Original article: 2023 – NEUROLOGICAL OCULAR FIP
Published 1/4/2021, updated 2/10/2023, Translation update 3/8/2023
Basic facts
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.
TABLE 1. VARIABILITY OF CLINICAL SYMPTOMS OF THE EFFECTIVE (WET) FIP IN CATS AVOIDED AT UC DAVIS
| Symptoms associated with: | occurrence (%) |
|---|---|
| Peritoneal cavity | 58% |
| Peritoneal and pleural cavities | 22% |
| Pleural cavity | 11% |
| Peritoneal cavity, eyes | 2,8% |
| Peritoneal cavity, CNS * | 1,9% |
| Peritoneal and pleural cavity, CNS | 0,9% |
| Peritoneal and pleural cavity, eyes | 0,9% |
| Pleural cavity, CNS, eyes | 0,9% |
| Peritoneal cavity, CNS, eyes | 0,9% |
* CNS - Central nervous system (brain, spine)
TABLE 2. VARIABILITY OF CLINICAL SYMPTOMS OF NON-FUSION (DRY) FIP IN CATS AVOIDED AT UC DAVIS
| Symptoms associated with: | occurrence (%) |
|---|---|
| Peritoneal cavity | 30% |
| CNS | 22% |
| Eyes | 14% |
| CNS and eyes | 8% |
| Peritoneal cavity, eyes | 7% |
| Peritoneal and pleural cavities | 4% |
| Peritoneal and pleural cavity, CNS | 3% |
| Peritoneal and pleural cavity, eyes | 2% |
| Peritoneal cavity, CNS, eyes | 2% |
| Pleural cavity | 1% |
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
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