Currently, there is no effective treatment or vaccine for FIP and its mortality is recognized as extremely high. Several approaches have been used to treat cats with FIP, including steroidal and interferon therapies to stimulate the immune system non-specifically in the hope that it will be able to overcome the infection.4, 5 Recently, some of in vitro experiments has revealed that itraconazole, classified as an azole anti-fungal agent, has a potential anti-viral therapeutic effect on the cats with early phase dry-type FIP.7 Another study has shown that extremely higher dosage of cyclosporine known as immunosuppressive drug can inhibit FIPV replication, but it may be more important to minimize its side effects including gastrointestinal disorders.8 These drugs have never shown any significant clinical benefits for FIP cats.4
In 2018, it was reported that the nucleoside analog designated as GS-441524 can exhibit a suppressive effect on FIPV.9 Phosphoramidate prodrug of GS-441524, designated as GS-5734 (Remdesivir; Gilead Sciences) has been previously shown to inhibit the replication of several taxonomically diverse RNA viruses such as Ebora. Exciting efficacy of GS-441524 against naturally occurring FIP has been proved by over 80% of recovery from disease onsets, although mortality rates of FIP is known to be almost 100% with the previous therapies.10
There is no information about anti-viral mechanism for main active component of Mutian X, with molecular structure similar to the adenosine nucleoside analogues including GS-5734, and the drug product possible to be administered orally has been reported as drastically effective on FIPV infections in particular experimental conditions.11 However, therapeutic effects of Mutian X on naturally occurring FIPs in the client-owned cats under variable dietary and environmental conditions have not been investigated yet. In our present study, the drug was administered to 141 client-owned cats onset with wet-type FIP in Japan according to the standard orally-administration schedule for 84 days, and consequently, about 82% of all (116/141 cats with wet-type) have survived and their quality of life could be obviously improved, confirming its apparent clinical benefits (Tables 3 and 4). These results demonstrated that most of the cats with wet-type FIP can be treated efficiently, even though its mortality rate had been known to be almost 100% at disease onset. Wet-type is well-known to account for majority of FIPs.1–3 Here, we have considered it is valuable to demonstrate Mutian X’s therapeutic efficacy on the wet-types, occupying majority of onset FIP cases. Only the cats with wet-type FIP were entered into our present study for the reason why a certain number of the subjects could be collected (n = 141). We also would like to obtain a larger number of the cats with dry or wet & dry-types in the future, enough to enable reliable statistical analysis, and hopefully, their results can be described in another report.
In our hospital, follow-up period for 3 months has been given to each of the cats after standard drug administration course for 84 days, and any of the stable subjects without apparent quality of life impairment could be judged as remissions. On our observation, most of rescuable FIP cats could exhibit significant improvements for their appetite and activity within 5 days after Mutian X administration started, but on the contrary, most of the residual subjects without disease improvement by the initial drug therapy were prone to decease (data not shown).
Levels for appetite and activity of the cats, strongly suspected or evidently diagnosed as wet-type FIP in our hospital, were transferred into our arbitrary scores and statistically analyzed in order to evaluate their physical conditions at owner’s home, simultaneously with our routine examination (body temperatures, weights, echography, auscultation and palpation). We have also measured whole blood cell counts, total protein levels and hepatic function parameters including glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT), in all of the cats entered in the study, but these clinical indicators were excluded from our statistical study because any significant characteristics could not be newly investigated and no previous reports described their relationship with FIP. Elevated T-bilirubin levels are not always correlated with higher GOT or GPT, as hyperbilirubinemia in cats with FIP is known to be caused by parenchymal liver disease but can be due to excessive erythrocyte fragility leading to hemolysis with decreased clearance of hemoglobin-derived products.4, 12 Levels of T-bilirubin, A/G ratio, SAS and α1AG were analyzed in our study, as each of them has been already described as correlated with onset or severity of FIP.3, 4, 13–15 In our present study, almost all of the cats with wet-type FIP showed extremely elevated levels of α1AG, which exceeds the upper limit of measurable concentration (2200µg/mL) and could not be accurately determined. Therefore, we have conducted to utilize categorical analysis of Fisher’s exact test in order to investigate differences between the groups, regarding cats as positive whose α1AG levels were higher than the upper limit of its normal range (736µg/mL). The positive rate of α1AG level in the cats with wet-type FIP was found to be approximately 99% (125/126 cats), apparently higher than those in non-FIP cats (60%; 15/25 cats), and thus, this marker has been confirmed as a subsidiary indicator for FIP diagnosis according to the previous data.4 Our present study revealed that multiple pre-dilution of plasma specimens will be necessary to quantify α1AG levels accurately because of their drastic elevations in the wet-type FIP.
In order to assess therapeutic effectiveness of Mutian X on the cats with wet-type FIP and predict their outcomes in the future, determination for several clinical parameters of 141 cats with wet-type FIP was conducted at first veterinarian’s examination, and then, statistical comparison of those numeral or categorical measures between survived subjects benefiting from Mutian X treatment and non-survived unresponsive to it consequently (Table 3). Here, in our present assessment, we have investigated for the first time that T-bilirubin levels were significantly elevated in the wet-type FIP cats to result in incurable condition, as well as body temperatures, appetite and activity scores were suspected to be indicators in our statistical analysis (Table 3). As described in the previous study, in serial blood examinations of the cats with wet-type FIP, anemia and increases in T-bilirubin were observed from 2 weeks to 0–3 days before death.17 Clinical indicators including the packed cell volume and bilirubin were established to predict disease staging and survival time, providing useful information for the ante-mortem diagnosis of FIP. In contrast, we have suggested here a distinctive scheme to discriminate promising wet-type FIP potential to be rescued by Mutian X treatment, just only at initial examination. These results demonstrated that classification of disease status for wet-type FIP by initial T-bilirubin concentration may be a valuable surrogate marker to contribute possible reduction of owner’s medical expenses on Mutian X therapy considered unnecessary in such a case.
In the case that ascites or pleural effusions could not be collected from the cats, we have routinely conducted qualitative PCR testing using blood samples for diagnosis of FIP, and resultantly 139 cats were defined as feline corona virus-positive at the rate for 98.6% (139/141 of all the cats with wet-type FIP). Corona virus gene detected by PCR-based technology were apparently decreased in 116 cats with wet-type FIP, consequently survived after standard Mutian X treatments, including 112 cats as virus-positive to negative conversion and 4 other case. We have observe, in addition, levels for body weights, HCT and A/G ratio of them were significantly elevated after drug treatments, and circulating levels for SAA, known as an inflammatory indicator, were drastically reduced, confirming apparent improvement of their quality of life (Fig. 1). It can be easily presumed that more prospective benefits of Mutian X on wet-type FIP cats can be obtained by utilizing T-bilirubin level as a predictive marker for their outcome, through veterinarian’s recommendation on aggressive therapy with Mutian X for their clients.
We also observed a few cases with recurrence, showing multiple symptoms including appetite loss, less activity, fever, neurologic manifestation, deposition of ascites or pleural effusions, within 4 weeks after standard drug administration completed. In such cases, we should perform the additional administration of Mutian X at increased dose (200mg/kg) to them for 42 days. Number of the recurrent cats were found to be small (2.1%, only 3 of 141 cats with wet-type FIP entered into our present study). We hope to further investigate these recurrent subjects in our next study.
In another study reported in 2020, minimum and short-term dose of Mutian X (4mg/kg, q24h for 4 days) ensure viral clearance from the faces of asymptomatic virus-shedding cats, resultantly lead to establish feline corona virus-free households of cats.17 Some previous studies have already revealed that widespread use of preemptive therapy with anti-viral drugs could be generally suspected as inefficient, because certainly increase risk factors of multi-drug resistance and epidemic infections.18–20 As far as considering severity and mortality rates for FIP at onset, potential epidemic of multi-drug resistant strains must be a great threat for us. Therefore, we are highly confident that Mutian X should be administered selectively to the FIP subjects possible to get certain therapeutic effects, leading to a variety of benefits on the cats and their owners.