2023 – Neurological and ocular FIP

Original article: 2023 – NEUROLOGICAL OCULAR FIP
Published 1/4/2021, updated 2/10/2023, Translation update 3/8/2023

Basic facts

Dr. Pedersen

What is FIP? – FIP is caused by a common and mostly harmless enteric coronavirus, similar to those that cause the common cold in humans and diarrhea in foals, calves and poultry. Most cats are infected with feline enteric coronavirus (FECV) at around 9 weeks of age and may be reinfected before 3 years of age, when cycles of infection become less frequent. Specific mutations that allow FECV to escape from the cells lining the lower intestine and infect the most basic cell of the immune system, the macrophage, occur in about 10 % infections. However, this macrophage infection is eliminated in all but 0.3–1.4 % cats. Predisposing conditions that lead to disease in this small proportion of cats include young age, genetic susceptibility, sex, overcrowding, poor nutrition, and a number of stressful events in the environment. The site of initial onset of the disease is in the lymphoid tissue in the lower small intestine, cecum, and proximal colon. Infected macrophages leave these initial sites of disease and migrate locally and in the bloodstream to small veins in the lining of the peritoneal cavity, the uveal tract of the eye, the ependyma, and the meninges and spine. Symptoms of the disease appear within days, weeks, sometimes months, and rarely a year or longer. The form of the disease that manifests itself is simply referred to as wet (effusive) or dry (non-effusive). The two forms are easily distinguishable, although there may be intermediate forms between them. Some cats may have symptoms of dry FIP but later develop wet FIP, or vice versa. Overall, about two-thirds of cats have wet FIP and one-third have dry FIP. The duration of illness until death, usually by euthanasia, used to be only a matter of days or weeks. Fewer than 5 % diseased cats, especially those with milder forms of dry FIP, survive longer than one year with the best symptomatic care.

Manifestations and forms of FIP

Clinical manifestations of FIP – The clinical manifestations of wet (Table 1) and dry (Table 2) FIP differ depending on the site(s) in the body where the infected macrophages end up causing inflammation. The intensity and nature of the inflammation are responsible for the form of the disease. Wet FIP is a more acute and severe form of FIP and is characterized by the accumulation of inflammatory fluid in either the abdominal cavity and/or the chest cavity. Involvement of the central nervous system (CNS) and eyes is relatively rare in the wet form of FIP (Table 1). The dry form of FIP is not characterized by diffuse inflammation and fluid discharge, but rather by fewer and more tumor-like lesions (ie, granulomas) in organs (e.g., kidneys, cecum, colon, liver, lungs, lymph nodes) in the abdomen or chest cavity or in the eyes and brain (Table 2). While the brain and/or eyes are involved in only 9 % cases of the wet form, neurological and/or ocular disease is the main clinical sign in 70 % cats with the dry form of FIP.


Symptoms associated with:occurrence (%)
Peritoneal cavity58%
Peritoneal and pleural cavities22%
Pleural cavity11%
Peritoneal cavity, eyes2,8%
Peritoneal cavity, CNS *1,9%
Peritoneal and pleural cavity, CNS0,9%
Peritoneal and pleural cavity, eyes0,9%
Pleural cavity, CNS, eyes0,9%
Peritoneal cavity, CNS, eyes0,9%

* CNS - Central nervous system (brain, spine)


Symptoms associated with:occurrence (%)
Peritoneal cavity30%
CNS and eyes8%
Peritoneal cavity, eyes7%
Peritoneal and pleural cavities4%
Peritoneal and pleural cavity, CNS3%
Peritoneal and pleural cavity, eyes2%
Peritoneal cavity, CNS, eyes2%
Pleural cavity1%

Blood-brain and blood-eye barrier

Basic facts - The eye and central nervous system (CNS) are protected from harmful substances by blood-eye barriers (blood-eye barrier) and blood-brain (blood-brain barrier). These barriers are of great evolutionary importance because they protect brain and eye functions from the effects of systemic toxins and infectious agents. Such barriers have been developed over millions of years by positive selection of the most capable individuals. The blood-brain barrier in cats does not pass about 80% most drugs, while the blood-eye barrier about 70%. Therefore, if a given dose of a drug such as GS-441524 reaches an effective blood level (plasma) of 10 μM, the levels in the brain (cerebrospinal fluid) will be only 2 μM and the level in the eye (ventricular water) will only be 3 μM. However, higher levels are likely to be reached in inflamed tissues and will decrease as inflammation subsides. This may be one of the explanations for the rapid improvement that is often observed in the first days of treatment.

Several other aspects of these two blood barriers need to be considered. First, their impermeability of undesirable substances varies from individual to individual. Second, the effectiveness of this barrier decreases in inflamed tissues and increases as inflammation subsides. This is good for treatment in the early stages of the disease, but bad for treatment in the final stages when the inflammation disappears and only the virus remains. Third, there are no simple, safe or effective means of weakening these barriers, and the only way to increase the level of the drug in the brain or eyes is to increase their level in the blood plasma by administering a higher dose, either orally or parenterally.

How these barriers affect forms of FIP - Paradoxically, ocular and neurological forms of FIP are also a consequence of the same barriers, but in this case in neurological and / or ocular FIP, the main problem is the entry of antibodies and immune lymphocytes. The phenomenon of neurological disease after a common systemic viral infection is well known in humans and animals. A typical example is polio-encephalomyelitis in humans and canine distemper in dogs. Poliomyelitis virus (polio) is a common intestinal pathogen and usually causes a mild or mild intestinal infection. However, in some people, the virus also penetrates the brain and spinal cord. Humans develop a strong systemic immune response to the polio virus, which is highly effective in eliminating the virus in all parts of the body, except the nervous system, where the limits of the blood-brain barrier are an obstacle to immunity. These unfortunates develop a classic neurological form of infection. A similar phenomenon occurs in canine distemper. Canine distemper virus, which is closely related to the human measles virus, causes an acute respiratory infection in young dogs, which manifests 7-14 days after exposure and lasts one to two weeks. Most of these dogs recover completely, but some develop neurological disease in three or more weeks. This highly lethal secondary form of canine distemper is caused by a virus that has escaped from the body to the brain and spinal cord during the respiratory phase of the infection and is protected from the host's immune system by the blood-brain barrier.

The distribution of the disease between the CNS and other parts of the body may also explain why blood tests are rarely abnormal in cats with primary neurological disease or in those who have relapsed to these forms during or after treatment with non-neurological forms of FIP. It appears that inflammation at privileged sites such as the CNS may not elicit a systemic inflammatory response and may not cause significant changes in hematology, nor an increase in total protein and globulin, and a decrease in albumin to globulin A: G ratio.

Preliminary diagnosis of ocular and neurological FIP

Preliminary diagnosis – Eye and neurological diseases are much less common in cats with wet than with dry FIP (Tables 1, 2). They also occur in primary and secondary forms. Primary disease accounts for approximately one-third of cases of dry FIP (Table 2), and lesions outside the eyes and central nervous system (CNS) are either absent or not readily discernible. Secondary neurological and ocular forms of FIP become much more common as a result of antiviral therapy and occur either during the initial treatment of the common extra-ocular/CNS forms or as a relapse during the 12-week post-treatment observation period.

The initial suspicion of neurologic and/or ocular FIP is based on age, origin, and presenting clinical signs. FIP occurs mainly in cats under 7 years of age, three-quarters of them under 3 years of age and with the highest incidence between 16 weeks and 1.5 years. Common symptoms in both ocular and neurological FIP were stunted growth in kittens and adolescent cats, weight loss in adults, and vague signs of ill health often associated with fever.

It is believed that the diagnosis of FIP, especially the dry form, is difficult. However, a preliminary diagnosis is relatively easy to establish due to stereotypic signaling, clinical history and physical findings, and the rarity of disease confusion in the group with the highest risk of FIP. Neurological and/or ocular forms of FIP can be confused with systemic feline toxoplasmosis, so many cats with these forms of FIP are tested for toxoplasmosis and treated with clindamycin. However, systemic toxoplasmosis is an extremely rare disease in cats, especially compared to FIP. FIP is easily distinguished by the cat's origin (breeding station, foster/rescue station, shelter), signaling (age, sex, breed) and basic blood test results. Deep fungal infections (coccidioidomycosis, blastomycosis, histoplasmosis) can cause ocular and sometimes neurological symptoms similar to FIP, but are still rare even in their endemic areas. Lymphoma can also be a differential diagnosis of dry FIP, but this disease is usually sporadic and occurs in older cats. A number of congenital disorders can also present with progressive neurological signs, but these occur mainly in younger cats and are not associated with the inflammatory manifestations of infectious diseases such as FIP, toxoplasmosis or deep mycoses.

Symptoms of ocular FIP - Ocular disease occurs as the sole or primary symptom in about one-third of cats with dry FIP and in two-thirds of cases associated with extra ocular lesions (Table 2). Eye disease is an unusual manifestation in cats that initially had wet FIP (Table 1). The initial clinical manifestation is unilateral or bilateral anterior uveitis, manifested by a change in iris color, turbidity and remnants of flocculant in the anterior chamber, keratic clots on the back of the cornea, and anisocoria (unequal pupil size). In some cats, retinitis (inflammation of the retina) is an accompanying feature, and is manifested by focal wallpaper hyporeflectivity associated with local inflammation and microhemorrhage (minor bleeding) of the retinal vessels. Less than one-third of cats with ocular FIP also show indeterminate or overt neurological symptoms (Table 2). In some cases, glaucoma, usually unilateral, and panopthalmlitis (inflammation of all layers of the eye) occur, which can lead to enucleation (removal of the eye).

Symptoms of neurological FIP - the same prodromal signs have often been observed in cats with neurological signs, but include vague signs of dementia, aggressive behavior, compulsive licking of inanimate objects and other cats, reluctance to jump to high places, spontaneous muscle twitching, abnormal swallowing movements and occasional seizures. Later symptoms include posterior ataxia, inability to jump to high places, physical and auditory hyperesthesia, hyperreflexia, and cerebellar-vestibular signs (cruciate extensor reflex, loss of conscious proprioception), seizures, and increasing incoordination and dementia. Symptoms of spinal involvement often include fecal and/or urinary incontinence, paralysis of the tail and hind limbs, pain in the lower back. Catastrophic decerebral symptoms are also associated with sudden and severe herniation of the brain into the spinal cord.

Confirmatory tests of ocular and neurological FIP

Basic facts - The definitive diagnosis of FIP is based on the identification of the presence of viral antigen or RNA in macrophages in typical effusions or lesions by PCR or immunohistochemistry (IHC). Definitive diagnosis can be a difficult and expensive process in many cats, and PCR / IHC can be false negative in up to 30% samples. In most cases, however, it is not necessary to go that far because of the diagnosis. A comprehensive set of historical, physical, and less direct laboratory abnormalities may be sufficient to make a diagnosis.

Laboratory symptoms - The diagnosis of ocular and neurological FIP can usually be made by combining characteristic changes in cerebrospinal fluid (CSF) and aqueous humor (high protein, high cell counts, neutrophils, lymphocytes, macrophages) with significant abnormalities in history and history, physical examination, CBC ), biochemistry, or MRI. Total protein concentration is often increased (mean, 9.4 g / l; median 3.6 g / l; range 0.85-28.8 g / l) as well as increased erythroblast (NRBC) count (mean 196 / μL median 171 / μL; range 15–479 / μL). Neutrophils are the dominant inflammatory cell in most cats, while lymphocytes and a mixture of neutrophils and lymphocytes are observed in a smaller proportion.

MRI is a useful tool for diagnosing neurological FIP, especially in combination with routine signaling / history, typical clinical signs, and CSF analysis. MRI identified three different clinical syndromes in 24 cats with an autopsy confirmed by neurological FIP (Rissi DR, JVDI, 2018.30: 392–399): 1) T3-L3 myelopathy, 2) central vestibular syndrome, and 3) multifocal CNS disease. In all cases, MRI abnormalities were found, including increased meningeal contrast, increased ependymal contrast, ventriculomegaly, syringomyelia, and foramen magnum herniation. 15 cases showed hydrocephalus (10 cases), cerebellar herniation through the foramen magnum (6 cases), swelling of the brain with flattened gyri (2 cases) and fibrin accumulation in the ventricles (2 cases) or leptomening (1 case). Histologically, 3 main different distributions of neuropathological changes were observed, namely periventricular encephalitis (12 cases), rombencephalitis (8 cases) and diffuse leptomeningitis with superficial encephalitis (6 cases).

In one study, the most useful anti-mortem indicator of neurological FIP was the positive titer of IgG anti-coronavirus antibodies in the CSF. Antibody titers in CSF 1: 640 or higher were found only in cats with FIP and RT-PCR was always positive. Initial studies indicated that the antibody present in the CSF was produced, at least in part, in the CNS. However, in another study, the antibody was detected only in cats with serum titers of 1: 4096 to 1: 16384, and the researchers concluded that the antibodies in the CSF were obtained passively. In another attempt to measure local CNS antibody production in cats with FIP, the albumin quotient and IgG index were measured to determine if the proteins in the CSF were of blood origin or of local origin. Neither the albumin quotient nor the IgG index identified a pattern consistent with intrathecal IgG synthesis in cats with the CNS form of FIP. In conclusion, anti-coronavirus antibodies appear to enter the CSF at high levels, when they are also at high serum levels. Indeed, IFA serum coronavirus antibody titers in cats with ocular and neurological FIP are among the highest in any form of FIP.

PCR test performed from a sample of CSF and aqueous humor with a higher number of proteins and cells is highly sensitive and specific for ocular and neurological FIP. However, it is recommended that only a PCR test targeting the FCoV 7b gene be used, and no less sensitive PCR to FIPV specific mutations in the S gene. This FCoV gene is often used for PCR because it is the most abundant viral transcript and is therefore likely to that it will be detected. In some PCR assays, the FCoV M gene was targeted because it is highly conserved in all isolates, but transcripts are less numerous than in the 7b gene.

Immunohistochemistry on cells collected from spinal fluid is as sensitive and specific as PCR on samples with higher protein and cell counts. The antigen is localized specifically to macrophage-like cells.

The rapid FIP response to GS-441524 is being used as a confirmatory test increasingly. However, it should only be used in cases where there is other supporting evidence for a diagnosis of FIP. However, the truth is that there are probably no other simpler or cheaper means available at the moment to facilitate the diagnosis.

Treatment of neurological and ocular FIP

Difficulties in obtaining authorization for veterinary use of medicinal products for human use – Pharmaceutical companies such as Gilead Sciences and Merck have refused to compromise the development and approval processes of their promising anti-coronavirus drugs such as GS-5734 (Veklury®/Remdesivir) and EIDD-2801 (Molnupiravir®) or their respective biologically active forms GS-441524 and EIDD -1931. Out of desperation, cat owners around the world have turned to the Chinese black market for drugs like GS-441524. This black market was not entirely motivated by profit – China's FIP problem also grew at the same time as the domestic cat population. Moreover, even if Gilead Sciences had approved the use of GS-441524 in animals, the immediate need for an effective treatment for FIP has overtaken the official approval and commercialization process, which takes many years. Chemical companies and a dozen or more vendors of injectable and oral products have been able to satisfy the demand for GS from tens of thousands of desperate cat owners around the world. Veterinarians have been reluctant to pressure human pharmaceutical companies like Gilead to license their promising antiviral drugs for use in animals, but they are increasingly involved in helping owners with treatments. It therefore appears that the unapproved use of human drugs such as GS-441524, which are also desperately needed in veterinary species, will be the norm for many years to come.

(This paragraph comes from the original article from 1/4/2021.)

Virus-specific inhibitors – Inhibition of viral genes regulating specific stages of infection and replication has become the mainstay of treatment for chronic RNA virus infections in humans, such as HIV and hepatitis C virus. Currently, two classes of antiviral drugs have been shown to be effective against FIP. The first class consists of RNA synthesis inhibitors and includes the nucleoside analogs GS-441524 (the active ingredient in Remdesvir) and EIDD-2801 (molnupiravir). The second class of drugs consists of viral protease inhibitors, such as GC376 (prodrug of GC373) and Nirmatrelvir (prodrug of nitrile modification of GC373). Protease inhibitors are much less effective at crossing the blood-brain and blood-ocular barriers than nucleoside analogues and are not recommended for the treatment of neurological or ocular FIP.

Treatment with GS-441524 – GS-441524 has become the drug of first choice for the treatment of cats with all forms of FIP, and both injectable (SC) and oral forms are available in the off-label Chinese market. However, oral absorption is less than 50 % effective compared to injection, thus requiring twice the dosage of oral GS-441524. Suppliers of oral GS-441524 almost never disclose the actual concentration of GS-441524 in tablets or capsules, but rather label them as an equivalent injection dose. There is also an upper limit to the absorption efficiency of oral GS, making it difficult to achieve the higher blood levels needed to reach sufficient amounts of the drug in the brain and eyes. Therefore, if cats with ocular and neurological disease fail despite high equivalent doses of oral GS-441524, a switch to injectable GS-441524 should be considered before switching to a drug such as molnupiravir is considered.

The starting dose for cats with wet or dry FIP and no signs of ocular or neurological disease is 4-6 mg/kg daily for 12 weeks, with younger and wet cases tending towards the lower end and dry cases towards the higher end. Cats with eye lesions and no neurological signs are started at 8 mg/kg daily for 12 weeks. Cats with neurological signs are started at 10 mg/kg daily for 12 weeks. If cats with wet or dry FIP initially develop ocular or neurological signs, they are switched to the appropriate ocular or neurological doses. The dose of GS is adjusted weekly to account for weight gain. Weight gain can be huge in many of these cats, either because they are in poor condition to begin with or because their growth has been stunted. If the cat does not gain weight during treatment, this is considered a bad sign. The initial dosage is not changed unless there are serious reasons for this, such as ineffectiveness of treatment or improvement in blood test values, improvement is very slow, low activity level, initial clinical symptoms have not resolved, or the disease form has changed with the appearance of ocular or neurological symptoms. If there are good reasons to increase the dosage, it should always be from +2 to +5 mg/kg per day and for at least 4 weeks. If these 4 weeks exceed the original 12-week treatment time, the treatment time is extended. A positive response to any increase in dosage can be expected, and if you don't see an improvement, it means that the dosage is still not high enough, drug resistance is emerging, the GS mark is not what it should be, the cat does not have FIP, or there are other diseases that confuse the treatment.

One of the most difficult decisions is determining when to stop treatment. Although some cats, often younger with wet FIP, can be cured as early as 8 weeks and possibly earlier, the usual treatment period is 12 weeks. Some cats may even require dose adjustments and even longer treatment periods. Critical blood levels such as hematocrit, total protein, albumin and globulin levels and absolute lymphocyte counts usually return to normal in curing cats after 8 to 10 weeks, when there is often an unexpected increase in activity levels. We believe, but there is no evidence yet, that after 8-10 weeks, the cat will have its own immune response against the infection. This is a situation that occurs in the treatment of people with hepatitis C, which is also a chronic RNA virus infection that often requires antiviral treatment for up to 12 weeks or more.

Cats with ocular disease and no neurological impairment show a rapid response to GS, and complete recovery of vision with minimal or no residual damage is expected in as little as two weeks. Cats that develop neurological abnormalities, develop neurological disease during the treatment of other forms of FIP, or develop neurological symptoms during the 12-week post-treatment observation period also improve rapidly, but the dose is much higher, the duration of treatment often longer and the cure rate slightly lower. Treatment failures in cats with neurological FIP are due to either insufficient dose or the development of drug resistance.

Unfortunately, there is no simple blood test that can determine when a cat with neurological impairment has fully recovered. Many cats with neurologic FIP show minimal blood abnormalities, especially those with primary neurologic FIP, and the abnormalities often disappear by the end of treatment, even though residual sites of inflammation remain in the brain or spinal cord. In addition, some cats that recover from the infection will have mild to moderate neurological deficits that are residual effects of the previous illness. These facts make it difficult to use blood test results or residual neurological deficits as indicators of cure or undertreatment. Although a thorough eye examination can clearly rule out active signs of disease, the true state of the disease in the brain and spinal cord can only be determined by an MRI, ideally together with an analysis of the cerebrospinal fluid. These procedures are expensive, not available to everyone, and may not provide definitive proof that the infection in the CNS has been cleared.

Fear of relapses means that many people involved in GS treatment are too cautious about a single blood parameter that is slightly abnormal (eg, slightly high globulin or slightly low A: G ratio), or final ultrasound results suggesting suspiciously enlarged abdominals. lymph nodes, small amounts of abdominal fluid or blurred irregularities in organs such as the kidneys, spleen, pancreas or intestines. It should be borne in mind that the normal range of blood values applies to most animals, but it is a bell-shaped curve, and that there are a few non-standard patients who will have values at the edge of these curves. Ultrasonographers must consider the degree of pathology that can occur in the FIP of the affected abdomen and how scars and other permanent consequences can change the normal appearance of successfully treated cats. In situations where such questions arise, it is better to focus in more detail on the overall picture and not just on one small part. The most important outcome of treatment is a return to normal health, which has two components - external signs of health and internal signs of health. External signs of health include a return to normal activity levels, an appetite, adequate weight gain or growth, and coat quality. The latter is one of the best criteria for cat health. Internal health symptoms include the return of certain critical values to normal based on periodic complete blood count (CBC) monitoring and serum chemical profiles. The most important values in CBC are hematocrit and relative and absolute total white blood cell, neutrophil and lymphocyte counts. The most important serum values for chemical analysis (or serum electrophoresis) are total protein, globulin, albumin and A: G ratio levels. Bilirubin is often elevated in cats with effusive FIP and may be useful in monitoring the severity and duration of inflammation. There are many other values in the CBC panels and serum, and it is not uncommon for some of them to be slightly higher or lower than normal, and it is better to ignore these values unless they are significantly elevated and associated with clinical signs. For example, high BUN and creatinine, which is also associated with increased water consumption, excessive urination, and urinary abnormalities. The number of machine-counted platelets in cats is notoriously low due to the trauma of blood collection and platelet aggregation and should always be verified by manual examination of blood smears. The final decision to discontinue or extend treatment when faced with unclear doubts about different testing procedures should always be based on external manifestations of health than on any single test result.

(This paragraph comes from the original article from 1/4/2021.)

Relapses usually refer to infections that have escaped into the central nervous system (brain, spine, eyes) during treatment for wet or dry FIP that are not accompanied by neurological or ocular symptoms. Doses of GS-441524 used to treat these forms of FIP are often insufficient to effectively cross the blood-brain or blood-ocular barrier. The blood-brain barrier is even more efficient than the blood-ocular barrier, which explains why eye lesions are easier to heal than brain and/or spinal cord infections. Post-treatment relapses involving the eyes, brain, or spine are usually treated for at least 8 weeks at an initial daily dose at least 5 mg/kg higher than the dose used during primary treatment (eg, 10, 12, 15 mg/kg per day). Cats that fail to clear the infection at doses up to 15 mg/kg per day are likely to have developed varying degrees of resistance to GS-441524. Partial resistance may allow suppression of disease symptoms but not cure, while complete resistance is manifested by varying severity of clinical symptoms during treatment.

Different groups focused on the treatment of FIP have made various modifications in the treatment protocols. Some groups will treat with an extremely high dose of GS from the beginning and not increase the dose when indicated, or will recommend discontinuing or extending the high dose for the last two weeks in the hope that this will reduce the risk of relapse. In addition to GS, systemic prednisolone is often prescribed, but should only be used temporarily to stabilize serious illness. Systemic steroids reduce inflammation but tend to mask the beneficial effects of GS, and if used for an unreasonably long time and in high doses, can interfere with the development of immunity to FIP. Restoration of immunity to FIP is thought to be an important part of successful GS treatment. Therefore, some people advocate the use of interferon omega or non-specific immunostimulants to further stimulate the immune system, and some come up with other modifications. There is no evidence that using an extremely high dose will improve the cure rate. Also, interferon omega and non-specific immunostimulants have not been shown to have beneficial effects on FIP, whether given as a single treatment or as an adjunct to GS. The practice of adding another antiviral drug, the viral protease inhibitor GC376, to the treatment of GS in cats that develop resistance to GS is also emerging, but this still requires further research. Finally, it is common for owners, treatment groups and veterinarians to add many supplements, tonics or injections (eg B12) to increase hematopoiesis or to prevent liver or kidney disease. However, such supplements are rarely necessary in cats with pure FIP.

Molnupiravir (EIDD-2801) – Molnupiravir is very similar to GS-441524, but is a cytidine rather than an adenine nucleoside analog. It is widely used as an oral treatment for early cases of COVID-19 in humans, but in the last 1-2 years it has been increasingly used to treat cats with FIP. Due to the toxicity observed in cats at higher doses and as yet unknown chronic side effects, it is most often recommended for cats that developed resistance to GS-441524 during primary treatment or relapsed with neurological/ocular signs after treatment with high doses of GS- 441524. Fortunately, molnupiravir has a different resistance profile than GS-441524.

The safe and effective dosing of molnupiravir in cats with FIP has not been established in properly controlled and monitored field studies such as those performed for GC376 and GS-441524. However, the estimated starting dose of molnupiravir in cats with FIP was derived from published EIDD-1931 and EIDD-2801 in vitro cell culture studies and other laboratory and experimental animal studies. Molnupiravir (EIDD-2801) has an EC50 of 0.4 µM/µL against FIPV in cell culture, while the EC50 of GS-441524 is approximately 1.0 µM/µL. Molnupiravir begins to show cellular cytotoxicity at concentrations of 400 µM or higher, while GS-441524 is non-toxic at 400 µM. Both have similar oral absorption of around 40-50 %. The current recommended starting dose of molnupiravir for neurologic and ocular FIP is 8–10 mg/kg orally every 12 hours for 84 days. Depending on the response to treatment, it may be necessary to increase it to a maximum of 15 mg/kg orally every 12 hours. At higher doses, molnupiravir toxicity is likely to occur as indicated by changes in the complete blood count.

Causes of treatment failure

Incorrect dosage adjustments - It is important to start treatment with the appropriate dosage and to monitor it closely with regular checks on temperature, weight and external signs of improvement. The CBC and serum chemical analysis panel, which contains baseline protein values (total protein, albumin, globulin (TP - albumin = globulin) and A: G), should be performed at least once a month. with GS-441524 Expensive serum protein electrophoresis does not provide much more valuable information.

Low quality GS-441524 - GS-441524 is not approved for marketing in any country and is sourced from a small number of Chinese chemical companies which sell it to distributors as pure powder. Vendors dilute it into injectable solutions or prepare oral forms for sale under their trade names. There is no independent mechanism to ensure the quality of the final product sold to cat owners. Nevertheless, the main providers of dilute forms for injectable solutions and / or oral preparations are surprisingly honest, and some even offer limited guarantees if treatment with some of their products does not cure the disease. However, the batches sold by some providers appear to be counterfeit and some are not in the specified concentration. There may also be differences between batches, probably due to occasional problems with the supply of raw GS by retailers or problems with meeting the needs and expectations of the cat owner. Various groups of FIP Warriors have good information about the most reliable brands.

Drug resistance - resistance to GS-441524 may already exist at the time of diagnosis, but this is unusual. It occurs more frequently during treatment and is initially only partial and requires only higher doses. In some cats, it may become complete. Resistance is the biggest problem in cats with neurological disease, or they develop brain infections during treatment or within a few days or weeks after stopping treatment. Many cats with partial drug resistance may be "treated" for their symptoms, but they relapse as soon as treatment is stopped, as is the case with HIV treatment, for example. There are cats that have been able to partially or completely treat the symptoms of FIP for more than a year, but without a cure. Resistance eventually worsens and the symptoms of the disease worsen, treatment difficulties become unbearable for the owner or the owner's financial resources run out.

GS side effects

GS-441524 treatment is incredibly free of systemic side effects. It can cause mild kidney damage in cats without significant kidney damage, but does not lead to latent disease or kidney failure. Systemic drug reactions such as vasculitis have been observed in several cats and can be confused with injection site reactions. However, these drug reactions are in places where injections are not given, and often stop on their own or respond well to short-term low-dose steroids. The main side effect of GS treatment is pain at the injection sites, which varies from cat to cat and according to the abilities of the person giving the injections (usually the owner). Swelling or ulcers at the injection site sometimes occur in owners who do not change the application site often enough (do not stay between the shoulder blades) and do not inject into the muscular and nervous layers under the skin. I recommend choosing places starting one inch behind the shoulder blades, down from the back to 1 to 2 inches in front of the root of the tail and one third to half way down to the chest and abdomen. Many people use gabapentin to relieve pain before injections. Swollen spots and ulcers at the injection site should be stripped of surrounding hair and gently cleaned 4 or more times a day with sterile cotton swabs soaked in homemade hydrogen peroxide diluted 1: 5. They usually do not require any more complicated treatment and will heal in about 2 weeks.

Prognosis of treatment with GS441524

Exact cure rate data with GS-441524 are not yet available, but it seems possible to cure more than 80% cats with confirmed FIP. Treatment failure is due to misdiagnosis of FIP, inadequate treatment monitoring and dose adjustment, complicating diseases, poor GS, resistance to GS, or economic difficulties. The cure rate is slightly lower in cats with neurological forms of FIP and in older cats. Older cats are more susceptible to other chronic diseases, which either predispose cats to FIP or complicate overall health.

Cats with neurological FIP may suffer permanent residual symptoms of the disease. This is especially true for cats with spinal involvement and urinary and/or fecal incontinence or hind paralysis. Hydrocephalus and syringomyelia are common complications of neurological FIP and often persist to some extent after the infection has cleared. Fortunately, most cats with neurologic FIP recover normal or near-normal function despite persistent traces of hydrocephalus and syringomyelia.

Legal treatment for FIP?

We hope that the legal form GS-441524 will be available soon. The drug, called Remdesivir, is the greatest hope of the present because Remdsivir breaks down into GS when given intravenously to humans, mice, primates and cats. Remdesivir (Veklury®) has been fully approved by the US FDA and similar approval is likely to follow in other countries. If so, it can be prescribed by any licensed human physician as well as veterinarians. However, the use of Remdesivir in the United States was initially limited to a specific subset of patients with Covid-19 and only under controlled conditions and with ongoing data collection. Until all restrictions are lifted, it will not be easily accessible for human use. We have no experience in treating cats with Remdesivir instead of GS-441524. The molar basis of Remdesivir is theoretically the same as GS-441524. GS-441524 has a molecular weight of 291.3 g / M, while Remdesivir is 442.3 g / M. Therefore, 442.3 / 291.3 = 1.5 mg of Remdesivir would be required to obtain 1 mg of GS-441524. The diluent for Remdesivir is significantly different from the diluent used for GS-441524 and intended for intravenous use in humans. How diluted Remdesivir will behave when given by subcutaneous injection over 12 weeks or more is not known. Mild signs of hepatic and renal toxicity were observed in humans. GS-441524 causes mild and progressive renal toxicity in cats, but without apparent hepatic toxicity. It is uncertain whether renal toxicity observed in humans receiving Remdesivir is due to its active substance (ie GS-441524) or to chemical agents designed to increase antiviral activity.

The GC376 approval process for cats (and humans) is ongoing at Anivive, but will take two or more years. GC376 is a viral protease inhibitor and, unlike GS-441524, which inhibits the initial stage of viral RNA replication, GC376 prevents viral replication in the final stage of its replication process. Therefore, it is unlikely to have a significant synergistic viral inhibitory effect and its use in combination will be much more important in inhibiting drug resistance (e.g. in combination antiviral therapy for HIV / AIDS).

Improper use of GS-441524

Some veterinarians, in collaboration with major Chinese supplier GS-441524, have advocated its use to eliminate feline enteric coronavirus (FECV) infection. The reason is to prevent the occurrence of a mutant virus causing FIP (FIPV) and thus prevent FIP. This approach was supported by limited and highly controversial studies with shelter cats, which were naturally exposed to the FECV. Although this approach is attractive at first glance, it is a very incorrect use of GS-441524 in cats. FECV infection originally occurs in kittens and is not associated with any significant symptoms of the disease. Elimination lasts for weeks, months, and in some cases indefinitely, but in most cats, it eventually stops when immunity develops. Most cats over the age of three will no longer shed the virus. GS-441524 treatment is highly unlikely to result in more permanent immunity than is observed in nature and to eliminate cycles of infection and reinfection in younger cats.

Although our current knowledge of FECV infection seriously challenges this approach, there are even more compelling reasons why we will not treat healthy cats GS-441525 or other antiviral agents in the future. We already know from published studies that some primary strains of FIPV are resistant to GS-441524 (and GC376). We also know that drug resistance has become a long-term problem in cats with long-term treatment for GS-441524, especially in neurological forms of FIP. Therefore, the use of drugs such as GS-441524 in a large population of healthy cats will undoubtedly lead to widespread resistance to enzootic FECV. This resistance will also manifest itself in FIP-causing FECV (FIPV) mutations from these populations, making it impossible to use GS-441524 in more and more FIP cats. Unfortunately, veterinary medicine does not have the means of human medicine, it is not stimulated by potential benefits, which would lead to the discovery, testing and approval of more and more antiviral drugs to circumvent either natural or acquired drug resistance, which is already the case in HIV / AIDS treatment. achieved (at least on time).

(This part comes from the original article from 1/4/2021.)

Niels C. Pedersen, DVM PhD
Distinguished Professor Emeritus
UC Davis, Center for Animal Health Companion January 4, 2021
, updated February 10, 2023

Current information about the treatment of FIP in the UK

Original article: An update on treatment of FIP in the UK (1.2.2022)

dr. Sam Taylor BVetMed(Hons) CertSAM DipECVIM-CA MANZCVS FRCVS Prof. Séverine Tasker BVSc BSc DSAM PhD DipECVIM-CA FHEA FRCVS, Prof. Danielle Gunn-Moore BSc(Hon), BVM&S, PhD, MANZCVS, FHEA, FRSB, FRCVS Dr. Emi Barker BSc BVSc PhD PGCertTLHE DipECVIM-CA MRCVS, Dr. Stephanie Sorrell BVetMed(Hons) MANZCVS DipECVIM-CA MRCVS

Given the current situation, Sam Taylor, Séverine Tasker, Danièlle Gunn-Moore, Emi Barker and Stephanie Sorrell discuss treatment protocols to help doctors manage this viral disease.


Figure 1: Remdesivir intended for intravenous or subcutaneous administration

In August 2021, remdesivir (Figure 1) became legally available to UK vets to treat FIP in cats. Since then, many cats and kittens have been and are still being successfully treated. As with any new product, protocol modifications are adopted with experience, and in light of the recent release (November 2021) of oral GS-441524 (50 mg tablets) from a specialist UK manufacturer (Figure 2), this article has been drafted to support general practitioners in the use of remdesivir and GS-441524 in the treatment of FIP. It should be kept in mind that treatment may need to be tailored to the individual cat based on the client's response, compatibility and financial capabilities. The specific protocols below may help veterinarians and their clients, but will not be appropriate for all cases.

Treatment protocols (updated November 2021)

The dosage of the drugs has been increased compared to previous recommendations based on the experience of our Australian colleagues, who have treated more than 600 cats so far. Although some cats responded to previously recommended lower doses, they found that relapse was possible at or near the end of the 84-day (12-week) treatment period, leading to the need to extend treatment with a higher daily dosage. This was ultimately more expensive than starting treatment at a higher dosage.

Figure 2: GS-441524 oral tablets

With the use of remdesivir and/or GS-441524, treatment options are now available including a 12-week course of injectable remdesivir, switching from injectable remdesivir to oral GS-441524, or an exclusively oral GS-441524 protocol.

Suggested dosing, benefits, and limitations of each protocol are listed below. Remdesivir cannot be taken orally. The recommended dosage of drugs (Table 1) depends on the clinical picture - ie whether there is an effusion or not and whether there is eye and/or neurological involvement - this is due to differences in drug penetration into tissues. In case of doubt, it is more appropriate to use a higher dosage.

Please note that these dosages of oral GS-441524 are higher than reported in some publications - this is because these publications used so-called black market preparations of GS-441524 in which the amount of active ingredient administered to cats was not confirmed. The dosages given in this article are based on experience using an oral formulation of known GS-441524 that is legally available in the UK and Australia. Therefore, extrapolation cannot be used for other oral preparations for which the active ingredient and/or its concentration is not known or is not indicated by the manufacturer.

Combined injection and oral treatment protocols

The decision when to switch from injectable remdesivir to oral GS-441524 may depend on tolerability of injections (or oral tablets), differences in product cost (including cost of needles, syringes, sharps disposal, losses), owner preference, and finances.

Experience suggests that this transition may occur between days 7 and 14 after initiation of intravenous or subcutaneous remdesivir therapy. The change can be made directly; remdesivir is given for one day and GS tablets are started the next day.

The protocol chosen depends on the severity of the FIP disease in the cat. Dosage is shown in Table 1.

Serious condition

If the condition is severe (anorexia, dehydration, the cat is usually hospitalized):

  • Initial treatment with remdesivir given once daily intravenously (Table 1) for three to four days – ie days 1, 2, 3 and/or 4. This will achieve the loading dose of the drug. Each day, dilute the required dose of remdesivir to a total volume of 10 mL with saline and administer slowly over 20 to 30 minutes by hand or pump.
  • Subsequently, administer SC remdesivir once daily at the same dose (Table 1) until days 7 to 14.
  • On days 8-15, switch to oral GS-441524 once (or twice) daily (Table 1) and continue until at least day 84.

Table 1: Overview of dosing recommendations for remdesivir and GS-441524

Clinical presentationRemdesivir - by injectionGS-441524 – oral
Cats with effusion and no ocular or neurological signs10 mg/kg once a day10-12 mg/kg once a day
No effusion and no ocular or neurological symptoms12 mg/kg once a day10-12 mg/kg once a day
Ocular symptoms present (effusive and non-effusive FIP)15 mg/kg once a day15 mg/kg once a day
Neurological symptoms (effusive and non-effusive FIP)20 mg/kg once a day10 mg / kg twice daily (ie 20 mg/kg in divided doses)
Translator's Note: the injectable form of GS-441524 is not used for legal treatment in the UK. Given that the molecular weight of remdesivir is approximately 2x higher than the molecular weight of GS-441524, the recommended dosage of remdesivir is approximately 2x higher than that of GS-441524. Coincidentally, the bioavailability of GS-441524 when administered orally is about 50%, so the dosage for tablets with the stated real GS content from the manufacturer BOVA is practically identical to the dosage for remdesivir injection.

Less serious condition

Regarding a less severe condition (normal hydration, food intake):

  • Initial treatment with remdesivir SC 1x a day (Table 1) until the 7th to the 14th day.
  • Change to 1x (or 2x if a very high neurological dose is required) daily oral administration of GS-441524 (Table 1) on days 8-15 and continue until at least day 84.

An exclusively oral protocol

In the event that injectable treatment is not tolerated/financially feasible, only the oral GS-441524 treatment protocol is recommended:

  • 1x (or 2x if a very high neurological dose is required) daily oral GS-441524 (Table 1) for at least 84 days.

Possible side effects of remdesivir:

Remdesivir appears to be well tolerated. However, the following side effects have been reported:

  • Transient local discomfort/stinging on injection (see prevention later).
  • Development/worsening of a pleural effusion (not always proteinaceous) during the first 48 hours of treatment, sometimes requiring drainage.
  • Cats may be depressed or nauseous for several hours after intravenous administration.
  • An increase in the activity of the enzyme alanine aminotransferase has been reported (whether due to the underlying disease of FIP or an adverse effect of the drug is unclear).
  • Mild peripheral eosinophilia has been reported.

A note on weighing cats

During treatment, it is very important to weigh cats weekly using an accurate scale - with successful treatment, kittens will gain weight and/or grow, which will require a dose increase to ensure that the dose of antiviral given is still appropriate for the type of FIP being treated.

Options for clients with a limited budget

Please note that ideally, treatment should be administered using the recommended preparations and dosage for as long as possible (up to 84 days) to increase the likelihood of a cure.

Use the options below only when absolutely necessary, as a relapse may occur, which then requires longer treatment, leading to increased costs:

  • Administer oral treatment with GS-441524 only for 84 days as above.
  • Administer injectable remdesivir or oral GS-441524 for as many days as the owner can tolerate, then switch to oral mefloquine 62.5 mg two to three times weekly (in large cats three times weekly) or 20 mg to 25 mg orally once daily (if possible to change the composition of the tablets - for example, Novalabs) to complete the 84-day treatment protocol; mefloquine is less expensive than remdesivir and GS-441524, but further research is needed to assess its effectiveness in this setting.
  • If it is necessary to increase the dose of remdesivir (for example, due to a neurological disease that appears during treatment), but it is not possible to afford it, mefloquine treatment can be added as an adjunctive treatment, because it is cheaper than remdesivir, although it is necessary to assess the effect of this combination further research.
  • Feline interferon omega has also been used in the post-remdesivir/GS-441524 treatment period, but further research is needed to assess whether this combination is necessary.

Is the oral treatment given with or without food?

  • GS-441524 is administered on an empty stomach (with some water) - food may be administered 30 minutes after administration of the drug.
  • Mefloquine is given with food, otherwise vomiting often occurs.

Remember to support clients when giving oral medications, as this can also be challenging for them. Direct clients to the website iCatCare, where you can find information and videos.

How can I help owners with remdesivir SC application?

Remdesivir injection may cause temporary local discomfort. The following measures can help reduce discomfort and improve cooperation:

  • Make sure owners use a new needle each time to withdraw medication from the vial (this will reduce the risk of bacterial contamination of the vial, as well as rubbing the top of the reusable seal vial with alcohol before inserting the needle).
  • Make sure owners change the needle after removing the medicine from the bottle and before giving the injection (puncturing the reusable seal will blunt the needle).
  • Needle size preferences vary; some prefer a 21G needle to make the injection faster; others find the finer 23G needle better tolerated, so it may be worth trying both if you have problems.
  • Alternate injection sites.
  • Allow remdesivir to warm to room temperature before administration.
  • Oral gabapentin (50 mg to 100 mg per cat) and/or intramuscular or SC buprenorphine given at least 30 to 60 minutes before remdesivir injection may be useful to induce mild sedation/analgesia.
  • The area to be injected may also be shaved to help owners locate a suitable injection site and to allow topical EMLA cream to be applied 40 minutes prior to injection, although superficial desensitization may not help as discomfort is usually caused by remdesivir under the skin.
  • Ensure that the full injection dose is always administered and encourage owners to report any failures as this may influence decisions in case of relapse.
  • Cats will need several weeks of treatment. Encourage owners to make the injection more enjoyable by using treats at the time of the injection or by petting, combing or playing with the cat if it is less motivated to eat. Suggest that owners spend time with their cat in a positive way each day to avoid any damage to the cat-owner relationship that may reduce cooperation.

What can I expect during treatment?

  • During the first two to five days, you should see an improvement in behavior, appetite, resolution of pyrexia, and a decrease in abdominal (Figure 3) or pleural fluid if an effusion is present (please note that in some cases pleural fluid may be transient in the first few days worsen - if the cat is at home, advise the owner to measure the resting respiratory rate and respiratory effort) - the effusion usually subsides within two weeks.
  • If discharge is still present after two weeks, consider increasing the dosage.
  • Serum albumin increases and globulin decreases (that is, normalizes) within one to three weeks, but note that globulins may initially increase when a large volume of effusion is absorbed.
  • The resolution of lymphopenia and anemia may take longer, up to 10 weeks.
  • Mild peripheral eosinophilia is a common finding and may be a favorable marker for disease resolution, similar to that seen in patients with COVID-19.
  • The size of the lymph nodes will decrease within a few weeks.
  • If progress is not as expected, consider reassessing the diagnosis (see below) and/or increasing the dosage.
Figure 2. Cat with FIP and ascites. Effusions should begin to subside within three to five days of starting treatment.

What should be observed during treatment?

  • Ideally, serum biochemistry and hematology after two weeks and monthly thereafter.
  • For clients on a limited budget, monitor only weight/behavior/effusion/neurological signs/key biochemical abnormalities (for example, measuring only globulin and bilirubin).
  • Note that the activity of the enzyme alanine transaminase (ALT) may increase - it is not clear whether this is due to the pathology of FIP or a reaction to the drug, and it is not usually a reason to stop treatment. It is not known whether the addition of hepatoprotective treatment (eg S-adenosyl-L-methionine) helps in these cases.
  • Ultrasonography in the outpatient clinic to monitor the resolution of the effusion and/or the size of the lymph nodes.

If I observe a positive response to the treatment, when should I stop the treatment?

  • Not earlier than after 84 days (12 weeks).
  • Verify the disappearance of previous abnormalities (clinical, sono, biochemical and hematological examination).
  • Discontinue treatment only after the cat has been normal (clinically, biochemically and hematologically) for at least two weeks (ideally four weeks).

What should I do if I have no or only a partial response to treatment?

  • Make sure the cat actually has FIP - reevaluate the diagnosis, look for other pathologies, consider repeated sampling (eg, external laboratory analysis of any fluid; cytology or lymph node biopsy).
  • If biochemical abnormalities (especially hyperglobulinemia and albumin-to-globulin ratio) remain after 6 to 8 weeks, increase the dosage as for relapse (see below) by 3 mg/kg to 5 mg/kg daily and continue treatment without stopping until parameters do not normalize for at least 2 weeks, as mentioned above in the section "when to stop treatment?". – This may also mean extending the treatment for more than 12 weeks.

What should I monitor after treatment?

  • Advise the owner to monitor the cat closely for recurrence of the clinical condition - this monitoring should continue for 12 weeks after the end of treatment.
  • Ideally, repeat serum biochemistry and hematology two weeks and one month after stopping treatment (to detect any changes that might indicate an early relapse).
  • Note that relapse may occur with clinical symptoms but without any significant biochemical/hematological abnormalities.


In case of relapse – e.g. recurrence of effusion, pyrexia, development of ocular or neurological symptoms, or return of hyperglobulinemia:

  • Make sure the cat has FIP - reassess the diagnosis, consider other pathologies, consider repeat sampling (for example, external laboratory analysis of any fluid, cytology or lymph node biopsy).
  • If relapse occurs during treatment, increase the dose of remdesivir or GS-441524 and monitor treatment as before, making sure that treatment is not stopped before the cat has been normal for at least two weeks. The increased dosage depends on the dosage the cat is receiving at the time of the relapse, the nature of the relapse and the financial possibilities, but can be up to the recommended dosage for neurological FIP (see above).
  • If relapse occurs after stopping treatment, restart remdesivir or GS-441524 at a higher dose (usually 3 mg/kg to 5 mg/kg daily higher than previously used doses) and continue treatment for an additional 12 weeks. The increased dosage used depends on the dosage the cat was receiving at the time of the relapse and the nature (eg severity and/or development of neurological signs) of the relapse, but may be up to the dosage recommended for neurological FIP (20 mg/kg - see Table 1). It is possible that some cats will respond to a shorter treatment, but ideally relapse treatment is continued for the full 12 weeks after treatment has been completed to prevent relapse.
  • If the dose of remdesivir or GS-441524 cannot be increased (for example, the highest neurologic dose of 20 mg/kg is already being used), consider mefloquine as adjunctive therapy (see above) while continuing remdesivir or GS-441524 at the same dose.

Castration and routine measures during the treatment of FIP

  • If the cat responds to treatment, castration is ideally carried out a month after its completion. However, if leaving an unneutered cat causes a lot of stress - for example, attempts to escape or stress when mothers are in heat, it is advisable to prioritize neutering during treatment. If the second option is necessary, neutering should ideally be done at a time when the cat is coping well with the treatment and has at least two weeks of treatment left after neutering (so antiviral treatment takes place at a time of potential "stress" after neutering).
  • There is no contraindication for routine deworming and flea treatment in cats treated with remdesivir or GS-441524.
  • No information is available on vaccination of cats treated for FIP. If the cat is well during treatment, it should be vaccinated as usual, as it is still likely that the vaccination will have a protective effect. For cats that have completed the initial round, consider giving a third dose of vaccine after completing FIP treatment (see WSAVA Vaccination Guidelines).
  • If veterinary procedures are required, the clinic stay should be minimized and protocols and handling should be implemented according to Cat Friendly Clinicto avoid stressing the cat.

Complementary treatment

  • If a cat is receiving prednisolone, it should be discontinued during administration of remdesivir or GS-441524, and then discontinued completely, unless needed for short-term treatment of a specific immune-mediated disease resulting from FIP—for example, hemolytic anemia.
  • Supportive therapy such as antiemetics, appetite stimulants, fluid therapy, and analgesics may be given along with remdesivir or GS-442415 as needed.

Possible future updates

We are constantly learning during treatment with these drugs, and recommendations may change over time. Other substances have been tested in cats, such as protease inhibitors (such as GC376) and other nucleoside analogues (such as molpurinavir), but these are not currently commercially available. How these agents and other immunomodulatory agents (such as polyprenyl immunostimulant) will fit into future protocols is currently unknown.

Translator's Note: The original article was published and updated in February 2022, since molnupiravir officially became available for the treatment of COVID-19 in humans, and there is also the possibility of its use in the treatment of FIP.


We thank Richard Malik and Sally Coggins for their advice in the preparation of this article.

dr. Richard Malik DVSc MVetClinStud PhD FASM graduated from the University of Sydney in 1981. He is a specialist in small animal internal medicine with a special interest in infectious diseases of dogs and cats. She works at the Center for Veterinary Education and helps organize CPD.

dr. Sally Coggins BVSc (hons I) MANZCVS (Feline Medicine) she graduated from the University of Sydney in 2007 with first class honours. Sally is currently investigating novel antiviral therapeutics for the treatment of feline infectious peritonitis and is conducting clinical trials open to national recruitment.

FIP advisory line

The above experts have teamed up to launch an email address “FIP advice” (fipadvice@gmail.com) where they volunteer to answer questions about the new treatment and spread the word among vets and vet nurses in the UK. So far they have answered more than 150 emails on the advice line.

Unlicensed molnupiravir is an effective rescue treatment after failure of unlicensed GS-441524 therapy in cats with suspected FIP

Meagan Roy 1, Nicole Jacque 2, Wendy Novicoff 3, Emma Li 1,Rosa Negash 1 , Samantha JM Evans 1 *

  1. Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA
  2. Independent Researcher, San Jose, CA 95123, USA
  3. Departments of Orthopedic Surgery and Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
  4. * Author to whom correspondence should be addressed.

Academic editors: Alessia Giordano and Stefania Lauzi
Pathogens 2022, 11(10), 1209; https://doi.org/10.3390/pathogens11101209
Received: 19/09/2022 / Revised: 9/10/2022 / Received: 19/10/2022 / Published: 20/10/2022
(This article is part of a special issue of Advances on Feline Coronavirus Infection)

Original article: Unlicensed Molnupiravir is an Effective Rescue Treatment Following Failure of Unlicensed GS-441524-like Therapy for Cats with Suspected Feline Infectious Peritonitis


Feline infectious peritonitis (FIP) is a complex and historically fatal disease, although recent advances in antiviral therapy have revealed treatment options. A newer therapeutic option, unlicensed molnupiravir, is used as first-line therapy for suspected FIP and as salvage therapy for cats that have persistent or recurrent clinical signs of FIP after treatment with GS-441524 and/or GC376. Treatment protocols for 30 cats were documented based on owner-reported data. 26 cats treated with unlicensed molnupiravir as rescue therapy were treated with a mean starting dose of 12.8 mg/kg and a mean final dose of 14.7 mg/kg twice daily for a median period of 12 weeks (IQR = 10-15). A total of 24 of the 26 cats were still living without signs of disease at the time of writing this report. One cat was euthanized after treatment due to persistent seizures and the other cat underwent retreatment due to relapse of clinical signs. Few adverse effects have been reported, with the most prominent - drooping ears (1), broken whiskers (1) and severe leukopenia (1) - occurring at doses above 23 mg/kg twice daily. This study provides proof of principle for the use of molnupiravir in cats and supports the need for future studies to further evaluate molnupiravir as a potentially safe and effective therapy for FIP.

Keywords: FIP; coronavirus; antiviral drug; EIDD-2801; black market

1. Introduction

Feline infectious peritonitis (FIP) is a complex and historically fatal disease caused by mutation of the ubiquitous feline enteric coronavirus (FECV) [1]. Recent advances in feline and antiviral medicine have revealed potential treatment options for FIP. The 3C-like protease inhibitor GC376 was the first targeted antiviral therapy used against this disease [2]. GC376 was highly effective in improving clinical signs of FIP in 19 of 20 naturally infected cats, but showed limited ability to manage long-term disease [2]. Pedersen et al. continued to investigate the antiviral compound GS-441524, a nucleoside analog and active metabolite of remdesivir (GS-5734). GS-441524 demonstrated superior ability to treat and control disease in naturally infected cats compared to GC-376, with 25 of 31 cats disease-free at the time of writing [3].
Since these discoveries, cat owners worldwide have obtained these mostly unlicensed drugs to treat their FIP cats with remarkably high success rates [4]. Legal FIP treatment is in high demand in the United States due to ethical and legal concerns regarding the unlicensed drugs GC376 and GS-441524. In addition, some cats with FIP have exhausted all current treatment options due to disease relapse and/or treatment failure after GS-441524, GC376 and/or combination therapy. Therefore, an effective and legal treatment option for FIP is urgently needed.
In connection with the recent outbreak of SARS-CoV-2, a number of new antivirals have entered the market. Molnupiravir (EIDD-2801), manufactured by Merck, is currently available under an emergency use authorization (EUA) from the FDA for the treatment of COVID-19 in adults [5]. It is an oral prodrug of the nucleoside analog BD-N4-hydroxycytidine, which increases guanine to adenine and cytosine to uracil nucleotide transition mutations in coronaviruses [6]. This mechanism increases the rate of mutations above the accepted limit, which in turn inactivates the virus [7]. Molnupiravir has been found to be safe and well tolerated at doses up to 800 mg twice daily in patients with COVID-19 [8]. Some studies have reported significant reductions in hospitalizations and deaths in mild-to-moderate COVID-19 patients, although efficacy appears to be lacking in severe COVID-19 patients [7].

Because of molnupiravir's strong potential to treat other coronavirus infections, cat owners have begun using unlicensed molnupiravir (or its active metabolite EIDD-1931) purchased over the Internet to treat FIP. However, the use of molnupiravir for the treatment of FIP is currently not documented in any scientific literature. Unlicensed molnupiravir can be used as first-line therapy for suspected FIP, but also as rescue therapy to treat cats that have persistent or recurrent clinical signs of FIP after GS-441524 and/or GC376 therapy. The aim of this study is to document this use and provide proof of principle for molnupiravir as a potential treatment for FIP based on owner-reported data.

2. Materials and methods

The survey was conducted using the Qualtrics XM program (Qualtrics Version May-August 2022, Provo, UT, USA) under license from Ohio State University. The survey (Supplementary Data S1) was written in English and consisted of 94 multiple-choice and free-response questions asking about FIP diagnosis, clinical signs, initial therapy (used before molnupiravir), molnupiravir treatment, adverse events, duration of treatment, and remission time. The number of free-response questions was limited to limit recall bias. The survey also allowed owners to upload relevant documents (eg veterinary medical records and laboratory results). The survey was formatted using questions from previous studies to maintain consistency of language and style, as well as newly developed questions specific to the experience of molnupivir treatment. The logic of the survey dictated that some questions appeared only after a particular answer was selected, while others were skipped when a particular answer was selected. This conditional logic was used to reduce questionnaire completion bias and questionnaire fatigue. The survey took approximately 20-30 minutes to complete and could be saved and completed later if needed. This study was approved by the Ohio State University Institutional Review Board (Protocol No. 2021E0162).

The survey was distributed to participants individually by email and data were collected from June to August 2022. Participants were selected from a subset of owners seeking molnupiravir therapy for their cat with suspected FIP through popular FIP therapy and social media support groups. Inclusion criteria were surveys of cats suspected of having FIP based on veterinary diagnosis, failure to respond to initial therapy, or recurrence of clinical signs after completion of initial therapy other than molnupiravir (eg, GS-441524 or GC376) and completion of 8–10 weeks of oral molnupiravir therapy (or those who subsequently died or were euthanized during therapy). This study also included a small group of cats that received molnupiravir for 8-10 weeks as initial and sole therapy, which will be referred to as first-line therapy in the rest of this paper, when FIP is suspected. Exclusion criteria were surveys with incomplete data or cats not diagnosed with FIP by a veterinarian.

3. Results

3.1 Demographic data

A total of 80 potential participants were identified through the FIP social media support group, and 37 questionnaire invitations were sent to those participants with available contact information. A total of 33 questionnaires were sent and follow-up emails were sent to 21 participants in order to obtain complete data from the questionnaires. Seventeen owners attached relevant documents to the sent questionnaires, and two other owners sent relevant documents to the study e-mail address, which included veterinary medical records, laboratory results and diagnostic images. These listed documents were used to document adverse reactions reported by one participant. One response was refusal to participate. Two cases were excluded because the cats did not have a veterinarian diagnosis of FIP (one was reportedly diagnosed based on the loss of a sibling to FIP, and the other was examined by a veterinarian who concluded that blood tests were not consistent with FIP). Thus, a total of 30 cats with suspected FIP were included in this study, 4 of which received no treatment prior to molnupiravir administration. These four cats were enrolled as a separate small cohort for first-line molnupiravir treatment. A block diagram of these cases is shown in Figure 1. The countries of origin represented were the United States (25), Germany (2), Poland (2), and Sweden (1). The sex/neuter status of the cats at the time of diagnosis was 40 % neutered males, 40 % spayed females and 20 % non-neutered males. The average age at diagnosis was 9.7 months, with a range from 1 month to 6 years. Most cats were of mixed or unknown breed (70 %); among them were seven purebred cats and two special crossbred cats (eg, a cross between a Balinese and ragdoll cat and a Siamese cat). Responses identifying the cat as "American Shorthair" or "American Longhair" were instead categorized as mixed breed, given the commonly reported confusion among American owners regarding the breed's nomenclature.

Figure 1. This flowchart represents the number of cases in each treatment block.

Regarding comorbidities, feline leukemia virus was reported in only one cat and calicivirus was reported in one cat. Several cats also had a history of external and/or internal parasitic infections (3), conjunctivitis/ocular infections (2), and bacterial skin infections (pyoderma) (1). A total of 16 cats had neurological signs of FIP. Three cats had both neurological and ocular manifestations of FIP, and two cats had only ocular manifestations of FIP. Of the remaining cases, seven were effusive, while five cases were non-effusive. The full breakdown of FIP types is shown in Table 1.

CatAge at diagnosis (months)Sex/castration status at diagnosisTribePrevious medical conditionsCountry of originFIP formDuration of initial treatment (weeks)Disease-free periodSecond therapyDuration of the second therapy (weeks)Disease-free periodThe third therapyDuration of the third therapy (weeks)Disease-free period
14MaleEuropean shorthairparasitic infections, URI at an early ageGermanyneurologicalinjectable oral GS-4415248noneinjectable and oral GS-44152415none
215neutered catBurmesenoneSwedeneffusive, non-effusive, neurologicalinjectable GS-44152412less than 4 weeksinjectable GS-4415241417 daysoral GS-4415245 weeksnone
39neutered catBritish ShorthairnonePolandeffusive, neurological, ocularinjectable GS-44152413less than 2 weeksinjectable GS-44152412more than 6 months, less than 1 year
45neutered catAbyssinianoneUSAeffusiveinjectable GS-44152412less than 2 weeksinjectable GS-44152414less than 4 weeks
54neutered catBalinese/Ragdol mixcalicivirus, conjunctivitis, giardiasis, tapeworm, URIUSAnon-effusiveinjectable GS-44152413less than 8 weeks
67neutered catSiamesenoneUSAneurologicalinjectable and oral GS-441524, injectable GC, injectable and oral molnupiravir12none
77neutered catAmerican ShorthairnoneUSAnon-effusiveinjectable and oral GS-4415245none
86neutered catAmerican Shorthair/Siamese mixtapeworm, FCoVUSAeffusive, neurologicalinjectable and oral GS-4415245none
94neutered catHomemade mixedbroken pelvisUSAeffusiveinjectable and oral GS-44152414less than 6 monthsoral GS-44152413less than 4 weeksoral GS-441524/injectable GC6 weeks in combination then 6 weeks of oral GSnone
104neutered catHomemade mixednoneUSAeffusiveinjectable GS-44152423less than 4 weeks
1172neutered catHomemade mixedFeLVUSAnon-effusiveoral GS-44152412less than 6 months
125MaleHomemade mixednoneUSAnon-effusive, neurological, ocularinjectable and oral GS-44152417none
1301.VMaleSavannahnoneUSAeffusive, neurologicalinjectable and oral GS-44152424less than 6 monthsinjectable and oral GS-44152412less than 4 weeks
144neutered catHomemade mixedSkin and eye infections, fleasPolandnon-effusive, neurologicalinjectable GS-44152412less than 2 weeksinjectable GS-44152417less than 4 weeks
1512neutered catAmerican ShorthairnoneUSAeffusiveinjectable GS-441524/GC01.Vnone
165neutered catHomemade mixednoneUSAeffusive, neurologicalinjectable GS-44152412less than 4 weeks
174MaleAmerican longhairnoneUSAocularinjectable and oral GS-441524, GC37613none
186neutered catHomemade mixednoneUSAeffusiveinjectable GS-44152412none
1912neutered catHomemade mixednoneUSAnon-effusiveinjectable and oral GS-44152412less than 2 weeksinjectable GS-44152412none
206neutered catUnknownnoneUSAnon-effusive, neurologicalinjectable GS-4415244noneoral GS-4415243none
214neutered catNorwegian forestnoneUSAneurologicalinjectable GS-44152412less than 6 monthsinjectable GS-44152401.VnoneMolnupiravir, GS-441524, GC12 weeksnone
226neutered catHomemade mixednoneUSAneurological, ocularoral GS-4415243none
2312neutered catUnknownnoneGermanyneurologicalinjectable GS-44152416less than 6 months
243MaleHomemade mixednoneUSAneurologicalinjectable GS-44152412less than 6 months
256neutered catAmerican ShorthairnoneUSAeffusiveoral GS-44152413less than 1 week
261MaleUnknownnoneUSAnon-effusiveinjectable GS-44152412less than 1 week
277neutered catHomemade mixednoneUSAnon-effusive, neurologicalMolnupiravir12less than 1 week*Molnupiravir
2824neutered catHomemade mixednoneUSAeffusiveMolnupiravir
2912neutered catHomemade mixednoneUSAnon-effusive, ocularMolnupiravir
3024neutered catHomemade mixednoneUSAneurologicalMolnupiravir
Table 1. Signaling and initial therapy characteristics of all 30 cats treated with unlicensed molnupiravir for suspected FIP.

3.2. Initial treatment before initiation of molnupiravir

A total of 26 of 30 cats received initial treatment for suspected FIP with unlicensed GS-441524 or a drug combination containing unlicensed GS-441524 as the main base drug (GS-441524-based). Half (13) of the cats were treated with injectable GS-441524. Only three cats were treated with oral GS-441524, while the other seven cats were treated with a combination of injectable and oral GS-441524 throughout the treatment period. Two cats were treated with a combination of the unlicensed drug GS-441524 and the unlicensed drug GC376. Cube no. 6 was treated with all previously mentioned drugs along with molnupiravir for 12 weeks of a very complicated regimen (Supplementary Data S2). Dosing of combination drugs used as part of primary therapy (eg, GC376 and molnupiravir) was not determined. Reported initial doses of the unlicensed GS-441524 ranged from 2 mg/kg to 10 mg/kg; the most frequently reported dosages were 5-6 mg/kg (eight cats) and 10 mg/kg (seven cats). Most (21) cats received a dose once a day. Only four were dosed twice daily, and one cat was dosed twice daily for one week at first, then switched to once daily dosing. The median duration of treatment based on GS-441524 was 12 weeks (IQR = 12-13). In fifteen cats, a change in daily doses was reported during treatment. For several cats, the daily dose was increased by body weight to maintain the same dosage in mg/kg. Others increased the mg/kg dosage because of insufficient clinical response or a change in route of administration (eg, from injectable to oral GS-441524). No participant reported dose reduction during treatment.

A total of 6 of 26 cats completed a shorter than average 12-week treatment with GS-441524 due to insufficient clinical response and were immediately started on another treatment. Two of the six cats initiated a different route or dose of unlicensed GS-441524 treatment as shown in Table 1. One cat switched from injectable to oral GS-441524 treatment on the second treatment. In the second cat, the dose of GS-441524 was simply increased during the second treatment. The remaining four cats started treatment with unlicensed molnupiravir at this time, as shown in Table 2. Of the 20 cats that completed at least 12 weeks of treatment with GS-441524, 16 experienced clinical remission. All 16 were in remission for less than 6 months, with 2 cats in remission for less than a week before clinical signs returned. All 16 started a second round of treatment, with 10 receiving a second round of GS-441524-based treatment and 6 starting molnupiravir at this time. Four cats that completed treatment with GS-441524 but did not achieve clinical remission were immediately started on molnupivir. A total of 26 cats received primary treatment with GS-441524 and all 26 relapsed or did not respond adequately. A total of 10 of 26 completed a second round of GS-441524-based treatment and 16 started molnupivir treatment.

CatClinical symptoms at the beginning of treatmentBrand nameInitial dosage and frequencyFinal dosage and frequencyDuration of treatment (weeks)Time to improvePersistent clinical symptomsThe resultAdverse effects
1diarrhea, vomitingAura Plus11 mg/kg twice daily11 mg/kg twice daily12less than 1 weeknoneclinical remissionnone
2none reportedAura12 mg/kg twice a day12 mg/kg twice a day12uncertainnoneclinical remissionnone
3anisocoria, colored spots in the eye, polydipsia, pica, weight lossAura 280128 mg/kg twice daily14 mg/kg twice a day12within 2 weeksnoneclinical remissionnone
4anorexia, lethargy, weight lossEIDD7 mg/kg twice a day7 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
5colored spots in the eye, diarrhea, hiding and lack of socializationAura 28016 mg/kg once daily13 mg/kg once daily10within 2 weeksnoneclinical remissionnone
6anisocoria, constipation, anorexia, fecal and urinary incontinence, lethargy, paralysis, seizures, pale gums, weight lossAura 280120 mg/kg twice a day20 mg/kg twice a day11less than 1 weeknoneclinical remissionnone
7anorexia, difficulty walking, hiding, lack of socialization, jaundice, lethargyCapella EIDD9 mg/kg twice daily13 mg/kg twice a day10less than 1 weeknoneclinical remissionnone
8anorexia, difficulty walking, urinary incontinence, paralysisAura 280117 mg/kg twice a day17 mg/kg twice a day15less than 1 weekdifficulty walking persisted for 2 months, still not normal but has a normal lifeclinical remissionnone
9cough, anorexia, hiding, lack of socialization, polydipsia, weight lossAura 280112 mg/kg twice a day16 mg/kg twice a day13within 2 weekspolydipsia persisted for 1 weekclinical remissionnone
10anorexia, lethargy, weight lossAura 280112 mg/kg twice a day12 mg/kg twice a day16within 2 weeksnoneclinical remissionnone
11anorexia, lethargy, URI, weight lossAura 193112 mg/kg twice a day12 mg/kg twice a day12within 2 weeksnoneclinical remissionnone
12blindness, head bobbing, difficulty walkingAura 280110 mg/kg twice a day14 mg/kg twice a day12within 3 weeksnoneclinical remissionnone
13difficulty walking, hiding, lack of socialization, polyuria, lethargy, anorexia, paralysis, tremorsAura 280112 mg/kg twice a day12 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
14anorexia, heavy walking, hiding, lack of socialization, lethargy, unusual timidityAura 280111 mg/kg twice daily16 mg/kg twice a day18more than 4 weeksnothing physical but the MRI is still not normalclinical remissionnone
15blindness, constipation, anorexia, diarrhea, enlarged abdomen, hiding, lack of socialization, lethargy, pale gums, weight lossAura 280116 mg/kg twice a day16 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
16anorexia, difficulty walking, lethargy, seizures, tremors, weight lossAura 280114 mg/kg twice a day14 mg/kg twice a day12less than 1 weeknoneclinical remissionnone
17cough, anorexia, difficulty breathing, hiding, lack of socialization, lethargy, vomiting, weight lossAura 2801 and Aura 193112 mg/kg twice a day17 mg/kg twice a day20within 3 weeksanorexiaclinical remissionnausea/vomiting, anorexia
18constipation, anorexia, difficulty walking, hiding, lack of socialization, weight lossAura 280112 mg/kg twice a day12 mg/kg twice a day8within 2 weeksnoneclinical remissionnone
19lethargy, anorexiaAura 280112 mg/kg twice a day12 mg/kg twice a day7within 2 weeksnoneclinical remissionnone
20trembling/shakingAura 280110 mg/kg twice a day23 mg/kg two to three times a day10less than 1 weekin remission about 1 1 weeks before the onset of seizureseuthanasiadecreased appetite when dosed three times a day, severe leukopenia, loss of beard, scaly skin on ears
21difficulty walking, fecal incontinenceAura 2801 and Aura 193113 mg/kg twice a day30 mg/kg twice a day14less than 1 weekdifficult walking, difficult jumping, fecal incontinence persisted during the study (1 week post treatment)relapse and euthanasiadrooping ear tips, muscle weakness
22colored spots in the eye, anorexia, difficulty walking, hiding, lack of socialization, lethargyAura 280116 mg/kg twice a day19 mg/kg twice a day9within 2 weeksnoneclinical remissionnone
23difficulty walking, anorexia, loss of balanceEIDD aura12 mg/kg twice a day15 mg/kg three times a day10within 2 weeksheavy walkingclinical remissionnone
24blindness, colored spots in the mouth, anorexia, difficulty breathing, difficulty walking, enlarged abdomen, urinary incontinence, jaundice, lethargy, paralysis, tremorsAura 280115 mg/kg twice a day15 mg/kg twice a day16less than 1 weeknoneclinical remissionnone
25difficulty breathing, difficulty walking, hiding, lack of socialization, lethargy, URIAura 28017 mg/kg twice a day7 mg/kg twice a day16within 2 weeksnoneclinical remissionnone
26lethargy, anorexiaAura 280114 mg/kg twice a day14 mg/kg twice a day15less than 1 weekneurological twitches, elevated liver enzymesclinical remissionnone
Table 2. Treatment and outcome characteristics of 26 cats receiving unlicensed molnupiravir as rescue therapy.

3.3. The second round of treatment before the initiation of molnupiravir

Overall, 10 of 26 cats that received initial GS-441524 treatment and subsequently relapsed were reported to have received a second round of unlicensed GS-441524 treatment prior to initiation of molnupiravir. Again, most cats received injectable GS-441524 (6), with two receiving oral GS-441524 and two receiving both injectable and oral GS-441524. Reported dosages ranged from 4-5 mg/kg to 15 mg/kg; the most frequently used dosages were 7-8 mg/kg (two cats) and 15 mg/kg (two cats). Most cats were dosed once daily (seven cats), one cat was dosed twice daily and one cat was dosed three times daily. In most cats, the dose was varied during treatment. The two doses were weight-adjusted to maintain the same dosage in mg/kg. Dosing in mg/kg was increased in five cats that did not respond adequately or developed new clinical signs (eg, neurological signs).
The median duration of treatment was 12.5 weeks (IQR 9.75–14.25). Only two cats did not undergo at least 12 weeks of therapy. One of the two added GC376 and molnupiravir to current GS-441524 therapy, and the other started molnupiravir as sole therapy. Of the eight cats that completed at least 12 weeks of GS-441524 therapy, two did not achieve clinical remission. Both cats started treatment with unlicensed molnupiravir at that time. The remaining six cats were reported to achieve clinical remission after a second round of treatment with GS-441524. Five of the six cats were in remission for less than 4 weeks, with the exception of one cat that was in remission for more than 6 months but less than a year. Seven out of ten cats started taking unlicensed molnupiravir at this time.

3.4. The third round of treatment before starting molnupiravir

The remaining three cats received a final round of GS-441524-based treatment before switching to molnupiravir. Cat no. 2 received oral GS-441524 for 5 weeks prior to initiation of molnupiravir. Cat no. 9 was treated for 6 weeks with oral and injectable GS-441524 and then continued for 6 weeks with oral GS-442524 alone. Dosing and frequency in both cats are unknown, as the survey collected data on only two therapies prior to molnupivir. Cat no. 21 received a combination of GS-441524, GC376 and molnupiravir for 12 weeks. The dosage, frequency and duration of each varied radically over the course of 12 weeks (Supplementary Data S3). All three cats started treatment with molnupiravir without clinical remission from this third round of treatment.

3.5. Molnupiravir as rescue therapy

Of the 26 cats receiving unlicensed molnupiravir as rescue therapy, most were using the Aura brand, with only 2 cats using a different brand of molnupiravir. More than 81 % cats (18) were treated with Aura 2801, 1 cat was treated with Aura 1931, and another 2 cats were treated with both Aura preparations. The mean initial dosage was 12.8 mg/kg twice daily. One cat was dosed only once a day and two cats were dosed 2 to 3 times a day. The most commonly used initial dosage was 12 mg/kg twice daily. Dosage ranged from 6 to 28 mg/kg twice daily. 11 dosage changes were reported, all but one being an increase in dosage. Reduction of dosage in cat no. 3 was not explained in any way. The mean final dosage was 14.7 mg/kg twice daily, with the same three cats differing in dosing frequency. The most common final dosage was also 12 mg/kg twice daily. The dosage range was 7 to 30 mg/kg twice daily.

Median duration of treatment was 12 weeks (IQR 10-15). Overall, a wide range of 7-20 weeks was reported. Only eight cats were treated for less than 12 weeks. A cat that completed only 7 weeks of treatment was reported to have discontinued treatment due to achieving clinical remission. All 26 cats completed treatment at 7 weeks or longer and all 26 cats survived. No cases of missed doses of molnupiravir have been reported.

Owners reported improvement in clinical signs in more than 92 % cats within three weeks of initiation of molnupiravir treatment, with 84.6 % cats showing improvement within two weeks and nearly half (46.2 %) within one week. Only two cases were reported differently, with one cat showing no signs of improvement for up to 1.5 months, and the owner of the other cat being unsure of the timescale and degree of improvement in clinical signs. A total of seven cats with persistent clinical signs of FIP were reported. In one of them, the disappearance of clinical symptoms was reported after one week of the observation period. Others are thought to have had residual symptoms such as difficulty walking or jumping, tremors, MRI changes and fecal incontinence. The full range of persistent clinical signs is shown in Table 2. Only three cats reported adverse reactions in response to molnupiravir, including nausea/vomiting, anorexia, drooping ear tips (Figure 2), brittle whiskers, leukopenia, scaly skin and muscle wasting. At the time of publication, 24 of 26 cats are living in clinical remission of FIP after oral molnupiravir treatment. One cat reportedly died 1 week after discontinuation of molnupiravir due to a prolonged seizure, and the other cat (No. 21) was disease-free 4 weeks before relapse. Cat no. 21 then started a second round of molnupiravir at the same dose, but was subsequently euthanized due to insufficient response to treatment.

Figure 2. Dropped ear tips were reported as an adverse effect of unlicensed molnupiravir treatment in cat no. 21.

In cat no. Severe leukopenia was reported in 22 cases. Through veterinary records, it was found that cat no. 22 has moderate panleukopenia with lymphopenia, neutropenia, and normal hem and thrombograms on 4 of 5 sequential complete blood counts, which were confirmed through veterinary records of sequential complete blood counts. The initial white blood cell count recorded was 10,700 cells per microliter (reference range 3,500–16,000 cells per microliter). Four more complete blood tests showed white blood cell counts ranging from 1,200 to 1,900 cells per microliter. The initial neutrophil count was 8560 cells per microliter (reference range 2500-8500 cells per microliter). The other four neutrophil counts ranged from 696 to 1292 cells per microliter. The initial lymphocyte count was 1177 cells per microliter (reference range 1200-8000 cells per microliter). The other four lymphocyte counts ranged from 330 to 532 cells per microliter.

3.6. Molnupiravir as primary therapy

A small group of four cats were treated with unlicensed molnupiravir as sole therapy for suspected FIP, as shown in Table 3. Three of them reportedly chose molnupiravir over the unlicensed counterpart GS-441524 due to financial constraints. Cat no. 29 received 12 weeks of oral molnupiravir 12 mg/kg twice daily prior to the treatment shown in Table 3. This cat was disease-free for less than one week prior to restarting oral molnupiravir 19 mg/kg twice daily for 10 weeks.

CatClinical symptoms at the beginning of treatmentBrand nameInitial dosage and frequencyFinal dosage and frequencyDuration of treatment (weeks)Time to improvePersistent clinical symptomsConclusionAdverse effects
* 27Hiding, lack of socialization, lethargy, anorexia, URI, vomiting, weight lossAura 280119 mg/kg twice a day19 mg/kg twice a day10less than 1 weeknoneclinical remissionnone
28Anorexia, difficulty walking, distended abdomen, hiding, lack of socialization, lethargyAura 28018 mg/kg twice a day8 mg/kg twice a day13in two weeksnoneclinical remissionnone
29Anisocoria, blindness, eye color changes, anorexia, hiding, lack of socialization, urinary incontinence, lethargy,Aura 280110 mg/kg twice a day10 mg/kg twice a day13in two weeksnoneclinical remissionnone
30Hiding, lack of socialization, lethargy, pale gums, weight lossAura 280110 mg/kg twice a day12 mg/kg twice a day10in two weeksnoneclinical remissionnone
Table 3. Treatment and outcome characteristics of 4 cats receiving unlicensed molnupiravir as primary therapy.* They received two rounds of molnupiravir treatment; the first round is documented in Table 1.

All four cats were treated with oral molnupiravir Aura 2801 at a mean starting dose of 11.75 mg/kg twice daily (range 8-19 mg/kg) and a mean final dose of 12.25 mg/kg twice daily (range 8-19 mg/kg ). The median duration of treatment was 11.5 weeks (IQR 10-13), with two cats treated for 10 weeks and two cats treated for 13 weeks. A Mann-Whitney test was performed and no significant difference was found between the median duration of molnupivir as rescue therapy (12) and the duration of molnupivir as initial therapy (11.5) (p = 0.692). All owners reported seeing clinical improvement within two weeks and one cat showed improvement within one week. All cats survived the treatment, were disease-free at the time of publication, and no adverse effects of the treatment were reported.

3.7. Molnupiravir by type of FIP

The above information was collected for all 30 cats and then further divided according to the clinical forms of FIP. First, 16 cats with a reported neurological form of FIP were evaluated. Subsequently, the other cats were divided according to ocular (2), effusive (7) and non-effusive (5) forms. The mean starting dose of molnupiravir in the neurological form of FIP was 14.4 mg/kg twice daily, with two cats treated 2-3 times daily. The mean final dosage was 16.4 mg/kg twice daily, with two cats treated 2-3 times daily. The most commonly used initial and final dosage was 12 mg/kg twice daily. Median duration of treatment for neurological FIP was 12 weeks (IQR 10-12,641).

In the two remaining cases of ocular FIP, the mean initial dose was 11 mg/kg twice daily and the mean final dose was 13.5 mg/kg twice daily. The treatment lasted an average of 16.5 weeks. Seven cases of effusive disease were treated with a mean initial dose of 10.5 mg/kg twice daily and a mean final dose of 11.1 mg/kg twice daily. Treatment lasted an average of 13 weeks (IQR 12–16). Five non-effusive cases were treated with a mean initial dose of 10.6 mg/kg twice daily and a mean final dose of 12.8 mg/kg twice daily. One cat was treated once a day. The average duration of treatment was 10 weeks (IQR 8.5-13.5).

3.8. Costs and owner satisfaction

The majority of cats in this study were switched to unlicensed molnupiravir due to treatment failure/relapse or insufficient response. In addition to cats that relapsed or did not respond to unlicensed GS-441524-based treatment, one cat was intolerant to the injectable form of GS and three owners were cost-restricted. Owners were not required to disclose the financial costs of treatment; this information was provided on a voluntary basis only. In addition, “0” responses that were reported were not included in the calculation of the following averages due to the inability to distinguish whether “0” means no cost or unknown cost. The mean reported cost of the first round of GS-441524-based treatment was $3448.83, and similarly the mean reported cost of the second round of GS-441524-based treatment was $3509.09. Only 4 owners reported paying for molnupiravir treatment, while 16 others reported “0” (or no cost/cost unknown). The overall mean for the 20 owners who responded to the financial cost survey question (including “0” responses) for molnupiravir was $209. The average cost of the four owners who did not answer “0” was $1045. While 90 % owners reported being "very" or "somewhat" satisfied with their cat's experience of treating their cat with molnupiravir, three were "very dissatisfied" with their experience. Unfortunately, no explanation was provided for the reported dissatisfaction.

4. Discussion

In this work, we describe the first known use of unlicensed molnupiravir for the treatment of suspected FIP in cats based on owner-reported data. For the treatment of cats using unlicensed molnupiravir as primary therapy for suspected FIP, the combined data from this study suggests that dosing at 12 mg/kg twice daily for approximately 12 weeks is effective in achieving clinical remission. For the treatment of cats receiving molnupiravir as rescue therapy when failing or relapsing after GS-441524-based therapy, the combined data from this study suggests that dosing at 12-15 mg/kg twice daily for 12-13 weeks is effective in achieving clinical remission. However, when broken down by clinical form of FIP, it was found that neurological cases of FIP were generally treated with a higher dosage than the average for all types of FIP. Ocular, effusive and non-effusive cases were treated with a dosage of around 12 mg/kg twice daily, with some variations. Therefore, dosing of 15 mg/kg molnupiravir twice daily for 12 weeks appears to be effective for neurological cases of FIP. For ocular, effusive, and non-effusive cases, 12 mg/kg molnupiravir twice daily for 12–13 weeks appears to be effective.

These data are somewhat inconsistent with the proposed treatment protocol of the company producing unlicensed molnupiravir under the trade name HERO Plus 2801. The recommended dosage in the package insert is 25 mg/kg once daily for effusive and non-effusive FIP, 37.5 mg/kg once daily for ocular FIP and 50 mg/kg once daily for neurological FIP [9]. The package leaflet of HERO Plus 2801 also includes the preliminary results of the study "Effect of treatment with oral nutrition on survival time and quality of life in feline infectious peritonitis", which includes 286 cats with a diagnosis of FIP. According to this package insert, 28 cats were cured after 4 weeks of treatment and 258 cats were cured after 8 weeks of treatment, with no deaths at the time of reporting [9]. Data from this study have not yet been published in the scientific literature.

However, the cats in this study were using molnupiravir from a different supplier, Aura, which did not provide specific treatment recommendations. The treatment protocols used were therefore based on advice and information shared in groups on social networks, worksheets published on the Internet [10,11] and information on possible adverse effects contained in information published as part of human drug approval applications [12].

The molnupivir treatment protocol derived from this study more closely matches an independently designed protocol [10] published on the Internet. Based on data from in vitro cell cultures of EIDD-1931 and EIDD-2801, laboratory and field studies of GS-441524, and human pharmacokinetic studies, these authors extrapolated the effective dosage of oral molnupiravir [10]. Their calculations suggested a dosage of 4.5 mg/kg every 12 h for effusive and non-effusive FIP, 8 mg/kg every 12 h for ocular FIP, and 10 mg/kg every 12 h for neurological FIP [10]. Although the dosage in this study was generally higher than the dosage suggested by the cited authors, the high survival rate and low relapse rate at the time of the study termination suggest that the manufacturer's unlicensed recommendations may not represent the lowest effective dosage. Ultimately, controlled scientific experiments are greatly needed to evaluate the lowest effective dosage of molnupiravir in cats with suspected FIP.

Several cats were treated with Aura 1931, which is the active metabolite of molnupiravir, EIDD-1931. The reported dosages used were in a similar range to those reported for molnupiravir. Nominally, because the molecular weight of EIDD-1931 is lower than that of EIDD-2801, these cats received more active drug than cats using molnupiravir. However, a previous study showed decreasing oral bioavailability with increasing doses in mice. Therefore, the difference in bioavailability may not be proportional [13]. Pharmacokinetic studies of both molnupiravir and EIDD-1931 in cats are unfortunately unknown.

No adverse effects were reported in the package insert for HERO Plus 2801, which is contrary to what was reported in this study. Among the reported side effects of molnupiravir, the most prominent were drooping ears, hair loss, and severe leukopenia. No skin or follicular lesions have been reported in the human medical literature to match the whisker shedding or ear folding reported here. However, it should be noted that the cats that experienced these side effects received the two highest doses of molnupiravir shown in this study: 23 mg/kg three times daily and 30 mg/kg twice daily.

Severe bone marrow toxicity was reported in dogs during a 28-day study that was discontinued due to severe drug effects [12]. At the dosage of 17 mg/kg/day and 50 mg/kg/day, all hematopoietic cell lines were affected [12]. Cat no. 22 received a maximum dosage of 23 mg/kg three times daily, which was much higher than the toxic dosage in dogs of 17 mg/kg once daily. In the study group with a dose of 17 mg/kg, the possibility of reversibility was noted when the treatment was stopped [12].

There are concerns about the content of unlicensed brands of molnuviravir, as these brands are not currently regulated and often do not list the actual ingredients. The Hero brand (same manufacturer as HERO Plus 2801) shown in Figure 3 was analyzed by our group in December 2021 through Toxicology Associates Inc. (Columbus, OH). It was found to contain 97.3 % of molnupivirus, with no other contaminants detected. The Aura 2801 product used by the majority of participants in this study was analyzed in September 2022 by the same laboratory. It was found to contain 96.8 % of pure molnupivirus. A more controlled assessment of the actual content and purity of the unlicensed preparations of both GS-441524 and molnupiravir is of great interest to the veterinary community and is an active research topic in our group.

Figure 3. Images of Hero brand unlicensed molnupiravir packaging.

Some limitations of this study result from the retrospective nature and legality of the therapies used. First, all data used in this study were obtained based on owner reports. Working closely with the owners and administrators of the social media websites that supported this group enabled a better understanding and interpretation of many of the survey responses. Due to the lack of a definitive ante-mortem diagnosis of FIP available for practical use, it was also not possible to confirm that the cats included in this study had FIP. In addition, the data are likely to be biased toward positive outcomes and may be burdened by recall error. During the distribution phase, a potential study participant responded by requesting to be removed from our email list and stating that he did not wish to participate in the study. Their cat did not respond to molnupiravir treatment and was eventually euthanized. We assume that others may have had the same feeling, since three other potential participants did not respond to the invitation to the study. This may have narrowed the number of participants with an adverse outcome and falsely inflated apparent survival rates. Therefore, the data presented here are intended to serve as evidence of the feasibility of using molnupiravir as primary or rescue treatment for FIP, not as an indication of the true rate of efficacy.

In cats using unlicensed molnupiravir as rescue therapy, the cause of failure to respond or relapse after GS-441524-based therapy was not determined. It could be related to the quality of the drug, the resistance of the virus or another factor. As there is currently no testing or regulation in the US, unlicensed versions of GS-441524 or GC376 may be of insufficient purity or concentration, leading to treatment failure. Another possible cause is natural or acquired resistance to GS-441524. These two causes may also be linked, as acquired resistance may be promoted when an insufficient amount of antiviral is used in treatment, for example with low-quality drugs.

A recent paper found no drug-induced viral mutations of SARS-CoV-2 during molnupivir treatment [14]. This suggests that SARS-CoV-2 is unlikely to develop resistance to molnupiravir. Therefore, treatment with molnupiravir may be similarly unlikely to induce FIPV resistance, making it an attractive therapeutic option.

However, there is clearly a need for (1) a legal (in the United States and elsewhere) alternative to unlicensed treatment with GS-441524 and (2) the availability of alternative rescue drugs, either alone or in combination, after failure of GS-441524 treatment. Molnupiravir has the potential to fill both of these gaps, and this is the first known report of its use in cats in the literature. Nevertheless, unlicensed preparations may continue to be used for the treatment of FIP given the cost and the widely established networks available for their acquisition.

In conclusion, based on owner-reported data, unlicensed molnupiravir appears to be an effective treatment for suspected FIP as both first-line and salvage therapy. At a dosage of 12-15 mg/kg every twelve hours, minimal side effects are reported and it provides survival with clinical resolution of FIP symptoms. Although the experiences of these owners in treating and apparently curing cats from FIP are unconventional and potentially illegal, they are undeniably remarkable and we can learn a lot from the experiments these "citizen scientists" are conducting. By reporting these experiences, we aim to provide a starting point for investigating molnupiravir for use in cats with suspected FIP and to document a "herd health" phenomenon that our profession should not ignore.

Supplementary materials

The following supplementary information can be downloaded at https://www.mdpi.com/article/10.3390/pathogens11101209/s1 Supplementary Data S1: retrospective review of molnupiravir trials; additional data S2: abbreviated diary of clinical history cat. no. 6; supplementary data S3: Cat #21 abbreviated clinical history log.


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Clinical and molecular links between COVID-19 and feline infectious peritonitis (FIP)

Arjun N. Sweet, Nicole M. André, Alison E. Stout, Beth N. Licitra and Gary R. Whittaker
Julia A. Beatty, Academic Editor and Séverine Tasker, Academic Editor

Original article: Clinical and Molecular Relationships between COVID-19 and Feline Infectious Peritonitis (FIP)


The emergence of severe acute respiratory syndrome 2 (SARS-CoV-2) has led the medical and scientific community to address questions regarding the pathogenesis and clinical presentation of COVID-19; however, relevant clinical models other than humans are still lacking. In cats, the ubiquitous coronavirus, described as feline coronavirus (FCoV), can manifest as feline infectious peritonitis (FIP), a leading cause of mortality in young cats characterized by severe systemic inflammation. The diverse extrapulmonary symptoms of FIP and the rapidly progressive course of the disease, together with the proximate etiologic agent, represent a degree of overlap with COVID-19. This article reviews the molecular and clinical relationships between FIP and COVID-19. Although there are key differences between the two syndromes, these similarities encourage further investigation of feline coronaviruses as a naturally occurring clinical model for human coronavirus disease.

Keywords: feline infectious peritonitis, SARS-CoV-2, COVID-19, cats

1. Introduction

In the 1960s, feline infectious peritonitis (FIP) was described as a disease in domestic cats and was subsequently found to be of viral etiology, specifically feline coronavirus (FCoV). [1,2]. In most cats, infection with FCoV results in mild to inconspicuous clinical signs, but a small proportion of cats develop severe disease and succumb to the systemic form of the disease known as FIP [3]. In the years since the discovery of FCoV, many features of FCoV have remained misunderstood. Similarly, the COVID-19 pandemic, caused by the emergence of SARS-CoV-2, has raised many equally challenging questions regarding pathogenesis, transmissibility, and treatment. The widespread transmission of FCoV/SARS-CoV-2 and the insidious onset of severe symptoms in both FIP and COVID-19 limit the ability to detect the disease early—what may begin as mild or even mild clinical signs or symptoms can quickly lead to systemic disease [3,4]. We believe that FIP may represent a valuable, naturally occurring extrapulmonary model of COVID-19.

Both FCoV and SARS-CoV-2 belong to the family Coronaviridae [4,5], although to different genera (Figure 1). FCoV, together with similar animal coronaviruses such as canine coronavirus (CCoV) and porcine gastroenteritis virus (TGEV), belong to the genus alpha-coronaviruses. Community respiratory (CAR) human coronaviruses 229E and NL63 are also included in the genus Alphacoronaviruses. [6], the latter being associated with the common cold, hail and possibly Kawasaki disease in children [7]. In contrast, SARS-CoV-2, together with SARS-CoV (the causative agent of the severe acute respiratory syndrome outbreak in 2002-2003) and the Middle East respiratory syndrome coronavirus (MERS-CoV) belong to the genus betacoronaviruses [8], wherein SARS-CoV-2 and SARS-CoV belong to line B (sarbecovirus) and MERS-CoV belong to line C (merbecovirus). Less related beta coronaviruses include human coronavirus CAR OC43 (associated with the common cold), mouse hepatitis virus (MHV), and bovine coronavirus, which is associated with pneumonia and diarrhea in cattle; these viruses are in line A (embekovirus).

Figure 1
Phylogenetic tree of spike proteins of selected coronaviruses. The phylogenetic tree of maximum likelihood was constructed using the MEGAX program (100 bootstraps) from multiple alignment of spike protein sequences. Tip amino acid sequences were obtained from GenBank NCBI. Relevant numbers are: transmissible gastroenteritis virus / TGEV (P07946), severe acute respiratory syndrome coronavirus 2 / SARS-CoV-2 (YP_009724390.1), middle eastern respiratory syndrome / MERS-CoV coronavirus (AFS88 /36) 1. -1 (ACN89742), severe acute respiratory syndrome coronavirus / SARS-CoV (AAT74874.1), feline coronavirus / FCoV-Black (EU186072.1), bovine coronavirus / BCoV (P15777), canine coronavirus / CCo37.14) , human coronavirus / HCoV-OC43 (NC_006213.1), HCoV-229E (NC_002645.1) and HCoV-229E (NC_002645.1).

FCoV can be classified in two ways, the first of which relates to the form of the disease. Feline enteric coronavirus (FECV) is thought to cause a mild gastrointestinal form of the disease, while feline infectious peritonitis virus (FIPV) is associated with a fatal systemic infection known as FIP. [3]. FIPV differs from FECV in its ability to infect and replicate efficiently in monocytes and macrophages [9], causing systemic inflammation. FIPV is associated with a spectrum of clinical sequelae. At one end of the spectrum is effusive or “wet” FIP, which progresses rapidly and involves the accumulation of a highly proteinaceous exudate in the abdominal and/or thoracic cavity. At the other end of the spectrum is non-effusive or “dry” FIP, which can affect many organ systems but is usually characterized by neurological and ocular symptoms. Non-effusive FIP generally has a longer course of disease and is less common than its effusive counterpart. FCoV can also be divided into two serotypes – type I or type II – based on major differences in the spike protein of the virus that affect receptor binding and antibody response [10]. The receptor for FCoV type II is feline aminopeptidase N (fAPN) [11], while the receptor for type I viruses is not identified. Type I FCoV accounts for the vast majority of FIP cases [12].

The classification of SARS-CoV-2 virus into different variants based on genetic mutations is still ongoing as the virus continues to evolve. Viral lines that show the potential for increased transmissibility, treatment resistance, vaccine resistance, or increased morbidity and mortality have been identified as VOCs. The spectrum of diseases associated with COVID-19 is broad, ranging from asymptomatic and mild infections to acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), and multiorgan failure and death. Systemic inflammation in SARS-CoV-2 is not associated with macrophages and monocytes (as in FIP), but is responsible for a wide range of extrapulmonary symptoms. The SARS-CoV-2 receptor, angiotensin converting enzyme-2 (ACE-2), which plays an important role in the renin-angiotensin system and the development of pro-inflammatory status, appears to be involved. [13]. Multisystem inflammatory syndrome (MIS) in children and adults, as well as the post-acute course of SARS-CoV-2 infection (PASC), also known as "long COVID", are potential consequences of infection with COVID-19.

2. Transfer

As a group, coronaviruses are known for their ability to cause both respiratory and intestinal diseases and are usually transmitted in one or both ways. While FCoV is considered faecal-oral and SARS-CoV-2 is primarily respiratory, patients with COVID-19 may excrete the infectious virus in the faeces. [14], often for a long time, and FCoV can easily become infected by the oronasal route, which is a common method of experimentally vaccinating cats [15].

In most cases, FCoV infection is self-limiting, and although the virus can be detected systemically, replication outside the intestinal epithelium is weak. This form of the virus, referred to as FECV, is easily transmitted by the fecal-oral / oronasal route, with common anchors and swallowing of virus particles during purification being common sources of infection. The current understanding of FIP development involves internal mutation: in a small subset of FECV cases, a complex combination of host and viral factors leads to mutation (s) that allow efficient replication in macrophages and monocytes. [16]. These lethal variants are classified as FIPV and are associated with systemic inflammation, organ failure, and death. FIPV is generally considered non-transmissible because factors that increase its tropism on troprophages appear to limit its faecal-oral spread. [17]. FIP outbreaks were recorded in kennels and shelters. In these situations, congestion stress and high levels of virus in the environment may promote the conversion of FECV to FIPV. There is evidence that some FCoV strains may be more susceptible to this rebirth than others [18,19].

SARS-CoV-2 virus infection is primarily targeted at the respiratory epithelium, but as with FCoV, the virus may appear systemically without appropriate symptoms of infection. [20,21]. Asymptomatic individuals are a well-documented source of SARS-CoV-2 [22,23,24] and delivery includes inhalation of aerosols as well as contact with droplets [25]. The incubation times of SARS-CoV-2 and FECV range from 2 to 14 days [26]. The incubation time of FIP is highly variable, influenced by the time to internal mutation and the individual's immune response. The onset of FIP can occur several weeks to months after the initial infection [27,28,29,30]. Multisystem inflammatory syndrome in children (MIS-C), a severe manifestation of SARS-CoV-2, is also delayed by an initial infection with a median onset of 4 weeks. No viral factors have been associated with the development of MIS-C, but an immune-mediated component is thought.

Vertical transmission of FIP via the placenta or milk is considered rare. In the first experimental study in which a suckling cat was infected, one in four kittens succumbed to FIP [28]. Maternal antibodies appear to be effective in preventing transmission until approximately six weeks of age, when antibody levels decrease and kittens are susceptible to fecal-oral transmission. [31]. However, this maternally acquired immunity can be overcome early in life by high levels of exposure to FCoV – a Swiss study showed that kittens in large herds show infection as early as two weeks of age [32,33]. Vertical transmission poses a risk of SARS-CoV-2 infection. Placental transmission is rare but has been documented in fetuses of SARS-CoV-2 infected mothers. [34,35,36], as evidenced by virus detection in amniotic fluid, neonatal blood, umbilical cord blood and placental tissue. Transmission cases have been documented in both early and late pregnancies, but infection of the neonate with SARS-CoV-2 may not always occur in the uterus. Infection can also occur during childbirth or in close contact with the mother. The neonatal outcomes of COVID-19 infected mothers remain under study, and it is difficult to distinguish between the effects of SARS-CoV-2 infection and maternal comorbidities. Nevertheless, neonatal infection does not appear to be without sequelae, with one analysis showing that approximately 50 % infected neonates exhibited COVID-19-related clinical symptoms, including fever and respiratory and gastrointestinal symptoms. [37].

3. General clinical presentation

Clinical signs associated with both FIP and COVID-19 include fever, diarrhea, depression, weakness, anorexia, and dyspnoea. [1]. Typical manifestations of COVID-19 commonly include non-specific symptoms including fever, dry cough, fatigue, dyspnea, and myalgia [38]. Anosmia (loss of smell) and ageusia (loss of appetite) have also been frequently reported in COVID-19 and are more specific symptomatic indicators of the disease. [39]. Pneumonia, acute respiratory distress syndrome (ARDS) and sepsis may occur. Men appear to be at higher risk of developing more severe manifestations of COVID-19 [40,41], with several small studies confirming the same relationship between males and the development of FIP in cats [42,43].

The classic manifestation of FIP is the formation of effusion in the abdomen and / or thoracic cavity; although this manifestation has also been reported in COVID-19 [44], is very rare. In addition, FIP is manifested in various bodily systems that are similar to the extrapulmonary manifestations of COVID-19 (Figure 2 and Figure 3). The most similar feature of both diseases is endothelial dysfunction. Vasculitis is a hallmark of FIP pathology [45,46] with lesions characterized by perivascular edema and infiltration, vascular wall degeneration and endothelial proliferation [47]. In the case of COVID-19, extrapulmonary symptoms are thought to be caused by virus-mediated endothelitis, which leads to vasculitis, especially in veins with minor arterioles [48,49]. In the following sections, we will describe these extrapulmonary symptoms and point out key similarities and differences.

Figure 2
Summary of systemic clinical signs and pathological conditions associated with FIP. FIP is known to be a systemic infection with a variety of manifestations. Summarized possible systemic clinical signs associated with FIP are summarized, which include organ systems that are also affected by COVID-19. The most common symptoms of FIP are highlighted in red.

Figure 3
Summary of systemic clinical signs, symptoms, and pathologies associated with COVID-19. Respiratory symptoms of COVID-19 are the main manifestation of the disease. However, SARS-CoV-2 infection in humans can also result in a variety of extrapulmonary symptoms. Summarized are the systemic clinical signs and symptoms associated with COVID-19, which include organ systems that are also affected by FIP. The most common symptoms of COVID-19 are highlighted in red. ARDS stands for Acute Respiratory Distress Syndrome.

4. Biomarkers

Inflammatory biomarkers are important as prognostic markers in COVID-19 and as a means of differentiating FIP from other diseases. In FIP, IL-6 expression appears to be increased in the ascitic fluid of FIP-infected cats, presumably through increased expression in the heart and liver. [50,51]. Other acute phase proteins are also elevated in FIP infection. Alpha-1-acid glycoprotein (AGP) has been studied as a diagnostic marker of FIP, but may be elevated in other conditions, thereby limiting its specificity. [52,53]. Serum amyloid A (SAA) is another acute phase protein that appears to distinguish between FIPV and FECV infection, with FIPV-infected cats showing higher levels of SAA compared to FECV-infected cats and control cats without SPF. [54], but has limited utility in distinguishing FIP from other effusive conditions [55].

As with FCoV, subjects with severe COVID-19 have higher SAA levels compared to subjects with milder COVID-19. [56]. Higher SAA levels are also reported in patients who died of COVID-19 compared with those who survived [57]. C-reactive protein (CRP) is another marker that has been shown to be a promising biomarker in both FCoV and SARS-CoV-2 infections. Liver CRP synthesis is induced by IL-6 expression in response to inflammation [58] and is increased in FIP cases [59]. Elevated CRP levels in the early stages of COVID-19 are associated with a more severe course of the disease and higher mortality [60,61,62], which led to the recommendation to use it as a prognostic indicator in risk assessment in patients hospitalized for COVID-19. In contrast, one meta-survey found that IL-6 levels were elevated, but at least one order of magnitude lower in patients with COVID-19 than in patients with ARDS and non-COVID-19-related sepsis, suggesting a different mechanism of immune dysregulation. [63].

The D-dimer, although not specific for COVID-19 or FIP, is another interesting biomarker. D-dimer is released upon fibrin breakdown and is used as a clinical tool to eliminate thromboembolism [64]. Thrombotic events have often been documented in COVID-19 in several organ systems [65,66] and elevated D-dimer levels are associated with higher morbidity and mortality [67,68]. Similarly, thrombotic events can occur in FIP, and high levels of D-dimers, along with other symptoms of disseminated intravascular coagulation (DIC), can be observed in the final stages of FIP in both natural and experimental infections. [69,70].

5. Pathophysiology

5.1. Neurological

FIP is one of the major infectious neurological diseases in cats and the symptoms associated with central nervous system (CNS) infection are well documented. [71]. CNS symptoms are reported in approximately 40 % cases of dry FIP and may manifest as nystagmus, torticollis, ataxia, paralysis, altered behavior, altered mentoring, and seizures [72]. The wide range of symptoms supports the conclusion that the infection is not limited to a specific part of the CNS [73]. CNS infection is restricted to the monocyte and macrophage lines and leads to pyogranulomatous and lymphoplasmacytic inflammation, which usually affects leptomening, choroidal plexus and periventricular parenchyma. [74].

Documentation of neurological symptoms associated with SARS-CoV-2 CNS infection is limited compared to other coronaviruses [75]. The symptoms observed range from headache and confusion to seizures and acute cerebrovascular events. [76]. Virus detection in the brain is rare, suggesting that symptoms may not be directly related to CNS infection. Viral particles have been observed in neural capillary endothelial cells and a subset of cranial nerves, although such detection does not correlate with the severity of neurological symptoms. [77]. There is often no clear evidence of direct infection. Instead, inflammatory mediators, such as activated microglia, have been reported to contribute to microvascular damage and disease. [78,79].

Further comparison of the neuroinflammatory properties of SARS-CoV-2 and FCoV may provide new insights into the neurological manifestations of COVID-19. Further understanding of the neurological symptoms associated with SARS-CoV-2 is necessary to understand the progression of COVID-19 and the extent of CNS infection.

5.2. Ophthalmological

Ocular manifestations of FIP are more common in the dry form of the disease [80]. Mydriasis, iritis, retinal detachment, conjunctivitis, hyphema and keratic precipitates have been observed [81]. The most common ocular manifestation of FIP is uveitis, which can affect both the anterior and posterior uvea [80]. Viral antigen can also be detected in epithelial cells of the nitrating membrane, but viral antigen detection does not distinguish between FECV and FIPV [82].

Ocular manifestations of COVID-19 include conjunctivitis, chemosis, epiphora, conjunctival hyperaemia, and increased tear production [83]. Uveitis—a common ocular presentation of FIP—has also been observed in SARS-CoV-2 infection [84,85]. Tear fluid virus detection has led to concerns about ocular transmission in the first months of the COVID-19 pandemic [83,86]. SARS-CoV-2 RNA was detected in tear secretions and was isolated from ocular secretions, supporting the possibility of ophthalmic transmission [87,88]. Interestingly, in the above case study in China, out of 12 patients with ophthalmic symptoms, only 2 patients returned positive conjunctival tests, suggesting limited sensitivity in detecting virus from conjunctival specimens. [83].

5.3. Cardiovascular

Pericardial effusion is a less common manifestation of FIP, but is well documented in the literature [26,89,90,91]. FCoV was detected in the pericardium of cats with recurrent pericardial effusion, which later developed neurological symptoms [92]. Direct FCoV infection of the heart was documented in a 2019 case study of FIP-associated myocarditis with severe left ventricular hypertrophy and atrial enlargement. [93]. Immunohistochemistry (IHC) revealed the presence of FCoV-infected macrophages and associated pyogranulomatous lesions. [26]. Interestingly, severe SARS-CoV-2 infection with evidence of viral replication in the heart and lungs has recently been documented in cats with pre-existing hypertrophic cardiomyopathy (HCM). [94].

Unlike FIP, heart damage associated with SARS-CoV-2 infection appears to be much more prevalent. A study of 187 patients found that 27.8 % cases of COVID-19 showed evidence of myocardial damage, as evidenced by elevated cardiac troponin (TnT) levels. [95]. High levels of TnT were in turn associated with higher mortality. In a retrospective multicenter study of 68 patients with COVID-19, 27 deaths were attributable to myocardial damage and / or circulatory failure as one of the leading causes of mortality, with elevated C-reactive protein and IL-6 levels associated with higher mortality [96]. The increase in such inflammatory biomarkers in the blood suggests that the rapid inflammatory nature of COVID-19 may have a particularly detrimental effect on heart function. Diffuse edema as well as increased wall thickness and hypokinesis have been reported with COVID-19 infection. [97]. Cardiac tamponade was also observed in patients with COVID-19, with SARS-CoV-2 levels detectable in pericardial fluid. [98]. In contrast to FIP, in which direct invasion of FCoV-infected macrophages into the myocardium was observed in myocarditis, myocardial infection with SARS-CoV-2 virus is not clearly associated with mononuclear cell infiltration or myocarditis. [99]. This leads to considerations of multiple systemic factors in adverse cardiac outcomes – particularly dysregulation of inflammatory cytokines. The impact of SARS-CoV-2 infection on the cardiovascular system is an important element in our increasing understanding of the morbidity and mortality associated with COVID-19.

5.4. Gastroenterological

FCoV is excreted in feces and transmitted by the oronasal route. Initial FCoV infection targets the intestinal tract – infection may be subclinical or cats may develop diarrhea and, less commonly, vomiting. The primary infection lasts for several months and the virus can be shed for months to years [100,101]. Colonic epithelial cells appear to serve as a reservoir for persistent infection and excretion. [21]. The symptoms tend to be mild and spontaneous and only a small proportion of the animals go into the FIP stage. Fibrinous serositis and pyogranulomatous lesions with vasculitis are classic FIP lesions and can be found in the small and large intestines of affected cats. [102]. FIP can cause solitary mass lesions in the intestinal wall, although this is considered a rare presentation (26/156 cats in one study) [103]. These are usually found in the colon or ileocecal junction and have a pyogranulomatous character.

Gastroenterological symptoms are often reported with COVID-19 infection. ACE2, the cellular receptor for SARS-CoV-2, is widely expressed in glandular cells of the gastric, duodenal and rectal epithelium. Viral RNA and nucleocapsid were detected in these tissues [104], which supports their suitability for SARS-CoV-2 replication. Gastrointestinal (GI) symptoms range from general anorexia to diarrhea, nausea, vomiting and abdominal pain [105,106]. Excluding a less specific anorexia symptom, multiple meta-analyzes estimate the prevalence of GI symptoms in patients with COVID-19 at approximately 10 % to 20 %, with diarrhea being the most commonly reported symptom. [106,107,108]. Interestingly, GI symptoms in COVID-19 were observed without accompanying respiratory symptoms [105].

Faecal virus excretion is a major concern for COVID-19, as SARS-CoV-2 RNA may continue to be present in faeces even after reaching undetectable levels in upper airway samples. [109]. Although the detection of viral RNA in faeces alone does not necessarily indicate the presence of infectious virions, viable viral particles have been detected in faeces. [110]. The viral antigen persists in the cells of the gastrointestinal tract as well as in the convalescent phase, up to 6 months after healing [20]. In one case study, persistent colonic infection was associated with persistent gastrointestinal symptoms in a case of "long COVID" [111], which draws a parallel to the role of the colon epithelium as a reservoir for FCoV.

5.5. Dermatological

Dermatological changes have been reported with both SARS-CoV-2 and FIPV infections. Although papular skin lesions are rare, they are the primary dermatological manifestation of FIP, with several available case reports documenting papules. [81,112,113,114]. On histological examination, pyogranulomatous dermatitis, phlebitis, periflebitis, vasculitis and necrosis were reported in several FIP cases. [81,112,113,114,115].

The first report of dermatological manifestations associated with COVID-19 was recorded at Lecco Hospital in Lombardy, Italy [116]. In this study, 18/88 patients (20.4 %) developed a skin disorder, with 8/18 patients observed at the onset of the disease and 10/18 after hospitalization [116]. Clinical signs included erythematous rash (14/18 patients), diffuse urticaria (3/18 patients) and smallpox-like vesicles (1/18 patients) [116]. Lesions were observed mainly on the trunk (torsion) and pruritus was mild or absent [116]. The continuation of the pandemic brought better characteristics of the first observed dermatological symptoms, as well as the identification of rarer presentations. The most common dermatological manifestation of COVID-19 appears to be rash, often characterized by maculopapular lesions. [117,118]. Another predominant dermatological symptom also appears to be urticaria [118,119]. Importantly, neither rash nor urticaria is specific for COVID-19, which limits their positive predictive value. Varicella-like rash has been observed with SARS-CoV-2 infection and may be more specific due to its low prevalence in viral diseases. In particular, with missing lesions in the oral cavity and pruritus observed in COVID-19-associated rash, together with a previous history of varicella infection, the specificity of this presentation is reinforced. [118].

5.6. Teriogenological

Orchiditis and periorchitis with fibrinopurulent or granulomatous infiltrates as well as hypoplastic testes have been observed in several cases of FIP. [1,26,120]. Inflammatory mediators from the tuna surrounding the testicles caused enlargement of the testicles in cats with FIP [26,120]. In effusive FIP, enlargement of the spinal cord due to edema and peritonitis of tuna was observed [16]. Despite the apparent pathology of the male reproductive system in cats, FCoV has not been detected in sperm, which reduces the likelihood of sexual transmission. [121]. The pathology of the female reproductive system in FIP is less documented in the literature, but macroscopic lesions present in the ovaries of FIPV-infected cats have been observed. The surrounding uterine and ovarian vessels of these cats were surrounded by lymphocytes, macrophages, plasma cells and neutrophils. [122].

As with FIP, the pathology of COVID-19 is manifested in the male reproductive system. One study examining the testes of 12 COVID-19 patients found edema as well as lymphocyte and histiocytic infiltration, consistent with viral orchitis. [123]. These samples were also characterized by damage to the seminiferous tubules with a significant effect on Sertoli cells, as well as a reduced number of Leydig cells. In a separate study, germ cell damage was more pronounced despite similar Sertoli cell counts between SARS-CoV-2-infected individuals and uninfected controls, which represents a more direct relationship between infection and fertility. [124]. The extent to which SARS-CoV-2 may persist in the male reproductive tract is still being investigated. Although SARS-CoV-2 has been detected in human semen, it is questionable whether this is a true testicular infection or a consequence of a disrupted blood-epididymal / deferent barrier. [125,126].

Our knowledge of COVID-19 in the female reproductive system is still limited by the amount of literature and sample size of existing studies. Nevertheless, an understanding of the extent of SARS-CoV-2 in the female reproductive tract is essential to recognize any adverse effects on fertility. ACE2 is expressed in the ovaries, oocytes, and uterus, but limited coexpression of proteases such as TMPRSS2 and cathepsins L and B with ACE2 raises questions about the likelihood of ovarian / uterine infection. [127,128]. While in one study of 35 women diagnosed with COVID-19, SARS-CoV-2 was not detected in vaginal fluid or in exfoliated cervical cells, in a case study from Italy, SARS-CoV-2 was detected in vaginal fluid by RT-PCR ( Ct 37.2 on day 7 and Ct 32.9 on day 20 from the onset of symptoms), suggesting that infection of the female reproductive system is possible [129,130].

5.7. Immunological response

FIP is classically characterized as an immune-mediated disease based on early observations of complement and immunoglobulin circulation, even in the form of immune complexes. [131]. Components of type III and IV immune responses have been described [132]. Vasculitis and vasculitis-like lesions are thought to play a role in COVID-19 systemic complications that cannot be explained by direct organ infection, such as microthrombosis in the brain, kidney, spleen and liver. [133]. One type III hypersensitivity report has been identified in the COVID-19 literature [134]; however, immune complexes do not appear to play an important role in COVID-19 pathology. The mechanism of viral clearance and the inflammatory effects of the immune response are important areas of study for both FIP and COVID-19. Previous work investigating SARS-CoV has demonstrated the need for CD4 + T cells for virus clearance [135,136]. T-cell depletion was a recognized consequence of FCoV and was observed to be associated with more severe cases of COVID-19 [137,138,139]. In addition, FIP reduces both regulatory T cells and NK cells in the blood, mesenteric lymph nodes and spleen. [140]. High levels of IL-6 have previously been demonstrated in FIP ascites [50], and similarly, elevated levels of IL-6 appear to be related to disease severity and outcome in patients with COVID-19. [141]. The cytokine storm, characterized by overexpression of inflammatory cytokines, has been implicated in the pathogenesis of both infections. In FIP, this pathology is associated with monocyte and macrophage activation, while in COVID-19, the association with macrophages and monocytes is less clear. [142]. When considering the balance between cell-mediated immunity and humoral immunity, early reports suggested a link to strong humoral immunity leading to FIP [143]. However, humoral immunity may play a more beneficial role in patients with COVID-19 [144], especially given the potential clinical benefit of convalescent plasma / serum [145].

During the development of the SARS-CoV-2 vaccine, the antibody-dependent infection enhancement process (ADE), in which virus-antibody complexes enhance infection, was particularly important. FIPV has been shown to exhibit ADE in the presence of anti-FIPV antibodies [146]. This increase in infection appears to be serotype specific, with passive immunization of cats against FIPV type I or type II leading to ADE only after challenge with the same serotype for which the immunization was performed. [147]. As a result, ADE is a major challenge for the development of FIP vaccines. In diseases caused by human coronaviruses, ADE has yet to be fully understood. SARS-CoV has been found to have higher concentrations of anti-spike antibodies having a higher neutralizing effect, while more dilute concentrations are thought to contribute to ADE in vitro. [148]. In SARS-CoV-2, ADE was observed in monocyte lines but was not related to the regulation of pro-inflammatory cytokines [149]. Spike protein sequence modeling has identified possible ADE mechanisms that involve interaction with Fc receptors on monocytes and adipocytes [150]. If ADE played a role in SARS-CoV-2, the most likely mechanism would be overactivation of the immune cascade through Fc-mediated innate immune cell activation. [151,152]. There is currently insufficient evidence to suggest an ADE with the pathogenesis of SARS-CoV-2 and further research is needed to assess the true extent of the risk.

6. Molecular similarities between FCoV and SARS-CoV-2 spike proteins

Spike protein is a major factor in tissue and cell tropism and binds the cell receptor [153]. It is now well known that SARS-CoV-2 binds angiotensin converting enzyme-2 (ACE-2) as a primary receptor, a common feature of SARS-CoV. There are other binding partners for SARS-CoV-2, including heparan sulfate as a non-specific binding and neuropilin-1 (NRP-1), which may cause viral tropism for the olfactory and central nervous systems. [154,155]. In contrast, most alpha-virus viruses, including FCoV type II, use aminopeptidase (APN) virus entry. [9,153,156]. The receptor for FCoV type I has yet to be elucidated. The spike protein also mediates membrane fusion, which is activated by a complex process controlled by host cell proteases. [153]. While type I FCoV has two protease cleavage activation sites, designated S1 / S2 and S2 ′, type II FCoV has only one cleavage activation site (S2 ′). [10]. In comparison, SARS-CoV-2 is similar to FCoV-1 (and currently unique to SARS-related viruses) in that it has two identified cleavage sites (S1 / S2 and S2 ′), the first of which, the furin cleavage site or FCS is considered a significant factor in pandemic spread [157,158,159]. In both cases, the presence of S1 / S2 cleavage sites distinguishes FCoV-1 and SARS-CoV-2 from their close relatives. The importance of the cleavage activation site appears to be directly related to the proteases required for viral infection, and thus to another component of tissue tropism. In FCoV type I, the transition from FECV to macrophage-tropical FIPV was first demonstrated by amino acid substitutions at the S1 / S2 cleavage site in FIP-confirmed pathological specimens that are thought to reduce proteolytic priming of furin by similar proteases prior to S2-mediated fusion process activation. [72,160,161]. In SARS-CoV-2, TMPRSS-2 or other trypsin-like related proteases are a major activator of fusion and entry at S2 ′ [162] (Table 1), wherein the furin-like proteases prim the tip and S1 / S2 [163] and in particular have been shown to be rapidly regulated after adaptation to Vero E6 cells in culture and possibly also in extrapulmonary human tissues [164]. Thus, there appear to be remarkable similarities in host cell adaptation between the two viruses.

VirusGroupReceptorConsensus sequence S1 / S2 in circulating virusesConsensus sequence S2 ′ in circulating viruses
SARS-CoV-2Beta-coronavirusACE2SPRRAR | S
(* SHRRAR | S and SRRRAR | S)
FCoV-1Alphacoronavirus (“clade A”)unknownSRRSRR | S (in FECV; mutated in FIPV)KR | S
FCoV-2Alphacoronavirus (“clade B”)APNabsentYRKR | S
Table 1
Summary of SARS-CoV-2 and two FCoV serotypes. The coronavirus spike glycoprotein, mediated by proteolytic cleavage, is a major driver of cell receptor binding and membrane fusion. The Taxonomic classification, host receptor, and amino acid sequences of the proteolytic cleavage site S1 / S2 and S2 ′ are summarized below.
*, Replaced in common variants.

7. Prevention and treatment: From social withdrawal to vaccines

Until now, the role of public health / public health measures has been a major driver in mitigating both the spread of FCoV and SARS-CoV-2. [3,31,165,166]. In this regard, many measures have been introduced for the affected population to reduce social distance, including orders to stay at home, the closure of unnecessary establishments and restrictions on public assemblies. [167]. Although not referred to as social distances, similar methods are often introduced or recommended in cat populations. [3]. Dreschler et al. summarize the methods that have been recommended in cat populations, especially in a multi-cat environment, including reducing the number of cats per room, frequent cage cleaning, and grouping cats according to excretion and / or serological status. [168]. Dreschler argues that quarantining cats exposed to FCoV / FIPV to limit the spread of FCoV in the population is neither effective nor beneficial given the likelihood of widespread FCoV infection in a multi-cat environment as well as the months required for development (and uncertainty in development) FIP. In contrast, quarantine people exposed to SARS-CoV-2 has the potential to reduce the spread of the disease and mortality [169]. Regardless of the extent of grouping or separation, the social difficulties caused by separation must be carefully considered for both cats and humans. In the case of cats, especially in connection with the premature weaning of their mothers, special attention must be paid in the weaning process to ensuring adequate socialization of the kittens. Similarly, in the case of COVID-19, the process of quarantine and / or isolation can be psychologically burdensome for individuals. A thorough cost-benefit analysis must often be carried out to compare the benefits of quarantine and isolation for public health with the negative psychological burden on the persons concerned in order to avoid unnecessary / ineffective quarantine. Where appropriate, justification as well as support to improve well-being should be provided [170].

Although the FIP vaccine is commercially available (Primucell), the benefit of FIP vaccination is still low. Primucell is an intranasal vaccine that uses an attenuated FIPV serotype 2 isolate. Although the FIP vaccine is commercially available (Primucell), the benefit of FIP vaccination is still low. Primucell is an intranasal vaccine that uses an attenuated FIPV serotype 2 isolate (FIPV-DF2), given in two doses 3 to 4 weeks apart to cats at least 16 weeks old. [171]. In a placebo-controlled experimental study in 138 cats, vaccinated cats did not show a significantly lower incidence of FIP compared to controls during the 12-month study period. After adjusting for FCoV titers, cats with lower antibody titers (100 or less) had a significantly lower incidence of FIP at the time of the first vaccination compared to cats with higher titers (400 or more). [172]. However, due to the high prevalence of FCoV, especially in multi-cat environments, attempts to alleviate FIP by vaccinating cats that are FCoV-naive at least 16 weeks of age may not be feasible due to the high potential for FCoV infection during the 16 weeks prior to vaccination. As a result, the American Association of Animal Hospitals and the American Association of General Practitioners for Cats do not recommend FIP vaccination. [173].

ADE remains a major concern of FIP vaccines. Several studies have attempted to reduce the incidence of FIP in experimentally infected cats with recombinant and other experimental vaccines, but ADEs have been reported repeatedly. In one placebo-controlled study in which purebred British Shorthairs and Specific Pathogen Free (SPF) Domestic Shorthairs were vaccinated with one of two recombinant FIPV type 2 (FIPV-DF2) vaccines, both candidate vaccines showed significantly reduced to no protection against challenge FIPV in non-SPF cats - with the majority of non-SPF animals showing ADE [174]. In a separate study, immunization of kittens with a vaccine virus recombined with the FIPV spike glycoprotein gene significantly shortened survival time after FIPV challenge compared to kittens immunized with wild-type vaccine virus. Importantly, low levels of neutralizing antibodies were observed in the group immunized against FIPV [175]. Concerns about ADE after FIPV immunization remain a challenging challenge in FIP prevention.

Unlike the FIP vaccination, the COVID-19 vaccines have played a more significant role in reducing the spread of the infection. Several types of vaccines have been produced that have demonstrated safety and efficacy in preventing symptomatic infection, severe disease, and death from COVID-19—including, but not limited to, mRNA vaccines (Pfizer/BioNTech and Moderna), viral vector vaccines (Janssen, AstraZeneca), and inactivated virus vaccines (Bharat Biotech, Sinovac) [176,177,178,179,180,181]. The first two vaccine platforms use the SARS-CoV-2 spike glycoprotein as the immunogen, while inactivated virus vaccines have the potential to elicit an immune response to viral components other than the spike glycoprotein. Despite the favorable safety profile of COVID-19 vaccines, adverse reactions occurred after vaccination, some of which were mediated by antibodies in analogy to ADE concerns with FIP vaccines. Thrombosis has been a documented problem, especially with AstraZeneca and Janssen vaccines. Although the exact mechanisms are being investigated, the inflammatory response is currently thought to lead to increased levels of platelet-activating antibodies, which bind to platelet factor 4 and lead to a hypercoagulable state. [182,183]. In contrast to the higher incidence of ADE in experimental FIP vaccines, the incidence of thrombotic events after administration of COVID-19 is low. [184].

In addition to the primary endpoints of vaccine studies, which focused on the prevention of symptomatic infection, serious illness, and death from COVID-19, many phase 3 vaccine studies did not address observations to assess the degree of prevention of asymptomatic infection. Beneficial efficacy against asymptomatic infection is important from a public health perspective, especially given that asymptomatic individuals can transmit COVID-19 and that routine monitoring testing is resource intensive and difficult to coordinate on a large scale. [22]. An important contribution towards this field is the real-world studies investigating the efficacy of the vaccine, which show a reduced risk of SARS-CoV-2 infection, as well as a reduced viral load in vaccine "breakthrough" infections. [185,186,187,188]. Such evidence supports the use of SARS-CoV-2 vaccines as a protective measure not only against severe COVID-19, but also as a crucial contribution in the management of the disease.

8. Clinical care and therapeutic options

In 1963, when the first clinical cases of FIP were described (before understanding the viral etiology), it was found that antibiotic treatment was often tried, but it clearly did not bring any benefit. [189]. Since this first report and without an effective vaccine, a number of therapies have been tried in cats with FIP. Ribavirin, a nucleoside analogue, has previously provided promising results against FCoV in an in vitro study [190], however, when administered to cats as an experimental treatment, led to poorer results in some cases [191]. Similarly, at the onset of the COVID-19 pandemic, ribavirin was used in several doses and in combination with other drugs. [192] and a study protocol was designed to examine the benefit in human patients [193]. However, another direct-acting antiviral drug (DAA) (remdesivir), a nucleoside analogue that acts as a chain terminator and raises minor toxicity concerns compared to ribavirin, is rapidly gaining prominence in the treatment of hospitalized patients with COVID-19. . Despite initial enthusiasm, remdesivir has not been shown to be effective in patients with such diseases in robust clinical trials; however, several reports have demonstrated the clinical benefit of the related nucleoside analog GS-441524 in the treatment of cats with FIP, including effusive, non-fusive, and neurological forms of the disease. [194,195,196,197]. At the time of writing, studies on the effectiveness of remdesivir in the treatment of FIP are being conducted in Australia and the United Kingdom. Interestingly, remdesivir is a prodrug form of GS-441524 [195]. Two orally available DAAs have recently entered clinical trials for COVID-19 and are currently awaiting FDA approval; molnupiravir (MK-4482 / EIDD-2801), a modified form of ribavirin, and Paxlovid (a protease inhibitor PF-07321332 in combination with ritonavir, which improves the half-life of PF-07321332) targeting the major protease (Mpro). It is noteworthy that the active substance Paxlovid is related to GC-376 and has previously been shown to be effective in a FIP clinical study. [196]. It will be very interesting to follow the development, FDA approval and use of these DAAs in relation to the relevant diseases caused by SARS-CoV-2 and FCoV.

Due to the inflammatory nature of both FIP and COVID-19, treatment often focuses on controlling the immune response. Although cats with FIP are often given glucocorticoids in an effort to alleviate the inflammatory symptoms of the disease, the clinical benefit is negligible. [198]. The use of corticosteroids in patients with COVID-19 does not appear to be insignificant, with some studies showing negative profiles [199]. However, their administration may be beneficial in severe cases of COVID-19 through the observed reduction in mortality [200,201]. Cyclosporine, an immunosuppressive drug that is often used to prevent organ rejection in transplant patients and to treat some autoimmune diseases, has been studied in both FIP and SARS-CoV-2. An in vitro study with cyclosporin A (CsA) using FCoV type II virus showed a reduction in virus replication [202], treatment of a 14-year-old cat CsA after unsuccessful IFN treatment resulted in clinical improvement, reduction in viral load and survival of more than 260 days [203]. Although there are currently no controlled studies on the use of CsA in the treatment of patients with COVID-19, in addition to safety concerns, potential mechanisms of action have been suggested. [204,205,206]. In addition, the cyclosporin A analogue, alisporivir, has shown in vitro effects on virus replication [207], similar to evidence that cyclophilin A blockade inhibits the replication of other coronaviruses [208].

Many antibiotics have been prescribed for both FIP and COVID-19, but not for their antimicrobial properties, but rather for their anti-inflammatory effects. [198]. For example, doxycycline may have helped prolong survival in cats with FIP [209]. Whether doxycycline would be of benefit to patients with COVID-19 is not currently known, but has been suggested as a possible part of the treatment of the disease. [210].

Interferons have also been studied in the treatment of FIP without a clear link to clinical improvement [211]. In human patients with COVID-19, combination therapy with interferon-β-1b with lopinavir, ritonavir and ribavirin compared with lopinavir and ritonavir alone was associated with a reduced duration of virus excretion and improved clinical outcomes in mild to moderate cases. [212].

Monoclonal antibodies targeting components of the immune response have the potential to reduce inflammatory cytokine levels. A small study in cats experimentally infected with FIPV-1146 demonstrated the benefit of anti-TNF-α in managing the disease [213]. Tocilizumab, an anti-IL-6 monoclonal antibody, was administered to patients with COVID-19 [214]. Due to the different clinical results reported, further research is needed with Tocilizumab [215,216].

The transfer of knowledge between species will undoubtedly affect cats as well as humans and even other species. Although many compounds are effective when studied in vitro, their use in vivo can lead to different results, including toxicity. In addition, the fact that a compound may show promising results in one species does not mean that the same effect will be observed in other species, especially when comparing similar but different viruses and virus-induced diseases.

9. MIS-C and PASC

In April 2020, the UK's National Health Service issued an alert about an increased incidence of multisystem inflammatory syndrome in children - many of whom tested positive for COVID-19 [217]. As the pandemic progressed, studies from other countries examining this inflammatory condition provided more detail towards a clinical understanding of what is now referred to as MIS-C, a rare presentation of COVID-19 in pediatric patients. MIS-C includes several organ systems. Cardiovascular dysregulation in MIS-C is often observed in the form of ventricular dysfunction, pericardial effusion and coronary artery aneurysms [218,219]. Gastrointestinal symptoms mimic appendicitis and include abdominal pain, vomiting, and diarrhea. Terminal ileitis is a common finding on imaging tests [220]. Many patients also experience neurocognitive symptoms, including headache and confusion. More serious neurological complications, including encephalopathy and stroke, are less common [218,221].

One area of significant clinical overlap between FIP and COVID-19 is the rare inflammatory manifestation of SARS-CoV-2 infection – multisystem inflammatory syndrome in children (MIS-C). MIS-C is seen in the pediatric population, just as FIP commonly affects young cats [43]. Like FIP, MIS-C has a systemic presentation involving multiple organ systems—including gastrointestinal, cardiovascular, and hematologic abnormalities [222]. As with the wet form of FIP, pleural effusions and ascites occur in MIS-C. [223]. Both syndromes also show overlap in vascular pathology. FIP shows granulomatous vasculitis, which overlaps with Kawasaki vascular syndrome observed in MIS-C [224]. MIS-C is thought to be a post-infectious disease associated with a previous SARS-CoV-2 infection [223,225]. FIP also has a delayed onset after the first exposure to FCoV and occurs only in a small subset of cases. Although cats with FIP can still shed FCoV in their feces, the mutations associated with the biotype switch from FECV to FIPV are thought not to be transmissible—supporting some degree of similarity in the limited infectious range of both FIP and MIS-C.

Recently, post-acute sequelae of COVID-19 (PASC) has been defined, which includes memory loss, gastrointestinal distress, fatigue, anosmia, dyspnea, etc. and is more often referred to as "long-term COVID". Along with MIS-C, PASC is a very active subject of research, which has been summarized by others [226], and together represent an excellent starting point for the use of feline medicine as a model of coronavirus-induced pathogenesis, possibly in an unexpected way [224].

10. SARS-CoV-2 infection in cats

Cats have now become widespread hosts for SARS-CoV-2 infections, in part due to the relative similarity of human and feline ACE2 receptors. Following cases reported in Hong Kong and Belgium in March 2020, the most notable early natural infection occurred at the Bronx Zoo in New York City, USA. In April, four tigers and three lions showed mild respiratory symptoms from their breeders, and SARS-CoV-2 was detected by PCR and sequencing. [227]. Consequently, infection of both domesticated and non-domesticated cats has become relatively common in cases where owners and caregivers are positive for SARS-CoV-2. From a clinical point of view, SARS-CoV-2 infection in cats is considered to be predominantly asymptomatic, with some animals showing mild respiratory symptoms. [228,229,230]. In general, severe respiratory symptoms do not appear to occur in cats, although severe respiratory distress may in some cases be related to the underlying hypertrophic cardiomyopathy (HCM) of cats. [94]. An increased incidence of myocarditis in dogs and cats has also been reported in the United Kingdom, associated with a sharp increase in variant B.1.1.7 (Alpha). [231]. There is a clear need for further studies in this area, as well as possible links between coronavirus infections in cats and multisystem inflammatory syndrome in children (MIS-C), which, as mentioned above, is a rare manifestation of COVID-19.

Laboratory animal studies have also been key to understanding SARS-CoV-2 infection in cats, which are very susceptible to infection by oronasal challenge. Experimentally infected cats showed mild respiratory symptoms or asymptomatic infection, virus shedding, virus-to-cat virus transmission, and a strong neutralizing antibody response. Recent studies have shown that long-term immunity exists after re-infection of cats, but cats may develop long-term consequences, including persistence of inflammation and other lung lesions. [232]. Overall, as with SARS-CoV in 2003, cats in particular can be an important source of information on the pathogenesis and immune responses elicited by SARS-CoV-2.


Thanks to Annette Choi for helping with Figure 1 and all Whittaker Lab members for helpful discussions during the preparation of this manuscript.

Author shares

All authors have contributed to this article. All authors have read and agreed to the published version of the manuscript.


The work in the author's laboratory is partly funded by research grants from the National Institutes of Health, the EveryCat Foundation and the Cornell Feline Health Center. AES was supported by the NIH Comparative Medicine Training Program T32OD011000. Studies on FIP are also supported by the Michael Zemsky Fund for Cat Diseases.

Conflict of interests

The authors do not indicate any conflict of interest.


Publisher Note: The MDPI remains neutral in terms of jurisdictional claims in published maps and institutional affiliation.


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Miscellaneous questions frequently arising during antiviral drug treatment for FIP and aftercare

NC. Pedersen, DVM PhD
Original article: Miscellaneous questions frequently arising during antiviral drug treatment for FIP and aftercare

Several issues often arise during FIP treatment. Before addressing these issues, it is important to mention the FIP treatment itself. Only antivirals that target specific viral proteins and inhibit FIP replication have been shown to have therapeutic effects. Currently, these include nucleoside analogs and RNA replication inhibitors GS-441524 (and a related prodrug Remdesivir), Molnupiravir (EIDD-2801) and the viral protease inhibitor GC376. Proper administration of these drugs has resulted in the cure of all forms of FIP in more than 90 % with minimal side effects. Most treatments are completed without complications. However, certain issues that are the subject of this article often arise.  

I pointed out the problems associated with unwanted sexual behavior in intact females and males treated with specific antivirals. The questions often come from countries where castration is either postponed or not common practice. They fear that the stress of castration and vaccines may affect the outcome of antiviral treatment. I believe that such concerns are exaggerated. If a cat is in treatment and in remission or is considered cured, it is okay to sterilize or neuter it, but preferably in the least stressful way possible. Cats can be neutered and sterilized quickly and efficiently and returned to their homes on the same day (castration) or within one day (sterilization) with minimal preoperative, operative and postoperative drug treatment and restrictions (eg cages, E-collars). Such operations will be less stressful for cats (and owners, which will then be reflected in their cats) than their sexual behavior. 

I am also not in favor of hormonal treatment to prevent unwanted sexual behavior in males or females, and I feel that effective castration and sterilization will be less stressful in the long run than such preventive measures. Therefore, if it is necessary to permanently change this behavior, surgical castration is more appropriate than chemical.  

Some owners seem to want to keep cured cats intact so that they can be used for breeding later. We know that FIP has both genetic and environmental components, which has led to the recommendation that purebred cats that breed FIP kittens should not be used for breeding. This should be even more true for cats that have been cured of the FIP.  

As far as vaccines are concerned, many already know that I am not a big fan of adult vaccines and the first annual booster vaccines because I feel that immunity is long-lasting. I also think that rabies vaccines cannot be used routinely in cats, whether in terms of public health or cats. Nevertheless, I accept that these views are not generally accepted and that the laws in several states require rabies to be vaccinated against rabbits, in some vaccination is not required and in others it is recommended but not required. I have not noticed the consequences of routine vaccinations in any of our cured cats. However, it is not something I would recommend for cats undergoing treatment. The immune system of these cats is responsible for other things than responding to vaccines.  

What are the indications for drugs other than specific antivirals for the treatment of FIP? During the initial illness, supportive (symptomatic) treatment may be required to keep the cats alive long enough for the antivirals to take effect. Drugs often used in this early stage usually include antibiotics (doxycycline / clindamycin), analgesics (opioids, gabapentin), anti-inflammatory drugs (corticosteroids, NSAIDS), immunostimulants (interferons, non-specific immunostimulants), and drugs. I have tried to avoid excessive use of these drugs except for temporary use and only if it is strongly justified, especially in severely ill cats during the first days. The most important goal of FIP treatment is to stop the replication of the virus in macrophages, which immediately stops the production of the numerous inflammatory and immunosuppressive cytokines that cause the symptoms of FIP. Although some drugs, such as corticosteroids (prednisolone) or NSAIDs (meloxicam), may inhibit inflammatory cytokines and cause clinical improvement, they are not curative. They can also mask the beneficial effects of GS treatment, which are often monitored to assess the effect and course of treatment. The response to antiviral treatment is also used for diagnostic purposes. The only drugs that completely suppress these harmful cytokines and cure FIP are antivirals such as GS-441524, molnupiravir or GC376, and related compounds. These antivirals cause a dramatic improvement in fever, activity, appetite, etc. within 24-48 hours. This improvement will be much greater than any improvement made with other drugs. Therefore, if the use of other drugs is not warranted, they should be discontinued as soon as the symptoms of FIP have steadily improved. 

I also do not believe in many supplements that are said to treat or prevent problems with the liver, kidneys, immune system or other organs. These supplements are expensive and have not been shown to be effective in what they claim. B12 injections only treat B12 deficiency, which is rare, and not anemia in FIP. The same goes for other vitamins. This also applies to a wide range of nutritional supplements and special diets for cats of many types. There is no essential ingredient in any of these supplements that could be provided by well-tested commercial cat food brands. There is also a possibility that some supplements interfere with the absorption of oral antivirals.  

How should cats be monitored after treatment and during the post-treatment observation period? From a technical point of view, no further blood tests are needed, especially if routine health assessments such as weight, appetite and temperature are continued during this period. Blood tests during this period do not change the outcome and can only increase the cost of treatment and increase the owner's stress. However, it is common for successfully treated cats to routinely test for blood during a 12-week post-treatment observation, usually every 4 weeks, but sometimes more frequently. In some cases, routine blood testing is continued for 12 weeks after treatment, even out of fear of possible relapse or recurrence. Relapses or new infections after a 12-week observation period are rare and are preceded by external signs of the disease, such as weight loss, lethargy, anorexia, poor coat and fever, which would be the best indicators for a blood test. Blood test panels also contain many values, and it is not uncommon for one or more values to be abnormal in healthy cats. Care must be taken not to over-interpret such abnormalities and to lead to excessive concern or additional testing in order to determine their significance. For example, a mild to moderate increase in one in three liver enzymes in a healthy cat is much less important than in another cat with symptoms of the disease.

FIP diagnostics overview

Original article: A review on the diagnosis of feline infectious peritonitis

Jehanzeb Yousufa | Riyaz Ahmed Bhatb | Shahid Hussain Darb | Alisa Shafib | Snober Irshadc | Mohammad Iqbal Yatoob | Jalal Udin Parrahb | Amatul Muheeb | Abdul Qayoom Mirb

Abstract: Feline infectious peritonitis, or simply FIP, is a coronavirus viral disease in cats, usually less than three years old. It is manifested by an extreme inflammatory reaction in the tissues in the abdomen, kidneys and brain. This review article discusses the various diagnostic tests and their benefits in diagnosing cases of suspected FIP for definitive diagnosis. This review can help compare different diagnostic parameters and also raise awareness of their advantages and disadvantages.

Keywords: acute phase proteins, coronavirus, feline infectious peritonitis, Rivalt's test.

1. Introduction

Feline infectious peritonitis (FIP) is a well-known and widespread coronavirus (CoV) -induced systemic disease in cats, characterized by fibrinous-granulomatous serositis with protein-rich exudates in the body cavities, granulomatosis-announcing phlebitis in the gallbladder and periphels Scott 1981; Kipar et al. 2005). Feline CoV (FCoV) spreads via the faecal-oral route and is primarily infected with enterocytes (Pedersen 1995), but subsequently spreads systemically via monocyte viremia (Meli et al 2004; Kipar et al 2005). The increased ability of the virus to replicate has been shown to be a key feature in the development of FIP, and FIP is also thought to be caused by mutations in common feline enteric coronavirus (FECV), which occurs in cats worldwide and is not a serious infection (Pedersen et al 2009; Healey et al 2022). Approximately 10 % infected cats have mutations that result in feline infectious peritonitis. In large multi-cat situations, FECV is excreted in the faeces of most seemingly healthy cats and the transmission occurs through direct contact with faeces or contaminated litter and other fomits (Pedersen et al 2004). Kittens become infected at approximately 9 weeks of age (Pedersen et al. 2008). The time between the onset of clinical signs and death also varies, but younger cats and cats with effusive disease have a shorter course of disease than older cats and cats with non-effusive disease (Pedersen 2014). Even with severe FIP, some cats can live for months. in multi-feline situations, feline enteric coronavirus (FECV) is extremely common and highly contagious. Almost all cats that come into contact with FECV from secreting cats become ill, but on the other hand, the infection is usually asymptomatic or causes only mild temporary diarrhea (Pedersen et al. 2008; Vogel et al. 2010; Ermakov et al. 2021). On the other hand, feline infectious peritonitis virus (FIPV) is not transmitted via the faecal-oral route, but originates from avirulent FECV in a small percentage of infected cats and causes feline infectious peritonitis (FIP) (Pedersen et al 1981; Vennema et al. 1998). Anorexia, lethargy, weight loss, pyrexia, ocular and neurological symptoms such as gait abnormalities or inappropriate mentoring are non-specific (Giori et al 2011; Kipar et al 2014). The infection takes two forms: "wet" and "dry". The dry form causes inflammatory changes around the vessels, seizures, ataxia and excessive thirst, while the wet form leads to enlargement of the abdomen due to excessive accumulation of fluid in the abdominal cavity. Specificity is always the most important diagnostic value to consider in order to avoid misdiagnosis of FIP in unaffected cats.

2. Diagnostic tests for feline infectious peritonitis

The diagnosis takes into account the age, origin, clinical signs and physical examination of the cat. Abdominal distension with ascites, dyspnoea with pleural effusion, jaundice, hyperbilirubinuria, marked masses of the kidneys and / or mesenteric lymph nodes, uveitis and various neurological symptoms are common in cats with effusive (wet) or non-fusive (dry) forms of FIP. and / or spinal cord. Ocular changes often occur in cats with FIP, with the most common ocular disorders being retinal changes. Retinal cuff cuffs may occur, which appear as blurred gray lines on either side of the vessels. Occasionally, granulomatous changes in the retina occur. FIPV infection has been found to be associated with T-cell depletion by apoptosis, although the virus cannot infect CD4 + and CD8 + T-cells (Haagmans et al. 1996; De Groot et al. 2005). Due to the high mortality rate, many veterinarians and pet owners are cautious about a diagnosis based on "reasonable assurance". The challenge is to decide whether the test increases the likelihood that clinical symptoms are caused by FIP (indirect tests) or offers a definitive diagnosis (direct tests). It is important to note that the sensitivity and specificity of any indirect test will vary depending on the likelihood that the cat is infected due to other factors. This means that a positive predictive value of the test, such as complete blood count (CBC) or albumin: globulin (A: G) ratio, to predict FIP will be much higher in cats with FIP-like signaling than in cats with non-FIP signaling. It should be noted that the results of other indirect tests are only estimates and the results of additional indirect tests have the potential to confuse and support the diagnostic process.

3. Diagnostic tests

The problem with FIP diagnostics is that non-invasive tests are not reliable enough. In general, effusion tests have a significantly higher predictive value than blood tests (Stranieri et al. 2018; Hartmann et al. 2003). As a result, the identification of FIP ante mortem in cats without significant effusion is particularly difficult. The most useful ante-mortem indicators are positive anti-Corona (IgG) antibody titers in cerebrospinal fluid (CSF), high total serum protein, and MRI changes such as periventricular contrast enhancement, ventricular dilatation, and hydrocephalus. However, monoclonal antibodies from affected tissues and coronavirus-specific polymerase chain reaction (PCR) are valuable in post mortem evaluations (Foley et al. 1998). As a clear diagnosis cannot be made on the basis of symptoms, medical history and clinical and laboratory indicators alone, these factors should always be considered as a whole, sometimes in combination with other factors such as molecular or even more invasive diagnostic procedures.

3.1. Analysis of effusion samples

If FIP with effusion is suspected, the effusion sample can be incredibly helpful in making a diagnosis and then in hematological findings, so obtaining effusion samples should always be a top priority. In the case of ascites, the sample can be obtained by ultrasound-guided thin-needle aspiration or the "flying cat" technique. To identify small amounts of fluid in the chest and abdomen, ultrasonography provides useful assistance in locating effusion bags in the abdomen, while evidence of pericardial effusions can be obtained through suppressed cardiac echoes and electrocardiographic changes. Ultrasonography should be used repeatedly to identify any small volume effluents, and ultrasonography may also be used to guide the sampling of small bags of fluid. In cats with pericardial effusions, auscultation of the heart detects muffled sounds and the ECG reveals typical changes.
FIP effusions are often clear, viscous / sticky, straw yellow and rich in protein (cytology often describes a dense eosinophilic protein background) with a total protein concentration> 35 g / l (> 50 % globulins). Chlootic effusions are rarely described. FIP effusions are often pyogranulomatous in nature with macrophages, non-degenerate neutrophils and a relatively small number of lymphocytes. As a result, effusions are often referred to as modified transudates based on cell number (<5 × 109 cells / L), but exudates based on protein concentration (greater than 35 g / L). Typical FIP effusions have a low A: G ratio (see above) and an increased AGP content, which is similar to the serum content. A recent study (Hazuchova et al. 2017) found that AGP concentrations in effusions (> 1.55 mg / ml) are more useful (sensitivity and specificity 93 %) in distinguishing FIP cases from cases without FIP than serum AGP levels or other APPs.
The rival test is a simple test that can be used to distinguish transudate from exudate in a effusion sample (Barker and Tasker 2020). Positive results simply suggest that the effluent is exudate and not specific to FIP; positive transudate results have been documented in situations other than FIP (eg, bacterial / septic peritonitis and lymphoma) (Fischer et al. 2012).

3.2. Serum biochemistry

Although the changes in blood biochemistry observed in FIP cases are variable and often non-specific, there are several key anomalies that need to be addressed in order to confirm the diagnosis of FIP.

3.2.1. Acute phase proteins

Many inflammatory and non-inflammatory diseases produce acute phase proteins (APPs) in the liver in response to cytokines released by macrophages and monocytes (particularly interleukins 1 and 6 and tumor necrosis factor α).
AGP is an abbreviation for α1-acid glycoprotein and its examination may help in the diagnosis of FIP. Although the increase in AGP levels (> 0.48 mg / ml) is not specific for FIP, patients with FIP often have significantly high AGP levels (> 1.5 mg / ml). As a result, the magnitude of the increase may be valuable in helping to diagnose FIP, with higher levels more effectively increasing the suspicion index (Giori et al 2011; Hazuchova et al 2017).

3.2.2. Hyperglobulinemia

In 89% cases, hyperglobulinemia is present; often in association with hypoalbuminemia or low-normal serum albumin levels (observed in 64.5 % cases) (Riemer et al. 2016). Hyperproteinemia may not always occur due to the existence of hypoalbuminemia. The albumin: globulin (A: G) ratio is low in hyperglobulinemia and hypoalbuminemia (low-normal albumin concentration) and this parameter can be used to assess the likelihood of FIP in a particular case.

3.2.3. Hyperbilirubinemia

Hyperbilirubinemia occurs in 21-63 % cases of FIP and is more common in effusive FIP, where alanine aminotransferase (ALT), alkaline phosphatase (ALP) and γ-glutamyltransferase enzymes are commonly high (although these may be slightly increased in FIP cases). FIP is rarely associated with hyperbilirubinemia due to immune-mediated hemolytic anemia (IMHA) (Norris et al. 2012) and cats are often not severely anemic. In the absence of high liver enzyme activity or severe anemia, the presence of hyperbilirubinaemia should suggest FIP (note that sepsis and pancreatitis may cause hyperbilirubinaemia without increased liver enzyme activity). Based on a stepwise evaluation of cats with FIP, it was documented that hyperbilirubinemia was more typically recognized in cats just before death or euthanasia than in the first presentation (Harvey et al. 1996). In addition, higher bilirubin levels were observed in cats just before death or euthanasia than in the first presentation.

3.3. Hematology

In FIP, hematological changes are non-specific; however, there are several abnormalities that need to be checked to confirm the diagnosis. Lymphopenia is the most common change (55 - 77%) in cases, with a recent study (Riemer et al. 2016) revealing lymphopenia in only 49.5 % cases of FIP, with neutrophilia (39 - 57 %), left-sided and mild to severe normocytic, normochromic anemia (37-54 %) (Riemer et al. 2016; Norris et al. 2012). Recently, an association between FIP and microcytosis (with or without anemia) has been discovered. FIP can cause severe IMHA with concomitant regenerative anemia; however, this is an unusual phenomenon.

3.4. Serology

ELISAs, indirect immunofluorescence antibody assays, and rapid immunocompromination assays are the most common assays for anti-FCoV antibodies in serum (Addie et al. 2015). In most studies, cells infected with CoV pigs or cats are used as substrate and titers are measured in multiples of serum dilutions. A positive anti-FCoV antibody test means that the cat has been infected with FCoV and has seroconverted (which lasts 2-3 weeks after infection). The tests are therefore of limited clinical importance. Breed-dependent differences in anti-FCoV antibody titers were found, which could indicate differences in the breed's response to FCoV infection (Meli et al. 2013).
Although cats with FIP had higher anti-FCoV antibody titers than cats without FIP, no difference was found between the median anti-FCoV antibody titers in healthy cats and cats with suspected FIP. As a result, the titer in one animal is only marginally useful in identifying cats with FIP (Bell et al. 2006). Many clinically healthy cats (especially those in multi-cat households) have positive and often very high anti-FCoV antibody titers, while 10 % cats with FIP are seronegative, which could be due to virus binding to the antibody and its inaccessibility for serological testing. which also points to problems with interpretation (Meli et al 2013). A negative FCoV antibody test if dry FIP is suspected may be more effective at excluding FIP (Addie et al. 2009). Nevertheless, negative results have been observed in neurological FIP situations (Negrin et al 2007). As a result, doctors disagree on whether to perform a serological test in suspected cases, even though a positive result almost always means FCoV exposure.

3.5. Current trends in diagnostics

The use of anti-coronavirus antibody testing in cerebrospinal fluid (CSF) for diagnosis in cases involving the central nervous system is another breakthrough in which IgG is detected in the CSF. However, in most cases, the antibody was detected only in cats with high serum IgG titers (Boettcher et al. 2007)
An important difference between feline coronavirus and FIP infection is the behavior of the NSP3c gene. The infected tissue isolates from the second case were found to have a disrupted gene 3c, while in the first case the gene was intact. Mutation of the S1 / S2 locus and modulation of the furin recognition site, which is normally present in the S-gene of the enteric coronavirus (Levy and Hutsell 2019), is also a crucial contributing factor.
The diagnostic utility of cerebrospinal fluid immunocytochemistry is also used to diagnose FIP manifested by severe central nervous system involvement. Immunocytochemical staining (ICC) of feline coronavirus antibodies in cerebrospinal fluid macrophages is a highly sensitive test, especially for the diagnosis of ante mortem with a sensitivity of 85 % and a specificity of 83.3 % (Gruendl et al 2017).

4. Conclusions

In cats with suspected FIP, anamnesis, clinical signs and clinicopathological examinations should be correlated. The dry form is more difficult to diagnose than the wet form. In the wet form, laboratory analysis of the fluid can be performed, such as the Rivalt's test. If the test is negative, the probability of FIP is small, but if the test is positive, additional diagnostic tests should follow to confirm FIP. In FIP, the A: G ratio is low because hyperglobulinemia and hypoalbuminemia (low normal albumin concentration) are present, and this parameter can be used to assess the likelihood of FIP in a particular case. Patients with FIP often have significantly high levels of AGP (α1-acid glycoprotein). When distinguishing FIP cases from non-FIP cases, AGP concentrations in effusions (> 1.55 mg / ml) have a sensitivity and specificity of 93 %.

Conflict of interests

The authors declare that they do not have a conflict of interest.


No financial support was provided from any institute or other source.

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Outbreak of feline infectious peritonitis in a shelter in Taiwan: epidemiological and molecular evidence of horizontal transmission of a new type II feline coronavirus

Ying-Ting Wang,1 Bi-Ling Su,2 Li-En Hsieh,1 and Ling-Ling Chueh1
Original article: An outbreak of feline infectious peritonitis in a Taiwanese shelter: epidemiologic and molecular evidence for horizontal transmission of a novel type II feline coronavirus
Czech translation partially taken from: Results Confirmation of the FIP outbreak in the cat shelter - Sevaron


Infectious feline peritonitis (FIP) is a fatal disease caused by feline coronavirus (FCoV) infection. FCoV can be divided into serotypes I and II. The virus that causes FIP (FIPV) is said to occur sporadically and does not often spread from one cat to another. An outbreak in one animal shelter in Taiwan was recently confirmed. FCoV from all cats in this shelter was analyzed to determine the epidemiology of this outbreak. Thirteen of the 46 (28,2%) cats with typical FIP symptoms were identified. Of these, FIP was confirmed in seven cats by necropsy or histopathological examination. Despite the fact that in this environment with more cats, more than one FCoV was identified, eight cats with symptoms of FIP were reliably found to be infected with FCoV type II. Sequence analysis revealed that FIPV type II, found from feline faeces, body effusions and granulomatous tissue homogenate from cats that underwent FIP, contained identical recombination in all cases. WITH gene. Two cats that succumbed to FIP were found to have an identical nonsense mutation in 3c gene. The excretion of this type II virus in faeces of the effusive form of FIP can be detected up to six days before the animal dies. In general, our data demonstrate that horizontal transmission of FIPV is possible and that FIP cats may pose a potential risk to other cats living in the same environment.


Infectious feline peritonitis (FIP) is a fatal disease of cats caused by feline coronavirus (FCoV) infection. FCoV is an enveloped RNA virus that belongs to the species Alphacoronavirus, family Coronaviridae and in order Nidovirales. The size of the FCoV genome is approximately 28.9 kb, including the nonstructural replication gene; four structural genes that encode spike (S), envelope, membrane, and nucleocapsid proteins; and five helper / nonstructural genes 3abca 7ab[1].

Feline coronaviruses cause mild, invisible, and transient bowel infections and are ubiquitous among cat populations worldwide [2]. They occur in two serotypes, I and II [man]3]. Type I FCoV predominates here, while type II virus represents only 2-30% infections [48]. Following the accumulation of genetic evidence, it is apparent that FCoV type II was formed by two homologous recombinations between FCoV type I and canine coronavirus CoV (CCoV) [9,10]. Both serotypes can mutate in the host, lead to macrophage tropism and a systemic disease called infectious feline peritonitis [cat]2,11,12]. Due to poor virus shedding in FIP studies in cats, mutant FIP viruses (FIP-inducing FCoV, FIPV) appear to be contained only in diseased tissues and are not naturally transmitted in cat-to-cat contact [2,11,13,14].

In this article, we report an epizootic FIP in a shelter in Taiwan that was caused by a new Type II FCoV. Epidemiological and molecular examination of isolates from various healthy and sick cats from this shelter strongly suggests that the virus was introduced by moving kittens from another shelter with subsequent horizontal spread to adult cats with which the new kittens shared the shelter.

Materials and methods

Animals and sampling

A total of 46 cats from a private shelter were included in this study, which ran from September 2011 to August 2012. This shelter houses adult cats and from time to time a few kittens. All the cats were either strayed or rescued, and some of them were obtained from the homes of various private rescue stations where the rescued cats were temporarily housed. Before the onset of the disease, all cats lived together in an indoor environment without cages, sharing food, drink and toilets. Some cats were siblings, others were not related to them (Table 1).

Table 1
Information on all cats from this shelter in which FIP was suspected and in which the disease was confirmed

Hot girlAge 1 Date of admission to the shelter Date of onset of fever Date of death Clinical findings Necropsy findings Effusive / non - fusive
13mJune 16, 2011August 17, 2011September 1, 2011Fever, anorexia, ascites, neurological symptoms  
2a4mAugust 6, 2011ON THE 2September 21, 2011Clinical signs are not available  
3b3mJuly 11, 2011August 18, 2011September 25, 2011Fever, anorexia, weight loss, neurological symptoms  
42.5mJun. 08, 2011August 16, 2011September 28, 2011Fever, ascites, neurological symptoms  
5a4mAugust 6, 2011August 15, 2011October 20, 2011Fever, pleural effusion, diarrhea  
67mApril 24, 2011ON THEOctober 22, 2011Anorexia, weight loss, neurological symptoms  
73y6mResidentON THEOctober 27, 2011 Ascites, jaundice, granulomatous lesions in the kidney, fibrinous peritonitisEffusive
86mJuly 11, 2011ON THEDecember 14, 2011 Granulomatous changes in the kidneys, liver, lungs, brain and eyes Non-fusible
92yResidentON THEDecember 28, 2011 Ascites, pleural effusion and pericardial effusion, granulomatous changes in the kidneys, liver and intestine.Effusive / non - fusive
10 b3mJuly 11, 2011ON THENovember 5, 2011 Granulomatous changes in the kidneys, liver and omentum Non-fusible
11 c1y6mResidentON THEFebruary 14, 2012 Ascites and pleural effusion, jaundice, fibrinous peritonitis, granulomatous changes in the kidneys, liver, lungs and spleen.Effusive / non - fusive
12 c1y6mResidentON THEMarch 19, 2012 Jaundice, fibrinous peritonitis, granulomatous changes in the thoracic and abdominal walls, kidneys, liver, lungs, spleen omenta and eyes.Effusive / non - fusive
131y7mResidentON THEApril 13, 2012 Jaundice, enlargement of the liver and mesenteric lymph nodes, granulomatous changes in the kidneys and lungs.Non-fusible

1 Age of cats at the time of clinical signs of FIP.
2 Not available. 
a, b, c : siblings.

Faeces or rectal samples were taken from all asymptomatic cats at least once to monitor for FCoV. Body swabs, blood samples, swab specimens, including rectal, nasal, oral and conjunctival specimens, were taken as standard from cats that already showed signs of the disease or were suspected of having FIP. In addition to supportive care, cats with suspected FIP were treated with prednisolone (Prelon®, YF Chemical Corp., New Taipei City, Taiwan), benazepril (Cibacen®, Novartis, Barbera del Valles, Spain) and recombinant human interferon alpha (Roferon®-A). , Roche, Basel, Switzerland). Cats that succumbed to the disease were necropsied for pathological confirmation. During necropsy, body exudates were first removed with a needle and syringe, followed by swabs, blood, urine and granulomatous lesions on the internal organs. All samples were frozen at -20 ° C until use. All samples were tested for FCoV nested reverse transcription polymerase chain reaction (RT-nPCR) [man]15]. Samples with positive results were subsequently subjected to further analysis.

Sample preparation and reverse transcription

Swab samples were suspended in 1 ml of water treated with 0.1% diethyl pyrocarbonate (DEPC). Stool samples were suspended with 9x treated water 0.1% DEPC by vortexing. The suspension was centrifuged and the supernatant was transferred to a new tube. About 0.5 g of tissue was frozen and then crushed with a mortar and pestle in the presence of 2 ml of Trizol [16]. Total RNA was extracted from 300 μl of swab suspension, whole blood, faeces suspension, tissue homogenate and body effusion using Trizol. Twenty-one microliters of isolated RNA was reverse transcribed with specific primer N1 (5′-gctacaattgtatcctcaac-3 ′) or P211 [15] with Moloney mouse leukemia reverse transcription (Invitrogen, CA, USA). The reaction was incubated at 37 ° C for 60 min, at 72 ° C for 15 min and finally at 94 ° C for 5 min.

FCoV type determination by nested PCR

Nested PCR was performed for FCoV typing according to the procedures of Addie et al. [5] with a slight modification. After reverse transcription, 5 μl of complementary DNA was added to 25 μl of PCR mix (Invitrogen, CA, USA) according to the manufacturer's instructions for the following primer sets: S1 and Iffs to determine FCoV type I and S1 and Icfs to determine FCoV type II. Nested PCR was performed on 2 μl of the first PCR product using nested primers. The expected size of the second PCR achieved for type I and type II FCoV was 360 and 218 bp. RT-nPCR products were electrophoresed and then the target DNA fragments were purified (Geneaid Biotech, Ltd, Taipei) and sequenced (Mission Biotech, Taipei, Taiwan) - from both orientations.

Gene amplification, sequencing and analysis 3a and 3c  from FCoV type II

For amplification 3a of the FCoV type II gene from FIP cats, a set of specific primers was designed that is able to amplify from WITH type II gene to gen 3a. Complementary DNA, amplified with a primer set, targeted the 3 'end WITH FCoV type II gene (Icfs) and 5 ′ end 3a FCoVe gene (3aR2: 5′-caccaaaacctatacacacaag-3 ′). The temperature cycle was as follows: 5 minutes preheating at 94 ° C; 35 cycles of denaturation at 94 ° C for 20 s, annealing at 50 ° C for 20 s and extension at 72 ° C for 30 s; and final extension at 72 ° C for 5 minutes. This was followed by a second series of amplification using primers nIcfs and 3aR2; the expected product size was about 600 bp. Amplicons were electrophoresed, purified, and sequenced from both orientations to confirm nucleotide sequences.

For amplification 3c of the FCoV type II gene from FIP cats, a set of specific primers was designed that is able to amplify from WITH type II gene to gen 3c. Complementary DNA was amplified with forward primer (Icfs) and reverse primer (E68R: 5′-aatatcaatataattatctgctgga-3 ′ and N21R: 5′-gttcatctccccagttgacg-3 ′, respectively). The temperature cycle was as follows: 5 minutes preheating at 94 ° C; 40 cycles of denaturation at 94 ° C for 30 s, annealing at 46 ° C for 30 s and extension at 72 ° C for 90 s; and final extension at 72 ° C for 7 minutes. Following a second series of amplification using primers nIcfs and E68R, the products were electrophoresed, purified and sequenced from both orientations to confirm nucleotide sequences.

Phylogenetic analysis and recombinant analysis of FCoV type II

Several sequence alignments were performed using ClustalW 2.0 with manual editing in EditSeq (DNASTAR, Madison, USA). Phylogenetic analyzes were performed using MegAlign, version 7.2.1 (DNASTAR, Madison, USA). Bootscan and similar graphs were compiled using SimPlot 3.5.1 software (SCRoftware, Baltimore, USA).

The results

Confirmation of the FIP outbreak in the cat shelter

The shelter has been operating for three and a half years. Prior to August 2011, there were no records of FIP. The kittens (cats 1, 3, 4, 8 and 10) were moved to this shelter between June and July 2011. After arrival, these kittens played together and lived together with adult cats that lived here before. Prior to the outbreak, the kittens were individually taken to a veterinarian for vaccination and adoption visits. Fever was first detected in four kittens (cats 1, 3, 4, 5) within a few days (from 15 to 18 August) (Table 1). Clinical symptoms, e.g. fever, anorexia, neurological symptoms, shortness of breath and enlargement of the abdomen were observed over the next two months and the kittens gradually died between 1 September and 22 October (Table 1). Shelters from the shelter asked for our help on September 27. All cats housed in the shelter for a long time were immediately examined for FCoV using the RT-nPCR method. All FCoV-positive cats were isolated and kept separately. Nevertheless, starting in September, adult cats with FIP (cats 7-13) showed clinical signs similar to kittens, and all of these cats later died.

Six kittens (cats 1-6) with body effusions or neurological symptoms that succumbed in the first two months were not confirmed for necropsy (Table 1). Cat 1 was once brought to our teaching hospital and ascites (free fluid in the abdominal cavity) was taken from her. In cats 7-13, typical symptoms were found, namely ascites or pleural effusions in the body cavity (effusive FIP) and granulomatous lesions in some organs, especially in the kidneys, nuclei, lungs, omentum (forecourt) and eyes (non-effusive FIP). In cats 9, 11 and 12, necropsy showed a mixed form of the disease (Table 2) 1).

A total of 13 of the 46 cats (28.3%) died between September 2011 and April 2012 at FIP. At this time, 33 cats (71.7%) appeared to be clinically healthy and 26 of these asymptomatic cats (78.7%) were positive at least once for FCoV - detected from faeces using the RT-nPCR method. The other seven of these asymptomatic cats were negative for FCoV (Table 2) 2).

Table 2
Detection of the occurrence and type of FCoV from faeces samples in healthy cats from the same shelter

Hot girl
Oct. 2011Feb. 2012Jun. 2012 Jul. 2012
15+ untypable
16++ untypable
19 +untypable
20 +untypable
22++++ untypable
24+ untypable
26 +untypable
33 ++untypable
34++   I
35 ++untypable
38  + untypable
39 ++++I
40 +untypable
41 ++untypable
42  +untypable
46  + untypable

++: FCoV detected in the first round of PCR.
+: FCoV detected only in nested PCR.

FIPV type II was found in all cats that succumbed to FIP

In order to further investigate the relationship between these seven histopathologically confirmed FIP cats, the amplified DNA was typed, sequenced and analyzed. FIPV type II was detected in all eight animals that succumbed to FIP, from swabs, faeces, urine, body effusions, cerebrospinal fluid, and tissue homogenates (Table 3). Type II viruses that cause FIP have been found not only in diseased tissue but also in faeces samples (cats 7, 11, 12 and 13), nasal / oral / conjunctival swab samples (cats 7, 8, 9, 11 and 12). ) and in urine collected by cystocentesis (cat 11) (Table 3). Although no necropsy was performed, ascites from cat 1 - the first cat to die in the shelter at FIP - were available for analysis. This cat was confirmed to be infected with type II virus. In healthy animals, only type I or FCoV was detected from faeces samples without type determination (Table 2) 2). Cats 8, 9 and 13 were infected with both types of FCoV (Table 2) 3). Although it has been found that in this environment with many cats there is more than one type of FCoV, ie. type I, II or non-typed viruses, FCoV type II infection was found in all eight FIP cats, whereas this was not the case in healthy animals (Tables 2 and33).

Table 3
Characteristics 3c FCoV genes obtained from different samples of FIP cats

Hot girlFCoV genotypeWITH instead of gene crossingIntegrity 3c geneb
1   II       4250and intact     
7IIII II IIIIIIIIII 4250intact intactintactintact intact
8III   +IIII+        
9III II +II IIII+4250 G210 *   G210 *G210 *
10     ++IIII II4250    intact  
11IIIIIIII+IIIIII + 4250   E47 *   
12IIII IIII+IIII II+4250G210 *G210 *     
13 I / II  +++IIII+ 4250     Q218 * 

NIGHT, nose / mouth / conjunctival swabs; R / F, rectal swabs or stool samples; A / P, ascites or pleural effusion; CSF, cerebrospinal fluid; Li, liver; Lu, lungs; Ki, kidney; Br, brain; Sp, spleen; Int, gut.
+: FCoV positive, but virus type cannot be determined. -: FCoV negative.
a: FCoV / NTU2 / R / 2003; GenBank: DQ160294.
b: E47 *, G210 * and Q218 *: truncated 3c proteins with premature stop codons at amino acids 47, 210 and 218 were found.

FIPV type II of the same origin was found in cats that succumbed to FIP

To further investigate the relationship of these disease-causing type II viruses, which were isolated from cats that succumbed to FIP, sets of specific primers capable of specifically amplifying from the 3 'end were used to analyze viral sequences. WITH the type II gene has a subsequent gene. The identity of the 620 bp amplicons derived from the seven FIPV type II was approximately 98.7% to 99.8%. Phylogenetic analysis found that the type II FCoVs derived from the outbreak described above were all grouped into a separate cluster, which differs from the other four type II FCoVs currently available at GenBank, i. FIPV 79-1146 (GenBank: {“Type”: ”entrez-nucleotide”, “attrs”: {“text”: ”DQ010921 ″,” term_id ”:” 63098796 ″}} DQ010921), FCoV 79-1683 (GenBank: {“Type”: ”entrez-nucleotide”, “attrs”: {“text”: ”JN634064 ″,” term_id ”:” 384038902 ″}} JN634064), FCoV DF-2 (GenBank: {“Type”: ”entrez-nucleotide”, “attrs”: {“text”: ”DQ286389 ″,” term_id ”:” 87242672 ″}} DQ286389) and FCoV NTU156 (GenBank: {“Type”: ”entrez-nucleotide”, “attrs”: {“text”: ”GQ152141 ″,” term_id ”:” 240015188 ″}} GQ152141) (data not shown).

Recombination at the 3 ′ end WITH of the putative recombination site at nucleotide 4250 was determined in all FCoV type II animals obtained from body effusions and tissue homogenates in cats 1, 7, 9, 10, 11, 12 and 13 (Additional set 1) (Table 3). Sequences above this site show greater similarity to CCoV, whereas sequences beyond this site were more similar to type I FCoV (Fig. 1). 1). Indeed, these findings suggest that FCoV type II, found in all FIP cats, has a common origin.

Figure 1
FIPV recombination from cats 1, 7, 9, 10, 11, 12 and 13 on the S gene. Alignment of the 3 ′ end of the S gene with subsequent FCoV genes isolated from seven FIP cats with FCoV type I and CCoV. The light and dark shaded regions include greater similarity to CCoV and FCoV type I. The predicted recombination event occurred at nucleotide 4250 based on comparison to FCoV NTU2 and is indicated by an arrow. Sequences were obtained from FIPV found in individual samples and tissues and are summarized. NIGHT: swabs from the nose / mouth / conjunctiva; RS: rectal swabs; As: ascites; PE: pleural effusion; Li: liver; Lu: lungs; Ki: kidneys; Br: brain; Sp: spleen; dbd: days before death. GenBank accession number: FCoV C1Je (GenBank: DQ848678), FCoV Black (GenBank: EU186072), FCoV NTU2 (GenBank: DQ160294) and CCoV NTU336 (GenBank: GQ477367).

Identical nonsensical mutation on 3c The gene was found in two cats that succumbed to FIP

In order to further analyze the relationship of these FIPVs, they were 3c genes, a proposed virulence-associated FIP, are amplified from the disease-causing FCoV type II. Mutated 3c genes with identical premature stop codon at nucleotides 628-630 (amino acids 210, G210 *) were found in two FIP cats, cat 9 (ascites, spleen and brain) and 12 (ascites and rectal swabs from the day the cat died and four days previously) (Fig. 2A). It is worth noting that FIPV, obtained from cat 12, showed the same nonsense mutation as the virus in its ascites. Intact 3c the genes were discovered in cats 1, 7 and 10, which had previously succumbed to FIP. Two other clear / different nonsense mutations were found in cats 11 (E47 *) and 13 (Q218 *) (Fig. 1). 2AB, Table 3).

Figure 2:
Alignment of complete FIPV 3c genes from cats 1, 7, 9, 10, 11, 12 and 13. (A) The full length 3c genes analyzed in this study were aligned with FCoV type I, FCoV NTU2. The sequences were obtained from FIPV found in individual samples and tissues and are listed together. The box represents the identified premature stop codons. (B) The diagram shows the location of premature stop codons (PT) of gene 3c from different samples from different FIP cats.

FIPV type II excretion can be detected in the terminal phase in FIP cats

The occurrence of FCoV was continuously analyzed to elucidate a possible route of FIPV secretion and transmission. Disease-associated FCoV type II was found to be excreted by the nasal / oral / conjunctival route and faeces (Table 4). Faecal and nasal / oral / conjunctival type II shedding can be detected from day 6 (cat 11) and from day 4 (cat 12) before death. Viremia can be detected during the terminal stage in cats suffering from FIP up to 18 days before death, and concomitant faecal excretion was detected in one cat (cat 12) (Table 4).

Table 4
Excretion and serotypes of feline coronavirus detected in FIP cats in a cat shelter

Hot girlSampleDays before death
9Feces I            I  II
 NIGHT tampons                 II
 Viremie              II  +
 Efuze              IIII II
11Feces            II II
 NIGHT tampons               II
 Efuze     +           II
12Feces+ +  IIII
 NIGHT tampons      IIII
 Viremie  II++   
 EfuzeII                II

+: FCoV positive; -: FCoV negative.
I, II: FCoV type I or type II.
*: Samples were taken immediately before euthanasia, except for cat 12, which were sampled after death.


The possibility of horizontal transmission is generally questioned in FIP because (i) the occurrence of FIP is sporadic and it is common for only one of them to develop FIP in an environment with a large number of cats [2]; (ii) internal mutation theory, which describes that FIPV is a mutant generated from enteric FCoV in one cat [12,17]; (iii) there is insufficient evidence that the mutant FIPV is eliminated from FIP cats; and (iv) mutations 3c gene is unique for every FIP cat [man]11,13,18]. The current belief is that cats that have succumbed to FIP do not excrete and pass FIPV to other cats [11,13,14,1820]. Our data indicate that this outbreak of FIP was caused by viruses of the same origin. First, all cats that died of FIP had a type II infection, and recombination of these seven type II viruses was located at the same site. Recombination of type II viruses currently available in the genetic bank, i.e. FIPV 79-1146, FCoV 79-1683 and FCoV NTU156, were all unique, specific and occurred independently [9,10]. Second, FIPV, found in three kittens that died within the first two months after the onset of fever, had an intact 3c gene, whereas viruses from cats that survived longer (died four to eight months later) all contained a nonsensical mutation, i. G210 * (cats 9 and 12), E47 * (cat 11) and Q218 * (cat 13). Because the three nonsense mutations found in FIPV in these animals were all located at different sites, the viruses that originally infected these cats should be intact. 3c gene - similar to the virus found in kittens that died earlier. Following infection, local mutations occurred during virus replication in individual cats, resulting in FIPV with 3c a gene that carries meaningless mutations in different places. The finding that viruses, which were identified not only in tissues but also in faecal samples in two cats (cats 9 and 12), had an identical mutation in 3c gene, further confirmed that there was a horizontal transfer (Table 2) 3). Taken together, all of these findings demonstrated that highly virulent FIPV spread horizontally from one animal to another.

This is the first report of an FIPV type II outbreak with evidence of horizontal disease-causing FCoV transmission. The FIP broke out after five kittens (cats 1, 3, 4, 8 and 10) entered this shelter between June and July 2011. Because causative type II viruses with a specific genetic marker in the S gene have been confirmed as feline and canine coronavirus recombination, and some of the kittens that died earlier were found to have lived together or next to dogs between rescue and transport to the shelter. of these kittens may have been the source of this type II virus. Dogs and especially young dogs often shed large amounts of canine coronavirus in their faeces in shelters, and recombination between feline-canine and canine-feline coronavirus is already well documented [man]2123]. In addition, type II causative viruses have been detected in a number of excreta and secretions in cats that have died of FIP (Table 3), demonstrating that it is possible to spread between cats.

Although immediately after the first examination of all animals from this FCoV shelter, FCoV-secreting cats were housed in separate cages and transmission subsequently ceased, mortality at the onset of the disease was high (28%, 13/46). The results of three studies that looked at the outbreak of FIP have been reported earlier. The results of a four-year study conducted at a nearby cat kennel showed an average mortality of 17.3% [24]; the mortality rate from a ten-year study conducted at a nearby kennel was 29.4% (5/17) [25]. Another epidemic study conducted in seven kennels / shelters revealed >10% mortality [20]. The high incidence of FIP in these closed breeding stations could be influenced by genetically predisposed breeding animals. In our study, only a few FIP cats in this shelter were siblings and the other cats were not genetically related. Our study shows that even without the influence of genetic predisposing factors, FIP mortality can be high in a confined environment with a large number of cats if the spread of FCoV, which causes the disease, remains undetected.

In this environment with a large number of cats, three FIP cats were infected not only with FCoV type II, but also co-infected with FCoV type I (Table 3). Type I FCoV was found only in faecal samples, while type II FCoV was found in various samples, including body effusions, granulomatous tissue homogenates, and cerebrospinal fluid. This finding indicates that FCoV type II was a major cause of FIP in these doubly infected animals. This finding is consistent with our previous finding that FCoV type II infection is significantly associated with FIP [4].

The presence of FCoV in whole blood in the terminal phase has been identified previously [26,27]; however, to our knowledge, the presence of FIPV in faeces prior to the final stage of the disease was not published anywhere until our study. The excretion of this type II virus in faeces and by the nasal / oral / conjunctival route can be detected in the effusive form of FIP up to six days before the death of the animal. Another experimental study of the infection showed that inoculated viruses could not be detected until about two weeks after inoculation, before clinical signs of the disease developed [14]. In summary, FIPV transmission could occur at the beginning, before the manifestations of the disease and in the terminal phase. When the disease broke out in our case, all the cats were initially placed together in an open room. After seven cats gradually succumbed to the disease, all FCoV-positive cats were housed separately in cages and kept separately. Isolation probably inhibited disease transmission. This outbreak of disease, which killed 13 cats, allowed us to make it clear that FIPV can be transmitted horizontally and to show that the isolation of sick cats should be taken into account in an environment where more cats are present.

Competitive interests

The authors claim that they have no competitive interests.

Contributions and contributions of authors

YTW performed sampling and preparation, FCoV detection, type determination, amplification 3c gene and other analyzes and compiled a manuscript. The BLS supervised the sampling and treatment of all FIP animals and contributed to the compilation of the manuscript. LEH participated in the amplification 3c gene, genetic analysis and manuscript preparation. The LLC devised the study, participated in the design of the study, coordinated and participated in the preparation of the manuscript. All authors read and approved the final version of the manuscript.

Additional material

Additional file 1:

FIPV recombination site analysis in cats 1, 7, 9, 10, 11, 12 and 13 at WITH gene. Analysis of the plot similarity using the Kimur (two-parameter) distance model, the model of adjacent interconnected trees, and 100 replicates of the bootstrap showed that recombination had occurred and the putative crossing point is indicated by an arrow. 


The authors would like to thank the caregivers in the mentioned cat shelter, without whose help this study would not have been possible.


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Origin of abdominal or thoracic effusions in cats with wet FIP and causes of their persistence during treatment

Niels C. Pedersen, DVM, PhD
Pet Health Center
University of California, Davis

Original article: Origin of abdominal or thoracic effusions in cats with wet FIP and reasons for their persistence during treatment

Origin of FIP exudates. Sweat in wet FIP comes from small vessels (venules) that line the surface of the abdominal and thoracic organs (visceral) and walls (parietal), mesentery / mediastinum, and omentum. The spaces around these vessels contain a specific type of macrophages that come from monocyte progenitors that constantly recirculate between the bloodstream, the interstitial spaces around the venules, the afferent lymph, the regional lymph nodes, and back into the bloodstream. Other sites of this recirculation are located in the meninges, brain ependyma, and uveal eye tract. A small proportion of these monocytes develop into immature macrophages (monocyte / macrophage) and eventually into resident macrophages. Macrophages are constantly looking for infections.

FIPV is caused by a mutation in feline enteric coronavirus (FECV) present in lymphoid tissues and lymph nodes in the lower intestine. The mutation changes FECV cell tropism from enterocytes to peritoneal-type macrophages. Monocytes / macrophages appear to be the first cell type to be infected. This infection causes more monocytes to leave the bloodstream and begin to turn into macrophages, which continue the cycle of infection. [2]. Monocytes / macrophages do not undergo programmed cell death as usually expected, but continue to mature into large virus-loaded macrophages. These large macrophages eventually undergo programmed cell death (apoptosis) and release large amounts of virus, which then infects new monocytes / macrophages. [1]. Infected monocytes / macrophages and macrophages produce several substances (cytokines) that mediate the intensity of inflammation (disease) and immunity (resistance). [1,2].

Inflammation associated with FIP leads to three types of changes in the venules. The first is loss of vascular wall integrity, micro-bleeding, and leakage of plasma protein rich in activated complement clotting and activation factors and other inflammatory proteins. The second type of damage involves thrombosis and blocking blood flow. The third injury occurs in more chronic cases and involves fibrosis (scarring) around the blood vessels. Variations in these three events determine the amount and composition of exudates according to the four Starling forces that determine the movement of fluids between the bloodstream and interstitial spaces. [3].

The classic effusion in wet FIP is mainly due to acute damage to the vessel walls and leakage of plasma into the interstitial spaces and finally into the body cavities. Protein that escapes into the interstitial spaces attracts additional fluids, which can be exacerbated by blocking venous blood flow and increasing capillary pressure. This type of effusion, known as exudate, also contains high levels of protein, which is involved in inflammation, immune responses and blood clotting.

This fluid also contains a large number of neutrophils, macrophages / monocytes, macrophages, eosinophils and a lower number of lymphocytes and red blood cells. This classic type of fluid has the consistency of egg white and forms weak clots containing a high amount of bilirubin. Bilirubin does not originate from liver disease, but rather from the destruction of red blood cells that escape into interstitial tissue cells and are taken up by monocytes / macrophages and macrophages. Red blood cells break down and hemoglobin is broken down into heme and globin. Globin is further metabolized to biliverdin (greenish color) and finally to bilirubin (yellowish color), which is then excreted by the liver. However, cats lack the enzymes used for conjugation and are therefore ineffective in removing bilirubin from the body. [4]. This leads to the accumulation of bilirubin in the bloodstream and gives the effusion a yellow tinge. The darker the yellow tint, the more bilirubin is in the effusion, the more severe the initiating inflammatory response and the more severe the resulting bilirubinemia, bilirubinuria and jaundice.

The opposite extreme of the classic and more acute effusion in FIP are effusions arising mainly from chronic infections and blockage of venous blood flow and consequent increase in capillary pressure. High capillary pressure results in effusion that is more distant to interstitial fluid than plasma, has a lower protein content, is watery rather than sticky, clear or slightly yellow in color, is not prone to clotting, and has a lower number of acute inflammatory cells such as neutrophils. There are also FIP effusions that are among these extremes, depending on the relative degree of acute inflammation and chronic fibrosis. These transient types of fluids are commonly referred to in the veterinary literature as modified transudate, but this is a misnomer. The modified transudate begins as a transudate and changes as it persists and causes mild inflammation. Low protein and cell effusions in FIP arise as exudates and not as transudates and do not conform to this description. The more correct term is "modified exudate" or "variant exudate outflow".

How long do sweats usually last in cats treated with GS-441524 or GC376? The presence of abdominal effusions often leads to a large dilation of the abdomen and is confirmed by palpation, hollow needle aspiration, X-ray or ultrasound. Cats with thoracic effusions are most often presented with severe shortness of breath and are confirmed by radiological examination and aspiration. Chest effusions are almost always removed to relieve shortness of breath and recur slowly compared to abdominal effusions. Therefore, abdominal effusions are usually not removed unless they are massive and do not interfere with respiration, as they are quickly replaced. Repeated drainage of abdominal effusions can also deplete proteins and cause harmful changes in fluid and electrolyte balance in severely ill cats.

Chest effusions disappear faster with GS-441524 treatment, with improved breathing within 24-72 hours and usually disappearing in less than 7 days. Abdominal effusions usually decrease significantly within 7-14 days and disappear within 21-28 days. The detection of exudates that persist after this time depends on their amount and method of detection. Small amounts of persistent fluid can only be detected by ultrasound.

Persistence of exudates during or after antiviral treatment. There are three basic reasons for the persistence of exudates. The first is the persistence of the infection and the resulting inflammation at a certain level, which can be caused by inappropriate treatment, poor medication or drug resistance. Inadequate treatment may be the result of incorrect dosing of the wrong drug or the acquisition of virus resistance to the drug. The second reason for fluid persistence is chronic venous damage and increased capillary pressure. This may be due to a low-grade infection or residual fibrosis from an infection that has been removed. The third reason for persistence is the existence of other diseases, which can also manifest as exudates. These include congenital heart disease, in particular cardiomyopathy, chronic liver disease (acquired or congenital), hypoproteinemia (acquired or congenital) and cancer. Congenital diseases causing effusions are more common in young cats, while acquired causes and cancer are more commonly diagnosed in older cats.

Diagnosis and treatment of persistent effusions. A thorough examination of the fluid, as described above, is a prerequisite for diagnosis and treatment. If the fluid is inflammatory or semi-inflammatory and the cell pellet is positive by PCR or IHC, the reason for the persistence of the infection must be determined. Was the antiviral treatment performed correctly, was the antiviral drug active and its concentration correct, was there evidence of acquired drug resistance? If the fluid is inflammatory and PCR and IHC are negative, what other diseases are possible? Low protein and non-inflammatory fluids that are negative for PCR and IHC indicate a diagnosis of residual small vessel fibrosis and / or other contributing causes such as heart disease, chronic liver disease, hypoproteinemia (bowel disease or kidneys). Some of the disorders causing this type of effusion may require an exploratory laparotomy with a thorough examination of the abdominal organs and a selective biopsy to determine the origin of the fluid. The treatment of persistent effusions will vary greatly depending on the end cause. Persistent effusions caused by residual small vessel fibrosis in cats cured of the infection often resolve after many weeks or months. Persistent discharges caused in whole or in part by other diseases require treatment for these diseases.

Identification and characteristics of persistent effusions. The presence of fluid after 4 weeks of GS treatment is unpleasant and is usually detected in several ways depending on the amount of fluid and its location. Large amounts of fluid are usually determined by the degree of abdominal dilation, palpation, X-ray and abdominal aspiration, while smaller amounts of fluid are best detected by ultrasound. Persistent pleural effusion is usually detected by X-rays or ultrasound. Overall, ultrasound is the most accurate means of detecting and semiquantitatively determining thoracic and abdominal effusions. Ultrasound can also be used in combination with thin needle aspiration to collect small and localized amounts of fluid.

The second step in examining persistent effusions is to analyze them based on color, protein content, white and red blood cell counts, and the types of white blood cells present. Fluids generated primarily by inflammation will have protein levels close to or equal to plasma and a large number of white blood cells (neutrophils, lymphocytes, monocytes / macrophages and large vacuolated macrophages). Fluids produced by increased capillary pressure are more similar to interstitial fluid with proteins closer to 2.0 g / dl and cell counts <200. The Rivalt test is often used to diagnose FIP-related effusions. However, this is not a specific test for FIP, but rather for inflammatory effusions. It is usually positive for FIP effusions that are high in protein and cells, but is often negative for very low protein and cell effusions. The effluents that are between these two types of effusions will be tested either positively or negatively, depending on where they are in the spectrum.

The third step is the analysis of exudates for the presence of FIP virus. This usually requires 5 to 25 ml or more of fluid. For fluids with a higher protein and cell count, a smaller amount may suffice, while for fluids with a low protein and cell count, a larger amount is required. The freshly collected sample should be centrifuged and the cell pellet analyzed for the presence of viral RNA by PCR or cytocentrifuged for immunohistochemistry (IHC). The PCR test should be for FIPV 7b RNA and not for specific FIPV mutations, as the mutation test does not have sufficient sensitivity and does not provide any diagnostic benefits [5]. Samples that are positive by PCR or IHC provide definitive evidence of FIP. However, up to 30 % samples from known cases of FIP may have a false negative test either due to an inappropriate sample and its preparation, or because the RNA level of the FIP virus is below the level of detection. It is also true that the less inflammatory the fluid, the lower the virus levels. Therefore, effusions with lower protein and white blood cell levels are more likely to be tested negative because viral RNA is below the detection limit of the test.


[1] Watanabe R, Eckstrand C, Liu H, Pedersen NC. Characterization of peritoneal cells from cats with experimentally-induced feline infectious peritonitis (FIP) using RNA-seq. Vet Res. 2018 49 (1): 81. doi: 10.1186 / s13567-018-0578-y.

[2]. Kipar A, Meli ML, Failing K, Euler T, Gomes-Keller MA, Schwartz D, Lutz H, Reinacher M. Natural feline coronavirus infection: differences in cytokine patterns in association with the outcome of infection. Vet Immunol Immunopathol. 2006 Aug 15; 112 (3-4): 141-55. doi: 10.1016 / j.vetimm.2006.02.004. Epub

[3] Brandis K. Starling's Hypothesis, LibreTexts. https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Book%3A_Fluid_Physiology _(Brandis)/04%3A_Capillary_Fluid_Dynamics/4.02%3A_Starling%27s_Hypothesis

[4]. Court MH. Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms. Vet Clin North Am Small Anim Pract. 2013; 43 (5): 10391054. doi: 10.1016 / j.cvsm.2013.05.002

[5]. Barker, EN, Stranieri, A, Helps, CR. Limitations of using feline coronavirus spike protein gene mutations to diagnose feline infectious peritonitis. Vet Res 2017; 48: 60.

Acute phase proteins in cats

April 2019
Rita Mourão Rosa, Lisa Alexandra Pereira Mestrinho
Original article: Acute phase proteins in cats

ABSTRACT: Acute phase proteins (APPs) are proteins synthesized and released mainly by hepatocytes during cell damage or invasion of microorganisms. This article provides an overview of the use of APP in cat diseases, identifies their usefulness in the clinical setting, and analyzes 55 published papers. Serum amyloid A, alpha-1 acid glycoprotein and haptoglobin are indicators that the authors consider useful in monitoring the acute inflammatory response in cats. Although APP measurement is still not routinely used in veterinary medicine, along with clinical signs and other blood parameters, they are clinically of interest and useful in diseases such as feline infectious peritonitis, pancreatitis, renal failure, retroviral and calicivirus infections. Although there are commercially available kits for measuring feline APPs, standardization of tests for technical simplicity, greater species specificity, and less associated costs will allow for routine use in feline practice, as is the case in the human field.
keywords: inflammation, acute phase proteins, cat.


Acute phase response (APR) is an early non-specific systemic innate immune response to a local or systemic stimulus that helps treat and restore homeostasis and minimize tissue damage when an organism is affected by trauma, infection, stress, surgery, neoplasia, or inflammation (GRUYS et al. , 2005; CRAY et al., 2009; ECKERSALL AND BELL, 2010). In this reaction, we observe several different systemic effects: fever, leukocytosis, hormonal changes - mainly cortisol and thyroxine concentrations, with secondary catabolic status and serum muscle, iron and zinc depletion (CERÓN et al. 2005, JAVARD et al. 2017).
Cytokines IL-1β, TNF-α, and especially IL-6, and approximately 90 minutes after injury, increase protein synthesis in hepatocytes, lymph nodes, tonsils, and spleen, as well as blood leukocytes. These newly formed proteins are called acute phase proteins (APPs) (TIZARD, 2013b).

Acute-phase proteins

APP concentrations may increase (APP positive) or decrease (APP negative) in response to inflammation (PALTRINIERI et al., 2008) (JOHNSTON & TOBIAS, 2018). They can activate leukocytosis and complement, cause protease inhibition, lead to blood clotting and opsonization - a defense mechanism that leads to the elimination of infectious agents, tissue regeneration and restoration of health (CRAY et al., 2009). APP can have two functions, pro- and / or anti-inflammatory, which must be fine-tuned to promote homeostasis (HOCHEPIED et al., 2003).

According to the size and duration of the reaction following the stimulus, three main groups of APP are distinguished (MURATA et al., 2004; PETERSEN et al., 2004; CERÓN et al.). Positive APP can be divided into two groups: the first group includes APP with an increase of 10 up to 1000-fold in humans or 10- to 100-fold in domestic animals in the presence of inflammation - e.g. c-reactive protein (CRP) and serum amyloid A (SAA). The second group are APPs, which increase 2 to 10-fold in an inflammatory response - e.g. haptoglobin and alpha-globulins. The last group included negative APP, in which the concentration decreases in response to inflammation - e.g. albumin (KANN et al., 2012).

Acute phase positive proteins

Positive APPs are glycoproteins whose serum concentrations, when stimulated by pro-inflammatory cytokines, increase by 25 % during the disease process and are released into the bloodstream. These concentrations can be measured and used in diagnosis, prognosis, monitoring of response to treatment, as well as general health screening. They can also be considered as quantitative biomarkers of the disease, highly sensitive to inflammation but not very specific, as an increase in APP can also occur in non-inflammatory diseases (CERÓN et al., 2005; ECKERSALL and BELL, 2010).

Positive APPs respond to cytokines differently, and these groups fall into two main classes. Type 1 APP, which includes AGP, complement component 3, SAA, CRP, haptoglobin and hemopexin, is regulated by IL-1, IL-6 and TNF-α as well as glucocorticoids. Type 2, which includes three fibrinogen chains (α-, β- and γ-fibrinogen) and various inhibitory proteases, is regulated by cytokines IL-6 and glucocorticoids (BAUMANN et al., 1990; BAUMANN & GAULDIE, 1994).

In cats, APP SAA or alpha-1-acid glycoprotein (AGP) is the most important. Blood SAA levels may indicate inflammatory conditions such as feline infectious peritonitis (FIP) and other infectious diseases such as calicivirus infection, chlamydia, leukemia and infectious immunodeficiency, as they increase 10- to 50-fold (TIZARD, 2013b). SAA can also be increased in other diseases, such as diabetes mellitus and cancer. Haptoglobin usually increases 2- to 10-fold and is particularly high in FIP (TIZARD, 2013b). Table 1 summarizes the individual positive APPs in the context of feline disease.

Acute phase negative proteins

The most significant negative APP is albumin, whose blood concentration decreases during APR due to amino acid aberrations towards the synthesis of positive APPs (CRAY et al., 2009; PALTRINIERI, 2007a). Other negative APPs are transferrin, transthyretin, retinol ligand, and cortisol binding protein, proteins involved in vitamin and hormone transport (JAIN et al., 2011).

Acute phase proteins in cat disease

Unlike cytokines, which are small in size and rapidly filtered by the kidney, acute phase proteins have a higher molecular weight (greater than 45 kDa) and consequently remain in plasma for longer (SALGADO et al., 2011).

APP levels can only indicate inflammation, and consequently their concentrations can help diagnose and monitor the disease. APP can help detect subclinical inflammation, distinguish acute from chronic disease, and predict its course (VILHENA et al, 2018; JAVARD et al., 2017). Because APRs begin before specific immunological changes occur, they can be used as an early marker of disease before leukogram changes occur, with their magnitude related to disease severity (PETERSEN et al., 2004; CÉRON et al., 2005; VILHENA et al., 2005). , 2018). For this reason, disease monitoring can be considered one of the most interesting and promising applications of APP.

APP levels along with clinical signs and blood tests have been evaluated in a variety of animal diseases (ie, FIP, canine inflammatory disease, leishmaniasis, ehrlichiosis, and canine pyometra) and have been shown to be useful in diagnosis, response to treatment, and prognosis (ECKERSALL et al. ), 2001; MARTINEZ-SUBIELA et al., 2005; SHIMADA et al., 2002; JERGENS et al., 2003; GIORDANO et al., 2004; PETERSEN et al., 2004; DABROWSKI et al., 2009; VILHENA et al., 2018).

To obtain complete information on APR, one major and one moderate positive as well as one negative APP should be evaluated simultaneously (CERÓN et al., 2008). High concentrations of major APP are usually associated with infectious diseases, usually systemic bacterial infection or immune-mediated disease (CERÓN et al., 2008; TROÌA et al., 2017). Although APPs should be analyzed along with white blood cell and neutrophil counts, they are most sensitive in the early detection of inflammation and infection (CERÓN et al., 2008; ALVES et al., 2010). However, the specificity of these proteins is low in determining the cause of the process, and also increases in physiological conditions such as pregnancy (PALTRINIERI et al., 2008).

APPThe disease
Induced inflammation and surgery
Various diseases (pancreatitis, renal failure, FLUTD, tumors, diabetes mellitus; kidney disease, injury, etc.)
FeLV; hemotropic mycoplasma infections
Hepatozoonfelis and Babesia vogeli infection
FIV cats treated with recombinant feline interferon
AGPChlamydophila psittaci infection;
Pancreatitis and pancreatic tumors
Lymphoma and other tumors
Induced inflammation and surgery
FIV cats treated with recombinant feline interferon
Abscesses, pyothorax, adipose tissue necrosis
Various diseases (FLUTD, tumors, diabetes mellitus, kidney diseases, injuries, etc.)
Induced inflammation and surgery
Abscesses, pyothorax, adipose tissue necrosis
Various diseases (FLUTD, tumors, diabetes mellitus, kidney diseases, injuries, etc.)
Hepatozoonfelis and Babesia vogeli infection
FeLV, hemotropic mycoplasmas
CRPFIV cats treated with recombinant feline interferon
Induced inflammation and surgery
Table 1 - Acute phase proteins studied for feline diseases.
Legend: Serum amyloid A (SAA), α1-acid glycoprotein (AGP), systemic inflammatory response syndrome (SIRS), feline lower urinary tract disease (FLUTD), feline infectious peritonitis (FIP), feline leukemia virus (FeLV), immunodeficiency virus cats (FIV); feline calicivirus (FCV).

Figure 1 shows the expected behavior of acute phase positive proteins based on revised studies. AGP, SAA and haptoglobin have been identified as useful indicators for monitoring the acute inflammatory response in cats (WINKEL et al., 2015; PALTRINIERI et al., 2007a, b; KAJIKAWA et al., 1999). APPs in cats were first identified after comparative measurements in the serum of clinically normal and diseased animals, in experimentally induced inflammation studies, and in postoperative studies (KAJIKAWA et al., 1999). The concentration of SAA reportedly increased first, followed by an increase in AGP and haptoglobin, in contrast to a less pronounced increase in CRP (KAJIKAWA et al., 1999). One study showed that CRP behaves similarly to SAA and AGP in cat inflammation (LEAL et al., 2014).

Serum Amyloid A

SAA is one of the major APPs in several species, important in both humans and cats (KAJIKAWA et al., 1999). It modulates the immune response by attracting inflammatory cells to tissues and leading to the production of multiple inflammatory cytokines (GRUYS et al., 2005; TIZARD, 2013a). Its concentration can increase more than 1,000 times in an inflammatory condition, which we then understand as inflammation (TAMAMOTO et al., 2013). However, such an increase can be observed in both non-inflammatory and inflammatory diseases and neoplasms (TAMAMOTO et al., 2013). According to a study in cats that underwent surgery, SAA levels begin to increase approximately 3 to 6 hours, peaking 21 to 24 hours after surgery (SASAKI et al., 2003).

Figure 1 - Idealized behavior of acute phase proteins in cats after inflammatory stimuli. The values representing the changes cannot be considered absolute. Increase in serum amyloid A (SAA) 3 to 6 h after challenge, peak at 21 to 24 h, peak size 10 to 50 times its basal plasma concentration. Alpha 1 acid glycoprotein (AGP) increases 8 h after challenge, peak at 36 h, size at peak time 2 to 10 times its baseline plasma concentration. Haptoglobulin (Hp) increase 24 h after challenge, peak 36 to 48 h, peak size 2 to 10 times its basal plasma concentration. C-reactive protein (CRP) increased 8 h after challenge, peak at 36 h, peak size 1.5 times its basal values.

Alpha 1-acid glycoprotein

Alpha 1-acid glycoprotein (AGP) is an acute phase-reactive protein found in the serum mucoid portion of serum (SELTING et al., 2000; WINKEL et al., 2015). Like most positive APPs, AGP is a glycoprotein synthesized predominantly by hepatocytes in APR and released into the bloodstream (CÉRON et al., 2005).

AGP can be used to monitor early interferon treatment in cats infected with feline immunodeficiency virus (FIV) (GIL et al., 2014). AGP as well as haptoglobin (Hp) are increased in anemic cats suffering from pyothorax, abscesses or fat necrosis (OTTENJANN et al., 2006).

Changes in AGP in feline neoplasia do not appear to be consistent across studies. Some of them do not describe any changes in cats with lymphoma (CORREA et al., 2001). Others point to an increase in both AGP and SAA in cats with sarcomas, carcinomas, or other round cell tumors (SELTING et al., 2000; TAMAMOTO et al., 2013; MEACHEN et al., 2015; HAZUCHOVA et al., 2017).

AGP is important as an indicator test for FIP, which is used specifically in Europe (CECILIANI et al., 2004). GIORI et al. examined the specificity and sensitivity of several tests in 12 cats, with 33.33 % cats being FIP negative based on histopathology and immunohistochemistry and 66.66 % cats being FIP positive confirmed by histopathology and immunohistochemistry. This author concludes that immunohistochemistry must always be performed to confirm FIP, but high concentrations of AGP can help support the diagnosis of FIP if immunohistochemistry cannot be performed and histopathology is not convincing.


Haptoglobin (Hp) is one of the most important acute phase proteins in cattle, sheep, goats, horses and cats (TIZARD, 2013a), synthesized mainly by hepatocytes but also by other tissues such as skin, lungs and kidneys (JAIN et al, 2011 ). Hp binds to iron molecules and makes them inaccessible to invasive bacteria, thereby inhibiting bacterial proliferation and invasion. Subsequently, it also binds to free hemoglobin, thus preventing its oxidation with lipids and proteins (TIZARD, 2013a), which justifies a reduction in Hp in case of hemolysis.

In cats, Hp usually increases 2- to 10-fold in inflammatory conditions, and is particularly high in FIP (TIZARD, 2013a). However, both Hp and SAA did not provide sufficient support to distinguish FIP from other causes of effusion compared to AGP (HAZUCHOVÁ et al., 2017).

Measurement APP

The serum is composed of a large number of individual proteins in which the detection of changes in its fractions can provide important diagnostic information (ECKERSALL, 2008).

Ideally, measurement of all serum proteins should be available so that they can be used as a diagnostic tool in relation to inflammatory diseases.
Currently, APPs (Table 2) can be determined by enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, nephelometry, immunoturbidimetry (IT), Western blot, and messenger ribonucleic acid (mRNA) analysis (CÉRON et al., 2005; PALTRINIERI et al., 2008; SCHREIBER et al., 1989). Although some human APP tests have been automated for veterinary medicine, species-specific tests are still limited. Cross-species differences in APP and the limited availability of cross-reactive agents have so far contributed to the low routine level of APP determination in veterinary laboratories, especially in cats. Regardless, the technology is evolving and routine monitoring of clinically relevant APPs in cats can be expected in the near future.


Acute phase proteins in cats are biomarkers suitable for monitoring inflammation, along with other clinical and laboratory findings that are useful in diagnosing subclinical changes, monitoring the development and effect of the disease in the body, as well as in evaluating the response to treatment.

In cats, SAA APP, which is most pronounced in response to inflammation, is followed by AGP and haptoglobin, in contrast to CRP, which is used in other species.

Although there are commercially available kits for determining feline APPs, standardization of tests for technical simplicity, higher species specificity with lower associated costs will allow routine use in feline practice, as is done in human medicine.

Radioimmunoassay24 to 48 hours to obtain results, specific operator skills required
ELISACommercially available species-specific kitsLack of automation, expensive, some "between-run" inaccuracy
Immunoturbidimetry30 minutes to obtain results, customizable with a biochemical analyzer
Western BlotLong time for immunoblot processing
Nephelometric immunoassaysThey depend on the cross-reactivity of the increased antiserum
Table 2 - Advantages and disadvantages of possible APP measurement techniques.

Appendix: APP and their position in the electrophoretogram

Although there are tests directly for a specific APP, it is useful to know in which region the electrophoretograms are located.

Electrophoretogram demonstration (Serum protein electrophoresis output)
Serum proteinElectrophoretic region
α1-acid glycoproteinα1 (alpha-1)
Serum Amyloid Aα (alpha)
Haptoglobinα2 (alpha-2)
Ceruloplasmin α2 (alpha-2)
Transferrinβ1 (beta-1)
C-reactive proteinγ (gamma)
Position of serum proteins in electrophoretogram


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Alternative treatments for cats with FIP and natural or acquired resistance to GS-441524

Niels C. Pedersen, Nicole Jacque, 3.11. 2021
Original article: Alternative treatments for cats with FIP and natural or acquired resistance to GS-441524

SC - subcutaneous
IV - intravenous
IM - to the muscle
PO - per os - orally
SID - once a day
BID - 2x this
q24h - once every 24 hours
q12h - once in 12 hours


Antiviral resistance is well documented in diseases such as HIV / AIDS and hepatitis C. In some cases, this resistance is present in the infecting virus, but is more often due to long-term drug exposure. Resistance to GC376 [1] and GS-441524 [2] has also been documented in cats with naturally acquired FIP. Resistance develops based on mutations in regions of the viral genome that contain targets for the antiviral drug. For example, several amino acid changes (N25S, A252S or K260N) were detected in the GIP376-resistant FIPV isolate (3CLpro). [3]. A change in N25S in 3CLpro was found to cause a 1.68-fold increase in 50 % GC376 inhibitory concentration in tissue cultures [3]. Resistance to GC376, although recognized in initial field trials, has not yet been described. GC376 is less popular in the treatment of FIP and is not recommended for cats with ocular or neurological FIP. [1].

Natural resistance to GS-441524 was observed in one of 31 cats treated for naturally occurring FIP [2]. One of the 31 cats in the original GS-441524 field study also appeared to be resistant, as viral RNA levels did not decrease throughout the treatment period and the symptoms of the disease did not abate. Although this virus has not been studied, resistance to GS-5734 (Remdesivir), a prodrug of GS-441524, has been established in tissue culture by amino acid mutations in RNA polymerase and corrective exonuclease. [4].

Resistance to GS-441524 has been confirmed in a number of cats that have been treated for FIP with GS-441524 in the last 3 years, especially among cats with neurological FIP [5]. Resistance to GS441524 is usually partial and higher doses often cure the infection or significantly reduce the symptoms of the disease during treatment. Interestingly, resistance to GS-441524 has also been found in patients with Covid19 treated with Remdesivir [12]. An immunocompromised patient developed a prolonged course of SARS-CoV-2 infection. Remdesivirus treatment initially alleviated symptoms and significantly reduced virus levels, but the disease returned with a large increase in virus replication. Whole genome sequencing identified an E802D mutation in nsp12 RNA-dependent RNA polymerase that was not present in pre-treatment samples and caused a 6-fold increase in resistance.

Although the history of molnupiravir and its recent use in the treatment of FIP has been described [6], there are currently no studies documenting natural or acquired resistance to molnupiravir. Molnupiravir has been shown to function as an RNA mutagen causing several defects in the viral genome [7]while remdesivir / GS-441524 is a non-binding RNA chain terminator [8], which suggests that its resistance profile will be different.

Overcoming resistance to GS-441524

Drug resistance can only be overcome in two ways: 1) by gradually increasing the dose of the antiviral to achieve drug levels in body fluids that exceed the resistance level, or 2) by using another antiviral that has a different mechanism of resistance, either alone or in combination. So far, the first option has been chosen, which has proved effective in many cases. However, resistance to GS-441524 may be complete or so high that increasing the dose is no longer effective. In such cases, the second option is increasingly used. Currently available alternatives to GS-441524, although still from an unapproved market, are GC376 and molnupiravir.

Antiviral drug treatment regimens for resistance to GS-441524

GC376 / GS-441524

The combined GS / GC regimen has been shown to be effective in cats treated with GS-441524 at doses up to 40 mg / kg without cure due to resistance to GS-441524. It is better to intervene as soon as resistance to GS-441524 is detected, which will allow the cat to be cured sooner and at lesser cost to the owner.

Rainman is the current supplier of GC376, which comes in 4 ml vials at a concentration of 53 mg / ml.

GS / GC dosage: The dose of GS (SC or PO equivalent) in combination antiviral therapy is the same as the dose needed to adequately control the symptoms of the disease. This is usually the last dose used before the end of treatment and relapse. To this dose of GS-441524, GC376 is added at a dose of 20 mg / kg SC q24h regardless of the form of FIP. This is sufficient for most cats, including many cats with neuro FIP, but some will need higher doses. If remission of clinical signs is not achieved or blood tests are of concern, the dose of GC376 is increased by 10 mg / kg up to 50 mg / kg SC q24h.

Duration of treatment: An eight-week combination GC / GS treatment is recommended, which is added to previous GS monotherapy. Some cats were cured at 6 weeks of combination therapy, but relapse is more likely than at 8 weeks.

Side effects: Most cats have no serious side effects. However, about one in five cats may experience nausea or discomfort at the beginning of treatment and sometimes longer. These side effects do not appear to be dose dependent and can be treated with anti-nausea drugs such as Cerenia, Ondansetron or Famotidine. Ondansetron appears to have performed better in some cats.


Molnupiravir has been reported to be effective in monotherapy in cats with FIP by at least one Chinese retailer GS-441524 [9], but there are no reports of its use in cats with resistance to GS-441524. However, resistance to GS-441524 is unlikely to spread to molnupiravir. The fact that it has been found to be effective as an oral medicine also makes it attractive for treatment alone, as many cats resistant to GS-441524 have suffered from injections for a very long time.

A field study of molnupiravir reportedly consisted of 286 cats with various forms of naturally occurring FIP, which were examined in pet clinics in the United States, the United Kingdom, Italy, Germany, France, Japan, Romania, Turkey and China. Among the 286 cats that participated in the trial, no deaths occurred, including seven cats with ocular (n = 2) and neurological (n = 5) FIP. Twenty-eight of these cats were cured after 4-6 weeks of treatment and 258 after 8 weeks. All treated cats remained healthy 3-5 months later, a period during which cats that were not successfully cured would be expected to relapse. These data provide convincing evidence of the safety and efficacy of molnupiravir in cats with various forms of FIP. However, we hope that this field study will be written in the form of a manuscript, submitted for review and published. Nevertheless, it is now sold to cat owners with FIP. At least one other major retailer of GS-441524 is also interested in using molnupiravir for FIP, indicating a demand for further treatment of cats with FIP antivirals.

Molnupiravir dosage: The safe and effective dosing of molnupiravir in cats with FIP has not been established based on closely controlled and monitored field studies such as those performed for GC376 [1] and GS-441524. [2]. However, at least one seller from China in his flyer for a product called Hero-2801 [9] provided some pharmacokinetic and field trials of Molnuparivir in cats with naturally occurring FIP. This information does not clearly state the amount of molnupiravir in one of their “50 mg tablets” and the actual dosing interval (q12h or q24h?). The dose used in this study also appeared to be too high. Fortunately, the estimated starting dose of molnupiravir in cats with FIP can be obtained from published studies on EIDD-1931 and EIDD-2801. [15] in vitro on cell cultures and laboratory and field studies GS-441524 [14,18]. Molnupiravir (EIDD-2801) has an EC50 of 0.4 μM / μl against FIPV in cell culture, while the EC50 of GS-441524 is approximately 1.0 μM / μl. [18]. Both have a similar oral absorption of approximately 40-50 %, so an effective subcutaneous (SC) dose of molnupiravir would be approximately half the recommended starting dose of 4 mg / kg SC q24h for GS441524. [14] or 2 mg / kg SC q24h. The oral (PO) dose would be doubled to account for less effective oral absorption per 4 mg / kg PO q24h dose. The estimated initial effective oral dose of molnupiravir in cats with FIP can also be calculated from the available Covid-19 treatment data. Patients treated with Covid-19 are given 200 mg of molnupiravir PO q12h for 5 days. This dose was, of course, calculated from a pharmacokinetic study performed in humans, and if the average person weighs 60-80 kg (70 kg), the effective inhibitory dose is 3,03.0 mg / kg PO q12h. The cat has a basal metabolic rate 1.5-fold higher than humans, and assuming the same oral absorption in both humans and cats, the minimum dose for cats according to this calculation would be 4.5 mg / kg PO q12h in neocular and non-neurological forms of FIP. If molnupiravir crosses the blood-brain and blood-brain barriers with the same efficacy as GS-441524 [3,18], the dose should be increased to 1,51.5 and 2,02.0-fold to ensure adequate penetration into aqueous humor and cerebrospinal fluid for ocular cats (88 mg / kg PO, q12 h), respectively. neurological FIP (~ 10 mg / kg PO, q12 h). These doses are comparable to those used in ferrets, where 7 mg / kg q12h maintains sterilizing blood levels of the influenza virus drug (1.86 μM) for 24 hours. [10]. Doses in ferrets of 128 mg / kg PO q12h caused almost toxic blood levels, while a dose of 20 mg / kg PO q12h caused only slightly higher blood levels. [10].

Molnupiravir / GC376 or Molnupiravir / GS-441524

Combinations of molnupiravir with GC376 or GS-441524 will be used more and more frequently, not only to synergy or complement their individual antiviral effects, but also as a way to prevent drug resistance. Medicinal cocktails have been very effective in preventing drug resistance in HIV / AIDS patients [11]. However, there is currently insufficient evidence on the safety and efficacy of the combination of molnupiravir with GC376 or GS-441524 as initial treatment for FIP.

Case studies

Rocky - DSH MN Neuro FIP

A 9-month-old neutered domestic shorthair cat obtained as a rescue kitten had several weeks of seizures with increasing frequency, ataxia and progressive paresis. The blood tests were unremarkable. FIP treatment was started at a dose of 15 mg / kg BID GS-441524, which decreased to SID for about a week. The cat showed improvement, seizures stopped, and mobility increased within 24 hours of starting treatment. Within 5 days of treatment, the cat was able to move again. However, approximately 2 weeks after the start of treatment, the cat experienced loss of vision, decreased mobility, recovery of seizures and difficulty swallowing. Dose adjustments of levetiracetam and prednisolone were made, as well as a change in the composition of GS-441524, followed by a temporary improvement in motility and swallowing and a reduction in seizures, but overall the cat's condition worsened. The dose of GS-441524 was gradually increased to 25 mg / kg, with little or no improvement. At this point, GS was taken orally at a dose of 25 mg / kg (estimated to be approximately 12.5 mg / kg) and within 3 days, the cat began to move, improved vision, and stopped seizures with increased energy and appetite. Improvement in cats continued for approximately 4 weeks with oral administration of GS-441524, then stopped for approximately 3 weeks before rapidly progressing paresis. Oral doses up to 30 mg / kg SC equivalent have been tested but have no effect. GS-441524 was then injected at a dose of 20 mg / kg and the cat was able to move again within 4 days with good appetite and energy. After 2 weeks, a dose of GC376 20 mg / kg BID was added to the dosing regimen. The cat terminated 6 weeks of the GS441524 and GC376 combination therapy and then discontinued the treatment. Although the cat has certain permanent neurological deficits, its condition is stable, it has good mobility, appetite and activity for 9 months after the end of antiviral treatment.

Rocky's video: https://www.youtube.com/watch?v=RXB_NnfcMOY

Bucky - DSH MN Neuro / Eyepiece FIP

A four-month-old neutered domestic shorthair cat obtained as a rescue kitten was presented with a monthly history of lethargy and a progressive history of ataxia, hind limb paresis, spades, uveitis, anisocoria, and urinary and stool incontinence. Blood tests were mostly uncommon, with the exception of mild hyperglobulinemia. The A / G ratio was 0.6. The cat was treated with 10 mg / kg GS-441524 SC SID for 3 weeks. Activity, mentation and uveitis improved within 72 hours of starting treatment. During the first 2 weeks, a slow improvement in mobility and eye symptoms was observed, but then a plateau was reached. After 3 weeks, the dose of GS-441524 was increased to 15 mg / kg GS-441524 SC SID due to persistent neurological and ocular deficits. In addition, enlargement of the left eye due to glaucoma was noted at this time and the eye continued to swell until it was removed at week 8 of treatment.
Due to persistent weakness / lack of pelvic coordination and increasing lethargy, dose GS-441524 was increased to 20 mg / kg SC SID [or equivalent oral dose] at week 9 and 20 mg / kg SC BID was added to the regimen a few days later. GC376. Significantly increased activity and willingness to jump on elevated surfaces occurred within 48 hours of starting GS376 treatment. The combination treatment of GS-441524 and GC376 was maintained for 8 weeks. The cat has residual incontinence problems after treatment, but is otherwise clinically normal 6 months after treatment.

Boris - Maine Coon MI wet eye FIP

The five-month-old intact (uncastrated) Maine Coon cat, obtained from the breeder, had lethargy, anorexia, abdominal ascites, cough, anemia and neutrophilia. No biochemical analysis was performed to establish the diagnosis. The cat was treated with 6 mg / kg GS-441524 SC SID for 8 weeks. After six weeks of treatment, X-rays revealed nodules in the lungs, and after 8 weeks, hyperglobulinemia persisted. The GS-441524 dose was then increased to 8 mg / kg SC SID for 4 weeks. There was little improvement in blood tests and X-rays and the dose of GS-441524 was increased to 12 mg / kg SC SID over 4 weeks, followed by an increase to 17 mg / kg over 11 weeks, 25 mg / kg over 4 weeks and 30 mg / kg for 4 weeks. After 25 weeks of treatment, ultrasound revealed pleural abnormalities on the left side and X-rays showed no improvement in the pulmonary nodules. In addition, uveitis and retinal detachment have been reported in the right eye. Pulmonary aspirates that showed FIP-compliant inflammation were collected. After 33 weeks of treatment, 20 mg / kg SC BID GC376 was added to the regimen and the combined treatment of GS-441524 and GC376 was continued for 12 weeks. Increased activity was noted over several days. Over the course of 5 weeks, the weight gain accelerated, the cough subsided and the energy level increased. Blood tests showed an improvement in the A / G ratio, and chest X-rays showed a reduction in the lungs. After 84 days of combination antiviral therapy, the A / G ratio was 0.85 and the cat appeared clinically normal. The cat is currently 3 months after treatment.


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