Cytomegalovirus infection after prophylactic valganciclovir therapy post-kidney transplantation: case reports

This report describes three patients who developed cytomegalovirus infection 4 months after high-risk donor+/recipient−(D+/R−) kidney transplantation, despite treatment with valgancyclovir (VGCV) for 3 months at low dose (450 mg/d).     

Cytomegalovirus infection in orthotopic liver transplantation

We retrospectively studied 175 orthotopic liver transplants in 151 patients. Of the 151 patients, 59 (39.1%) were diagnosed as having cytomegalovirus (CMV) infection. The rate of infection in patients treated for rejection was 48.8% as compared to 26.2% in patients without rejection (P less than 0.01). Antirejection therapy was associated with culture-positive cases in 33 out of 43 patients as compared to 9 out of 16 patients who had CMV antibody titer elevations. Patients were treated with gancyclovir if they had simultaneous positive cultures from multiple sites and were seriously ill. Eighteen of the 19 patients thus treated had side effects, one of which was serious (bone marrow hypoplasia). Cultures became negative in 15 out of 17 (88%) of the surviving patients. Patient survival was similar to our overall survival rate of 87%.     

Cytomegalovirus infection in orthotopic liver transplantation

Abstract. We retrospectively studied 175 orthotopic liver transplants in 151 patients. Of the 151 patients, 59 (39. 1%) were diagnosed as having cytomegalovirus (CMV) infection. The rate of infection in patients treated for rejection was 48. 8% as compared to 26. 2% in patients without rejection ( P < 0. 01). Antirejection therapy was associated with culture-positive cases in 33 out of 43 patients as compared to 9 out of 16 patients who had CMV antibody titer elevations. Patients were treated with gancyclovir if they had simultaneous positive cultures from multiple sites and were seriously ill. Eighteen of the 19 patients thus treated had side effects, one of which was serious (bone marrow hypoplasia). Cultures became negative in 15 out of 17 (88%) of the surviving patients. Patient survival was similar to our overall survival rate of 87%.     

Cytomegalovirus infection in simultaneous pancreas-kidney transplantation

INTRODUCTION: In this open-label multicenter study, 205 simultaneous pancreas-kidney (SPK) transplant recipients between 1998 and 2000 were randomly assigned to tacrolimus or cyclosporine-microemulsion (ME). All patients received concomitant rATG induction therapy, mycophenolate mofetil and short-term corticosteroids. We report the 3-year data related to the occurrence, severity and effect of cytomegalovirus (CMV) infections. The type of CMV prophylaxis and treatment was at the discretion of the investigator. RESULTS: The overall incidence of CMV infection was 34% with no difference in incidence between the tacrolimus and cyclosporine-ME treatment arms. Statistically significant fewer CMV infections occurred among patients who received ganciclovir (22%) than those who did not receive prophylaxis (42%; P = .0075) or were treated with acyclovir (43%; P = .0066). The CMV infection rate according to donor recipient CMV serological status was: D-/R- group 11%, which was lower than the D-/R+ group at 40% (P = .0035), the D+/R+ group at 37% (P = .0024), or the D+/R- group at 52% (P = .00001). Among the last three groups, the infection rate was lower in patients on ganciclovir than those with no prophylaxis or on acyclovir (22% vs 64%; P = .00001). The incidence of acute rejection episodes was higher among patients without ganciclovir prophylaxis. No difference was observed in actuarial patient, kidney, or pancreas survival rates between patients with versus without infection. CONCLUSIONS: Ganciclovir prophylaxis effectively prevented CMV infection in SPK transplant recipients, especially in higher risk groups. An effect of CMV prophylaxis on the incidence of rejection is possible.     

肝移植术后巨细胞病毒感染的防治研究

目的探讨肝移植患者术后巨细胞病毒 (CMV)感染情况及其与急性排斥反应的关系。方法应用PCR和ELISA方法检测 78例肝移植受体手术前后、78例供体及 70例接受上腹部手术的非肿瘤患者血清中的CMV DNA和CMV抗体 ,用免疫组织化学方法检测肝组织中CMV抗原。结果供、受体术中肝脏活体组织学检查的CMV早期抗原 (EA)和晚期抗原 (LA)全部为阴性。术前CMV DNA或CMV IgM阳性的受体术后均为阳性 ;术前CMV DNA或CMV IgM阴性的受体术后CMV DNA或CMV IgM转为阳性的分别有 2 6 %和 10 %。 78例受体CMV DNA阳性率由术前的 5 %增加到术后的 31% ,两者比较差异有显著意义 (P <0 0 5 )。 2 6例患者发生了 33次急性排斥反应 ,16次 (49% )CMV DNA检测阳性、11次 (33% )CMV IgM检测阳性 ,而在术后常规检测血CMV DNA和CMV IgM的阳性率分别不超过 13%和 9% ,两者比较差异有显著意义 (P <0 0 5 )。 2 6例发生急性排斥患者肝脏活体组织学检查CMV EA和CMV LA阳性者均为 9例 (2 7% ) ,与术后的常规肝脏穿刺结果比较差异有显著意义 (P <0 0 5 )。结论 1.肝移植术后CMV感染率明显升高。 2 .CMV感染可能是发生急性排斥反应的危险因素。 3.发生急性排斥反应时 ,应使用抗CMV药物 ;未感染CMV的受体接受感染供体的肝脏时应预防用药。     

Cytomegalovirus infection after renal transplantation: selective prophylaxis and treatment

We have reviewed our experience in selective cytomegalovirus (CMV) infection prophylaxis and treatment in our renal transplant population. Between 1996 and 2001, 263 cadaveric renal transplant recipients had at least 6 months follow up. Immunosuppression was based on cyclosporine Neoral (n=108) or tacrolimus (n=155). CMV infection prophylaxis (oral acyclovir or gancyclovir at half usual doses) was only prescribed in recipients receiving a CMV positive ve kidney and in recipients treated with OKT3. CMV infection was diagnosed by a positive pp65 antigenemia upon appearance of CMV-related symptoms, leading to specific treatment (IV ganciclovir) only if symptoms were intense or there was visceral involvement. Thus, no preemptive treatment or programmed or periodic antigenemia was performed in any case. Nineteen episodes of symptomatic CMV infection were diagnosed (prevalence 7.2%). The frequency was similar for all immunosuppressive regimens. Only 9 of 19 (47%) of patients were given IV ganciclovir; the others were not treated. All patients survived without apparent complications, relapses, or recurrences. No oral gancyclovir was delivered after IV treatment. Our CMV prophylaxis protocol was limited to high-risk patients, using lower gancyclovir dosages than those usually advocated. It does not include programmed or scheduled search for CMV antigenemia in asymptomatic renal transplant patients. Despite these factors, our CMV infection rate and severity were similar to those reported with more aggressive protocols, with extended prophylaxis, preemptive therapy, or intense surveillance.     

小肠移植术后巨细胞病毒感染二例的治疗体会

目的 总结小肠移植术后巨细胞病毒(CMV)感染的治疗经验.方法 1994年至2009年间完成15例小肠移植,分为3个阶段:1994-1995年为第1阶段(3例),2003-2006年为第2阶段(7例),2007年以后为第3阶段(5例).第1阶段术后未进行CMV感染的预防;第2阶段通过肠镜、病理检查和血清学检查(CMV IgM、CMV pp65和CMV DNA)进行CMV感染的诊断,术后静脉注射更昔洛韦2~3周,口服阿昔洛韦3个月以预防CMV感染;第3阶段在第2阶段的基础上,应用实时定量PCR技术检测CMV DNA,并制定计划性监测方案,术后静脉注射更昔洛韦2~3周,口服更昔洛韦3个月预防CMV感染,采用CMV感染的抢先治疗方案.结果 15例患者中有2例(13.3 %)术后发生CMV感染.其中第2阶段1例术后45 d发生移植肠CMV肠炎,术后64 d并发CMV肺炎,应用更昔洛韦和胸腺肽,并停用他克莫司,最终转为重度排斥反应后死亡;第3阶段1例术后第3个月发生CMV感染,经CMV抢先治疗后治愈.结论 小肠移植术后应进行CMV的预防性治疗,严密监测CMV血清学指标,适时进行抢先治疗.对于CMV侵袭性疾病在进行有效治疗的同时应注意排斥反应的发生.

Abstract：

Objective Cytomegalovirus (CMV) has remained the most significant pathogen that threatens the outcome of small bowel transplantation (SBTx). This paper To outline preliminary experience of prophylaxis and treatment of cytomegalovirus (CMV) in 15 cases subject to small bowel transplantation (SBTx) and also review current progress of diagnosis and treatment of CMV.Methods Fifteen cases of SBTx were divided into 3 eras: era Ⅰ (1994-1995)-3 SBTx treated with cyclosporine-based immunosuppression; era Ⅱ (2003-2006)-7 SBTx treated with tacrolimus-based immunosuppression; and era Ⅲ (2007-present)-5 SBTx treated with Alemtuzumab induction therapy and maintenance tacrolimus monotherapy. No antiviral prophylaxis after SBTx was applied during era Ⅰ; in era Ⅱ, ileoscopic and pathological diagnosis of CMV graft enteritis was defined, and plasma diagnosis tools including CMV-IgM, CMV pp65 and CMV DNA with PCR were introduced. 2-3 weeks intravenous ganciclovir prophylaxis of CMV was underway, followed by 3 months oral acyclovir; In era Ⅲ, more precise real-time PCR technique was used to detect CMV DNA copies, and the schedule of the CMV surveillance was set up, antiviral prophylaxis therapy was modified to 2-3 weeks intravenous ganciclovir and 3 months oral ganciclovir, and preemptive therapy to halt the progression of asymptomatic infection to clinical disease was also introduced.Results Two of 15 SBTx recipients suffered from CMV with the occurrence rate of 13.3%. One recipient in era Ⅱ suffered from CMV graft enteritis on postoperative day 45, and CMV pneumonia on postoperative day 64, he received intravenous ganciclovir and thymus peptide, paused tacrolimus maintenance, and finally he died from severe acute cellular rejection. 94 100 copies/ml of CMV DNA in periphery blood of a recipient in era Ⅲ was detected with real-time PCR at 3rd month after SBTx, and a preemptive therapy successfully halted the CMV infection.Conclusion Antiviral prophylaxis therapy and close surveillance of CMV infection after SBTx should be performed, and preemptive therapy can also halt the CMV infection. When CMV disease occurs, the recipient should receive effective antiviral therapy, and acute cellular rejection also should be closely monitored at same time.     

Cytomegalovirus in transplantation - challenging the status quo

BACKGROUND: Cytomegalovirus (CMV) infection of solid organ transplant (SOT) recipients causes both 'direct' and 'indirect' effects including allograft rejection, decreased graft and patient survival, and predisposition to opportunistic infections and malignancies. Options for CMV prevention include pre-emptive therapy, whereby anti-CMV agents are administered based on sensitive viral assays, or universal prophylaxis of all at-risk patients. Each approach has advantages and disadvantages in terms of efficacy, costs, and side effects. Standards of care for prophylaxis have not been established. METHODS: A committee of international experts was convened to review the available data regarding CMV prophylaxis and to compare preventative strategies for CMV after transplantation from seropositive donors or in seropositive recipients. RESULTS: Pre-emptive therapy requires frequent monitoring with subsequent treatment of disease and associated costs, while universal prophylaxis results in greater exposure to potential toxicities and costs of drugs. The advantages of prophylaxis include suppressing asymptomatic viremia and prevention of both direct and indirect effects of CMV infection. Meta analyses reveal decreased in mortality for patients receiving CMV prophylaxis. Costs associated with prophylaxis are less than for routine monitoring and pre-emptive therapy. The optimal duration of antiviral prophylaxis remains undefined. Extended prophylaxis may improve clinical outcomes in the highest-risk patient populations including donor-seropositive/recipient-seronegative renal transplants and in CMV-infected lung and heart transplantation. CONCLUSIONS: Prophylaxis is beneficial in preventing direct and indirect effects of CMV infection in transplant recipients, affecting both allograft and patient survival. More studies are necessary to define optimal prophylaxis regimens.     

Cytomegalovirus infection and graft rejection in renal transplantation

BACKGROUND: Cytomegalovirus (CMV) infection and CMV disease have been associated with acute and chronic graft rejection. The introduction of the sensitive CMV antigenemia pp65 assay for detection of CMV infection allowed us to study the time course of CMV infection and acute rejection and the long-term outcome in renal transplant recipients with and without a CMV risk constellation. METHODS: Prospective single center study including 48 renal transplant recipients at risk for CMV infection (donor and/or recipient CMV seropositive) and a control group of 36 CMV seronegative recipients of CMV seronegative kidney donors. Evidence of CMV infection was monitored by the CMV antigenemia pp65 assay every 1 to 2 weeks and compared with the occurrence of acute rejection in the posttransplant period and graft function at 5 years. RESULTS: CMV infection developed in 83% (40/48) of patients of the CMV risk group within 4 months posttransplant. A total of 18 of patients experienced an acute rejection episode (control group 16/36; P=0.65). In 12/18 CMV infection followed rejection and in three patients antigenemia preceded the diagnosis of rejection. In three patients CMV antigenemia remained negative. Five-year follow up: Patient survival (44/48 vs. 31/36; P=0.48), graft survival (38/48 vs. 27/36; P=0.79), number of patients with at least one acute rejection episode: CMV risk group: 42.1%, control group 51% (P=0.46), serum creatinine: CMV risk group:130 +/- 66 micromol/iter, control group: 126 +/- 37 micromol/ liter (P=0.56), proteinuria: CMV risk group: 0.02 +/- 0.02 g/mmol creatinine, control group: 0.02 +/- 0.02 g/mmol creatinine (P=1.0). CONCLUSION: CMV infection within 4 months posttransplant, as defined by a positive antigenemia assay was not found to be a risk factor for acute graft rejection or chronic graft dysfunction at 5 years.     

Living donor lobar lung transplantation: current status and future directions

Living lobar lung transplantation was developed as a procedure for adult and pediatric patients considered too ill to await cadaveric transplantation. One hundred thirty-eight living lobar transplants have been performed in 133 patients at our institution between January 1993 and September 2004. Actuarial 1-, 3-, and 5-year survival are similar to ISHLT registry data. There has been no donor mortality, and morbidity has been relatively low. Long-term postoperative pulmonary function studies demonstrate the relatively smaller-sized lobes can provide similar pulmonary function and exercise capacity to bilateral cadaveric lung transplants. Living lobar lung transplantation should be considered a viable option in patients with end-stage lung disease deemed unable to await a cadaveric organ and in those patients in which further deterioration would make cadaveric transplantation inappropriate.     

Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation

Twenty-seven patients received pulmonary transplants during the period since we began routine use of cytomegalovirus-seronegative blood products for CMV-seronegative recipients. Preoperative serologic status of the recipient and the occurrence of cytomegalovirus infection in the postoperative period were correlated with development of obliterative bronchiolitis (OB) as diagnosed by transbronchial biopsy (TBB). Patients included 20 heart-lung and 7 double-lung recipients. OB occurred in 18 of 27 patients. All 3 CMV seronegative recipients receiving lungs from a seropositive donor and 9 of 10 CMV recipients seropositive at the time of transplantation developed OB compared with only 6 of 14 CMV seronegative patients receiving seronegative grafts (P = 0.018). CMV infection occurred in 10/27 patients, of whom 5 were asymptomatic; 90% of these patients developed OB. Donor-specific alloreactivity, based on primed lymphocyte testing (PLT) of bronchoalveolar lavage cells was found at the time of diagnosis of OB in 23 of 27 patients. A positive PLT was significantly associated with the presence of OB (P = 0.017). We conclude that preoperative seropositive status for CMV, grafting of organs from seropositive donors, and postoperative CMV infection are significant risk factors for developing OB. That OB is, in part, an immunologically mediated form of injury and represents chronic rejection is supported by the presence of donor-specific alloreactivity in BAL lymphocytes from all recipients with OB.     

Cytomegalovirus infection in the first year after pediatric kidney transplantation

Cytomegalovirus is common in adult recipients (prevalence of 40–90%). Children are typically seronegative but immunosuppression may prone to primary-infection or viral reactivation, with potentially severe consequences. CMV infection incidence in pediatric kidney transplant recipients has seldom been investigated. The aim of our study was to evaluate the incidence and timing of CMV infection during the first year after renal transplantation. We assembled a retrospective cohort of 136 children who had received a kidney transplant between 2003 and 2014 with a year follow-up. The patients were classified regarding CMV infection as high risk (D+/R?), intermediate risk (R+) or low risk (D?/R?). CMV infection was defined by the viral replication remaining asymptomatic whereas CMV disease concerned viral replication with clinical and/or biological symptoms. Oral valganciclovir was used as prophylaxis for high-risk recipients. A total of 38 patients (27.9%) developed CMV infection, 13 (40.6%) of the 32 D+/R?, 24 (45.3%) of the 53 R+ and 1 (2.0%) of the 51 D?/R?. Of these 38 infected patients, 10 developed tissue-invasive disease. During the first year after kidney transplantation, 27.9% of recipients developed CMV infection. This study confirms the influence of donor and recipient CMV status on infection propensity and highlights the importance of adequate follow-up for intermediate risk patients.     

Cytomegalovirus infection of the native ureter after liver-kidney transplantation

We report a case of invasive cytomegalovirus (CMV) infection in the native ureter of a patient 7 years after liver-kidney transplantation. Previous reports of CMV ureteritis in transplant patients have involved only the allograft ureter, usually within 3 months of transplantation. The common characteristics of these patients, the possible risk factors, and the diagnostic findings of CMV ureteritis are discussed. Combined surgical and medical intervention are required for successful treatment.