Incidence Of CMV Infection Research Articles

Prophylaxis of Cytomegalovirus (CMV) Infection and Disease after Unrelated-Donor Umbilical Cord-Blood Transplantation (UCBT) with Intravenous Ganciclovir or Oral Valganciclovir.

Prophylactic antiviral treatment for prevention of CMV infection and disease could be valuable after UCBT, where the incidence of CMV infection is very high. The purpose of this study was to evaluate the efficacy and safety of a strategy of prophylaxis of CMV infection and disease in patients undergoing UCBT. From May 1997 to May 2005, 52 CMV-seropositive adults with hematologic malignancies (15 in advanced phases) underwent UCBT at our institution. CMV prophylaxis consisted of high-dose intravenous acyclovir from day −5 until engraftment followed until day +100 by intravenous ganciclovir (GAN, 5 mg/kg per day 3 to 7 days per week) in the first 38 patients and by oral valganciclovir (VALGAN, 900 mg per day as a single daily dose) in the last 14 patients. All patients received thiotepa, busulfan, cyclophosphamide and antithymocyte globulin as conditioning, cyclosporine and prednisone as GVHD prophylaxis, and filgrastim from day +7 until engraftment. All 52 patients were considered as evaluable for efficacy and those actually receiving the scheduled CMV prophylaxis with GAN or VALGAN were considered evaluable for toxicity. Median age was 33 yr (range, 18–47), HLA match was 6/6 in 2 (4%), 5/6 in 19 (37%), and 4/6 in 31 cases (60%), and median number of nucleated and CD34+ cells infused was 2.1 x 10E7/kg (range, 0.9–5) and 0.9 x 10E5/kg (range, 0.1–5.7) respectively. The cumulative incidence of CMV infection was 46% at day 100 and 54% at days 180 and 365, and the cumulative incidence of CMV disease was 2% at day 100, 8% at day 180 and 15% at day 365. No clear differences between patients taking GAN or VALGAN were observed in the cumulative incidence of CMV infection (45% and 50% at day 100 and 53% and 57% at days 180 and 365, respectively; P=0.89) and CMV disease (3% and 0% at day 100, 10% and 0% at day 180 and 16% and 14% at day 365, respectively; P=0.75). Twenty-two patients assigned to receive GAN and 8 patients assigned to receive VALGAN experienced 31 and 11 episodes of other severe infections respectively. GAN was withdrawn in 2 patients due to renal toxicity and VALGAN in 2 patients due to neutropenia. Ten patients (7 receiving GAN and 3 receiving VALGAN) experienced at least one episode of recurrent CMV infection. Two of the 8 patients who developed CMV disease, both with GAN, died from CMV. Higher doses of nucleated (P=0.008) and CD3+ (P=0.04) cells infused, presence of acute GVHD below grade II (P=0.01), and use of Thymoglobulin (P=0.008) were associated with a lower risk of CMV infection. The CD3+ cell dose was inversely associated with the risk of CMV disease (P=0.01). These results suggest that CMV prophylaxis with intravenous GAN or oral VALGAN is both safe and effective to reduce and/or delay the occurrence of CMV infection and disease after UCBT. Further, these data show, for the first time, the importance of the CD3+ cell dose infused and of other characteristics in the development of CMV infection and disease after UCBT.

A Randomized, Prospective, Pharmacoeconomic Trial of Tacrolimus versus Cyclosporine in Combination with Thymoglobulin in Renal Transplant Recipients

To date, the clinical trials of tacrolimus (TAC) versus cyclosporine modified (CsA), have not defined which agent is more cost-effective for immunosuppression in renal transplant recipients especially in a quadruple immunosuppressive regimen. The objective of this randomized, prospective study was to compare the clinical and economic outcomes of TAC versus CsA, in a regimen that consisted of Thymoglobulin induction, an antimetabolite, and prednisone. Between December 2000 and October 2002, 200 patients were enrolled and randomized in a 2:1 fashion (TAC n=134, CsA n=66). At 1 year, acute rejection (4% TAC vs. 6% CsA), patient survival (TAC 99% vs. CsA 100%), and graft survival (95% TAC versus 100% CsA, P=0.059) were similar. Serum creatinine levels were lower in the TAC group compared with the CsA group (1.3+/-0.3 vs. 1.6+/-0.7 mg/dL, P=0.03). The incidence of CMV infection was similar between the groups and two patients, both in the TAC arm, developed malignancy. Anti-hypertensive requirement (32% TAC vs. 32% CsA) and the incidence of posttransplant diabetes mellitus (4% TAC vs. 2% CsA) were similar. Pretransplant, fewer TAC patients received dyslipidemia treatment (40% TAC vs. 67% CsA, P=0.0005), while more CsA patients were able to discontinue these medications posttransplant (absolute change 25% TAC vs. 47% CsA). Total 12-month medication costs were similar (17,723 +/- 11,647 dollars TAC vs. 16,515 +/- 10,189 dollars CsA). When combined with Thymoglobulin induction, an antimetabolite, and corticosteroids, TAC and CsA are comparable in safety, efficacy, and cost in renal transplantation.

The Role of Cytomegalovirus Infection in Chronic Allograft Nephropathy

In the letter “The Role of Cytomegalovirus Infection in Chronic Allograft Nephropathy” in the January 27, 2004 issue of Transplantation (1), Dr. Mahawar makes a few comments about our article published in the June 15, 2003 issue of Transplantation (2). Approximately 150–200 renal transplantations are performed in the Helsinki University Hospital Transplantation Center annually. The patients included in our retrospective study were selected from a population of renal transplant recipients, transplanted between 1994 and 2000, who were at follow-up at the Helsinki University Hospital Division of Nephrology and who had had a suspicion of CMV infection (n=172). The patients are not monitored for the presence of CMV, and samples for the detection of CMV are only taken when infection is suspected. Those 11 patients, with no evidence of CMV infection despite several samples at different time points, were selected as control patients. In addition, only patients with a protocol biopsy taken at 6 months after transplantation were included in the study. Thus, the numbers of positive and control patients in our study do not reflect the incidence of CMV infection in our centre. Dr. Mahawar refers to the definitions of “CMV infection” and “CMV disease” by the International CMV Workshop from 1995 (3). The definitions of CMV-related terminology have been updated during the past years and recently 2 years ago with some changes (4). According to the latest update, CMV end-organ disease in the kidney, “CMV nephritis”, is defined as histologic features of CMV infection in the kidney together with detection of CMV in the kidney biopsy. In addition, the term “CMV syndrome” should be avoided, according to the latest update. Therefore, we believe, that the term “CMV infection” was relevant to describe the patients in our study. It is also in agreement with the updated definitions of CMV infection (4). Ilkka Helanterä Raisa Loginov Irmeli Lautenschlager Transplant Unit Research Laboratory Department of Virology Helsinki University Hospital and University of Helsinki Helsinki, Finland Ilkka Helanterä Petri Koskinen Tom Törnroth Carola Grönhagen-Riska Department of Medicine Division of Nephrology Helsinki University Hospital and University of Helsinki Helsinki, Finland

Valganciclovir for the prophylaxis of early cytomegalovirus (CMV) infection after allogeneic stem cell transplantation

The use of highly immunosuppressive therapies prior to and after transplantation and the use of matched unrelated (MUD) and mismatched related (MRD) donors have increased the incidence of CMV infection and disease. Methods: Twenty-four (24) out of 50 patients have been enrolled into a prospective trial evaluating the safety and efficacy of valganciclovir for the early prophylaxis of CMV infection. Patients are either CMV seropositive or CMV seronegative receiving CMV seropositive stem cell products.

Coronary perfusion pressure is a critical determinant of expression of B-type natriuretic peptide in pulmonary arterial hypertension

dent risk factor for acute rejection in HT recipients. Despite the known high risk for CMV disease of D /R serostatus, these patients receiving a Gan/CMVIG prophylaxis had a significantly lower incidence of CMV infection and rejection as compared to the group regarded to be at lower risk (R ). These data support the need for sustained suppression on CMV activation and may have important implications for long-term outcomes such as graft function and allograft vasculopathy.

Valganciclovir for the Early Prophylaxis of Cytomegalovirus (CMV) Infection after Allogeneic Stem Cell Transplantation.

Despite improvements in methods for the early diagnosis of CMV infection, 5% of HSCT patients receiving preemptive therapy develop CMV disease. In addition, the use of highly immunosuppressive therapies prior to and after transplant and the use of matched unrelated (MUD) and mismatched related (MRD) donors have increased the incidence of CMV infection and disease. We designed a prospective trial examining the safety and efficacy of valganciclovir for the prophylaxis of early CMV infection.Methods: CMV seropositive patients or CMV seronegative patients receiving CMV seropositive stem cell products with an estimated creatinine clearance of ≥ 50 mL/min, platelet count ≥ 50,000/μL, and WBC count ≥ 1,000/μL are eligible. Patients receive valganciclovir 900 mg daily Mondays through Fridays starting 21 to 35 days after transplant and continuing through Day 100, with dosage adjustments for myelosuppression and/or reduced creatinine clearance. Patients are monitored with weekly CMV PCR analysis at a central lab according to the Roche assay.Results: Twenty four (24) out of 50 planned subjects have been enrolled to date (MUD 9, MRD 15). All were CMV seropositive at the time of transplant. Stem cell source included peripheral blood = 21, bone marrow = 3. A total of 7 patients required corticosteroids for treatment of graft versus host disease. Three patients developed myeloid toxicity related to valganciclovir (absolute neutrophil count < 1,000/μL = 1, platelets < 50,000/μL = 2). All three (3) patients recovered their counts and restarted valganciclovir with dose adjustments. A total of 11 patients required dose adjustments due to myelosuppression (3), creatinine clearance (4), weight (1), institutional decision (3). Twelve (12) patients have not completed therapy due to: progressive disease or death before day +100 = 4, CMV infection =2, too early for analysis = 6. CMV infection occurred in 2/24 and CMV disease occurred in 0/24. The two (2) patients with positive CMV-PCR developed infection one (Day 40) and two (Day 36) weeks after starting valganciclovir. These two (2) patients were successfully treated with IV ganciclovir. Ten (10) patients have been followed between day +100 and 6 months post transplant. Three (3) of these 10 patients continued valganciclovir off study and had no evidence of CMV infection. Two (2) of the 10 patients who were not receiving valganciclovir developed CMV infection but were successfully treated with valganciclovir. Survival is 80% (16/20) at day +100 and 82% (9/11) at 6 months post transplant.Conclusions: We conclude that valganciclovir at the dose used in this study is well tolerated with minimal reversible myelosuppression. These preliminary findings suggest that prophylaxis with oral valganciclovir appears to be a promising strategy to prevent CMV infection and disease.

EVOLVING TRENDS IN ACUTE REJECTION AND CMV INFECTION EPISODES AMONG KIDNEY TRANSPLANT RECIPIENTS FROM 1995 TO 2003: A SINGLE-CENTER STUDY

P351 Aims: Acute rejection and CMV infection episodes are two important risk factors in renal transplantation. We performed a retrospective study to determine the incidence of both events, and their evolution over time with respect to changes in immunosuppressive protocols and anti-CMV prophylaxis strategies. Methods: All patients who received kidney transplants at our institution from January 1995 to November 2003 (with the exception of those who died peri-operatively or did not have a minimal follow-up of at least 3 months) were included in the study. Immunosuppressive regimens were as follows: from 1995 to 1999 (period I), after various induction regimens, patients received CsA and prednisone. From 2000 to march 2003 (period II), basiliximab induction was followed by administration of CsA, prednisone +/- mycophenolate mofetil. Since April 2003 (period III), patients received basiliximab (or thymoglobuline) for induction, and then tacrolimus, prednisone and mycophenolate mofetil. Acute rejection episodes were defined for the purpose of the study by anti-acute rejection therapy (i.e., ≥3 daily pulses of methylprednisolone or antilymphocyte therapy). Acute rejection episodes had been diagnosed by the team based on clinical or histological criteria during the first 6 months after transplantation. No anti-CMV prophylaxis was prescribed during period I, whereas valaciclovir was administered to high risk patients (D+/R-) during period II, and valganciclovir to all D+/R-, D+/R+ and D-/R+ combinations during period III. For the monitoring of CMV infection, blood cultures (shell vial method) were performed weekly for the first 6 weeks and once every two weeks for the next 6 weeks. Weekly cultures for 4 weeks and biweekly cultures for an extra 4 weeks were proposed after the treatment of a rejection episode. CMV viremia was defined as a positive culture from blood leucocytes, and classified either as CMV infection (in the absence of symptoms) or CMV disease. Results: 208 patients underwent kidney transplantation, 126 in period I, 64 in period II and 18 in period III. CMV serostatus patterns were not significantly different between the 3 periods (D+/R- 17-24%; D+/R+ 39-50%; D-/R+ 22-35% and D-/R- 11-17%). Acute rejection episodes were treated in 73 patients (58%), 22 patients (34%) and 1 patient (6%) during period I, II and III, respectively (p<0.0001). CMV infection or disease was diagnosed in 82 (65%), 27 (42%) and 3 patients (17%) during period I, II and III, respectively (p<0.0001). Conclusions: We observed a marked decrease in the frequency of acute rejection episodes in period III when newer immunosuppressive combinations were introduced. Importantly, the simultaneous implementation of daily valganciclovir prophylaxis decreased incidence of CMV infection despite the more potent immunosuppressive therapy used.

Cytomegalovirus infection as a common complication following liver transplantation

The aim of our study was to assess the incidence course, influence on liver function, diagnostic methods, prophylaxis of, and cost treatment effectiveness of CMV infection among 123 consecutive liver transplant recipients. All patients received immunoglobulin and parenterall gancyclovir as prophylaxis. CMV IgM and IgG antibodies were determined using an ELISA method. Thirty seven patients (30.0%) developed CMV infection. Main indications for primary LTX were: immune liver disease ( n = 22), viral hepatitis ( n = 5), and other ( n = 10). CMV infection occurred between the days 5 and 416. Ten patients (27.0%) developed more than one infection (52 infections in total). Asymptomatic CMV infection was diagnosed in six cases (16.2%), CMV syndrome in 11 cases (29.7%), and hepatitis in 35 cases. All patients were treated with gancyclovir and immunoglobulin (18 cases). The intensity of infection was mild or moderate. There was no case of pneumonia or neurological disease, nor the need to use foscarnet. The correlations between the incidence of CMV infection and acute rejection, tacrolimus versus cyclosporine regimens, dual versus triple immunosupressive schemes were not statistically significant, whereas anti-IL-2R-ab antibodies markedly reduced the incidence of CMV infection ( P < .05). The values of CMV IgM significantly differred before/during infection ( P < .001) and before/after infection ( P < .05). In conclusion, prophylaxis and antiviral treatment result in a mild or moderate intensity of CMV infection with acceptable costs. Among immunosuppressive drugs, only anti-IL-2Rab was proved to significantly reduce the incidence of CMV.

Does prophylactic ganciclovir therapy after heart transplantation decrease CMV-infection properly?

Objective: CMV-infection is a common risk factor for the postoperative course after heart transplantation (HTx). The prophylactic use of Ganciclovir (in order to avoid CMV-infection) is costly and the efficacy is discussed controversly. In a randomised, prospective, clinical trial, CMV-prophylaxis on incidence of CMV-infection, transplant vasculopathy (TVP) and clinical outcome was compared to a untreated control group.

The risk of transfusion-acquired CMV infection in seronegative solid-organ transplant recipients receiving non-WBC-reduced blood components not screened for CMV antibody (1984 to 1996): experience at a single Canadian center.

The use of CMV-safe cellular blood components has been recommended for CMV-sero- negative recipients of CMV seronegative (R-D-) solid- organ transplants. The incidence of CMV infection in 281 CMV-seronegative patients receiving renal, heart, heart-lung, lung, and liver transplants at our center between January 1984 and October 1996 was studied. The blood components that these patients received were neither WBC reduced nor screened for CMV antibody. One hundred thirty-one of 154 (85.1%) patients receiving organs from CMV-seropositive donors (R-D+) developed CMV infection compared with three cases of presumptive transfusion-acquired (TA) CMV infection in 127 R-D- recipients (2.4%) (relative risk, 36.0; 95% CI, 11.8-110.4). The organ-specific incidence of TA CMV infection in R-D- patients was as follows: renal, 0 of 57 (0%); heart, 0 of 29 (0%); heart-lung and/or lung, 1 of 6 (16.7%); and liver, 2 of 20 (10%). There was no significant difference in the transfusion requirements of CMV-infected and -uninfected R-D- patients. False-positive results were often (40%) observed when posttransfusion serum samples were used for determination of the organ donor CMV serostatus. The low risk of TA CMV infection observed in transplant patients who received standard blood components in our study should be considered when evaluating the efficacy of programs that provide CMV-safe blood components for this population.

Incidence of cmv infection and cmv disease in allogeneic transplanted patients

Abstract During the last decade, CMV prophylaxis and preemptive therapy has considerably changed the outcome of CMV seropositive patients (pts). We have thus reviewed retrospectively our experience in 138 AlloBMT from 1984 to 2000 according to our anti CMV policy that evolved from no prophylaxis (1984–1990) to IVIG and acyclovir prophylaxis (1990–1995) and finally to prophylaxis and PCR based preemptive therapy with gancyclovir and IVIG (1995 to present). First period : 32 adult pts were allografted, 27 (72%) were CMV + , 7 pts (22%) developed a CMV disease (CMVD): 4 interstitial pneumonitis (IP), 2 pancytopenia and 1 pancytopenia with IP. Five (71%) died from CMVD (100% mortality for IP). Second period : 36 pts were allografted, 26 (72%) were CMV positive. Pts were treated for CMV infection when a positive sample by immunofluorescence or culture was reported. 4 pts (11%) were treated : 1 pancytopenia with retinitis, 2 IP and 1 skin infection with pancytopenia. 1 pt died (25%) from IP. Third period : 70 pts were allografted. PCR were monitored biweekly during 3 months after BMT. After 2 positive PCR tests on buffy coat, pts were preemptly treated. 17 pts (24%) received a preemptive treatment for positive PCR on buffy coat. 9 pts have positive PCR and cytopenia. 7 pts (10%) developed CMVD: 2 IP, 2 retinitis, 1 colitis, 1 oophoritis and 1 pt died from generalized CMVD. Those 7 pts had MUD. The pt who died from CMVD was allografted with an unrelated T depleted BM. In the setting of familial allo BMT, CMV disease is no longer a major complication in contrast with MUD.

87 Decrease incidence of CMV infection in liver transplantation with gancyclovir and cytogam prophylaxis

87 Decrease incidence of CMV infection in liver transplantation with gancyclovir and cytogam prophylaxis

THE IMPACT OF MYCOPHENOLATE MOFETIL (MMF) ON CYTOMEGALOVIRUS (CMV) DISEASE

597 While our group has recently shown that MMF does not increase the overall incidence of CMV infection in kidney transplant recipients, its role in CMV disease remains to be addressed. Adult kidney transplant recipients who developed CMV disease between January/1994 and June/1996, were classified according to the use of Azathioprine (AZA) or MMF, in addition to the universal use of cyclosporin A and steroids. Severity scores of CMV disease were compared using Chi-square, interval time to developing CMV disease was analyzed with Kaplan-Meier and compared with log-rank test, and categorical data was analyzed using Fisher's Exact Test. Seventeen patients on the AZA group and 12 on the MMF group developed CMV disease. Between the AZA and MMF groups there were no differences in age(mean±SD age: 43±15.4 and 41±13 years); gender(ratio male:female 9:8 and 8:4); CMV D+/R- (8/17, and 6/12), and etiology of the renal disease, respectively. Patients on AZA had more episodes of rejection (13/17 vs. 6/12) and were given OKT3 more frequently (10/17 vs. 3/12). However, patients in the MMF group had a higher frequency of organ involvement (7/12 vs. 3/17) (p=0.03), a higher severity score (5.5 vs. 4.0) (p=0.07) and a higher number of organs involved with CMV (p=0.015). In addition, there was a trend towards an earlier development of CMV disease in the MMF group (p=0.09). Conclusions from this study indicate that while MMF does not increase the overall incidence of CMV infection in renal transplant recipients, it appears to influence the rate and severity of CMV disease.

SINGLE CENTER EXPERIENCE OF 50 CONSECUTIVE PANCREAS TRANSPLANT RECIPIENTS RECEIVING MYCOPHENOLATE MOFETIL (MMF) AND TACROLIMUS (TAC) AS PRIMARY MAINTENANCE IMMUNOTHERAPY

687 In an attempt to contribute useful data on the use of MMF and TAC as primary maintenance immunotherapy in a meaningful number of pts, we describe our experience with 50 consecutive pancreas tx recipients (47 SPK, 2 PTA, 1 PAK) receiving tx from 7/95 to 1/98. The mean (±SD) follow-up time was 10±7 months (range 1-30). All pts were given MMF (3 gm/d × 6 mo, then 2 gm/d), TAC (target 12 hr trough level 10 ng/ml), anti-lymphocyte globulin induction (20 mg/kg/d × 7-14 d), and prednisone. The tx outcomes in terms of 2 yr actuarial pt and graft survival, and1 yr actuarial rejection rates were evaluated. The incidence of CMV infection, PTLD, and length of initial post-operative stay were determined. Pt demographics: 33M:17F; mean age: 36 yrs; race: 40 caucasian, 6 black, 4 hispanic; mean duration of diabetes: 24 yrs; mean HLA match: AB=0.86, DR=0.3; mean peak PRA: 9%. In all cases bladder drainage was used. MMF was tolerated in all pts. 7 pts on TAC were converted to Neoral® due to: alopecia (n=1), GI distress (n=3), or hyperglycemia (n=3). 2 yr actuarial pt, kidney and pancreas survivals, and1 yr actuarial rejection rates are shown for the entire group(N=50) and stratified as to whether conversion from TAC to Neoral® occurred: Table The 2 yr actuarial patient and graft survivals were all >90%. There was one death (suicide); 2 kidney losses (1 death, 1 rupture); and 3 pancreas losses (death, thrombosis, pancreatitis). 9 pts out of 50 had a rejection episode within a year (24.1%). However, among the 43 pts maintained on MMF/TAC, only 5 pts had rejection (14.4%), versus 4 of 7 (42.8%) pts that had rejection after conversion to Neoral®. This is a statistically significant difference(p<0.006). There have been 3 cases of CMV (all tissue invasive, all successfully treated). 2 of 20 pts with CMV were high risk (+ donor/ - recipient combinations). No cases of PTLD occurred. The mean initial hospital stay post-tx was 6.9 ± 2.1 d.Conclusion: The combination of MMF and TAC resulted in excellent pt and graft survival rates, a very low rate of rejection, and rare CMV.

BASILIXIMAB (SIMULECT???) REDUCES ACUTE REJECTIONS, CMV-INFECTIONS AND DURATION OF HOSPITAL STAY IN RENAL ALLOGRAFT PATIENTS

709 Purpose: Basiliximab (Simulect™, SDZ CHI 621) is a chimeric mAb against the α-chain of the IL-2 receptor (CD25). Its efficacy and safety in renal transplantation was determined in a multicenter, randomised, double-blind, placebo controlled phase-III trial. Here we present the data of 41 consecutive patients treated at our institution. Methods: Fourty-one recipients of primary mismatched cadaveric kidney allografts were enrolled in this study between 4/95 and 1/96. Twenty-one patients received two 20-mg doses of basiliximab and twenty patients received placebo on day 0 and 4, respectively. Baseline immunosuppression consisted of the new CyA-microemulsion (Neoral™), target levels: 150-200 ng/ml, and low dose corticosteroids. Primary objective was the incidence of acute rejections during the first six month. Secondary objectives were the safety and tolerability of basiliximab, as well as patient and graft survival up to 12 month post-transplantation. Results: [1] No significant differences regarding sex, height, weight, cold ischemic time, initial non function, time on dialysis, or history of end-stage renal disease could be observed between both treatment groups. [2] Biopsy proven acute rejections were significantly reduced in the basiliximab treated group compared with the placebo group: 28,6 % versus 55%,(p<0.05). [3] No steroid resistant acute rejections were seen in the basiliximab group vs. five (25%) in the placebo group (p=0.02). [4] One CMV-infection (4%) was observed in the basiliximab treated group, compared with five CMV-infections (25%) in the placebo group (p=0.02). [5] The incidence of bacterial infections (mainly UTI) was slightly decreased in the basiliximab group. [6] Patient survival at 24 month was 100 % in both groups.[7] Two patients lost their graft in the basiliximab group (venous thrombosis of the graft) and one patient in the placebo group (anaemic infarction of the kidney). [8] No post-transplant lymphoproliferative disorders occurred up to 24 month. [9] Acute tolerability was excellent, with no signs of cytokine release syndrome. [10] The initial hospital stay was longer in the placebo group (35 days; range: 7-73) compared with the basiliximab group (25 days; range: 4-58). Conclusion: Basiliximab was well tolerated in kidney transplanted recipients. Prophylactic treatment with 40-mg of basiliximab significantly reduces the incidence and severity of acute rejections, the incidence of CMV-infections and the duration of hospital stay in renal allograft patients.

THE IMPACT OF MYCOPHENOLATE MOFETIL (MMF) ON CYTOMEGALOVIRUS (CMV) DISEASE.

597 While our group has recently shown that MMF does not increase the overall incidence of CMV infection in kidney transplant recipients, its role in CMV disease remains to be addressed. Adult kidney transplant recipients who developed CMV disease between January/1994 and June/1996, were classified according to the use of Azathioprine (AZA) or MMF, in addition to the universal use of cyclosporin A and steroids. Severity scores of CMV disease were compared using Chi-square, interval time to developing CMV disease was analyzed with Kaplan-Meier and compared with log-rank test, and categorical data was analyzed using Fisher's Exact Test. Seventeen patients on the AZA group and 12 on the MMF group developed CMV disease. Between the AZA and MMF groups there were no differences in age(mean±SD age: 43±15.4 and 41±13 years); gender (ratio male:female 9:8 and 8:4); CMV D+/R- (8/17, and 6/12), and etiology of the renal disease, respectively. Patients on AZA had more episodes of rejection(13/17 vs. 6/12) and were given OKT3 more frequently (10/17 vs. 3/12). However, patients in the MMF group had a higher frequency of organ involvement(7/12 vs. 3/17) (p=0.03), a higher severity score (5.5 vs. 4.0) (p=0.07) and a higher number of organs involved with CMV (p=0.015). In addition, there was a trend towards an earlier development of CMV disease in the MMF group(p=0.09). Conclusions from this study indicate that while MMF does not increase the overall incidence of CMV infection in renal transplant recipients, it appears to influence the rate and severity of CMV disease.

SINGLE CENTER EXPERIENCE OF 50 CONSECUTIVE PANCREAS TRANSPLANT RECIPIENTS RECEIVING MYCOPHENOLATE MOFETIL (MMF) AND TACROLIMUS (TAC) AS PRIMARY MAINTENANCE IMMUNOTHERAPY.

687 In an attempt to contribute useful data on the use of MMF and TAC as primary maintenance immunotherapy in a meaningful number of pts, we describe our experience with 50 consecutive pancreas tx recipients (47 SPK, 2 PTA, 1 PAK) receiving tx from 7/95 to 1/98. The mean (± SD) follow-up time was 10 ± 7 months (range 1-30). All pts were given MMF (3 gm/d × 6 mo, then 2 gm/d), TAC (target 12 hr trough level 10 ng/ml), anti-lymphocyte globulin induction (20 mg/kg/d × 7-14 d), and prednisone. The tx outcomes in terms of 2 yr actuarial pt and graft survival, and1 yr actuarial rejection rates were evaluated. The incidence of CMV infection, PTLD, and length of initial post-operative stay were determined. Pt demographics: 33M:17F; mean age: 36 yrs; race: 40 caucasian, 6 black, 4 hispanic; mean duration of diabetes: 24 yrs; mean HLA match: AB=0.86, DR=0.3; mean peak PRA: 9%. In all cases bladder drainage was used. MMF was tolerated in all pts. 7 pts on TAC were converted to Neoral® due to: alopecia (n=1), GI distress (n=3), or hyperglycemia (n=3). 2 yr actuarial pt, kidney and pancreas survivals, and 1 yr actuarial rejection rates are shown for the entire group (N=50) and stratified as to whether conversion from TAC to Neoral® occurred:TableThe 2 yr actuarial patient and graft survivals were all >90%. There was one death (suicide); 2 kidney losses (1 death, 1 rupture); and 3 pancreas losses (death, thrombosis, pancreatitis). 9 pts out of 50 had a rejection episode within a year (24.1%). However, among the 43 pts maintained on MMF / TAC, only 5 pts had rejection (14.4%), versus 4 of 7 (42.8%) pts that had rejection after conversion to Neoral®. This is a statistically significant difference (p<0.006). There have been 3 cases of CMV (all tissue invasive, all successfully treated). 2 of 20 pts with CMV were high risk (+ donor / - recipient combinations). No cases of PTLD occurred. The mean initial hospital stay post-tx was 6.9 ± 2.1 d. Conclusion: The combination of MMF and TAC resulted in excellent pt and graft survival rates, a very low rate of rejection, and rare CMV.

Coincidence of Epstein-Barr virus reactivation, cytomegalovirus infection, and rejection episodes in renal transplant recipients.

Reactivation of the Epstein-Barr virus was reported to occur frequently under immunosuppressive therapy following organ transplantation. However, little is known about the clinical significance of these EBV reactivations. Therefore, we searched for correlations among the treatment with various immunosuppressive drugs, the incidence of CMV infections, rejection crises, and serological signs of EBV reactivation. EBV-specific antibodies were measured with novel ELISAs, utilizing the recombinant antigens p72 (for anti-EBV nuclear antigen [EBNA]1-IgG), p54, and p138 (anti-early antigen [EA]-IgM, -IgG, -IgA) in a follow-up study of 79 renal transplant recipients. Patients receiving antithymocyte globulin or antilymphocyte globulin therapy showed increasing anti-EA-IgG and -IgA more often than did patients not receiving antithymocyte globulin or antilymphocyte globulin therapy (P < 0.05). In patients receiving OKT3 antirejection therapy, anti-EA-IgM seroconversion was found more frequently (P < 0.01). A significant correlation was also found between groups of patients who had had at least one rejection episode versus patients without any sign of organ rejection, and the incidence of increasing anti-EA-IgG (P < 0.05). Since in most of these patients signs of EBV reactivation followed the appearance of the rejection episode, this may not be due to viral-induced rejection but may be caused by the reinforced immunosuppression during antirejection therapy. As opposed to patients with no signs of CMV infection and with nonsymptomatic CMV infection, patients undergoing symptomatic CMV infection showed anti-EA-IgM seroconversion (P < 0.01), increasing anti-EA-IgA (P < 0.01), and decreasing anti-EBNA-IgG (P < 0.01) more frequently. Our results confirm the role of immunosuppressive therapy in the pathogenesis of EBV reactivation. We further demonstrate a striking coincidence of EBV reactivation and symptomatic CMV infection.

Pneumocystis carinii pneumonia in renal transplant recipients

In 1991 and 1992 Pneumocystis carinii pneumonia (PCP) was diagnosed in 28 renal transplant recipients. The incidence of PCP in our renal transplant centre was remarkably increased from 1.1% before 1991 to 11.5% in 1991-1992. We compared 28 PCP patients with a control group of 27 renal transplant recipients, matched for transplantation day and without an episode of PCP. The mean age was significantly higher in the PCP group (50 +/- 13 versus 38 +/- 13 years). We observed no differences in basic immunosuppressive and rejection treatment nor in antibiotic consumption, number of hospitalization days, and incidence of CMV infection. In March 1993 we introduced PCP prophylaxis. More than 140 renal transplant recipients received co-trimoxazole, starting 1 day after transplantation and continued for a period of 4 months. To the time of writing no one in this group had developed PCP.

CLINICAL IMPACT OF REPLACING MINNESOTA ANTILYMPHOCYTE GLOBULIN WITH ATGAM

In August 1992, we replaced Minnesota antilymphocyte globulin (MALG) with lymphocyte immune globulin, antithymocyte globulin (equine) (ATGAM) in our immunosuppression protocols. The clinical impression of increased graft rejection prompted our assessment of the effect of this change on patient and graft outcome. The initial study group consisted of 426 renal transplant recipients transplanted between October 1, 1987, and September 21, 1993. After exclusions, 388 transplant events, with a minimum 8-month follow-up, made up the final study cohort: 323 patients received MALG and 65 received ATGAM. Immunosuppression included intravenous methylprednisolone, oral prednisone, oral AZA, CsA in some cases, and intravenous MALG or ATGAM, 15 mg/kg/day, for 7 to 14 days. Acute rejection was treated with high dose intravenous steroids and steroid-resistant episodes were treated additionally with either MALG or OKT3. Statistical comparisons were stratified for multiple patient characteristics and treatment variations. There was a greater incidence of rejection in general, and a higher incidence of steroid-resistant episodes requiring subsequent antilymphocyte globulin therapy (P = 0.0073) in patients receiving ATGAM versus MALG. No difference was seen in the incidence of CMV infection or blood-borne sepsis. Lymphoma occurred in 3 MALG and 2 ATGAM recipients. MALG recipients were significantly less likely to experience rejection within the first 60 days after transplant (P = 0.0127 using unstratified data; P < 0.0001 when data were stratified for patient characteristics). The relative risk of acute rejection for posttransplant days 5, 7, 10, and 14 was consistently higher for ATGAM-treated patients. We conclude that MALG and ATGAM are not equivalent drugs, and that MALG is a more effective immunosuppressant, and is just as safe as ATGAM in our protocol environment.