Randomized controlled trial of oral ganciclovir versus oral acyclovir after induction with intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in cytomegalovirus-seropositive liver transplant recipients

BACKGROUND: Without effective antiviral prophylaxis, cytomegalovirus (CMV) disease is a common cause of morbidity and mortality after liver transplantation. In this randomized, controlled trial, we compared the efficacy and safety of oral ganciclovir with oral acyclovir after induction with intravenous (IV) ganciclovir for long-term prophylaxis of CMV disease in CMV-seropositive liver transplant recipients. METHODS: Patients were initially administered IV ganciclovir at a dose of 6 mg/kg per day from day 1 to day 14 after transplantation followed by either oral ganciclovir (1 g every 8 hr) or oral acyclovir (800 mg every 6 hr) from day 15 to day 100 after transplantation. RESULTS: CMV disease occurred in only 1 of 110 patients (0.9%) receiving ganciclovir compared with 8 of 109 patients (7.3%) receiving acyclovir within the first year after transplantation (P =0.019). There was one case of CMV colitis in the ganciclovir group, whereas four cases of CMV syndrome, three cases of CMV pneumonia, and one case of CMV hepatitis developed in the acyclovir group. The only death from CMV disease occurred in an acyclovir-treated patient with CMV pneumonia. Both oral ganciclovir and oral acyclovir were generally well tolerated. Reversible leukopenia (decline in white blood cell count to <3.0 x 10(9)/L) was more common with oral ganciclovir (38/110 patients, 35%) than with oral acyclovir (20/109 patients, 18%) (P =0.009). The emergence of ganciclovir-resistant strains of CMV was not found during the study. CONCLUSIONS: A prophylactic regimen of 2 weeks of IV ganciclovir followed by an additional 12 weeks of oral ganciclovir is superior to a similar regimen of IV ganciclovir followed by oral acyclovir and almost completely eliminates CMV disease after liver transplantation. This superior protection against CMV disease extends up to 1 year after transplantation and is not associated with ganciclovir resistance.     

Randomized controlled trial of sequential intravenous and oral ganciclovir versus prolonged intravenous ganciclovir for long-term prophylaxis of cytomegalovirus disease in high-risk cytomegalovirus-seronegative liver transplant recipients with cytomegalovirus-seropositive donors

Cytomegalovirus (CMV)-seronegative liver transplant recipients with CMV-seropositive donors have the greatest risk for CMV disease. We performed a randomized, controlled trial comparing sequential intravenous (IV) and oral ganciclovir with prolonged IV ganciclovir for long-term prophylaxis of CMV disease in these high-risk patients. Patients were initially given IV ganciclovir at a dose of 6 mg/kg per day from days 1 to 14 after transplantation. Patients then either received oral ganciclovir (1 g every 8 hr) or continued IV ganciclovir (6 mg/kg once per day on Monday-Friday of each week) from days 15 to 100 after transplantation. CMV disease occurred in 3 of 32 patients (9.3%) receiving oral ganciclovir and in 4 of 32 patients (12.5%) receiving IV ganciclovir within the first year after transplantation (P>0.2). All cases of CMV disease occurred more than 90 days after transplantation (median time of onset day +137 for oral ganciclovir and day +135 for IV ganciclovir). There were no deaths from CMV in either study group. Both oral and IV ganciclovir were generally well tolerated. These results indicate that, after induction with 14 days of IV ganciclovir, oral ganciclovir can be as effective as IV ganciclovir for long-term prophylaxis of CMV disease in high-risk CMV-seronegative liver transplant recipients with CMV-seropositive donors and eliminates the need for prolonged IV access.     

Randomized controlled trial of total immunosuppression withdrawal in liver transplant recipients: role of ursodeoxycholic acid

BACKGROUND: Total immunosuppression withdrawal (TIW) without causing rejection has been reported in stable liver recipients. The role of ursodeoxycholic acid (UDCA) and patient characteristics that predict the success of this tolerance are unclear. There are two goals, to determine: 1) whether TIW is frequently associated with rejection; and 2) whether UDCA decreases the risk of liver disease (both rejection and recurrence) after TIW. METHODS: Twenty-six liver recipients who had been free of rejection while on immunosuppressive agents for a minimum of 2 years were randomized to receive either (15 mg/kg) of UDCA (n=14) or identical placebo (n=12) followed by sequential withdrawal of their immunosuppressive regimen over several months. Endpoints were defined as biochemical and histological evidence of rejection, graft dysfunction without rejection, recurrence of pretransplant disease, or 6 months without immunosuppression and no rejection or dysfunction on repeat liver biopsy. RESULTS: Rejection occurred in 6 of 14 (43%) of the UDCA group and 9 of 12 (75%) of those receiving placebo (P=0.09). Degree of rejection was mild, moderate, and severe in 73%, 20%, and 7% of patients respectively. All responded to rescue therapy and none developed chronic rejection. Nine of the remaining 11 patients (eight of the UDCA recipients and three of controls) who did not develop rejection developed graft dysfunction which responded to reintroduction of immunosuppressive agents in each case. Disease recurrence was most common in patients with underlying immune-mediated disorders of the liver. One year after withdrawal only two patients were free of immunosuppression, 80% were able to discontinue prednisone therapy (steroid free), and 50% were able to reduce their dose of cyclosporine. Age, underlying cause of liver disease, and regimen of immunosuppression were favorable predictors. CONCLUSIONS: The results of this study suggest that TIW: 1) is frequently associated with subsequent rejection, 2) increases the risk of underlying disease recurrence, and 3) is not facilitated by UDCA use and responds properly to the reintroduction of immunosuppressive therapy.     

Invasive fungal infections in renal transplant recipients

Invasive fungal infections are a significant and often lethal problem in transplant patients. Infections caused by geographically limited endemic fungi are infrequent, and Aspergillus species, Mucorales species, Candida species, and Cryptococcus neoformans are the opportunistic fungi responsible for most such infections. The symptoms of systemic fungal infections are nonspecific, particularly in their early stages. The high rates of mortality and graft loss owing to fungal infections render early diagnosis and treatment imperative in immunosuppressed patients. Current methods for the diagnosis of systemic fungal infections include imaging procedures, endoscopic methods and biopsies, microscopic and culture techniques, antibody and antigen-based serologic testing, and the detection (via polymerase chain reaction) of fungal deoxyribonucleic acid in blood or bronchoalveolar lavage fluid, as well as the careful analysis of signs and symptoms. Antifungal therapy should be initiated early in patients with a suspected fungal infection (even before laboratory findings have confirmed that diagnosis) and should be administered with appropriate adjustment of immunosuppressive regimens. To manage fungal infections in patients with renal failure, optimizing the pharmacokinetics of antifungal drugs to reduce the risk of nephrotoxicity is crucial.     

Prophylactic fluconazole in liver transplant recipients: A randomized,double-blind,placebo-controlled trial

Background:Among persons who receive solid organ 0842 transplants, liver transplant recipients have the highest incidence of invasive fungal infection; however, no antifungal prophylaxis has been proven to be effective.Objective:To evaluate the efficacy and safety of prophylactic0842 fluconazole in liver transplant recipients.Design:Randomized, double-blind, placebo-controlled trial. 0842Setting:University-affiliated transplantation center.0842Patients:212 liver transplant recipients who received fluconazole0842 (400 mg/d) or placebo until 10 weeks after transplantation.Measurements:Fungal colonization, proven superficial 0842 or invasive fungal infection, drug-related side effects, and death.Results:Fungal colonization increased in 0842 patients who received placebo (from 60% to 90%) but decreased in patients who received fluconazole (from 70% to 28%). Proven fungal infection occurred in 45 of 104 placebo recipients (43%) but in only 10 of 108 fluconazole recipients (9%) (P < 0.001). Fluconazole prevented both superficial infection (29 of 104 placebo recipients became infected [28%] compared with 4 of 108 fluconazole recipients [4%]; P < 0.001) and invasive infection (24 of 104 placebo recipients became infected [23%] compared with 6 of 108 fluconazole recipients [6%]; P < 0.001). Fluconazole prevented infection by most Candida species, except C. glabrata. However, infection and colonization by organisms intrinsically resistant to fluconazole did not seem to increase. Fluconazole was not associated with any hepatotoxicity. Patients receiving fluconazole had higher serum cyclosporine levels and more adverse neurologic events (headaches, tremors, or seizures in 13 fluconazole recipients compared with 3 placebo recipients; P = 0.01). Although the overall mortality rate was similar in both groups (12 of 108 [11%] in the fluconazole group compared with 15 of 104 [14%] in the placebo group; P > 0.2), fewer deaths related to invasive fungal infection were seen in the fluconazole group (2 of 108 patients [2%]) than in the placebo group (13 of 104 patients [13%]) (P = 0.003).Conclusions:Prophylactic 0842 fluconazole after liver transplantation decreases fungal colonization, prevents superficial and invasive fungal infections, and has no appreciable hepatotoxicity. Although fluconazole prophylaxis is associated with fewer deaths from fungal infection, it does not improve overall survival. Patients receiving prophylactic fluconazole require close monitoring of serum cyclosporine levels to avoid neurologic toxicity.     

Fungal infections in liver transplant recipients

Sixty-two adults who underwent orthotopic liver transplantations between February 1981 and June 1983 were followed for a mean of 170 days after the operation. Twenty-six patients developed 30 episodes of significant fungal infection. Candida species and Torulopsis glabrata were responsible for 22 episodes and Aspergillus species for 6. Most fungal infections occurred in the first month after transplantation. In the first 8 weeks after transplantation, death occurred in 69% (18/26) of patients with fungal infection but in only 8% (3/36) of patients without fungal infection (P less than 0.0005). The cause of death, however, was usually multifactorial, and not solely due to the fungal infection. Fungal infections were associated with the following clinical factors: administration of preoperative steroids (P less than 0.05) and antibiotics (P less than 0.05), longer transplant operative time (P less than 0.02), longer posttransplant operative time (P less than 0.01), duration of antibiotic use after transplant surgery (P less than 0.001), and the number of steroid boluses administered to control rejection in the first 2 posttransplant months (P less than 0.01). Patients with primary biliary cirrhosis had fewer fungal infections than patients with other underlying liver diseases (P less than 0.05). A total of 41% (9/22) of Candida infections resolved, but all Aspergillus infections ended in death.     

Fungal infections in liver transplant recipients

A retrospective analysis of 462 consecutive orthotopic liver transplantations was undertaken to evaluate incidence, risk factors, clinical course, and outcome of fungal infections. Infections involving Aspergillus (6 cases), Candida (5 cases), Mucor (1 case), and Cryptococcus (1 case) were observed in 2.8% (13/462) of our patients. Twelve of the 13 episodes developed during the first 2 postoperative months. None of the potential risk factors for fungal infections described by other authors (i.e., age, rejection treatment, dialysis, mechanical ventilation, graft failure, long operation time, second transplant, serious nonfungal infection) correlated significantly with the episodes in our patients. However, in patients who exhibited three or more of these potential risk factors the incidence of fungal infections was elevated (P<0.001). Six of seven exogenous infections (Aspergillus, Mucor) began before July 1991 when our department moved from Charlottenburg to Wedding, thus indicating that the incidence of these infections is highly influenced by exposure (P=0.01). Exposure prophylaxis should therefore by meticulously followed, particularly when severely compromised patients are involved, in order to prevent exogenous infections (i.e., Aspergillus/Mucor). Infections involving such patients are combined with a very high mortality (57%). We observed Candida infection as a pathological overgrowth of physiological oropharynx flora into the esophagus and/or trachea in five patients. In each case treatment led to full recovery.

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Pilzinfektionen nach Lebertransplantation

Zusammenfassung Um Inzidenz, Risikofaktoren, klinischen Verlauf und Prognose von Pilzinfektionen nach Lebertransplantation zu klären, wurden die Verläufe von 462 Patienten retrospektiv untersucht, die zwischen Oktober 1988 und Februar 1994 konsekutiv transplantiert wurden. Bei 13 unserer Patienten (2,8%) beobachteten wir Infektionen mit Aspergillus (6mal), Candida (5mal), Mucor (1mal) und Cryptococcus (1mal) Dabei trat die Infektion bei 12 der 13 Patienten bereits während der ersten 2 postoperativen Monate auf. Von den von anderen Autoren beschriebenen potentiellen Risikofaktoren (Alter, Abstoßungsbehandlung, Dialyse, maschinelle Beatmung, Graftversagen, lange Operationszeit, Retransplantation, schwere Allgemeininfektion) korrelierte bei unseren Patienten keine einzige mit den Infektionen. Allerdings war die Inzidenz der Pilzinfektionen bei Patienten, die 3 oder mehr dieser Risikofaktoren zeigten, signifikant erhöht (p<0,001). Ferner traten 6 von 7 exogenen Infektionen (Aspergillus, Mucor) vor dem Umzug unserer Transplantationsstation aus dem 1. Stock eines alten, efeubewachsenen Ziegelbaus in den 7. Stock eines Neubaus im Juli 1991 auf (p=0,01). Dies zeigt, daß die Exposition die Inzidenz von Pilzinfektionen nach Lebertransplantation wesentlich beeinflußt. Daraus folgt, daß insbesondere schwer kompromittierte Patienten einer strengen Expositionsprophylaxe unterzogen wurden müssen, um Infektionen mit Aspelgillus/Mucor zu vermeiden, die bei unseren Patienten eine Letalität von 57% aufwiesen. Bei 5 Patienten beobachteten wir Candidainfektionen als pathologisches Überwuchern der oralen Standortflora in Trachea und/oder Speiseröhre, die unter Therapie ausnahmslos ausheilten.

     

Cytomegalovirus antigenemia directed pre-emptive prophylaxis with oral versus I.V. ganciclovir for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, controlled trial

BACKGROUND: The efficacy of pre-emptively administered oral ganciclovir in preventing cytomegalovirus (CMV) disease has not been documented in liver transplant recipients. We sought to compare the efficacy of pre-emptive oral ganciclovir with that of i.v. ganciclovir for the prevention of CMV disease after liver transplantation, and to determine whether withholding prophylaxis in the absence of CMV antigenemia, reliably identified patients in whom no prophylaxis was necessary. METHODS: Surveillance cultures for CMV pp65 antigenemia were performed in all patients at weeks 2, 4, 6, 8, 12, and 16. Patients with CMV antigenemia were randomized into two study groups. The experimental group received oral ganciclovir for 6 weeks (2 g t.i.d. for 2 weeks, then 1 g t.i.d. for 4 weeks), and the control group received i.v. ganciclovir (5 mg/kg q 12 hr) for 7 days. RESULTS: Of 72 consecutive liver transplant recipients studied, CMV antigenemia occurred in 31% (22 of 72). Twenty-two patients with asymptomatic antigenemia were randomized to two study groups. CMV disease (viral syndrome) occurred in 9% (1 of 11) of the patients in the i.v. ganciclovir group and in 0% (0 of 11) of the patients in the oral ganciclovir group. None of the study patients developed tissue invasive CMV disease. The median reduction in antigenemia level with oral ganciclovir was 55% at week 1, and 100% at week 2. Overall, 64% of the patients by week 1, 93% by week 2, and 100% by week 4 had antigenemia levels below the baseline after oral ganciclovir. Of 50 patients without CMV antigenemia, none developed CMV disease. CONCLUSIONS: Pre-emptive prophylaxis based on CMV antigenemia can effectively target the patients for CMV prophylaxis; 69% of the patients never received antiviral prophylaxis and did not develop CMV disease. Antiviral therapy instituted upon detection of antigenemia prevented tissue invasive CMV in both ganciclovir groups. Pre-emptively administered oral ganciclovir was effective as prophylaxis for CMV disease after liver transplantation.     

Randomized trial of tacrolimus versus cyclosporine in steroid withdrawal in living donor renal transplant recipients

The introduction of new immunosuppressants has prompted trials of steroid withdrawal. However, several groups have reported a higher incidence of rejection. We conducted a randomized two-arm, parallel-group, open-label, prospective study to compare steroid withdrawal (at 6 months posttransplant) from the regimens of tacrolimus + mycophenolate mofetil (MMF) (FK group) versus cyclosporine + MMF (CSA group). The entry criteria were recipients of first living donor transplants with no diabetes mellitus (DM), congestive heart failure, chronic liver disease, or acute rejection within 6 months posttransplant. The primary endpoint was a biopsy-proven acute rejection episode or treatment failure within 1 year posttransplant. While 87 recipients were assigned to FK (n = 43) and CSA groups (n = 44) before transplantation, 76 recipients (FK 39, CSA 37) could be tapered off steroids at 6 months posttransplant, since 11 were excluded due to acute rejection within 6 months posttransplant (FK two, CSA three) or protocol violations (FK two, CSA four). After steroid withdrawal, the incidence of acute rejection episodes was 0% in the FK group and 13.5% in the CSA group (P < .05). Other results at 12 months posttransplantation were comparable: the incidences of DM 7.8% versus 0% (FK group vs CSA group), hypercholesterolemia 41.0% versus 59.5%, hypertensives 48.7% versus 59.6% as well as the levels of plasma creatinine 1.21 +/- 0.24 versus 1.31 +/- 0.50 mg/dL (P > .05 in every variable). These data suggest that steroid withdrawal is successful in first living donor renal transplant recipients. Tacrolimus may be significantly more effective than cyclosporine to prevent acute rejection after steroid withdrawal.     

伊曲康唑序贯治疗恶性血液病患者侵袭性肺部真菌感染的疗效及安全性评价

目的评价伊曲康唑注射液与口服液序贯治疗恶性血液病患者合并侵袭性肺部真菌感染的临床疗效及安全性。方法回顾性分析自2009年1月至2011年12月本院收治的54例恶性血液病合并肺部真菌感染的患者,均给予伊曲康唑联合重组人粒细胞集落刺激因子（rhG-CSF）治疗。结果54例患者中确诊组6例、临床诊断组26例、拟诊组22例;三组患者治疗有效率分别为16.67%（1/6）、69.23%（18/26）和72.73%（16/22）,确诊组有效率低于临床诊断组（P=0.029）与拟诊组（P=0.022）;有效组疗程为（29.97±4.71）d,无效组疗程为（15.42±3.24）d,差异具有统计学意义（t=13.36,P=0.000）。根据治疗时机的选择,将患者分为抢先/经验性治疗组和目标/挽救组。抢先/经验治疗组有效率为74.42%（32/43）,高于目标/挽救治疗组的27.27%（3/11）,差异具有统计学意义（χ2=6.595,P=0.010）。中性粒细胞缺乏为恶性血液病患者侵袭性肺部真菌感染的独立危险因素。结论伊曲康唑是治疗恶性血液病患者肺部真菌感染的有效安全药物;rhG-CSF能够协同其抗真菌疗效。     

Prospective screening in liver transplant recipients by panfungal PCR-ELISA for early diagnosis of invasive fungal infections.

Invasive fungal infections after liver transplantation (LT) have resulted in high mortality and potentially fatal complications. This study was undertaken to determine the accuracy of the panfungal polymerase chain reaction enzyme link immunosorbent assay (PCR-ELISA) method in early diagnosis of invasive fungal infections in liver transplant recipients (LTRs). A total of 48 liver recipients (cadaver donors) were followed for fungal infections for a period of at least 6 months. All clinical samples were cultured and a direct microscopic examination was performed. Blood samples were cultured by bedside inoculation onto BACTEC medium. Whole blood specimens were collected prospectively once per week and were evaluated for any invasive fungal infections by panfungal PCR and PCR-ELISA. Among 48 transplant recipients between September 2004 and January 2006 (22 females, 28 males, mean age = 34.4 yr), 40 recipients (83.3%) had Candida colonization in different sites of their body before LT. In proven and probable recipients for panfungal PCR-ELISA, the sensitivity, specificity, and positive and negative predictive values were 83.3%, 91.7%, 76.9%, and 94.3%, respectively. By PCR assay, fungal infections were diagnosed in 10 recipients (20.8%). The mean interval time from transplantation to development of fungal infection was 61.4 days (range, 20-150 days) and time of infection in blood before any clinical signs was 7-70 days with mean of 21.4 days. The etiologic agents were Candida albicans (9 cases) and Aspergillus fumigatus (1 case). Use of PCR-ELISA in LTRs may not only improve the ability of early diagnosis of invasive fungal infections (IFIs) when positive results are obtained, but also would provide more confidence to exclude a diagnosis of IFIs when negative results are obtained.     

Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients

BACKGROUND: Early enteral nutrition with solutions containing prebiotics (fiber) and probiotics (Lactobacillus) is suggested to reduce bacterial translocation and minimize the incidence of infections after liver transplantation. METHODS: In a prospective, randomized placebo-controlled trial consisting of 95 patients, we compared the incidence of postoperative infections and other complications after liver transplantation among three different groups, all supplied with early enteral nutrition: (a) standard formula plus selective bowel decontamination (SBD), (b) fiber-containing formula plus living Lactobacillus plantarum 299, and (c) fiber-containing formula plus heat-killed L plantarum 299. RESULTS: The groups were comparable regarding preoperative American Society of Anesthesiologists classification, Child-Pugh classification of cirrhosis, operative data, and degree of immunosuppression. The patients who received living lactobacilli plus fiber developed significantly fewer bacterial infections (13%) than the patients with SBD (48%). The incidence of infections was 34% in the group with inactivated lactobacilli and fiber. Cholangitis and pneumonia were the leading infections and enterococci the most commonly isolated bacteria. In the living Lactobacillus group, the mean duration of antibiotic therapy, the mean total hospital stay, and the stay on the intensive care unit were also shorter than in the groups with inactivated lactobacilli and fiber as well as with SBD. However, these differences did not reach statistical significance. CONCLUSIONS: Early enteral nutrition with fiber-containing solutions and living L plantarum 299 was well tolerated. It decreases markedly the rate of postoperative infections both in comparison with inactivated L plantarum 299 and significantly with SBD and a standard enteral nutrition formula. As it is a cheap and feasible alternative to SBD, further studies should evaluate whether this ecoimmunonutrition should be already started while patients are on the waiting list for transplantation.     

肝移植术后真菌感染患者免疫抑制方案的调整

目的 探讨肝移植术后真菌感染患者的免疫抑制方案。方法 我院器官移植中心从2004年1月至2005年12月实施376例成人肝移植，对术前、术中存在真菌感染危险冈素的59例患者采用IL-2（interleukin-2）受体单克隆抗体诱导方案，对术后发生真菌感染的患者在应用有效抗真菌药物的同时，调整其免疫抑制方案。结果 共有36例患者发生真菌感染，发生真菌感染的中位时间为术后19d（4～75d），其中无临床症状仅真菌培养阳性16例，20例患者出现临床感染症状，感染部位以呼吸道（11/20，55%）为主，4例患者死于严重感染。真菌菌株培养多为白色念珠菌（24/41，58.5%）。16例患者减少免疫抑制剂，20例有临床表现的患者停用免疫抑制剂，减药或停药过程中仅1例患者出现排斥反应。结论 真菌感染是肝移植术后的重要并发症，术前或术中存在真菌易感因素患者应采用IL-2受体单克隆抗体诱导方案，术后发生真菌感染的患者在应用有效抗真菌药物同时，应减少或停用免疫抑制药物。