Abstension from treatment of low-level pp65 cytomegalovirus antigenemia after liver transplantation: a prospective study

BACKGROUND: Ganciclovir is a highly effective and relatively safe drug to treat cytomegalovirus (CMV) infection in liver transplant patients; CMV resistance to ganciclovir is progressively emerging due to the extensive use of the drug in transplant and AIDS patients; CMV pp65 antigenemia allows early diagnosis of CMV infection and quantitation of the viral load; preemptive antigenemia-guided therapy of CMV infection can prevent CMV disease but the threshold of antigenemia value above which treatment has to be instituted is unclear. METHODS: To demonstrate the safety of abstention from preemptive treatment in the presence of low levels of antigenemia 77 consecutive liver transplant recipients were prospectively evaluated. Antigenemia was tested twice a week from transplantation until discharge, then once a week until the third postoperative month. In absence of risk factors for CMV disease, namely donor positive/recipient negative CMV serology, treatment with antibodies to lymphocytes and retransplantation, only patients with antigenemia of more than 50 or symptoms possibly related to CMV infection had preemptive treatment. RESULTS: A total of 32 patients had at least one positive antigenemia test with a value less than 50; 22 (68.7%) spontaneously cleared the virus, 3 were treated with i.v. ganciclovir for the presence of fever, and the other 7 (21,8%) progressed to values of antigenemia of more than 50 and were treated even if asymptomatic. No CMV disease was observed in these patients. CONCLUSION: CMV antigenemia less than 50 in liver transplant recipients with low and intermediate risk for CMV disease does not mandate preemptive ganciclovir treatment. Close surveillance with repeated determination of antigenemia until its negativization and careful clinical and laboratory monitoring is advisable.     

Preemptive Therapy for the Prevention of Cytomegalovirus Disease in Renal Transplant Recipients: Our Preliminary Experience

Background

Cytomegalovirus (CMV) disease represents an important cause of morbidity in renal transplant recipients. We report our preliminary evaluation of the efficacy and security of preemptive therapy to manage renal transplant recipients with evidence of active CMV replication.

Methods

Preemptive therapy with gancyclovir and/or valgancyclovir (VGCV) was recently substituted for CMV antiviral prophylaxis at our institution. Between May 2006 and December 2007, all patients undergoing renal transplantation were included in a CMV infection surveillance program. Blood samples to determine CMV viral load were obtained weekly during the first 4 months. Asymptomatic patients, with a viral load determined using polymerase chain reaction (PCR) with CMV DNA >100,000 copies/mL, were treated with VGCV for 3 months or until resolution of viral replication. Until April 2006, patients undergoing renal transplantation received CMV prophylaxis with oral acyclovir and pp65 antigenemia was the test for CMV infection surveillance. The group on preemptive therapy was compared with a historical group on prophylaxis therapy: 100 renal patients who underwent transplantation between April 2004 and 2006.

Results

Among 96 recipients, quantitative determination of viral DNA in blood was elevated in 14 asymptomatic patients, who were treated with oral VGCV for 3 months. The patients were followed up for a median time of 13.3 months. None of the 14 patients who received VGCV developed CMV disease.

Conclusion

VGCV administered as preemptive therapy was safe and efficacious to prevent CMV disease.     

Efficacy and limitations of preemptive therapy against cytomegalovirus infections in heart transplant patients

OBJECTIVES: Cytomegalovirus (CMV) disease often represents a serious complication that promotes opportunistic infections in heart transplant recipients. In this study we evaluated the impact of preemptive gancylovir therapy, guided by pp65 antigenemia on the morbidity associated with viral reactivation. PATIENTS AND METHODS: We have performed a CMV infection surveillance program since March 1999, with antigenemia pp65 determinations weekly for the first 2 months biweekly in the third months, and monthly to the sixth month. Patients with pp65 antigenemia value >/= 10 positive cells per 2 x 10(5) polymorphonuclear cells (PMN) were treated with intravenous gancyclovir followed by 1 month of oral gancyclovir. RESULTS: Among the 107 patients who underwent the virological monitoring, 80 were pp65 antigenemia-positive with preemptive therapy administered in 48 cases. Five patients displayed symptomatic CMV disease (4.7% vs 18% rate in the period of 1988 to 1998 before the introduction of virologic monitoring; P <.01). We observed only one case of gancyclovir-resistant pneumonia which was successfully treated with foscarnet. CMV recurrence in 10 patients required a second cycle of gancyclovir treatment. Our experience included 13 opportunistic infections (12.7%) with 11 antigenemia-positive. CONCLUSIONS: Preemptive therapy drastically reduces the incidence of CMV disease and the associated morbidity. Compared to universal prophylaxis, this approach may avoid unnecessary pharmacologic treatment in more than 50% of transplant recipients. Indeed, preemptive therapy does not fully prevent CMV disease, because it may manifest at the first antigenemia determination, and furthermore may select gancyclovir-resistant strains.     

Preemptive Therapy for Cytomegalovirus Disease in Allogeneic Stem Cell Transplant Recipients

Cytomegalovirus (CMV) infection causes high morbidity and mortality among allogeneic stem cell transplant recipients. Preemptive therapy with oral valganciclovir or intravenous ganciclovir has replaced universal prophylaxis. We prospectively studied 19 consecutive adult recipients of allogeneic peripheral blood stem cell transplants from May 2005 through February 2007 to analyze the safety and efficacy of preemptive therapy for the treatment of CMV infection. The antigenemia test was persistently negative in 8 patients (42%) and positive at least once in 11 (58%). Eight patients were treated with oral valganciclovir on an outpatient basis and they all became CMV negative after the first week of treatment. The other 3 patients received intravenous ganciclovir and were also CMV negative after the first week of treatment. No patient abandoned treatment, no severe secondary toxicity was noted, and there was no CMV-associated mortality.     

Prospective randomized trial to assess the value of preemptive oral therapy for CMV infection following liver transplantation

BACKGROUND: With the development of sensitive tests to detect cytomegalovirus (CMV) viremia, preemptive approaches become a reasonable alternative to general CMV prophylaxis. We performed a randomized trial comparing pp65-antigenemia guided preemptive therapy using oral ganciclovir with symptom-triggered intravenous ganciclovir treatment. METHODS: Eighty-eight of 372 liver transplant recipients developed antigenemia early after orthotopic liver transplantation. Twenty-eight symptomatic patients with antigenemia were excluded from randomization and treated with intravenous ganciclovir. Sixty pp65-antigen-positive asymptomatic patients were randomized to receive either oral ganciclovir 3x1 g/day for 14 days (group 1) or no preemptive treatment (group 2). Patients that developed CMV disease were treated with intravenous ganciclovir 2x5 mg/kg body weight for 14 days. The high-risk (Donor+/Recipient-) patients were equally distributed in the two study groups. RESULTS: Three of 30 (10%) patients on oral ganciclovir developed mild to moderate CMV disease compared with 6/30 (20%) patients in the control group. In the Donor+/Recipient- patients, the incidence of CMV disease was 1/6 and 3/7. All disease episodes resolved after intravenous treatment. The 1- and 3-year patient and organ survival was the same in the study groups and in the patients with or without CMV infection. No deaths related to CMV occurred. CONCLUSIONS: The positive predictive value of pp65-antigenemia for the development of CMV disease was very low, and, in 28/88 patients (32%), antigenemia did not precede symptoms. Therefore, pp65-antigenemia is of limited value in deciding on the timing and need for ganciclovir therapy after liver transplantation.     

Long-term oral ganciclovir prophylaxis for prevention of cytomegalovirus infection and disease in cytomegalovirus high-risk renal transplant recipients

BACKGROUND: Although specific therapy is available with ganciclovir, cytomegalovirus (CMV) disease remains a major problem after renal transplantation especially in CMV seronegative recipients of organs of seropositive donors (D+R-). METHODS: In an open-labeled prospective controlled trial we evaluated the effect of long-term oral ganciclovir prophylaxis (3 g/day for 3 months posttransplantation) in a cohort of 31 CMV-high risk (D+R-) renal transplant recipients (GC) compared with a cohort of 28 high-risk patients with targeted CMV prophylaxis (CO) receiving i.v. ganciclovir during antirejection therapy. Primary end-points were CMV infection, diagnosed by pp65 antigenemia assay or serologic method, and CMV disease. Additionally severity of CMV disease quantified by a scoring system was evaluated. RESULTS: CMV prophylaxis significantly reduced the incidence of CMV infection (CO: 75%, GC: 45%; P<.05) and CMV disease (CO: 60%, GC: 29%; P<.05) without relevant side effects and without any clinical suspicion of ganciclovir resistance. Severity of CMV disease as quantified by a scoring system was reduced from 8.3+/-6.7 points in controls to 3.3+/-2.6 points in ganciclovir-treated patients (P<.05). Mortality did not differ significantly between the two groups (CO: n=3, GC: n=1; NS). However, there was one lethal CMV disease and a second death possibly attributable to CMV disease in the control group, whereas in ganciclovir-treated patients there was no CMV-associated fatal outcome. CONCLUSION: Long-term oral ganciclovir prophylaxis is effective and safe in CMV high-risk renal transplant recipients.     

Efficacy and safety of preemptive anti-CMV therapy with valganciclovir after kidney transplantation

BACKGROUND: CMV infections still pose a potentially serious threat to kidney transplant recipients and have a significant impact on graft as well as patient survival. The antiviral agent valganciclovir (VGCV) has a greater bioavailability after oral administration than oral ganciclovir (GCV) and can be considered a substitute for GCV. The substance is approved in North America and Europe for anti-CMV prophylaxis after organ transplantation. In this pilot study, we examined if VGCV could also be administered in preemptive treatment of CMV infections. METHODS: Twenty-eight renal transplant recipients suffering from 32 asymptomatic episodes of CMV infection were treated with VGCV and followed up. CMV infection was diagnosed by routine controls of pp65-antigenemia in pre-defined intervals. All patients received sequential quadruple immunosuppression. VGCV was given for up to 12 wk in a dosage adapted to renal graft function. Efficacy and safety parameters were monitored for 16 wk. RESULTS: Twenty-seven episodes of CMV antigenemia, two patients progressing to CMV syndrome and three patients progressing to CMV disease were treated. Primary efficiency was 79%, Four patients relapsed and were treated with a second course resulting in serological recovery. Two patients did not respond to oral VCGV and were switched to another antiviral agent. Graft function remained stable during and after treatment. Serious side effects were seen in seven patients, four patients complained of diarrhea and gastrointestinal pain, three patients suffered from leucopenia, in one of these treatment had to be temporary paused. Fifty-nine percent of all episodes were treated in a completely ambulatory setting. CONCLUSIONS: VGCV can be considered as an option also for preemptive treatment of CMV infections after renal transplantation. The antiviral potency seems to be adequate, potential side effects are comparable with IV GCV. Because of the improved pharmacokinetics of VGCV the substance can be used to abbreviate or even completely avoid in-hospital care of CMV infections.     

Efficacy of valganciclovir administered as preemptive therapy for cytomegalovirus disease in liver transplant recipients: impact on viral load and late-onset cytomegalovirus disease

BACKGROUND: The efficacy of valganciclovir used as preemptive therapy for cytomegalovirus (CMV) disease in liver transplant recipients is not known. METHODS: Between 1996 and 2004, surveillance testing using CMV antigenemia was performed at weeks 2, 4, 6, 8, 10, 12, and 16 posttransplant. A total of 28.8% (17/59) of the patients from 2001 to 2004 with antigenemia who received valganciclovir as preemptive therapy were compared with 26.2% (21/80) of the patients from 1996 to 2000 who received oral ganciclovir as preemptive therapy. RESULTS: The mean decline in the antigenemia level after initiation of valganciclovir and oral ganciclovir was 80.5% versus 50.7% at 1 week, 99.5% versus 89.4% at 2 weeks, and 100% versus 97.7% at 4 weeks, respectively. A higher proportion of patients who received valganciclovir (64.7%) belonged to the high-risk group (R-/D+) than patients who received oral ganciclovir (33.3%, P=0.10). Recurrent shedding was documented in 47.1% (8/17) of the patients in the valganciclovir group and 28.6% (6/21) of the patients in the oral ganciclovir group (P>0.20). Recurrent shedding correlated significantly with R-/D+ CMV serostatus and baseline CMV antigenemia level, regardless of the study group. No patient in either group developed CMV disease during or after the period of surveillance monitoring. The incidence of opportunistic infections and patient outcome did not differ for the valganciclovir group versus the oral ganciclovir group or patients without CMV infection (P>0.20). CONCLUSION: Antigenemia-directed valganciclovir as preemptive therapy seems to be effective for the prevention of CMV disease in liver transplant recipients, including high-risk patients.     

Real-time PCR assay compared with antigenemia assay for detecting cytomegalovirus infection in kidney transplant recipients

Human cytomegalovirus (CMV) infection is a major cause of morbidity and mortality among kidney transplant recipients. The CMVpp65 antigenemia assay has been used for preemptive therapy. Real-time polymerase chain reaction (PCR) technology for CMV DNA quantification in blood has demonstrated a good correlation with the currently employed CMV antigenemia assay. In this study, 90 renal transplant recipients were prospectively enrolled from July 2004 and May 2005. Monitoring of CMV infection was routinely performed with CMV antigenemia and real-time PCR assays. Real-time plasma PCR and CMV antigenemia assays were assessed on 797 samples. CMV antigenemia correlated with a positive CMV PCR (chi(2) = 78.05; P < .0001). Not only the positive rate but also the number of positive cells correlated with the number of PCR DNA copies (F = 26.07, r(2) = .25, P < .0001). To define an optimal cutoff value of CMV DNA load to initiate treatment in kidney transplant patients, we considered a CMV antigenemia titer of >50 positive cells per 400,000 leukocytes as the gold standard in our previous study. The optimal cutoff value for the quantitative real-time PCR assay was predicted to be 86 copies/microL. Thus, we observed that CMV real-time PCR assay would not completely replace antigenemia assay in kidney transplant recipients, but can be used complementarily to screen antigenemia and monitor preemptive therapy.     

Safety and efficacy of foscarnet for preemptive therapy against cytomegalovirus reactivation after unrelated cord blood transplantation

In association with the increased use of unrelated cord blood transplantation (UCBT) in adults, numerous patients have developed cytomegalovirus (CMV) reactivation concomitant with cytopenia. Although foscarnet appears to offer similar efficacy and higher safety as a preemptive therapy against CMV infection than ganciclovir, little is known about the usefulness of foscarnet in such patients. Foscarnet was administered as preemptive therapy against CMV antigenemia in 10 UCBT recipients who were unable to receive ganciclovir due to cytopenia or poor response to ganciclovir. Fatal CMV disease developed in one patient, whereas CMV antigenemia resolved without progression to CMV disease in the remaining nine patients. Foscarnet was well tolerated without serious hematotoxicity and was not discontinued due to adverse events in any patient. Foscarnet represents a safe and effective agent for preemptive therapy against CMV infection and may offer a feasible alternative to ganciclovir in UCBT recipients.     

Preemptive therapy with intravenous ganciclovir for the prevention of cytomegalovirus disease in lung transplant recipients

The most effective strategy for the prevention of cytomegalovirus (CMV) disease in lung transplantation has not been conclusively established. The aim of this study was to determine the efficacy of preemptive ganciclovir therapy for this purpose. Twenty-five consecutive adult patients positive for CMV before transplantation and surviving more than 30 days after the procedure were studied. Mean follow-up was 732.2 days (range, 210-1125). All patients received intravenous (IV) ganciclovir prophylaxis for the first 21 days and subsequently underwent frequent CMV antigenemia monitoring: weekly for the first 3 months, every 15 days between 3 and 6 months, and monthly thereafter. IV ganciclovir was given when antigenemia results were greater than 10 infected cells per 100,000 polymorphonuclears. The study group was compared with a historical group of 30 consecutive patients who had received IV ganciclovir prophylaxis and continued on oral ganciclovir up to day 120 posttransplantation. Eighteen of the 25 patients (72.0%) presented episodes of CMV infection. Six of the 25 patients (24.0%) had CMV disease, including 3 viral syndromes and 3 cases of pneumonitis. Four patients debuted with CMV disease, 1 of them with pneumonitis. CMV resistance to ganciclovir was observed in 2 patients. The incidence of infection was higher than in the historical group (72.0% vs 46.7%; P < .05), but there were no significant differences in the incidence of CMV disease (24.0% vs 40.0%; P = not significant [NS]). Mean time before onset of the first episode of disease was lower in the preemptive therapy group than in the comparison patients (82.8 days; range, 42-240 vs 175 days; range, 90-243; P < .05). In conclusion, preemptive therapy for CMV disease is as effective a prevention strategy as oral ganciclovir prophylaxis. However, the early appearance of CMV disease with preemptive therapy can make this approach inadvisable.     

Significance of cytomegalovirus infection in renal transplantation

The aim of this study was to establish the relationship between vascular lesion chronic allograft nephropathy (CAN) and the presence of cytomegalovirus (CMV) in kidney transplanted patients. We studied 259 consecutive kidney transplant recipients with a minimum follow-up of 6 months; the induction immunosuppressive therapy included a calcineurin inhibitor, mycophenolate mofetil, steroids, and the use of an antilymphocyte serum if the patients developed delayed graft function. CMV early antigen detection (pp65) was performed on a weekly basis between days 30 and 90 post transplantation. Prophylactic treatment was administered in the donor +/recipient-risk group, and preemptive therapy delivered for positive antigenemia namely 3 days of intravenous [IV] gancyclovir [GCV] plus 11 days of oral therapy [in the case of infection], or 14 days of IV GCV [in the case of disease]). An acute kidney allograft rejection episode preceded CMV in 64.3% of the patients, and CMV preceded acute rejection in 35.7% of the cases. We conclude that CMV disease is an independent risk factor for CAN. CMV infection is probably associated with CAN, suggesting that the greater the viral load, the higher the risk of CAN. It may be advisable to perform universal prophylaxis to lower the viral load and CAN.     

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.     

Cytomegalovirus PP65 antigenemia monitoring as a guide for preemptive therapy: a cost effective strategy for prevention of cytomegalovirus disease in adult liver transplant recipients.

BACKGROUND: The aim of the study was to assess the incidence of cytomegalovirus (CMV) infection and disease in adult liver transplant recipients, using routine preemptive therapy guided by the pp65 antigenemia test. METHODS: Antigenemia was monitored weekly after liver transplantation (OLTX) for the first 3 months, and once a month for another 3 months. CMV seronegative recipients were treated preemptively for the first positive antigenemia. Seropositive recipients were treated only when their antigenemia count reached a threshold of > or =100 positive cells per 200,000 leukocytes. RESULTS: A total of 144 patients were included between June 1994 and April 1995, of which 137 (95%) were primary OLTX. The percentage of positive antigenemia and CMV disease was 55 and 8%, respectively. Seventy-eight (54%) patients were protocol-monitored for the entire follow-up (group 1) and received appropriate preemptive therapy, although 66 (46%) patients had protocol violation by having missed blood samples or blood drawn at unscheduled times (group 2). Using Cox's proportional hazards model, patients with a first antigenemia count of >11 leukocytes had a significantly higher rate of CMV disease compared to patients with an antigenemia count < or =11 leukocytes (RR = 7.3, 95% confidence interval = 2.2 to 24.5). In a multivariate Cox regression analysis, adjustments were made to control for: group 1 versus group 2, use of OKT3, and serology risk categories. This analysis showed that the relative rate of CMV disease was still significantly higher among patients with antigenemia count >11 leukocytes (adjusted RR = 4.9, 95% confidence interval = 1.3 to 18.1). The estimated cost of preemptive therapy was less than that of prophylaxis with i.v. (14-day course) or oral (90-day course) ganciclovir. CONCLUSIONS: Preemptive therapy guided by pp65 antigenemia is a useful and cost effective strategy for prevention of CMV disease.     

Cytomegalovirus prophylaxis using oral ganciclovir or valganciclovir in kidney and pancreas-kidney transplantation under antibody preconditioning

We investigated retrospectively the risk factors for cytomegalovirus (CMV) infection under ganciclovir or valganciclovir prophylaxis (oral ganciclovir 1 g tid, valganciclovir 450 mg/d) in our kidney and simultaneous pancreas-kidney (SPK) transplant patients undergoing transplantation between July 1, 2001 and February 28, 2003. Two hundred eleven patients receiving prophylactic oral ganciclovir or valganciclovir were included in the study. All patients were given antibody preconditioning (thymoglobulin 178, alemtuzumab 33). Duration of prophylactic treatment was between 3 and 8 months. Fifteen (7.1%) patients developed a positive CMV antigenemia in the first 6 months after transplantation, and 18 of 176 (10.2%) patients developed a positive CMV antigenemia during the first year. No patient developed tissue invasive CMV disease. At 6 months after transplantation, valganciclovir was slightly more effective than ganciclovir prophylaxis (P=.052). Positive donor CMV serology significantly increased the risk of CMV infection compared to CMV-negative donors (P=.014 and P=.003 at 6 and 12 months, respectively). Duration of CMV prophylaxis for more than 3 months decreased the risk of CMV infection (P=.04 and P=.009 at 6 and 12 months, respectively). Either valganciclovir prophylaxis (450 mg/d) or high-dose oral ganciclovir (1 g tid) is effective in preventing tissue-invasive CMV disease, and results in a low incidence of CMV antigenemia in patients undergoing kidney and SPK transplantation.     

Intravenous ganciclovir prophylaxis for cytomegalovirus in heart, heart-lung, and lung transplant recipients

Cytomegalovirus (CMV) disease has had a significant clinical impact on the heart, heart-lung and lung transplant recipients in our centre. CMV disease has been so severe with CMV antibody-negative heart-lung transplant patients receiving organs from CMV antibody-positive donors (CMV-mismatched patients) that in 1986 we adopted the policy of not transplanting CMV-positive organs into CMV-negative heart-lung or lung recipients. In December 1992, we instituted a policy of providing intravenous ganciclovir (5 mg/kg twice a day for 28 days) during the immediate postoperative period for CMV-mismatched heart recipients and CMV antibody-positive heart-lung and lung patients, who have been the patients at greatest risk of severe CMV disease in our centre. A placebo group was not employed because of ethical considerations, ganciclovir having been shown to be effective for the treatment of CMV infections among transplant patients. Compared with a historical control group of patients receiving no prophylaxis, prophylactic ganciclovir reduced the incidence of CMV infection (39 % vs 91 %, P = 0.0006) and CMV disease (17 % vs 74 %, P = 0.0004) among CMV antibody-positive heart-lung recipients. Prophylactic ganciclovir did not significantly reduce the incidence of CMV infection or disease among heart or isolated lung recipients. Ganciclovir was well tolerated, with few adverse reactions. In the case of heart-lung transplant patients, one month of intravenous prophylactic ganciclovir significantly reduced the incidence of both CMV infection and disease when compared with patients who received no prophylaxis. With the lung transplant and heart transplant patients, there were no significant differences between the prophylaxis and nonprophylaxis groups, although there was a consistent trend towards less infection and disease in the prophylaxis groups. Received: 14 April 1998 Received after revision: 24 September 1998 Accepted: 18 December 1998     

A prospective study of the natural course of cytomegalovirus infection and disease in renal allograft recipients

BACKGROUND: Cytomegalovirus (CMV) infection is the single most frequent infectious complication in renal transplant recipients. Because no CMV-prophylaxis is given and ganciclovir is used only as deferred therapy for CMV disease at our center, we have been able to study the natural course of CMV infections. The aim was to assess risk factors for CMV infection and disease and thus identify subgroups of patients likely to benefit from CMV prophylaxis or preemptive therapy. METHODS: Between October 1994 and July 1997, 477 consecutive renal transplant recipients (397 first transplants and 80 retransplants) were included in the study. The patients were followed prospectively for 3 months with serial measurements of CMV pp65 antigen for monitoring activity of CMV infections. RESULTS: The incidence of CMV infections in first transplants was 68% in D+R- and D+/-R+ serostatus groups, whereas the incidence of CMV disease was higher in D+R- (56%) than in D+/-R+ (20%, P<0.001). No difference in severity of CMV disease in D+R- and D+/-R+ was seen except for an increased incidence of hepatitis in primary infections. One of 14 deaths could be associated with CMV disease in a seropositive recipient. Cox regression analysis showed that rejection (RR 2.5, P<0.01) and serostatus group D+R- (RR 3.9, P<0.001) were significant risk factors for development of CMV disease. The maximum CMV pp65 antigen count had significant correlation to disease only in CMV seropositive recipients, P<0.001. Conclusion. Renal transplant recipients can safely be given deferred ganciclovir therapy for CMV disease if they are intensively monitored for CMV infection. Patients with primary CMV infection (D+R-), CMV infected patients undergoing anti-rejection therapy and R+ patients with high CMV pp65 counts seem to have a particular potential for benefit from preemptive anti-CMV-therapy.     

Is gammaglobulin anti-CMV warranted in lung transplantation?

The usefulness of anti-CMV hyperimmune gammaglobulin (IgG-CMV, Cytotec) in lung transplant patients (LTx) is controversial. The objective of this study was to analyze the effectiveness of IgG-CMV in our LTx receptors. PATIENTS AND METHODS: A retrospective study of LTx recipients treated with IgG-CMV as prophylaxis or as treatment for invasive disease. We used IgG-CMV associated with IV ganciclovir (GCV) as treatment for invasive disease. High-risk patients (CMV-negative recipients from CMV-positive donors; CMV-/+) were also with IgG-CMV prophylaxis during the first year. Other prophylactic uses of IgG-CMV were as an alternative to GCV in patients with related GCV toxicity, and as preemptive therapy in cases of persistent positive viral load (antigenemia > or = 1 cell and/or a PCR > or = 400) although oral GCV administration. RESULTS: Between January 2000 and August 2003, 14 of the 74 lung transplant recipients (19%) received IgG-CMV as treatment for invasive disease (4 cases: 2 gastritis, 1 esophagitis, 1 hepatitis) and/or as prophylaxis (14 cases). All patients treated for invasive disease evolved favorably. No therapeutic failure were observed in CMV-/+ patients during treatment. Three of the six patients treated with IgG-CMV developed positive antigenemia despite treatment. The four patients treated for persistent antigenemia while receiving oral GCV achieved neutralization during the first month of treatment. CONCLUSION: IgG-CMV associated with Gancyclovir is effective as treatment for invasive disease and as pre-emptive therapy in patients with persistent positive viral load. In CMV-/+ recipients, IgG-CMV prevents pneumonitis and delays the development of invasive disease after the first year.     

Improvement in Long-Term Renal Graft Survival due to CMV Prophylaxis with Oral Ganciclovir: Results of a Randomized Clinical Trial

Oral ganciclovir prophylaxis and intravenous preemptive therapy are competitive approaches to prevent cytomegalovirus (CMV) disease after renal transplantation. This trial compared efficacy, safety and long-term graft outcome in 148 renal graft recipients randomized to ganciclovir prophylaxis (N = 74) or preemptive therapy (N = 74). Hierarchical testing revealed (i) patients with CMV infection had more severe periods of impaired graft function (creatinine clearance_max-min 25.0 ± 14.2 mL/min vs. 18.1 ± 12.5 mL/min for patients without CMV infection; p = 0.02),(ii) prophylaxis reduced CMV infection by 65% (13 vs. 33 patients; p < 0.0001) but (iii) creatinine clearance at 12 months was comparable for both regimes (54.0 ± 24.9 vs. 53.1 ± 23.7 mL/min; p = 0.92). No major safety issues were observed, and patient survival at 12 months was similar in both groups (5 deaths [6.8%] vs. 4 [5.4%], p = 1.0000). Prophylaxis significantly increased long-term graft survival 4 years posttransplant (92.2% vs. 78.3%; p = 0.0425) with a number needed to treat of 7.19. Patients with donor +/recipient + CMV serostatus had the lowest rate of graft loss following prophylaxis (0.0% vs. 26.8%; p = 0.0035). In conclusion, it appears that routine oral prophylaxis may improve long-term graft survival for most renal transplant patients. Preemptive therapy can be considered in low risk patients in combination with adequate CMV monitoring.     

Hyperimmunoglobulin prophylaxis,monitoring and preemptive ganciclovir treatment eliminate the risk of CMV infection to improve patient and renal allograft survival

Abstract This study was designed to investigate whether the introduction of ganciclovir to clinical use for anti‐CMV treatment changes the risk of CMV infection in renal transplant patients. A total of 1545 cases who had received cadaveric renal transplants were divided into two groups: group 1 (n = 721) was made up of patients who received their transplants within 6 years before the introduction (1991) of ganciclovir and group 2 (n = 824), of individuals transplanted thereafter. Patient and graft survival of CMV D+/R‐ patients was uni‐ and multivariately compared with non‐CMV D+/R‐ patients. In CMV D+/R‐ patients in group 1, survival was significantly lower, and their relative risk for graft loss was 1.32‐fold (P = 0.0483) that of non‐CMV D+/R‐ patients. In group 2 patient and graft survival was identical regardless of whether the patients were at risk for CMV infection or not. The risk of CMV infection can be eliminated by hyperimmunoglobulin prophylaxis, CMV monitoring and preemptive ganciclovir treatment in renal transplant patients.