Comparative study of prophylactic oral ganciclovir and valacyclovir in high-risk kidney transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) is a major pathogen in renal transplant patients causing significant post-transplant morbidity and mortality. Prophylactic antiviral therapy, currently implemented in most kidney transplant centres, has significantly reduced the incidence of CMV infection after transplantation. Oral ganciclovir has been shown to be an effective prophylactic agent in preventing CMV disease and infection with a demonstrated superior efficacy over oral acyclovir. Valacyclovir, a prodrug of acyclovir with a higher level of bioavailability than acyclovir, has also been shown to be effective in preventing CMV disease when given as prophylactic treatment. METHODS: In a retrospective analysis of 150 renal transplant recipients in our centre, we compared the efficacy of oral ganciclovir with valacyclovir in preventing CMV infection. Seventy-seven consecutive renal transplant recipients prophylactically treated with oral ganciclovir for 12 weeks after transplant were compared with 73 consecutive recipients treated with oral valacylovir for an equal length of time. RESULTS: No difference was noted in the incidence of CMV infection between the two treatment groups (5.1 vs 5.4%) after a 6 month follow-up. Likewise, the incidence of acute rejection was similar in both groups (11.6 vs 6.8%). All cases of CMV infection occurred in high-risk patients (donor positive/recipient negative). CONCLUSION: The prophylactic use of oral valacylovir is as effective as oral ganciclovir in reducing CMV infection and disease after kidney transplantation.     

Risk factors and impact of cytomegalovirus disease in simultaneous pancreas-kidney transplantation.

BACKGROUND: The relevance of cytomegalovirus (CMV) in simultaneous pancreas kidney (SPK) transplant recipients in the modern era of immunosuppression and antiviral therapeutics is largely unquantified. We sought to determine the risk factors of CMV disease and its impact on SPK transplant outcomes in recipients all receiving a consistent regime of maintenance immunosuppression and CMV prophylaxis. METHODS: This is a retrospective, single center study of 100 consecutive SPK transplant recipients. All received maintenance immunosuppression with mycophenolate mofetil, tacrolimus, and prednisone. CMV prophylaxis consisted of a short course of parenteral gancyclovir followed by oral gancyclovir. Recipients at high-risk (D+/R-) for CMV also received CMV hyperimmune globulin. Multivariate analysis of risk factors for CMV disease and risk factors for adverse outcomes in SPK transplantation were determined. The effect of duration of prophylaxis on timing and severity of CMV disease in high-risk (D+/R-) SPK transplant recipients was also evaluated. RESULTS: The actual 1-year rate of CMV disease was 17.0% (12.0% noninvasive, 5.0% tissue invasive); and according to donor and recipient CMV serological status was: D-/R+: 0%; D-/R-: 2.8%; D+/R+: 25.6%; and D+/R-: 40.6%. Multivariate analysis showed transplantation of organs from a donor with positive CMV serology to be predictive of CMV disease with a relative risk of 63.37 (P=0.0052). In the high-risk (D+/R-) subgroup, the duration of prophylactic therapy delayed onset of CMV disease, but had minimal effect on severity. Invasive CMV disease was an independent predictor of mortality but did not decrease kidney or pancreas allograft survival. CONCLUSIONS: Outcomes of SPK transplantation have improved in the current era of modern immunosuppression, yet CMV remains an important pathogen. The serological status of the organ donor and the duration of CMV prophylaxis are predictive of who and when CMV disease may occur. Nevertheless, new strategies that reduce risk and severity of CMV disease are still needed.     

Failure of acyclovir to prevent cytomegalovirus infection in renal allograft recipients

Cytomegalovirus (CMV) is the most common opportunistic pathogen following renal transplantation and remains a major concern in transplantation centers owing to its high morbidity and impact on renal allografts. Pending more effective antiviral drugs, efforts have been directed toward prevention strategies. We conducted a retrospective analysis to evaluate the efficacy of various prophylactic options used at our institution during the period April 1986 to August 1990. All CMV-negative patients with CMV-negative kidneys (D-R-) received screened, CMV-negative blood products (n=19). CMV-specific immunoglobulins (CMV Ig) were used in 6 patients at increased risk for primary CMV infection and acyclovir was administered to 21 patients at an initial intravenous dose of 5 mg/kg body weight; then oral doses of 800–3200 mg per day were given according to the patients' estimated creatinine clearance. Thirty-two patients did not receive any CMV prophylactic treatment and served as controls. CMV monitoring of the patients during the first 6 months after transplantation showed an overall infection and disease rate of 81% and 38.1%, respectively, in the acyclovir-treated group. Compared with controls, the incidences of infection and disease were higher in the acyclovir-treated patients, with a significant difference for CMV infection (P=0.002, generalized Wilcoxon test). Only 1 of the 19 D-R-patients presented with CMV infection. CMV Ig-treated patients tended to have less severe disease without any apparent reduction in infection incidence. Given the high rate of infection in patients at risk, we infer that high-dose acyclovir does not prevent CMV infection in our setting of renal transplantation. We advocate the use of screened, CMV-negative blood products in D-R-patients.Part of this study has already been published as a letter to the editor in the Annals of Internal Medicine     

Evaluation of a Cytomegalovirus Prophylaxis Protocol in Cytomegalovirus-IgG Positive Renal Transplant Recipients (R+)

BackgroundThe aim of the study was to evaluate the efficacy of a unique cytomegalovirus- (CMV) prophylaxis protocol in terms of CMV infection and disease progression in CMV IgG positive kidney transplant recipients.MethodsAchievement of negative CMV load, using concurrent prophylactic intravenous ganciclovir therapy during induction immunosuppression, combined with a 6-month prophylactic course of acyclovir, would yield a reduced incidence of early CMV infection and disease. CMV DNA was tested for at discharge, at the third, and sixth post-op months, and at the occurrence of any event that could be associated with CMV infection. CMV DNA positive patients received ganciclovir treatment until the viral load became negative. CMV replication was monitored using a quantitative PCR method capable of detecting as few as 42.5 copies/mL. All patients were given a maintenance dose of acyclovir.ResultThe file data of 267 patients who had undergone kidney transplantation between 2007 to 2016 were examined. Thirty-four patients were excluded from the study for various reasons, unrelated to the protocol. Of the remaining 233 patients, 42 (18%) had CMV DNA infection. Three patients had CMV disease (1.3%), 1of whom died of pneumonia. Diabetes mellitus (DM) was a risk factor for CMV DNA positivity (P < .004).ConclusionThe incidence of CMV infection and disease is low in renal transplant recipients whose CMV viral load is eliminated after concurrent ganciclovir administration with induction immunosuppression.     

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.     

Acyclovir plus CMV immunoglobulin prophylaxis and early therapy with ganciclovir are effective and safe in CMV high-risk renal transplant pediatric recipients

Abstract Cytomegalovirus (CMV) infection is still a major cause of morbidity in high-risk renal transplant recipients. In the present report, we have reviewed our records of renal transplant pediatric recipients (RTPR; mean age 14.1 ± 4.9 years) since 1991, when we started a policy of CMV prophylaxis constituting high-dose oral acyclovir plus CMV hyperimmune immunoglobulins (Hlg) followed by early i.v. ganciclovir therapy in high-risk patients (i.e., CMV donor +/ recipient -). Four patients received a kidney from a living relative (LR), 2 patients had one previous transplant, and 1 had a combined liver -kidney transplant. Thirty-three patients who were negative for CMV antibodies (ab) before transplantation received a kidney from CMV ab positive donors. The immunosuppressive regimen included cyclosporin A and steroids, with the addition of azathioprine in the 4 patients who received an LR kidney. Serial assessments for CMV antigenemia (pp 65) were routinely performed for 6 months after transplantation to define CMV infection. Among the 33 CMV seronegative recipients (R -) who received the graft from a CMV seropositive donor (D +), 18 (54.5 %) experienced CMV infection, whereas among the 28 CMV R +, who received a graft from a CMV D +, 11 (39.3 %) experienced CMV infection. With regard to CMV - related symptoms, only 2 patients suffered from a CMV syndrome (fever and leukopenia in 1 patient, fever and arthralgia in the other). In no case did the spectrum of CMV disease occur; only minor symptoms were present in 7 of the remaining CMV-infected patients (fever in 6 and leukopenia in 1). Rejection episodes and renal function did not differ between CMV-infected and non-CMV-infected patients. Our experiences support the use of prophylactic acyclovir plus CMV HIg followed by early therapy with i.v. ganciclovir to combat the risk of increased morbidity in high risk RTPR.     

Acyclovir plus CMV immunoglobulin prophylaxis and early therapy with ganciclovir are effective and safe in CMV high-risk renal transplant pediatric recipients

Cytomegalovirus (CMV) infection is still a major cause of morbidity in high-risk renal transplant recipients. In the present report, we have reviewed our records of renal transplant pediatric recipients (RTPR; mean age 14.1 ± 4.9 years) since 1991, when we started a policy of CMV prophylaxis constituting high-dose oral acyclovir plus CMV hyperimmune immunoglobulins (Hlg) followed by early i. v. ganciclovir therapy in high-risk patients (i. e., CMV donor + / recipient ?). Four patients received a kidney from a living relative (LR), 2 patients had one previous transplant, and 1 had a combined liver – kidney transplant. Thirty-three patients who were negative for CMV antibodies (ab) before transplantation received a kidney from CMV ab positive donors. The immunosuppressive regimen included cyclosporine A and steroids, with the addition of azathioprine in the 4 patients who received an LR kidney. Serial assessments for CMV antigenemia (pp 65) were routinely performed for 6 months after transplantation to define CMV infection. Among the 33 CMV seronegative recipients (R ?) who received the graft from a CMV seropositive donor (D +), 18 (54.5 %) experienced CMV infection, whereas among the 28 CMV R +, who received a graft from a CMV D +, 11 (39.3 %) experienced CMV infection. With regard to CMV ? related symptoms, only 2 patients suffered from a CMV syndrome (fever and leukopenia in 1 patient, fever and arthralgia in the other). In no case did the spectrum of CMV disease occur; only minor symptoms were present in 7 of the remaining CMV-infected patients (fever in 6 and leukopenia in 1). Rejection episodes and renal function did not differ between CMV-infected and non-CMV-infected patients. Our experiences support the use of prophylactic acyclovir plus CMV HIg followed by early therapy with i. v. ganciclovir to combat the risk of increased morbidity in high risk RTPR.     

Surveillance for CMV infection in orthotopic liver transplant recipients.

Infection with cytomegalovirus is a major cause of morbidity and mortality following orthotopic liver transplantation. In order that preventive strategies may be devised, a detailed assessment of risk factors for infection and disease is required. We have prospectively assessed 46 orthotopic liver transplant recipients for CMV excretion from multiple sites in order to determine incidence of, and risk factors for, CMV infection and disease. Risk factors for posttransplant CMV infection were donor CMV seropositivity, an increased volume of peritransplant whole-blood transfusion and an increased dose of extra steroid therapy to treat rejection episodes. These findings implicate, respectively, transfer of virus with donor organ, transfer of virus with blood transfusion, and stimulation of reactivation of latent virus in recipients through augmented immunosuppression. The possible ways of preventing or ameliorating these effects are discussed.     

Cytomegalovirus infections following renal transplantation – effects of antiviral prophylaxis: a report of the North American Pediatric Renal Transplant Cooperative Study

Post-transplant cytomegalovirus (CMV) infections are a source of significant morbidity. However, the extent of the problem and the benefits of various antiviral prophylactic therapies remain incompletely understood. The North American Pediatric Renal Transplant Cooperative Study registry was screened to identify patients hospitalized for CMV infections during the 1st post-renal transplant year between 1987 and 1993. Using a control group of transplant recipients, we performed a retrospective analysis of risk factors for CMV disease among these hospitalized patients and studied the effects of various viral prophylactic strategies on CMV risk, clinical manifestations, and outcome. We identified 142 patients hospitalized with CMV infections, the majority of which included major organ involvement. A CMV-positive kidney donor was the most significant risk factor for hospitalization [odds ratio (OR) = 5.2, P<0.0001] irrespective of recipient age or CMV immune status. As opposed to antiviral agents (acyclovir, ganciclovir) or pooled IgG, prophylaxis with enriched anti-CMV IgG significantly reduced the risk of CMV hospitalization (OR = 0.31, P = 0.03). The prophylactic use of antiviral agents was associated with a decreased risk of major organ involvement during the CMV infection (OR = 0.34, P<0.005). Among the patients with CMV, the 3-year graft survival was significantly better for those who received any form of prophylaxis compared with those who received none (88% vs. 52%, P<0.001). Our findings suggest a role for combined CMV-enriched IgG and antiviral agent prophylaxis for post-transplant CMV disease. Such an approach could diminish the incidence and severity of CMV infection and appears to have an independent favorable effect on graft outcome. Received November 14, 1996; received in revised form March 21, 1997; accepted April 11, 1997     

Cytomegalovirus Infection Renal Transplant Recipients: Risk Factors and Outcome

Objective

Cytomegalovirus (CMV) is the most common viral infection after allotransplantation; it can be a major cause of morbidity and mortality. Our aim was to analyze the main risk factors that lead to development of CMV infection and disease.

Patients and Methods

We retrospectively analyzed 207 patients who received a renal allograft from May 2003 to December 2007. Three patients (D−/R−) were excluded. CMV infection was defined by the detection of 2 or more positive tests for pp65 antigenemia and CMV disease by evidence of attributable symptoms in need of antiviral treatment.

Results

Thirty-two patients (15.7%) presented active CMV infections and another 35 (17.2%), CMV disease. The mean follow-up was 27.8 ± 17 months. Prior to transplantation, 9.2% of patients were seronegative (D+/R−) and 77.9% seropositive (D+/R+). Compared with noninfected patients, those with CMV infection/disease were older and received an allograft from an older donor. Upon logistic regression analysis, recipient age older than 55 years, induction therapy with Thymoglobulin, and maintenance immunosuppression with cyclosporine were the major risk factors to develop CMV disease. An early acute rejection episode was more frequent and renal function measured by serum creatinine poorer until 18 months posttransplantation among CMV-infected versus noninfected patients.

Conclusions

Our data showed that CMV infection is a common complication after kidney transplantation associated with older age, induction treatment with antilymphocyte globulin, worse renal function, and increased patient morbidity.     

The prevention of cytomegalovirus disease in renal transplantation.

Primary cytomegalovirus (CMV) disease can be prevented in renal transplant recipients with the use of either CMV hyperimmune globulin (CMVIg) or acyclovir. Started within 72 hours of transplantation and continued for 16 weeks posttransplant, CMVIg decreases the incidence of primary CMV disease from 60% to 21%. Acyclovir administered preoperatively and for 3 months thereafter decreases the incidence of CMV disease from 29% to 8% and is the most cost-effective therapy. The effectiveness of these preparations in preventing CMV reinfection or reactivation has not been established. The utility of therapies other than CMVIg or acyclovir for the prevention of CMV disease has not been proven; CMV vaccination is ineffective, polyvalent immunoglobulins require further study, and interferon alpha (IFN-alpha) has been associated with frequent irreversible rejection reactions and therefore should not be used for CMV prophylaxis. Although further investigation is necessary, patients at risk for primary CMV disease should receive prophylactic therapy with either CMVIg or acyclovir.     

Prevention of cytomegalovirus infection in the pediatric renal transplant recipient

Cytomegalovirus (CMV) infection is the most important single infectious complication of organ transplantation, affecting more than 70% of transplant recipients. Its emergence as a major pathogen has coincided with the use of cytotoxic therapy. Manifestations of serious CMV disease include: pneumonia, hepatitis, gastrointestinal disease, leukopenia and chorioretinitis. CMV is associated with superinfection with opportinistic organisms, graft failure and increased mortality. Serious infection most frequently occurs with primary CMV infection in which latently infected cells from CMV-positive donors are given to seronegative recipients. Pediatric patients who have a lower pre-transplant rate of CMV seropositivity are at particularly high risk of developing serious CMV disease. Preventative efforts range from the ideal but impractical use of only CMV-negative donors (organ and blood products), to the use of CMV hyperimmune globulin and antiviral chemotherapy. Data support the use of prophylactic hyperimmune globulin and preliminary information supports the use of prophylactic high-dose acyclovir in renal transplant patients. Prophylactic gancyclovir alone or with hyperimmune globulin and pre-transplant vaccination with live-attenuated Towne strain CMV vaccine remain investigational.     

Influence of anti-rejection therapy on the timing of cytomegalovirus disease and other infections in renal transplant recipients

Infections are an important cause of mortality and morbidity in renal transplant recipients. To study the impact of anti-rejection therapy on the timing of infections, the records of 599 consecutive renal transplants, performed prior to 31 December 1996 at the Royal Melbourne Hospital, were reviewed. Patients were grouped according to acute rejection (AR) episode and treatment during the first 6 months after transplantation. Group 1 [n = 168 (35%)] patients did not experience any episode of AR. Group 2 [n = 169 (35%)] patients had one or more episodes of AR and received high doses of steroids. Group 3 [n = 141 (30%)] patients had more than one episode of AR and received anti-lymphocyte antibodies in addition to high doses of steroids. Infections were more common in Groups 2 and 3 but only cytomegalovirus (CMV) disease occurred earlier in patients treated with lympholytics. Given the high incidence and early onset of CMV disease in patients receiving lympholytics and considering that an effective prophylactic protocol remains undetermined, pre-emptive treatment with ganciclovir in this high risk group appears justified.     

Pre-transplant risk factors predicting post-transplant cytomegalovirus infection in liver transplant recipients

Cytomegalovirus (CMV) infection causes significant morbidity and mortality among transplant recipients. Although it is still not clear if a preemptive strategy is superior to a prophylactic strategy, many transplant programs elect for preemptive treatment for post-transplant CMV infection. In order to improve the preemptive strategy, we analyzed a series of liver recipients by means of quantitative real-time polymerase chain reaction (PCR). Ninety-one liver transplant recipients were monitored by real-time PCR for CMV, and the results were analyzed in terms of preoperative conditions. Multivariate analysis revealed fulminant hepatic failure as an underlying disease (odds ratio, 6.8; 95% CI, 1.2-39.2), while an ABO-incompatible graft (odds ratio, 5.0; 95% CI, 1.3-19.1), and a serological combination of the donor (D) being positive with the recipient (R) being negative for CMV (D+/R-) (odds ratio, 5.8; 95% CI, 1.3-26.0) were independently associated with the development of significant CMV infection. Patients with risk factors had higher peak CMV DNA concentrations than those without, and developed CMV infections faster (P = 0.0002). Screening of recipients according to risk factors and PCR monitoring may result in an optimization of the preemptive strategy.     

Infectious complications after simultaneous pancreas-kidney transplantation

Simultaneous pancreas-kidney transplantation (SPKT) improves long-term survival of insulin-dependent diabetes mellitus patients with diabetic nephropathy. The increasing success of SPKT is a result of improved surgical technique, better organ preservation, potent antirejection therapy, and effective use of antibiotics to prevent and treat infectious complications. However, morbidity and mortality following SPKT remain high mainly owing to infection. From 1988 to 2004, the 51 patients who underwent SPKT were 32 women and 19 men of mean age 34 +/- 4 years old with diabetes and end-stage renal disease. The mean duration of diabetes mellitus was 23 +/- 4 years. The incidence of HCV and HBV infections were 19.6% and 13.7%, respectively. Preoperative work-up included identification and elimination prior to surgery of potential sources of infection. All patients prior to SPKTx had been treated by dialysis (26 +/- 20 months). The kidneys were always placed into the left retroperitoneal space first; at the same time the pancreatic grafts were prepared on the back table. The reconstruction of the superior mesenteric and the splenic arteries was performed using a Y graft of donor iliac artery to the common or external donor's iliac artery. The pancreas was transplanted intraperitoneally to the right iliac vessels. The portal vein was sutured to the common or external iliac vein and the arterial conduit of donor iliac artery. In 20 of the patients, bladder drainage and in 31, enteric drainage was used for the pancreatic juice exterioration. Patients received immunosuppression with a calcineurin inhibitor (tacrolimus or cyclosporin), mycophenolic acid or azathioprine, and steroids. Antibody induction (alternatively anti-IL-2 monoclonal antibody or ATG) was used in last 38 patients. Antibacterial (tazobactam) and antifungal (fluconazole) as well as antiviral (gancyclovir) prophylactic treatment was given to all patients for 7 to 10 days after transplantation. Thirty-eight recipients are alive, 26 with function of both grafts; 8 with functioning kidney grafts; and 4 with nonfunctioning grafts on dialysis treatment from 1 to 14 years after transplantation. Thirteen patients (24.5%) died during the first year after transplantation. Infectious complications were the main cause of death. Systemic infections accounted for the death of five patients and CNS infection for death of another five patients. Three patients died with functioning grafts due to cardiopulmonary disorders (myocardial infarction, pulmonary embolus) early in the postoperative period. A total of 102 infections were diagnosed in 51 patients during the posttransplant course. Twenty-one episodes of CMV infection (systemic 20, duodenal site 1), 73 bacterial infections (systemic 13, pulmonary 13, urinary tract 15, intestinal 8, wound 23), and 8 fungal infections (central nervous system 5, gastrointestinal tract 3). Some patients had more than one type of infection. Overall mortality in the investigated group was 24.5%. Infectious complications were the main cause of death (77%), including systemic infection (38.5%) and CNS infection (38.5%). The predominant etiology of the systemic infections was bacterial. The etiology of CNS infections was fungal. In conclusion, infectious complications are the main cause of morbidity and mortality following SPKT. The early diagnosis of infection, particularly fungal complications, is necessary. The administration of broad-spectrum prophylactic antibiotics, antifungal, and antiviral agents is recommended.     

Does valganciclovir hydrochloride (valcyte) provide effective prophylaxis against cytomegalovirus infection in liver transplant recipients?

INTRODUCTION: Cytomegalovirus (CMV) infection after solid organ transplantation is one of the most common viral infections, causing significant morbidity and mortality if not treated promptly. Ganciclovir has proven to be effective for the prophylaxis and treatment of CMV. However, oral absorption of ganciclovir is poor. Recently, oral administration of valganciclovir hydrochloride (Valcyte) has been observed to display 10-fold better absorption than oral ganciclovir. Valganciclovir has increasingly been used as prophylaxis against CMV after solid organ transplantation. The purpose of this study was to examine the efficacy of valganciclovir prophylaxis therapy after primary liver transplantation. PATIENTS AND METHODS: Between July 2001 and May 2003, 203 consecutive liver transplant recipients, including 129 men and 74 women of overall mean age 53 +/- 11 years, received valganciclovir (900 mg/d or 450 mg every other day depending on renal function) for 3 to 6 months after primary liver transplantation. All patients were followed up for a minimum of 6 months. Mean follow-up was 19 +/- 5.8 months. CMV DNA in peripheral blood was tested using polymerase chain reaction (PCR) amplification. Symptomatic CMV was stratified according to the CMV immunoglobulin (Ig)G status of the donor and recipient at the time of liver transplantation. Donors and recipients were classified preoperatively into groups according to the presence or absence of CMV as follows: group 1 (n = 73; donor CMV+, recipient CMV+); group 2 (n = 41; donor CMV-, recipient CMV+); group 3 (n = 54; donor CMV+, recipient CMV-; high-risk group); and group 4 (n = 35; donor CMV-, recipient CMV-). RESULTS: Twenty-nine patients (14.3%) developed symptomatic CMV disease at 169 +/- 117 days after liver transplantation: group 1, 16.4% versus group 2, 7.3% versus group 3, 25.9% versus group 4, 0%. Of these patients, 5 also had invasive CMV on liver biopsy, which was performed owing to abnormal liver functions. All 29 patients were treated with intravenous ganciclovir. One patient died owing to disseminated CMV, whereas the remaining 28 patients responded to treatment. Interestingly, 8 patients, including 1 who had invasive CMV hepatitis, developed symptomatic CMV within 90 days of liver transplantation even while on prophylactic valganciclovir. CONCLUSION: Valganciclovir failed to provide adequate prophylaxis following liver transplantation in our patients. The overall rate of CMV in seropositive donors and/or recipients was 17%, and in the high-risk group was 26%. Further prospective studies with measurement of ganciclovir concentrations are needed to elucidate the reasons for this unexpected failure.     

Cytomegalovirus infection in lung transplantation; current status, detection, prophylactic treatment

The control of the postoperative infectious disease is one of the important elements in transplantation. Among them, the control of the cytomegalovirus (CMV) infection may be said the most important in the management of the transplant recipient who is under the immunosuppression. This time, we review the status of the pre-transplant CMV infection in the donors and recipients of both brain-death and living-related lung transplantation that we performed, and report our prophylactic treatment for CMV infection and its results. The CMV positive rate of the recipients and donors of the lung transplantation that we experienced in Okayama University was 87%. We experienced 4 cases that developed CMV infection after lung transplantation. However, there is no case that died of a CMV-related infectious disease after lung transplantation to date. By the CMV mismatch transplant, it seemed that the frequency of the postoperative CMV disease was high in comparison with the transplant of recipient CMV (+). But, the control of the CMV infection after lung transplantation is thought to be possible if we give a proper prophylactic treatment even in CMV mismatch transplantation.     

Risk factors for cytomegalovirus reactivation after CD6+ T-cell-depleted allogeneic bone marrow transplantation

BACKGROUND: Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Recipients of T-cell-depleted (TCD) transplants may be more susceptible to CMV infection as a result of the reduction in transferred T cell immunity. We sought to determine the effect of prior donor and patient CMV exposure on the incidence of CMV infection after TCD allogeneic HSCT. METHODS: We retrospectively examined CMV antigen testing results in all patients who had undergone CD6+ TCD related and unrelated donor allogeneic HSCT at our institution from 1996 to 1999. All 124 patients who had documented donor and recipient CMV serologies pretransplant and had undergone CMV antigen testing before day +100 posttransplant were included in the analysis. RESULTS: Forty-one percent of seropositive recipients and 1% of seronegative recipients developed evidence of CMV reactivation (odds ratio 54.1, 95% confidence interval [CI] 6.9-424.1, P<0.001). Prior donor CMV exposure did not place seronegative recipients at increased risk of CMV conversion. Multivariable analysis indicated that prior donor CMV exposure significantly reduced the risk of CMV reactivation in seropositive recipients by 81% (odds ratio 0.19, 95% CI 0.04-0.91, P=0.04). Grades II to IV acute graft-versus-host disease (GVHD) was associated with CMV conversion (P=0.04) when seropositive recipients underwent HSCT from CMV-negative donors, but not when the donor was CMV-seropositive (P=0.54). CONCLUSIONS: The CMV serology status of the recipient, rather than the donor, was the primary determinant of risk for CMV conversion after TCD allogeneic HSCT. Despite CD6+ T-cell depletion, immunity against CMV seemed to be transferred with the donor graft and protected seropositive HSCT recipients from CMV reactivation.     

The economic impact of cytomegalovirus infection after liver transplantation

BACKGROUND: We studied the economic impact of cytomegalovirus (CMV) disease and its effective reduction with antiviral prophylaxis in liver transplant recipients. METHOD: Analysis of institutional charge data accumulated during a prospective, randomized, controlled trial comparing oral acyclovir 800 mg four times daily for 120 days (ACV) and intravenous ganciclovir 5 mg/kg every 12 h for 14 days followed by ACV for 106 days (GCV) was performed. RESULTS: Liver transplant recipients who developed CMV disease had significantly higher charges (median: $148,300) than those who developed asymptomatic CMV infection ($119,600) or experienced no CMV infection ($114,100) (P<0.01). A multiple linear regression analysis indicated that CMV disease is associated with a 49% increase in charges, independent of other factors influencing increased hospitalization charges. In CMV-seronegative patients who received a CMV-seropositive donor organ, GCV prophylaxis was associated with a significant reduction in charges, as compared to ACV prophylaxis ($113,900 vs. $153,300, respectively; P=0.02). CONCLUSIONS: CMV disease is an independent risk factor for increased resource utilization associated with liver transplantation. The use of an effective prophylactic antiviral regimen provides savings in health care resources, particularly in patients at high risk for developing CMV disease.     

Valacyclovir prevention of cytomegalovirus reactivation after heart transplantation: a randomized trial.

BACKGROUND: Cytomegalovirus (CMV) is a major cause of serious morbidity following solid organ transplantation via both direct and indirect mechanisms. The aim of this study was to investigate the efficacy and safety of valacyclovir prophylaxis in heart transplant recipients. METHODS:Twenty-seven CMV seropositive adults due to receive a heart transplant were included in a single-center, randomized, double-blind study. Patients were randomized to receive either oral valacyclovir 2000 mg or oral acyclovir 200 mg four times daily starting within 3 days of heart transplant and continuing for 90 days. The primary outcome measure was time to development of CMV antigenemia assessed for 6 months after surgery. Other measures were time to asymptomatic CMV infection, symptomatic CMV infections, and end-organ CMV disease. Patients were monitored for other herpes infections, other opportunistic infections, and acute graft rejection. Safety was assessed by evaluating changes in hematology and clinical chemistry parameters and by the occurrence of adverse events. RESULTS: The median time to CMV antigenemia was 19 days for the acyclovir group compared with 119 days for the valacyclovir group (hazard ratio 0.42; 95% CI, 0.18-0.99; p = 0.049). Similar delays of approximately 100 days were found for CMV infection, symptomatic CMV infection, and CMV disease. There was also a trend for delayed acute rejection, and fewer opportunistic or other herpesvirus infections occurred in the valacyclovir group. Valacyclovir was well tolerated in the study population. CONCLUSION: Oral valacyclovir is a safe and effective mode of prophylaxis of CMV after heart transplantation.