, based on clinic surveys, should be available soon.
Dr. J. Scott Weese, an infectious disease veterinarian at the Ontario Veterinary College at the University of Guelph, said in an email to VIN News that the epidemiology of the outbreak is not well described, adding that it is "a common problem in field studies where information is piecemeal and often anecdotal."
According to Weese, the number of cases confirmed by PCR - 165 - is very small, especially for a country with a lot of feral cats. He also said that the rate of diagnosis based on questionnaires begs the question: Are more diagnoses due to a significant increase in the disease, a significant increase in testing, or both?
"There appears to be an increase in FIP in Cyprus. It's hard to say by how much," he said. "As there is more discussion and awareness, there are also more diagnoses of an endemic disease that may have been there all along, just ignored. Often times these are mixed situations where there is a real increase or a small local cluster, but the increased discussion and testing leads to an overestimation of the rate of change."
He added: "I'm not ruling out that this was a real epidemic or that this is a worrying new strain. We just don't know (or at least I don't know). This work shows that we need to look more closely at this issue."
Introducing FCoV-23
Basic information of FIP
If you find the specifics of feline infectious peritonitis difficult to understand, take a cue from Dr. Brian Murphy: It is. “FIP is probably the most complicated virus in veterinary medicine,” said Murphy, a veterinary pathologist and FIP researcher at the University of California, Davis, School of Veterinary Medicine. Much of what science knows about FIP was pioneered by Murphy’s now-retired mentor, Dr. Niels Pedersen.
FIP is caused by mutations in a ubiquitous and otherwise insignificant pathogen called feline enteric coronavirus. These mutations allow the virus to infect immune system cells called macrophages, which multiply and cause deadly inflammation. FIP is estimated to affect 1.3 % cats, most often kittens in catteries and shelters.
There are two forms of FIP: wet and dry. Cats may initially have one form and later develop another. In wet FIP, the fluid created as a result of inflammation accumulates most often in the abdomen, less often in other parts of the body. In dry FIP, the patient develops tumor-like lesions in the abdomen, chest, eyes, and/or brain. Early symptoms of FIP include fever, loss of appetite, weight loss, and depression. Cats with neurological FIP may develop lack of coordination, seizures, and dementia. Eye disease can cause inflammation, discoloration, or clouding of a cat's eyes, which impairs vision.
No test can diagnose every case of FIP with absolute sensitivity and specificity. Therefore, the diagnosis is often established based on a summary of clues from the patient's history, physical examination, and various diagnostic tests.
First identified in the 1950s, FIP was considered a death sentence for decades. However, in recent years, antivirals – including those used against the coronavirus that causes Covid-19 in humans, such as remdesivir, molnupiravir and Paxlovid – have been shown to reverse the course of FIP in cats. None of these antivirals are approved for veterinary use in the United States (except at universities that are researching these drugs in cats with FIP). These medicines are variously available for veterinary use in several European countries, including Cyprus, Finland, Norway, Sweden and the United Kingdom, as well as Australia and New Zealand.
In countries where the treatment is not approved by regulators, pet owners have resorted to buying unlicensed antivirals, mostly made in China, to treat sick cats themselves.
Understanding why the new strain behaves differently than what some researchers call “traditional FIP” requires a closer look at how FECV leads to FIP.
For reasons that are not fully understood, FECV sometimes mutates inside a cat. These changes allow it to escape from intestinal cells and infect a key cell of the immune system, the macrophage. This macrophage-infecting virus is known as the FIP virus or FIPV. It can now travel throughout the body, “ravaging the environment,” Gunn-Moore says, causing potentially fatal inflammation.
Once established, the FIPV coronavirus has two important characteristics: First, it is no longer an enteric virus, so it can only very rarely return to the gut to be excreted as FIPV in the feces. Second, FIPV has a gene sequence that is unique to a given cat.
FCoV-23, as the new strain has been named, appears to violate both of these schemes. Gunn-Moore said it thrives in the intestines of Cypriot cats. Furthermore, based on RNA sequencing from PCR samples, the virus in many cats had the same genetic sequence. The genetic sequencing was carried out by researchers at the Roslin Institute, an animal science research center at the University of Edinburgh.
Gunn-Moore had some early hypotheses about what might have caused the outbreak, but genetic analysis points to her main theory — that a pantropical canine coronavirus combined with a feline enteric coronavirus. Pantropic viruses can spread to different tissues in the body, a property that would allow FCoV-23 to enter other organs and nerves, as well as continue to multiply in the intestinal tract.
"I think a dog came to Cyprus and defecated on the floor. The cat, who already had FECV, then got dog feces on its feet, licked its paws and got both viruses," she said. "And that's what these viruses do, they recombine, they're party animals. They get together and go, 'Hey, do you want some of this? I'll give you some of that?'"
Gunn-Moore added that further work is planned to confirm the case for their direct transmission.
"We are currently conducting experiments to sequence the virus from feces because we need to sequence the virus and prove that it is the same sequence as in the blood," she explained.
dr. Brian Murphy, a veterinary pathologist and FIP researcher at the University of California, Davis, School of Veterinary Medicine, said the recombinant feline and canine coronavirus described in the Cyprus paper had been identified before, including by a team at Washington State University's School of Veterinary Medicine. Medicine in the 1970s.
"This is a replication of this virus, but it's a highly virulent form of the virus," Murphy said of the evidence so far. He welcomes the scientists' plans for further genetic analysis and suggests further investigation.
“Sequencing an enteric corona or a virus that comes from the gut is compelling, but it’s not proof,” he said. “It wouldn’t be a bad experiment to take fecal material containing the virus that comes from the gut, infect cats with it, and then when they get sick, save those cats with antiviral treatment. That would be good evidence of transmission of a virulent form of the virus.”
Murphy acknowledged that this kind of testing on companion animals is essentially banned in Europe and would likely be very controversial. “I think most people probably wouldn’t agree with me,” he said. “But I think it can be done ethically because we have high-quality, highly effective drugs.”
Dr. Maria Lyraki, an internal medicine specialist in Athens, Greece, who coordinates treatment protocols with veterinarians in Cyprus and is an author of the paper, said Murphy is right that the experiment would be proof, although some of the infected cats may not get sick if they develop an adequate immune response.
"However, it is something that we would not be able to implement from an ethical point of view," she said.
Thousands of sick cats
If the Cypriot epidemic had occurred 10 years ago, countless cats would probably have died because until recently there was no known way to stop the disease.
Antivirals have changed this situation.
Two promising products are remdesivir, made by pharmaceutical company Gilead to treat Covid-19 in humans, and the related compound GS-441524. GS, as it's called for short, was shown to be effective in reversing FIP in cats in an infectious disease study at the University of California, Davis in 2018.
Gilead has not granted a license to develop GS-441524 as a veterinary medicinal product. Remdesivir is not approved as a veterinary medicine in the United States, Canada, and some European countries.
However, since August, Cypriot vets have been able to import compounded versions of GS and remdesivir, manufactured by Bova, a veterinary pharmaceutical company based in the UK and Australia, under a special permit, to based on instructions UK Veterinary Medicines Directorate.
GS and remdesivir “are the first line of drugs that we use because we have the most literature on them,” Lyraki said. “But they are really expensive … which is really challenging, especially for such a large number of stray cats.”
According to Epaminondas, treating one cat with these drugs can cost from €3,000 to €7,000 ($3,250 to $7,580).
“We contacted people around the world who treat FIP cases,” Lyraki said. “And the specialists advised us that they were using molnupiravir. There is published literature on this drug and we have a lot of anecdotal discussion among FIP specialists around the world that it is indeed effective.”
The government's decision to allow veterinary use of molnupivirus has made a huge difference.
“It actually works quite well,” Lyraki said. Initially, boxes of molnupiravir were donated to the PVA to help fight the epidemic. They were available at an exceptionally low price of around 100 euros ($108) per cat, a significant saving. The actual price of the drug is much higher, but still significantly cheaper than GS.
However, the replacement of molnupivir will not last long. Merck Sharp and Dohme BV, which sells the antiviral under the name Lagevrio, will stop making it for Europe next year after the European Medicines Agency decided earlier this year not to support the registration of molnupiravir based on its finding that the antiviral's benefit in treating Covid in adults has not been proven.
"We are now working to find alternatives," Lyraki said.
Limitation of dissemination
In addition to the immediate situation in Cyprus, there are fears that the strain could spread to other countries or that it is already in other countries from which it has reached Cyprus, as yet unrecognized.
The new strain was confirmed in a cat imported to the UK from Cyprus in August. This cat has been quarantined and is responding to treatment.
Keeping the cats on the island under control can be a challenge. Cyprus is home to many cat rescue activities. Stray cats are regularly collected and taken to other parts of Europe where they are given a new home. According to Epaminondas, there are no regulations regarding the export of cats from Cyprus.
But veterinarians like Lyraki are urging rescue groups to be cautious. “Our team of experts has issued a recommendation that cats be tested before traveling outside Cyprus and that only cats with negative antibodies to FCoV be exported,” said Dr. Lyraki. Once the cats arrive at their destination, they should be quarantined for three weeks and then retested for antibodies “until the outbreak is under control and the number of affected cats has significantly decreased.”
Meanwhile, Greece, which has its own large stray cat population, has also seen an increase in FIP cases, according to Lyraki.
"We believe it's a matter of time before this outbreak spreads to Greece because Greece and Cyprus are very, very close culturally, geopolitically. There is a lot of exchange and travel between them," she said. "So it's something we're actively monitoring."
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