Rapid remission of non-fusive FIP uveitis during treatment with oral adenosine analogue and feline omega interferon

Diane D. Addie, Johanna Covell-Ritchie, Oswald Jarrett, and Mark Fosbery
Original article: Rapid Resolution of Non-Effusive Feline Infectious Peritonitis Uveitis with an Oral Adenosine Nucleoside Analogue and Feline Interferon Omega
27.10.2020; Translation 23.3.2021

Abstract

This is the first report of successful treatment of a case of non-fusive FIP uveitis using the oral form of the adenosine analog and feline interferon omega, and alpha-1 acid glycoprotein (AGP) as an indicator of recovery. A 2-year-old neutered Norwegian Forest Cat has been affected by uveitis, keratic clots, mesenteric lymphadenopathy and weight loss. He was hypergammaglobulinemic and had non-regenerative anemia. Feline coronavirus (FCoV) RNA was detected by thin-needle aspiration of mesenteric lymph nodes using polymerase chain reaction reverse transcription (RT-PCR) - non-fusive FIP was diagnosed. Prednisolone acetate eye drops were administered three times daily for 2 weeks. Treatment with an oral form of an adenosine analogue (Mutian) was started. After 50 days of Mutian treatment, the cat gained more than one kilogram, the globulin level decreased from 77 to 51 g / l, and the hematocrit increased from 22 to 35%; uveitis subsided and vision improved. Serum AGP levels decreased from 3100 to 400 μg / ml (within normal limits). Symmetric dimethylarginine (SDMA) was above normal at 28 μg / dl, declining to 14 μg / dl at the end of treatment; It is not known whether the increase in SDMA was due to FIP lesions in the kidney or Mutian. After cessation of Mutian treatment, low doses of the oral form of recombinant feline interferon omega were started - recovery of the cat continued.

Keywords: feline infectious peritonitis, coronavirus, uveitis, Mutian, adenosine analog, feline interferon omega, mesenteric lymph nodes, alpha-1 acid glycoprotein, symmetric dimethylarginine

1. Introduction

Feline coronavirus (FCoV) is a highly infectious enteric virus that causes subclinical infection or diarrhea in most infected cats. ^[1], but in about 10% it causes potentially fatal immune-mediated monocyte-associated granulomatous vasculitis ^[2], known as feline infectious peritonitis (FIP). FCoV is an alpha coronavirus with positive polarity, a member of the Coronaviridae family of the Nidovirales family. ^[3].

Although treatment of FIP with an injectable nucleoside analog has been described in the past ^[4] and cure of enteric FCoV infection by oral form of adenosine analog (Mutian, Nantong Biotechnology, China) ^[5], this is the first reported case of recovery of a cat with a systemic FCoV infection - i.e. FIP - using Mutian.

2. Case study

Skywise was a 2-year-old neutered male Norwegian Forest Cat from a household with five cats; he developed uveitis in the remaining eye (in the right, he lost his left eye as a kitten) and occasional diarrhea. Its iris was unnaturally colored and grainy fat precipitates were visible (Figure 1a).

His medical history included bringing two 11-month-old Norwegian Forest Cats (Link and Zelda) into the home three months ago and the onset of uveitis five days after revaccination (Leucofeligen, Virbac, France). Skywise was tested for FCoV antibodies and was found to have a very high titer above 10,240 (Idexx Laboratories, Wetherby, UK) three weeks before presentation due to the contact cat (Paddy) being persistently pyrexic and malaise. . Paddy was negative for FeLV p27 antigens and FIV antibodies (Idexx Laboratories, Wetherby, UK), but his anti-FCoV antibody titer was found to be very high (Table 1), so all other domestic cats were tested for FCoV antibodies to decided whether they should be isolated from Paddy, but since they were also found to have high FCoV antibody titers (Table 1), segregation was not necessary.

At presentation, the patient's body weight was 2.89 kg (Figure 2) and the fitness score was 2/9. Ultrasound confirmed the absence of abdominal or thoracic effusion, but mesenteric lymphadenopathy was present. Mesenteric lymph node (MLN) aspirate was collected by ultrasound-guided thin-needle aspiration biopsy (FNA) and tested for FCoV reverse transcription polymerase chain reaction (qRT-PCR) (Idexx Laboratories, Wetherby, UK). The assay was positive for the M1058L mutation and negative for the S1060A mutation ^[6].

The blood results are shown in Table 2. Hematology revealed mild to moderate non-regenerative anemia with hematocrit (HCT) 22%, lymphocyte count 2.07 × 10⁹/ la by eosinopenia below the detection level (reported as 0.0 × 10⁹/ l). Biochemical analysis of the blood showed hyperglobulinemia (77.2 g / l) and an albumin to globulin (A: G) ratio of 0.31. Bilirubin was 11 micromoles per liter (μmol / l) (0.64 mg / dl). Alpha-1 acid glygoprotein (AGP) was increased to 3100 μg / ml (Idexx Laboratories, Wetherby, UK) (normal level is ≤ 500 μg / ml ^[7]).

Only parameters that have been monitored repeatedly are shown in this table; others for which few (or no) results were available (eg aspartate aminotransferase) or which were not relevant to the procedure in this case are omitted. FCoV antibody titers and faecal FCoV qRT-PCR results are shown in Table 1. Day 0 is the day of FIP diagnosis in the first cat; Mutian was administered between days 6 and 56, after which the cat was treated with 100,000 units of the oral form of feline interferon omega.

Systemic treatment was initiated with prednisolone 5 mg for uveitis (Table 3). The dose was reduced to 2.5 mg sid, then stopped after 7 days and replaced with topical prednisolone-acetate 1% eye suspension (Pred Forte®, Allergan, Dublin, Ireland) applied every 8 hours for two weeks. On the sixth day after the presentation, treatment with an oral adenosine analogue began (Mutian 200, Nantong Biotechnology, Nantong, China). ^[5] at a dose of 8 mg / kg every 24 hours in divided doses: this was twice the normal dose, in an effort to ensure penetration into the eyeball. S-adenosyl-L-methionine supplementation was recommended to support the liver during treatment with Mutian. The dose of Mutian was reduced to 6 mg / kg on day 25, but by then the weight of the cat had increased, so the same number of capsules per day was required.

To evaluate the susceptibility of the FCoV strain to the antiviral drug used, faecal samples were subjected to an FCoV qRT-PCR test (Veterinary Diagnostic Services, University of Glasgow, Scotland) ^[5]; the result was weakly positive in the threshold cycle (CT) 30, then negative, indicating that the virus was sensitive to the antiviral (Table 1). The faeces of three of the other four domestic cats were also positive for FCoV RNA (Table 1).

After starting Mutian treatment, the cat's weight increased rapidly, while it decreased by 30 g (2.89-2.86 kg) during prednisolone treatment (Figure 2). After 40 days of Mutian, the cat gained one kilogram (Figure 2). The dose of Mutian was adjusted during treatment in accordance with weight gain.

Blood tests were repeated on day 13 of Mutian treatment (18 days after diagnosis) (Table 2). Most importantly, the anemia reversed, HCT increased from 22.0 to 34.4%, and bilirubin decreased from 11 to 6 μmol / L. Globulin decreased to 57 g / l and albumin increased by 2 g / l, so the albumin: globulin ratio increased from 0.31 to 0.46, which was still a small but still improvement (Figure 3). Clinical examination revealed that iris color had returned to normal (Figure 1, Table 3) and vision improved; the caregiver reported an increase in activity - playing with other cats - and that the cat was trying to catch a bird. His droppings regained their normal consistency and frequency.

The dose of Mutian was reduced to 6 mg / kg on day 20 and treatment with Mutian was stopped after 7 weeks for two reasons: AGP levels returned to normal (400 μg / ml - normal is <500 μg / ml), and because SDMA rose to 28 μg / dl (reference range is below 14 μg / dl). Recombinant feline interferon omega (rFeIFN-ω; Virbagen Omega, Virbac, France) started at 100,000 units every 24 hours orally. SDMA decreased to 19 μg / dl on day 62 (one week after the end of Mutian treatment) and to 14 μg / dl on day 90, which was 35 days after the end of Mutian treatment (Table 2). Urine analysis performed at days 62, 90, and 153 revealed no abnormalities and specific gravities were 1,050, 1,055, and 1,050, respectively. Weight gain continued after stopping Mutian treatment and using feline interferon omega (Figure 1), albeit at a slower rate (average 9g / day instead of 23g / day).

Cohabiting cats were successfully treated with Mutian at a dose of 4 mg / kg for five days to prevent coronavirus secretion and thus recurrent recovery of the recovered cat; the faeces of all five cats were confirmed as negative by RT-PCR (Table 1).

3. Discussion

The successful treatment of FIP with antiviral drugs was first published by Dr. Pedersen ^[4,9]. Cat owners can obtain various anti-FCoV drugs, including Mutian, an oral form of adenosine analog, over the Internet. However, such medicines are not licensed for veterinary use, which puts treating veterinarians in a dilemma: they cannot prescribe or supply such treatment, but they can help clients who choose to take these medicines by providing diagnostic and routine supportive care. It is particularly useful to make an accurate diagnosis that will prevent the treatment of about 40% cats that would otherwise be misdiagnosed (data not shown). Our view is that it would be more appropriate for cat owners to use such drugs under proper veterinary supervision, even if these products are unlicensed. The purpose of this case study is to report what has worked for us in monitoring a case of non-fusible FIP treated with Mutian followed by feline interferon.

Diagnosis of non-fusive FIP is challenging because the symptoms are diverse and the list of differential diagnoses is often lengthy. Dunbar et al. 2019 ^[10], reported that detection of FCoV RNA from the Mesenteric Lymph Node (MLN) FNA (Fine Needle Aspiration) is 96% specific for FIP diagnostics. Unfortunately, the lab initially erroneously performed the FCoV RT-PCR test on a blood sample from day 2, instead of the MLN FNA as required - and the test turned negative. FCoV RT-PCR on blood samples is not useful in the diagnosis of FIP because most cats with FIP are not viremic at the time of clinical manifestations. ^[11] and also because about 5% cats do not test positive for FIP ^[12,13] because FCoV-infected cats undergo transient viremia ^{[12,13,14,15]}. FCoV RNA was found in feline MLN FNA and revealed to be positive for the M1058L mutation, which was further evidence to support the diagnosis of FIP ^[6,11]; although substitution with methionine for leucine at position 1058 in the FCoV spike protein was found in 89% tissue samples from 14 cats without FIP, suggesting that the mutation indicates systemic spread of FCoV from the gut rather than a virus with the potential to cause FIP ^[16].

Despite laboratory delays in confirming the diagnosis of FIP, we initiated Mutian treatment based on history, clinical signs, blood scores, and elevated AGP, which had previously been shown to be very specific for distinguishing FIP from other diseases with similar manifestations. ^[17]. There was an urgency to start treatment because the FIP male staging score was 6, indicating death within two weeks. ^[18]. The HCT of the cat decreased rapidly (from 25.7 to 22% in two days), which proved to be an indicator of imminent near death: Tsai et al., (2011) ^[18] found that HCT levels drop dramatically 2 weeks before death and bilirubin increases one week before death.

The history of the cat was typical of many cases of FIP: two new 11-month-old purebred cats were introduced into the household, which were probably the source of a recent coronavirus infection; the cat was vaccinated five days before the onset of uveitis. Introducing new cats and vaccinations are stressful for cats - it is known that stress causes FIP in cats infected with FCoV ^[19] and Riemer et al., (2016) ^[20] found that vaccination was a suspected stress factor in 6.9 % cases of FIP. Unfortunately, the weight of the cat between the introduction of new cats and vaccination was not recorded, so it is not known whether he lost weight during revaccination (ie was subclinically ill with FIP) or whether weight loss started later. This case nevertheless illustrates that vaccination of FCoV-infected cats may pose a risk to the development of FIP, and that optimal vaccination should be performed after the cat has stopped shedding the virus, which occurs within a few months for most FCoV type 1 infections. ^{[21 ]}.

Clinical signs of weight loss, appetite, diarrhea and uveitis were also consistent with the diagnosis of non-fusive FIP. FIP is a major cause of uveitis in young cats - ophthalmologists from the North Carolina Veterinary School diagnosed FIP in 19 of 120 cats (15.8%) with uveitis ^[22]. Uveitis was reported in 17 of 59 (29%) cats with non-fusive FIP ^[23].

Although treatment with an injectable nucleoside analogue has been documented previously in the treatment of FIP ^[4], to our knowledge, oral treatment of FIP with an adenosine analogue has not been previously reported, although it has been used to treat FCoV infection in asymptomatic or diarrhea cats. ^[5]. The patient was given twice the normal therapeutic dose of FIP (ie, 8 mg / kg vs. 4 mg / kg) to potentially increase the concentration of the drug in the eye and to rule out any virus that might be present in the brain because only 20% of the absorbed drug passes through the blood-brain barrier (T Xue, personal communication). The response to treatment was rapid, dramatic and extremely positive. Although we tried to reduce the dose of Mutian as soon as possible in the event of possible side effects, in practice the amount of medication did not change significantly because the cat gained weight at the same time. Pedersen et al., (2019) ^[4] stated that the simplest indicator of response to treatment was weight gain, which was staggering in this case, as the cat gained 1.1 kg during the first 50 days of treatment. In contrast, he lost 30g during the week on prednisolone, before starting treatment with Mutian.

In two studies, cats with FIP treated with corticosteroids had a median survival of 7.5 days ^[24] and 8 days ^[25], which is significantly shorter than the 21 - day average reported by Tsai et al., 2011 ^[18] (although the potential adverse effects of biopsies on survival need to be considered in the two studies and many deaths were due to secondary bacterial infection due to extensive corticosteroid-induced immunosuppression ^[25]). In addition, prednisolone treatment was previously found to shorten survival in FIP cats that were co-treated with polyprenyl immunostimulant. ^[23]. Therefore, in our case, systemic corticosteroids were replaced by topical corticosteroids for the treatment of uveitis.

We do not know if it was Mutian, systemic and topical steroids, or a combination of all treatments that affected the overall cure of uveitis. The cat owner reported a partial return of vision on day 6, which was the day Mutian treatment was started, suggesting that steroids were responsible for return vision (Table 3). Legendre et al., (2017) ^[23] reported progress in 3 of 17 cats with ocular FIP treated with polyprenyl immunostimulant (PI). Their initial symptoms included anterior uveitis (all three cats), clots of ceramic origin (one cat), iris discoloration (one cat) and anisocoria (one cat). In two cats, anterior uveitis significantly improved or resolved after 2 months of PI treatment without corticosteroids. In the third cat, uveitis did not improve; the cat received topical ocular corticosteroids at the same time as PI and the eyes were enucleated ^[23]. Whether or not Mutian alone can affect the treatment of FIP-associated uveitis without current topical corticosteroids remains to be seen. Systemic corticosteroids appear to have little or no significance in these cases.

No clinical side effects were observed during treatment with Mutian and the biochemical parameters of the liver and kidney were within the reference range, with the exception of plasma symmetric dimethylarginine (SDMA), which increased (Table 2). SDMA is an early indicator of kidney disease ^[26,27]. There are three possible explanations for increased SDMA: first, it may be due to FIP lesions in the kidneys. Azotemia is more likely in non-effusive than effusive FIP ^[20], but as far as we know, no study has been conducted to determine whether SDMA is rising in cats with FIP - veterinary pathologists speculate that transient FCoV infection of the kidneys may be the cause of interstitial nephritis observed in many older cats (W Jarrett and S Toth, personal communication ). Second, predisposition to the breed may be a factor - Birm cats have been found to have elevated SDMA levels. ^[28], but no study has been performed on SDMA levels in Norwegian Forest Cats and in cats, SDMA levels have fallen to normal levels, suggesting that the increased SDMA levels did not appear to be related to his breed. Third, increased SDMA may have been a side effect of Mutian treatment - SDMA decreased within seven days after the end of Mutian treatment and returned to normal within 35 days after the end of Mutian treatment. However, because we did not test it earlier during the disease, we do not know if it was increased before the deployment of Mutian. During treatment, cat creatinine and urea were always within normal limits, although a progressive increase in creatinine was observed (Table 2), which will be closely monitored in the future.

Because the recommended time of administration of GS-441524 was 84 days ^[4], cat owners using other antivirals have been treating their cats with FIP for the same length of time. The optimal duration of FIP oral Mutian treatment has not been established. However, this case illustrates that treatment can be stopped after a much shorter cycle if laboratory indicators for FIP return to normal. We believe that in our case, complete recovery occurred after 50 days of treatment for the following reasons - uveitis subsided, the cat recovered from anemia, lymphopenia reversed, bilirubin decreased and AGP decreased permanently. Nevertheless, we did not want to leave the cat completely without antiviral coverage, so a low oral dose of rFeIFN-omega was used as described above. ^[29]. This drug has antiviral and immunomodulatory properties and was an optional treatment for FIP with meloxicam prior to the onset of specific antiviral drugs against FCoV. ^[30]. The cat continued to gain weight with rFeIFN-omega, although more slowly than before, stabilized at 4.35 kg after 100 days (Figure 2) and hematological parameters continued to improve (Table 2, Figure 3).

FIP relapse did not occur in this - or in other - cases whose treatment we monitored. We attribute our success primarily to assessing the effectiveness of an antiviral agent against the FCoV strain in an infected cat by monitoring the amount of virus excreted in the stool (by qRT-PCR) to ensure that the viral load decreased in response to the antiviral agent; second, preventing FIP-cured re-infection by identifying other sources of viruses in the same household and stopping FCoV shedding by Mutian ^[5]; third, short-term treatment with a dose that eliminated the virus from the brain; fourth, after treatment with a nucleoside analogue (or protease inhibitor) by initiating a low dose of oral feline interferon until the FCoV antibody titer has decreased - an indicator that no coronavirus remains in the body.

Skywise and his roommates are alive and well 6 months after diagnosis.

4. Conclusions

To our knowledge, this is the first published case of curing a non-fusive FIP cat using an oral adenosine analogue, followed by a recombinant feline interferon, and AGP used as a recovery marker from FIP. To protect the liver and monitor liver enzymes, we recommend taking SAMe with Mutian. SDMA levels in future cases following this FIP treatment protocol require further investigation. We suggest that systemic corticosteroids be contraindicated in the treatment of FIP for non-palliative purposes.

Acknowledgement

We would like to thank the reviewers for their time in thoroughly reviewing our work and for their helpful comments: Table 1 and Table 3 were added thanks to their comments.

Author's contributions

Conceptualization, DDA and JC-R .; methodology, MF, OJ and DDA .; validation, OJ, DDA, JC-R. and MF .; formal analysis, MF and DDA .; investigation, MF and JC-R .; sources, JC-R. and MF .; data management, DDA, JC-R. and MF .; writing - preparation of the original proposal, DDA; writing - reviews and edits, OJ, DDA, JC-R. and MF .; visualization, DDA and JC-R .; supervision, DDA and JC-R .; project administration, JC-R., MF. financing acquisition, JC-R. and DDA All authors have read and agreed to the published version of the manuscript.

Financing

Cat treatment and lab tests were funded by JC-RDDA Thank you subscribers www.catvirus.com for support during this study and we are very grateful to the Angelica Fund donor for the payment of publication fees.

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