Two grams daily of oral acyclovir reduces the incidence of cytomegalovirus disease in CMV-seropositive liver transplant recipients

Our objective in this study was to determine the efficacy of 2 grams a day of oral acyclovir administered for 16 weeks after transplantation for the prevention of cytomegalovirus (CMV) infection and disease in CMV-seropositive liver transplant recipients. Seventy-three adult liver transplant recipients, seropositive for CMV, were randomized to receive either 2 grams a day of oral acyclovir for 16 weeks after transplantation or no prophylaxis. The incidence of CMV disease was significantly lower in the acyclovir group (5 %) than in the control group (27 %; P < 0.05). By log-rank analysis, the differences in the probability of presenting CMV disease over the first 16 weeks and over the 1st year were also significant (P < 0.05). We conclude that 2 grams a day of oral acyclovir provides effective prophylaxis against CMV disease in CMV-seropositive liver transplant recipients. Received: 14 March 1997 Received after revision: 30 May 1997 Accepted: 9 June 1997     

Risk factors for cytomegalovirus infection and disease in renal transplant recipients: HLA-DR7 and triple therapy

In a prospective study, an analysis of risk factors for the development of cytomegalovirus (CMV) infection and disease was performed on 77 renal allograft recipients. Twenty-five out of the 77 recipients (32%) had a CMV infection. Twenty-two of the recipients received triple immunosuppressive therapy (cyclosporin A, prednisolone, and azathioprine) while the remaining 55 received standard therapy (cyclosporin A and prednisolone). In 23 recipients (30%) acute rejection was diagnosed and the first positive parameter of infection occurred 22 days after rejection therapy. Infection occurred in 10 out of 18 HLA-DR7-positive recipients (56%) and in 15 out of 59 HLA-DR7-negative recipients (25%; P< 0.02). In multiple regression analysis, HLA-DR7 was found to be a significant predictor of CMV infection (P< 0.005). CMV disease was diagnosed in only 9 out of 25 recipients with an acute infection. Six recipients (67%) with CMV disease received triple therapy for maintenance immuuosuppression; this was significantly correlated to CMV disease (P< 0.05) as compared to three recipients (33%) with CMV disease maintained with standard therapy. Our data suggest that HLA-DR7-positive recipients are more susceptible to CMV infection and that CMV disease is associated with triple immunosuppressive therapy.     

Neutropenia in kidney and liver transplant recipients: Risk factors and outcomes

No studies have directly compared the key characteristics and outcomes of kidney (KTx) and liver transplantation (LTx) recipients with neutropenia. In this single‐center, retrospective, cohort study, we enrolled all adult patients who received a KTx or LTx between 2000 and 2011. Neutropenia was defined as 2 consecutive absolute neutrophil count (ANC) values <1500/mm³ in patients without preexisting neutropenia. The first neutropenia episode occurring during the first year post‐transplantation was analyzed. A total of 663 patients with KTx and 354 patients with LTx met the inclusion criteria. Incidence of neutropenia was 20% in KTx and 38% in LTx, respectively. High‐risk CMV status and valganciclovir (VGCV) use were significant predictors of neutropenia for KTx recipients, but only VGCV use vs nonuse in LTx recipients. Neutropenia was associated with worse survival in KTx recipients (adjusted HR 1.95, 95% CI 1.18‐3.22, P<.01), but not in LTx recipients (adjusted HR 0.75, 95% CI 0.52‐1.10, P=.15). Sixteen acute rejection episodes were associated with preceding neutropenia in KTx recipients (HR 1.77, 95% CI 1.16‐2.68, P=.007) and 24 acute rejection episodes in LTx recipients (HR 1.41, 95% CI 0.97‐2.04, P=.07). Incidence of infection was similar in patients with and without neutropenia among KTx and LTx recipients.     

Cytomegalovirus infection-associated generalized immune activation in heart allograft recipients: a study of cellular events in peripheral blood and endomyocardial biopsy specimens

An association between cytomegalovirus (CMV) infection, heart allograft rejection, and arteriosclerosis has been reported. To investigate the mechanisms of this association, the cellular immune response in peripheral blood and the inflammation in heart allografts during antigenemia were studied. CMV antigenemia occurred in 13 recipients. In recipients with severe CMV infection, a significantly weaker immune response was recorded in peripheral blood: fewer lymphoid blast cells (max. 2.4%±0.4%) and large granular lymphocytes (LGL; max. 9.3%±1.4%) were seen than in patients with mild or asymptomatic CMV infection (lymphoid blast cells max. 6.5%±0.8% P<0.01 and LGLs max. 20%±2.3%, P<0.05). Thus, a strong immune response with lymphoid activation was associated with clinically good outcome of CMV infection. In heart allograft histology, subendothelial inflammation of small intramyocardial vessels was a characteristic finding during CMV antigenemia compared to CMV-free recipients (at the peak P<0.01). However, no difference in this mild and short-lived inflammatory response was observed between clinically mild or severe CMV infection. The CMV-linked generalized immune activation and inflammation of the vascular structures might contribute to the initiation of allograft vasculopathy and to the pathogenesis of chronic heart allograft rejection.     

Cytomegalovirus infection following renal transplantation in patients administered low-dose rituximab induction therapy

Anti-CD20 antibody (rituximab) is recently being used as a B cell-depleting agent in renal transplantation (RTx). However, the incidence of infectious complications associated with rituximab therapy remains uncertain. We evaluated the incidence of cytomegalovirus (CMV) infection associated with rituximab therapy in RTx. A total of 83 patients were enrolled. The immunosuppressive regimen consisted of tacrolimus or cyclosporin, mycophenolate mofetil, methylprednisolone and basiliximab. In 54 patients, only one dose of rituximab (200 or 500 mg/kg body weight) was given before RTx. A total of 25 of 43 (58.1%) recipients who were CMV seropositive prior to RTx and who received rituximab induction therapy developed CMV infection, compared to 18 of 24 (75%) CMV seropositive recipients who did not receive rituximab therapy ( P  = 0.1676). A total of 8 of 11 patients who were CMV seronegative prior to RTx and who received rituximab developed CMV infection. However, CMV seroconversion was seen in all 8 of these infected patients. Low-dose rituximab induction therapy in renal transplant recipients appears to have no influence on the incidence of CMV infection and CMV seroconversion. However, we have to consider anti-CMV prophylaxis therapy, because of high incidents of CMV infection, especially for CMV seronegative recipients who received rituximab.     

Early detection of primary cytomegalovirus infection after heart and kidney transplantation and the influence of hyperimmune globulin prophylaxis

A randomized study of prophylaxis with hyper-immune globulin (HIg) was performed in 28 cytomegalovirus (CMV)-seronegative heart and kidney recipients with CMV-seropositive donors who were extensively monitored for active CMV infection and CMV disease. Detection of CMV antigen in peripheral blood granulocytes (antigenemia) was the first sign of primary CMV infection, generally occurring several weeks before IgM or IgG anti-CMV antibodies were detected and before positive cultures appeared. A correlation was found between rejection treatment with OKT3 or ATG, severity of CMV disease, and graft loss. Rejection treatment had no influence on incidence of CMV transmission. Primary CMV infection occurred most often in older patients with older donors. No beneficial effects were seen with HIg prophylaxis, which was administered from week 1 until week 7 after transplantation. Incidence of primary CMV infection was equal in both groups (50%) and no influence on the severity of primary CMV infection was seen. The only effect that was seen was on the time from transplantation to detection of active CMV infection, which was prolonged by HIg prophylaxis.     

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     

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     

Role of CMV pneumonia in the development of obliterative bronchiolitis in heart-lung and double-lung transplant recipients

Obliterative bronchiolitis (OB) is the main cause of late mortality after lung transplantation. Cytomegalovirus infection has been associated with late graft failure. The aim of this study was to determine whether the development of OB was related to CMV pretransplant serological status and to CMV infections. The study group comprised 36 lung transplant recipients (27 HLT and 9 DLT) who survived more than 4 months, of whom 47% developed OB (defined by the persistence of an unexplained obstructive disease: FEV1/VC < 0,7). OB occurred more frequently: (1) in seronegative recipients with seropositive donors (8/9) than in seropositive recipients (7/19) or seronegative well-matched recipients (2/8); and (2) in patients who experienced CMV pneumonia (11/16) and CMV recurrence (11/16). Since matching seronegative recipients is the best way to prevent CMV infection, we believe that seronegative grafts must be reserved for seronegative recipients.     

Infections in human liver recipients: different patterns early and late after transplantation

The first 49 consecutive patients who underwent orthotopic liver transplantation between 1984 and 1989 in our department were studied with regard to symptomatic and asymptomatic post-transplantation infections. The major infections carrying a risk of fatal outcome are presented. During the first 4 weeks, fungal and bacterial infections predominated, the percentages of patients affected being 27% and 35%, respectively. Eight patients (17%) suffered from bacterial septicemia, which in six cases was due to gram-negative micro-organisms. The bacterial septicemia was often associated with severe ischemic damage to the graft, rejection, or cholangitis. In addition, a concomitant invasive fungal infection supervened in seven out of eight septic patients, further aggravating the patients' condition. Seventeen of the 49 patients (35%) died after transplantation within 3.3 years. Infection was the cause of death in nine patients (18%), with bacterial septicemia and/or fungemia in eight of these. Cytomegalovirus (CMV) disease was the dominant cause of illness after the 1st month. While only 5 of the 49 patients developed CMV disease during the 1st month (10%), as many as 16 of the 40 recipients who survived beyond that time suffered from symptomatic CMV viremia (40%). CMV mismatching, i.e., the donation of a CMV-positive organ to a CMV-seronegative recipient, entailed the highest risk for CMV disease. Pneumocystis carinii pneumonia occurred within 4 months in 10% of the patients. The four liver recipients affected were among the 20 patients not receiving trimethoprim-sulfamethoxazole prophylaxis. None of the 28 patients who received this prophylaxis over a 12-month period developed this complication (P<0.05). The time-related panorama of infectious complications observed in this study has immediate clinical implications for the screening, prophylaxis, and therapy of infections following liver transplantation.     

Cytomegalovirus infection accelerates cardiac allograft vasculopathy: correlation between angiographic and endomyocardial biopsy findings in heart transplant patients

In order to determine the impact of cytomegalovirus (CMV) infection on cardiac allograft vasculopathy (CAV), we quantitated angiograms and endomyocardial biopsy (EMB) specimens obtained from 53 heart transplant recipients. CMV infection was particularly associated with the development of discrete stenosis in major branch vessels (P<0.03). Also, the number of diffusely affected vessel segments was significantly higher in CMV patients than in CMV-free recipients after the 2nd post-operative year (P<0.05). The EMB histology correlated well with angiography. Significantly higher levels of arteriolar endothelial cell proliferation and intimal thickness were recorded in biopsies of CMV patients than in those of CMV-free recipients during the 1st postoperative year (P<0.02 and P<0.005, respectively). The CMV-associated vascular changes in EMB histology clearly preceded angiographically detectable CAV findings. Taken together, CMV infection accelerated heart allograft arteriosclerosis. The histological changes appeared prior to changes detected by coronary angiography. The CMV effect was particularly pronounced during the first 2 post-transplant years but leveled off thereafter. Thus, CMV-accelerated allograft arteriosclerosis may be linked in particular with early graft loss of CMV-infected heart transplant recipients.     

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     

CMV infection, diagnosis and antiviral strategies after liver transplantation

Cytomegalovirus (CMV) is a significant pathogen complicating the post-transplant course of organ recipients. In liver transplant patients, the febrile clinical illness caused by CMV may be associated with end-organ disease, such as hepatitis or infection of the gastrointestinal tract. In addition to direct effects, CMV may have indirect effects including the risk of other infections or graft rejection. Recently, major advances in the management of CMV infection have been achieved through the development of new diagnostic techniques and antiviral strategies to prevent CMV disease. Quantitative nucleic acid testing to monitor viral load is now commonly used to diagnose and guide the treatment of CMV infections. The standardization of the testing, however, needs to be improved. There are two main strategies to prevent CMV disease after liver transplantation: prophylaxis and pre-emptive therapy. Both strategies are effective, but also have disadvantages. The disadvantages of prophylaxis include prolonged drug exposure, the development of resistance and, most of all, the development of delayed and late-onset CMV disease. On the other hand, the pre-emptive strategy is based on frequent laboratory monitoring of viral loads, and some patients may develop symptomatic infection before the diagnosis of CMV. This overview summarizes the current status of CMV in liver transplantation.     

Definitions of cytomegalovirus disease after heart transplantation: Antigenemia as a marker for antiviral therapy

In this prospective study, cytomegalovirus (CMV) antigenemia was defined as the marker for initiation and episodes of antigenemia as the indicator for the duration of antiviral therapy (CMV hyperimmune globulin and ganciclovir). The CMV antigenemia assay and CMV-specific IgM and IgG antibody tests were used to monitor CMV infection in 22 heart transplant recipients who, between October 1992 and July 1994, were followed up for 6 months. A total of 178 out of 627 antigenemia assays tested positive. The highest number of positive cells was greater after primary infection than after either reactivation (43.3 vs 0.3; P<0.01) or reinfection (43.3 vs 9.3; P=NS). Sixty episodes of antigenemia were observed. More episodes of antigenemia were seen after primary infection than after either reactivation (4.6 vs 0.2; P<0.01) or reinfection (4.6 vs 2.2; P=NS). The detection of antigenemia indicated the initiation of antiviral therapy within 24 h after the blood sample was harvested. Therapy was stopped immediately after a subsequent negative result became available. Our experience indicates that antigenemia directed antiviral therapy prevents CMV disease after primary and secondary infection in heart transplant recipients.     

Cytomegalovirus transmission in mismatched solid organ transplant recipients: Are factors other than anti-viral prophylaxis at play?

Although antiviral prophylaxis has reduced cytomegalovirus (CMV) DNAemia and disease in seronegative solid organ transplant (SOT) recipients (R-) receiving seropositive donor organs (D+), its impact on CMV transmission is uncertain. Transmission, defined as CMV antigenemia/CMV DNAemia and/or seroconversion by year 2, and associated demographic risk factors were studied retrospectively in 428 D+/R- and 429 D-/R- patients receiving a SOT at our center. The cumulative transmission incidence was higher for lung (90.5%) and liver recipients (85.1%) than heart (72.7%), kidney (63.9%), and pancreas (56.2%) recipients (p < .001) and was significantly lower in living (50.1%) versus deceased donor (77.4%, p < .001) kidney recipients despite identical antiviral prophylaxis. In multivariate analysis, only allograft type predicted transmission risk (HR [CI] lung 1.609 [1.159, 2.234] and liver 1.644 [1.209, 2.234] vs kidney). For 53 D+ donating to >1 R- with adequate follow-up, 43 transmitted to all, three transmitted to none, and seven transmitted inconsistently with lungs and livers always transmitting but donor-matched heart, kidney or kidney-pancreas allografts sometimes not. Kidney pairs transmitted concordantly. CMV transmission risk is allograft-specific and unchanged despite antiviral prophylaxis. Tracking transmission and defining donor factors associated with transmission escape may provide novel opportunities for more targeted CMV prevention and improve outcome analysis in antiviral and vaccine trials.     

Prophylaxis of CMV disease by ganciclovir (DHPG) in seronegative recipients of renal allograft from seropositive donors

In an open-label randomized study of prophylactic treatment by ganciclovir, 23 seronegative recipients of kidney allograft from seropositive donors were randomized to receive from day 14 to day 28 after transplantation either no treatment (n = 11) or ganciclovir, 5 mg/kg twice daily (n = 12). Both groups were similar in age, immunosuppressive therapy, number of acute rejections and in steroid bolus. Seroconversion occurred in ten patients of the control group (91%) and in ten of the ganciclovir group (84%). CMV disease occurred in ten patients of the control group (91%) and in eight patients of the ganciclovir group (66%), three of whom had asymptomatic viraemia. The delay between transplantation and onset of CMV disease was significantly increased by ganciclovir prophylaxis (78.5 ± 7.7 vs 46.5 ± 7.5 days, P < 0.05). We conclude that in renal transplant recipients at risk of CMV disease, ganciclovir prophylaxis delays the onset of the disease and seems to decrease its incidence and its severity.     

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.     

High incidence of anticytomegalovirus drug resistance among D+R- kidney transplant recipients receiving preemptive therapy

Anti‐cytomegalovirus (CMV) prophylaxis is recommended in D+R? kidney transplant recipients (KTR), but is associated with a theoretical increased risk of developing anti‐CMV drug resistance. This hypothesis was retested in this study by comparing 32 D+R? KTR who received 3 months prophylaxis (valganciclovir) with 80 D+R? KTR who received preemptive treatment. The incidence of CMV infections was higher in the preemptive group than in the prophylactic group (60% vs. 34%, respectively; p = 0.02). Treatment failure (i.e. a positive DNAemia 8 weeks after the initiation of anti‐CMV treatment) was more frequent in the preemptive group (31% vs. 3% in the prophylactic group; p = 0.001). Similarly, anti‐CMV drug resistance (UL97 or UL54 mutations) was also more frequent in the preemptive group (16% vs. 3% in the prophylactic group; p = 0.05). Antiviral treatment failures were associated with anti‐CMV drug resistance (p = 0.0001). Patients with a CMV load over 5.25 log₁₀ copies/mL displayed the highest risk of developing anti‐CMV drug resistance (OR = 16.91, p = 0.0008). Finally, the 1‐year estimated glomerular filtration rate was reduced in patients with anti‐CMV drug resistance (p = 0.02). In summary, preemptive therapy in D+R? KTR with high CMV loads and antiviral treatment failure was associated with a high incidence of anti‐CMV drug resistance.     

Late-onset cytomegalovirus disease in liver transplant recipients despite antiviral prophylaxis

BACKGROUND: The incidence and impact of cytomegalovirus (CMV) disease that occurs despite CMV prophylaxis among liver transplant recipients have been incompletely defined. METHODS: The incidence and risk factors for CMV disease during the first posttransplant year in a cohort of liver transplant recipients who received antiviral prophylaxis with oral ganciclovir were retrospectively analyzed using Cox proportional-hazard regression models. RESULTS: CMV disease developed in 19 of 259 recipients (7% [95% confidence interval 0.04-0.11]) at a median of 4.5 months posttransplant, included syndrome (63%) or tissue-invasive disease (37%), and was independently associated with an increased risk of mortality during the first posttransplant year (hazard ratio 14 [95% confidence interval 3.8-54], P=0.0007). The incidence was higher (10/38 [26%] vs. 8/180 [4.5%], P<0.0001) in seronegative recipients (R-) of an organ from a seropositive donor (D+) compared with seropositive (R+) patients, respectively. D+R- status was the only variable significantly associated with CMV disease in multivariate analysis. CONCLUSIONS: Late CMV disease develops in a substantial proportion of D+R- recipients after prophylaxis is discontinued, is not accurately predicted by patient factors, and is associated with increased mortality. New strategies to identify D+R- patients at risk and to reduce the incidence and impact of late CMV disease in this group are warranted.     

Effect of prophylactic ganciclovir on cytomegalovirus infection in renal transplant recipients

Cytomegalovirus (CMV) infection is the most frequent infectiouscomplication observed in renal transplant recipients and inducesa significant morbidity in these patients due to CMV diseaseitself and to associated renal dysfunction or opportunisticsuperinfection. In order to evaluate the effect of ganciclovirprophylaxis we conducted an open-label prospective randomizedstudy of ganciclovir administration in CMV seronegative recipientsof a renal allograft from CMV seropositive donors. Ganciclovir(5 mg/kg b.i.d./day for 14 days) was started on day 14 aftertransplantation. Thirty-two patients were included in this study(15 in the control group, 17 in the ganciclovir group). Therewas no significant difference between the two groups for age,immunosuppressive regimen, number of rejection, steroid pulses,and OKT3 treatments. Renal and patient outcomes were similarin both groups. The rate of CMV infection and CMV disease weresimilar in both groups (80% and 73.3% in the control group versus70.6% and 47.1% in the ganciclovir group; P=NS). Less severeCMV disease was observed in the ganciclovir group compared tocontrols. The delay between transplantation and CMV infectionwas significantly longer in the ganciclovir group compared tocontrol group (68.1±5.1 versus 44.0±5.2 days,P<0.005). Twelve control patients (80%) versus nine (53%)of the ganciclovir group required curative treatment with ganciclovirafter the diagnosis of CMV infection (NS). All the patientsrecovered from CMV disease and no significant side-effect wasobserved during ganciclovir administration. We conclude that prophylactic ganciclovir administration fromday 14 to day 28 after transplantation does not prevent CMVinfection in seronegative recipients of renal allograft fromseropositive donors but prolongs the incubation period. Longerprophylaxis by ganciclovir in these patients should be tested.