貓傳染性腹膜炎不同治療策略之評估

Abstract

貓傳染性腹膜炎 (Feline infectious peritonitis, FIP)為貓冠狀病毒媒介的免疫性疾病，過去有許多治療相關的研究被報告，依其致病機轉治療策略可分為抑制病毒的抗病毒藥及調整免疫反應的免疫抑制劑或免疫調整藥物等，但至目前為止，仍未建立有效的治療方式，安樂死仍是最被建議的治療。本研究的目的為評估FIP發病貓不同治療策略之成效，以建立較具潛力的治療策略。 自2003至2011年共有119隻高度懷疑為FIP發病貓至台大動物醫院就診，其中64隻經死後解剖確診為發病貓，另外2隻濕式發病貓之滲出液為直接免疫化學染色 (IFA)及反轉錄聚合酶連鎖反應 (PCR)陽性，其中一隻進行腹腔生檢確診為發病貓，另外一隻則至今仍存活。由這66隻發病貓中再選擇35隻存活超過14天且初次就診血液學檢查符合蔡等人所發表之預估存活期超過兩週的貓隻，依不同治療策略分組，評估其治療後一系列的各項檢驗結果及存活時間。根據不同使用藥物將35隻貓區分為group1和group2，group1使用藥物包括prednisolone、血管收縮素轉化酶抑制劑(angiotensin converting enzyme inhibitor, ACEI)與人類基因重組干擾素 (rHuIFN-α)，group2為其他不同藥物合併治療。Group1依據是否給予nelfinavir區分為group1a與1b，於治療期間兩組的血液學及生存天數比較並無差異，推測此藥對於抑制病毒效果在此組合治療策略中並無加強之效果。Group2依據干擾素來源之不同可區分為給予貓來源干擾素 (fIFN-ω) 的subgroup 2a與rHuIFN-α的subgroup 2b，兩組於治療期間血檢值與生存天數皆無差異。本研究首次將ACEI使用於FIP發病貓的治療策略，給予beanzapril的group1與未給予benazapeil的group2a+2b於治療期間的比較，group1 的平均血紅素、血容比、紅血球總數與白蛋白呈現上升的趨勢，由此推測，給予血管擴張劑或許可改善因免疫複合體造成血管炎的現象，使白蛋白漏出降低 。在整體治療策略評估方面， 於治療後第六週group1的 皆顯著高於group2，而且group1的總膽紅素則顯著低於 group2。由此推測，group1 的治療方式對於發病貓較有幫助，可改善疾病造成的貧血與蛋白質滲漏的情形，且有保護肝臟的效果。此外在group1中也有3隻就診時為濕式經過治療變為乾式，此現象在其他組別並未出現，進一步佐證此治療策略未來發展之可能性。 進行group1與group2生存時間的比較，Group1有50%的發病貓存活超過14週，而group2只有11.54% 的發病貓存活超過14 週。Group1和group2的生存中位天數分別為74.5與27天，將兩組進行生存分析計算其累積生存率，顯示group 1的累積生存率比group2高，且生存時間較長，於統計上具有顯著差異 (p<0.05)。就診為溼式FIP的發病貓中， group1與group2的生存中位天數分別為74.5天和22天，且 group1的累積生存率比group2高，且生存時間較長，也有統計顯著之差異 (p<0.05) 。 總之，合併類固醇、人類干擾素、血管擴張劑與有或無抗病毒藥的治療方式，在治療期間相對其他治療方式可觀察到貧血與白蛋白狀況改善，與總膽紅素上升的趨勢減緩。尤其針對就診時溼式FIP發病貓，此治療方式較顯著延長生存時間與提高累積生存率，顯示這些藥物合併治療方式的潛力，若可再找尋到合併更能抑制病毒複製或殺滅病毒且副作用小的抗病毒藥物，應可作為首選治療FIP發病貓的治療策略。

Feline infectious peritonitis, FIP, is an immune-mediated disease caused by feline coronavirus. Many combinations of drugs, including antiviral drugs, immune-modulator and immunosuppressive agents, were used to control the disease. However, euthanasia is still the most suggested method. The aim of this research is to evaluate of different therapeutic strategies in treatment of FIP and to state a potential therapeutic strategy. One hundred nineteen FIP highly suspected diseased cats, presented at National Taiwan University Animal Teaching Hospital between June 2003 and May 2011, were enrolled in this study. Sixty-four cats were confirmed to have FIP via pathological confirmation after death and another two cats were confirmed with positive IFA and PCR tests, one of the two cats were further confirmed with biopsy and another is still alive. Thirteen-five of the 66 cats were selected with the criteria of survival over 2 weeks and algorithm of the disease staging and therefore included in the analysis. Antiviral drug (nelfinavir): there was no difference in hematological changes and survival time between the subgroup1a (w/o nelfinavir) and subgroup1b (w/ nelfinavir). These may indicate that nelfinavir had no additional effect in this combination. Interferon: there was no difference in hematological changes and survival time between the subgroup2a (w/ feline interferon-omega) and subgroup2b (w/ human recombinant interferon-alpha). These may indicate that different origin of interferon had no effect in this combination and no obvious side effect. ACEI (angiotensin converting enzyme inhibitor, benazepril) was first time used in treatment of FIP. We compared group1 (w/benazepril) and subgroup2a+2b (w/o benazepril), increasing of albumin and potassium were observed in subgroup 2a+2b. These may indicated that ACEI conduced to the treatment by improvement of vasculitis caused by immune-complex. The drug-combinations of group1 included prednisolone, ACEI, human recombinant interferon-alpha, and with/out nelfinavir. The other combinations were assigned to group2. The PCV, Hb, RBC counts and albumin were significantly higher and total bilirubin was lower in group1 than in group2 at 6th weeks after treatment. These indicated that the combination of group1 had better effect in improvement of anemia and leakage of protein. Besides, 3 cats with effusive FIP in group1 became non-effusive FIP during therapy indicated the potential therapeutic strategy fro FIP. Fifty percentage of group1 survived over than 14 weeks and only 11.54% of group2, respectively. The medians of survival time were 74.5days and 27days of group1 and group2, respectively. Both Kaplan-meier survival analysis and cumulative survival rate were significant higher in group1 than in group2 (p<0.05). In effusive FIP, the medians survival time of group1 and group2 were 74.5days and 22days, respectively. Both Kaplan-meier survival analysis and cumulative survival rate were significant higher in group1 than in group2 (p<0.05). In conclusion, improvement of anemia and albumin and increasing of Kaplan-meier survival analysis and cumulative survival rate after treatment of the combinations, including prednisolone, ACEI, human recombinant interferon-alpha, and with/out nelfinavir, showed a potential therapeutic strategy, However, more cases and further study were still needed.