Developed Cytomegalovirus Infection Research Articles

A Largely Preemptive Strategy for Prevention of Cytomegalovirus (CMV) Disease Less Practical in D+/R- Liver Transplant Recipients Receiving Anti-Thymocyte Globulin (rATG) Than D+/R+ Recipients.

Background: Our institution utilizes a hybrid method for prevention of CMV infection (CMVI) with two weeks of prophylaxis followed by preemptive therapy. We evaluated this strategy in CMV D+/R- and CMV D+/R+ liver transplant (LT). Methods: For D+/R- and D+/R+ LT recipients from 4/09-4/12, baseline and clinical data for 6 months from the date of LT were collected retrospectively. Primary outcomes were CMV viremia, symptomatic CMVI, and tissue- invasive disease (CMV-TID). Secondary outcomes included patient and allograft survival, number of CMVI, and viral load (VL). Results: We identified 191 LT recipients; 18/71 D+/R- patients (23%) developed symptomatic CMV infection vs 5/ 120 (4%) D+/R+ patients (P <0.001). 2/71 (3%) and 1/120 (1%) of D+/R- and D+/R+ patients developed CMV- TID respectively (P= 0.556). 2 deaths occurred in the D+/R- group (3%) vs 6 (5%) in D+/R+ (P= 0.712). 24/52 (46%) of D+/R- and 10/32 (31%) of D+/R+ patients with CMVI required IV therapy (P= 0.481); 24/52 (46%) and 12/32 (38%) respectively required hospitalization (P= 0.500). Median log peak VL were 3.22, 3.7, and 4.17 in D+/R- patients vs D+/R+ patients receiving no induction, basiliximab, and rATG (P= 0.016). Differences after Bonferroni correction were not statistically significant. 100% of D+/R- receiving rATG developed CMV vs 4/11 (36.4%) of D+/R+ patients. Time to CMVI differed between D+/R- and D+/R+ patients receiving rATG with infection in D+/R- patients occurring earlier (P= 0.016). The median number of CMVI in D+/R- patients receiving rATG vs basiliximab was 2 vs 1 respectively, and 0 in all others (P<0.001). Conclusion: A primarily preemptive strategy was efficacious in preventing CMV- TID. 100% of D+/R- patients receiving rATG developed CMV infection; while sample size is limited, a higher number of CMV episodes in D+/R- patients receiving rATG and significant difference in time to development of CMVI suggest that preemptive therapy may not be optimal in this subset of patients. DISCLOSURES:Yen- Lieberman, B.: Speaker's Bureau, Qiagen.

A Prospective Randomized Trial Aimed to Reduce the Incidence of Cytomegalovirus (CMV) Infection in Kidney Transplant Recipients.

Introduction: CMV infection is associated with inferior long-term patient and graft survival. This single center prospective randomized study compares the influence of 3 immunosuppressive regimens on the incidence of CMV infection in kidney transplant recipients. Methods: This is a single center prospective randomized study included 288 low immunological risk kidney transplant recipients to receive: (G1, N=85) single 3 mg/kg dose of antithymocyte globulin, reduced exposure tacrolimus (TAC<5 ng/ml), everolimus (EVR: 4-8 ng/mL) and prednisone; (G2, N=102) basiliximab, reduced exposure TAC (6 ng/ml for 3 months then <5 ng/mL thereafter), EVR (4-8 ng/mL) and prednisone; (G3, N=101) basiliximab, TAC (6-8 ng/ml), mycophenolate (MPA) and prednisone. None of the patients received any CMV prophylaxis. CMV viral replication was monitored weekly using pp65 antigenemia and PCR. The primary outcome is the incidence of CMV infection (viremia or disease) during the first year of transplantation. This report includes data of all patients up to 6 month after transplantation. Results: There were no differences in demographic characteristics including pre-transplant CMV donor/recipient serostatus. The incidence of first CMV infection episode was lower in EVR groups (4.7 vs. 7.8 vs. 35.6%, p<0.0001). There was no difference comparing mean time to first CMV infection episode or mean time of ganciclovir treatment. The total number of CMV infection episodes was also lower in EVR groups (4 vs. 14 vs. 55) because there were no recurrent episodes in G1 but 6 in G2 and 19 in G3. Twelve patients were converted from MPA to EVR due to CMV infection. There were no differences in incidence of biopsy proven acute rejection (8 vs. 20 vs. 14%, p=0.085), wound-healing adverse events (28 vs. 35 vs. 25%, p=0.2), delayed graft function (48 vs. 53 vs. 45%, p=0.4), mean estimated GFR (64±24 vs. 58±23 vs. 66±29 ml/min, p=0.06) and mean protein/creatinine ratio (0.5±1.0 vs. 0.4±0.7 vs. 0.3±0.9, p=0.5). There were 8 deaths (G1=2; G2=3; G3=3) and 6 graft losses (G1=0; G2=3; G3=3). Conclusions: This 6 month analysis indicates that patients receiving EVR are at lower risk of developing CMV infection compared to patients receiving MPA. Patients receiving EVR showed efficacy and safety profiles comparable to those receiving MPA. DISCLOSURES:Tedesco, H.: Grant/Research Support, Novartis.

Outcome of Kidney Transplantation in Bahrain.

Pupose: Renal transplantation is considered the optimal form of renal replacement therapy for patients with end stage renal disease. Kidney transplantation was started in Bahrain in 1995 at our unit. Methods: Between June 1995 and December 2013, 125 renal transplants in 124 patients were performed at our unit. There were 115 living related donor and 20 deceased donor transplants (DD), including 81 male and 44 female patients. Most of the recipients were Bahraini (94.1%) and 116 (92.8%) of them received their first graft. Diabetic nephropathy was responsible for 22.4% of end-stage kidney disease. Their age ranged from 3 to 66 years and the follow up period was 1 to 216 months postoperatively. Results: Dialysis before transplantation was done in 85.4% of patients. All patients received triple drug immunosuppression and induction therapy with baziliximab. There were a total of 22 (17.7%) episodes of acute rejection diagnosed clinically and/ or by graft biopsy. Most of the rejection episodes occurred within the first month post-transplantation. Seven (5.6%) grafts had primary non-function due to acute tubular necrosis (ATN), and all of them were from DD. There were 15 episodes of severe infection. Seven patients died from their infection including three due to severe respiratory tract infection. Three patients developed cytomegalovirus infection which was diagnosed on clinical and serological grounds. Three patients developed malignancy (one lymphoma, one Kaposi sarcoma and one brain tumor). There were 3 surgical and urological complications encountered in our patients. At the last follow-up visit, there are 86 patients (68.8%) have good graft function. Thirty-eight patients lost their graft, 16 of them due to death with functioning grafts. The commonest cause of graft loss was chronic rejection. Conclusions: The overall results in our center are comparable to those published from other centers in the Arab World. Our main challenge is shortage of kidney donors.

Pretransplant CD8 T-Cell Response to IE-1 Discriminates Seropositive Kidney Recipients at Risk of Developing CMV Infection Posttransplant

Cytomegalovirus (CMV) infection is an ongoing clinical problem in solid-organ transplantation (SOT). Pretransplant CMV serology is currently the only tool for assessing the risk of CMV infection, although cellular immune responses driven by CMV-specific CD4 and CD8 T lymphocytes are important for controlling viral replication. Therefore, the analysis of CMV-specific T cells may be useful for estimating the risk of infection. This is a prospective study of patients with kidney transplants and no prophylactic treatment for CMV replication. CD4 and CD8 T-cell responses to the major CMV pp65 and IE-1 antigens in 15 seropositive patients at intermediate risk of CMV infection were investigated, according to current algorithms. Intracellular flow cytometry was employed to determine IFN-γ production as a functional readout. The response was analyzed in pretransplant samples and prospectively at 1 and 6 months and at 1 year posttransplant. It was observed that the CD8 responses to IE-1 antigen were practically absent pretransplant in patients who developed CMV infection posttransplant. Within the group of patients free of infection, CD8 responses to IE-1 were detected more frequently and were significantly higher (P=0.0083). In a receiver operating characteristics curve analysis (AUC=0.929; P=0.010; 95% CI: 0.078-1.0), low CD8 responses to IE-1 (≤0.05%) pretransplant predicted the development of CMV infection under the immunosuppressive regime after transplant with 100% specificity and 85.7% sensitivity. Assessment of IE-1-specific CD8 T-cell frequencies pretransplant may be a useful tool for identifying seropositive SOT patients at risk of developing CMV infection posttransplant.

Alemtuzumab with corticosteroid minimization for pediatric deceased donor renal transplantation: A seven‐yr experience

Alemtuzumab is a monoclonal antibody targeting CD52 receptors on B and T lymphocytes and is an effective induction agent in pediatric renal transplantation. We report a seven-yr experience using alemtuzumab induction and steroid-free protocol in the pediatric population as safe and effective. Twenty-one pediatric deceased donor renal transplants were performed at a single academic institution. All received induction with single-dose alemtuzumab and were maintained on a steroid-free protocol using TAC and MMF immunosuppression. There were 15 males and six females in the study whose ages ranged from one to 19 yr. The average follow-up was 32 months (range from 12 to 78.2 months and median 33.7 ± 23.7 months). All patients had immediate graft function. Graft survival was 95%, and patient survival was 100%. Mean 12 and 36 months eGFR were 63.33 ± 21.01 and 59.90 ± 15.27 mL/min/1.73m(2), respectively. Three patients developed acute T-cell-mediated rejection due to non-adherence while no recipients developed cytomegalovirus infection, PTLD, or polyoma BK viral nephropathy. Steroid avoidance with single-dose alemtuzumab induction provides adequate and safe immunosuppression in pediatric deceased donor renal transplant recipients receiving TAC and low-dose MMF maintenance therapy.

Replacement of Mycophenolate Acid With Everolimus in Patients Who Became Neutropenic After Renal Transplant

Neutropenia after kidney transplant is an adverse event usually treated with a dosage reduction of mycophenolic acid. We evaluated the efficacy and safety of substituting mycophenolic acid with everolimus in patients with persistent neutropenia after kidney transplant. This study was a retrospective analysis. A total of 17 patients who were initially treated with mycophenolic acid (1912 ± 196 mg/d), calcineurin inhibitors, and methylprednisolone for kidney transplant were included. In 15 patients, neutropenia occurred within the first 3 months (during valganciclovir administration), and in 2 patients between the fourth and sixth month after transplant. One hundred eighteen episodes of neutropenia were recorded, originally treated by reducing the dosage of mycophenolic acid (765 ± 390 mg/d) and administering granulocyte colony-stimulating factor. Three patients experienced acute rejection 5 to 10 days after reducing the dosage of mycophenolic acid, and they were successfully treated with pulse steroids. Five patients developed cytomegalovirus infection 108 ± 65 days after the onset of neutropenia. After replacing mycophenolic acid with everolimus, episodes of neutropenia were observed in 6 patients. In 1 patient, discontinuing everolimus was necessary after 1.5 months of treatment. In 5 patients with cytomegalovirus infection, neutropenia subsided after termination of valganciclovir treatment. In the remaining 11 patients, no episodes of neutropenia were observed. No episodes of acute rejection occurred, and renal function remained stable during a followup of 47 ± 30 months (estimated glomerular filtration rate [eGFRMDRD6]: 45 ± 14 mL/min/1.73 m2→47 ± 22 mL/min/1.73 m2]. Replacing mycophenolic acid with everolimus appears to be a safe and effective alternative treatment in neutropenic renal transplant recipients.

CMV Infection Alone Does Not Affect The Survival In Patients After Umbilical Cord Blood Transplantation: Can We Put Off The Time Of Preemptive Therapy?

ObjectiveAnalysis and discuss the time of cytomegalovirus (CMV) preemptive therapy after umbilical cord blood transplantation (UCBT). Analysis the risk factors of CMV infection and the effect on survival of CMV infection after UCBT. MethodFrom April 2000 to March 2013, 176 cases of patients undergo UCBT who were detected plasma CMV-DNA twice a week routinely. Preemptive antiviral therapy was initiated with ganciclovir or foscarnet for positive PCR of 103 DNA copies or more per ml. Results125 of 176 patients developed CMV infection (71%) at a median of 32d (range 19 to 98) post-transplant and only 4 patients developed CMV disease (2.3%). The 5-year overall (OS) was 59.4% in the patients with CMV infection and 64.9% in patients without CMV infection (P=0.193). The study identified that younger age, high-risk disease, infused little CD34 positive cells, developed III-IV degree acute graft-versus-host disease (GVHD), high-dose methylprednisolone, and treated with basiliximab and other strong immunosuppressive agent as significant risk factors for developing CMV infection. It had nothing to do with the gender of patients, transplantation of UCB units, the conditioning regime, the day of neutrophil recovery and chronic GVHD. Preemptive therapy when the CMV-DNA copies are greater than 103 does not increase the incidence of CMV disease, and the survival has not been impacted. ConclusionPreemptive therapy can be initiated when CMV-DNA copies are greater than 103 which can achieve the same effects in UCBT. Disclosures:No relevant conflicts of interest to declare.

Critical analysis of valganciclovir dosing and renal function on the development of cytomegalovirus infection in kidney transplantation

Cytomegalovirus (CMV) infection is one of the most common and important opportunistic infections following kidney transplantation. It causes significant morbidity and mortality. Valganciclovir (VGCV) is the drug of choice for prophylaxis to prevent CMV infection. We conducted a post-hoc analysis of a randomized controlled trial in 187 kidney transplant recipients to evaluate the impact of VGCV dosing and renal function on the development of CMV infection. The results demonstrate that the following variables were independent risk factors for the development of CMV infection: high-risk CMV serostatus (donor positive/recipient negative; hazard ratio [HR] 1.4, 95% confidence interval [CI] 1.46-5.28, P = 0.002); anti-thymocyte globulin induction therapy (HR 2.1, 95% CI 1.08-4.07, P = 0.028); higher mean tacrolimus trough concentration (HR 1.4, 95% CI 1.09-1.74, P = 0.007); creatinine clearance <60 mL/min (HR 3.4, 95% CI 1.64-6.85, P = 0.001); and body weight >80 kg (HR 2.1, 95% CI 1.05-4.37, P = 0.037). VGCV dosing was appropriate for most patients, in those who did and did not develop CMV infection. These results strongly suggest that the currently recommended dose adjustments of VGCV dosing based on estimated renal function calculated using ideal body weight may underestimate the renal function of overweight patients and indirectly result in underexposure of overweight patients to VGCV. Based on these findings, further VGCV pharmacokinetic analyses are warranted in kidney transplant recipients with moderate-to-severe renal dysfunction.

Pretransplant Immediately Early-1-Specific T Cell Responses Provide Protection for CMV Infection After Kidney Transplantation

Cytomegalovirus (CMV) infection is still a major complication after kidney transplantation. Although cytotoxic CMV-specific T cells play a crucial role controlling CMV survival and replication, current pretransplant risk assessment for CMV infection is only based on donor/recipient (IgG)-serostatus. Here, we evaluated the usefulness of monitoring pre- and 6-month CMV-specific T cell responses against two dominant CMV antigens (IE-1 and pp65) and a CMV lysate, using an IFN-γ Elispot, for predicting the advent of CMV infection in two cohorts of 137 kidney transplant recipients either receiving routine prophylaxis (n = 39) or preemptive treatment (n = 98). Incidence of CMV antigenemia/disease within the prophylaxis and preemptive group was 28%/20% and 22%/12%, respectively. Patients developing CMV infection showed significantly lower anti-IE-1-specific T cell responses than those that did not in both groups (p < 0.05). In a ROC curve analysis, low pretransplant anti-IE-1-specific T cell responses predicted the risk of both primary and late-onset CMV infection with high sensitivity and specificity (AUC > 0.70). Furthermore, when using most sensitive and specific Elispot cut-off values, a higher than 80% and 90% sensitivity and negative predictive value was obtained, respectively. Monitoring IE-1-specific T cell responses before transplantation may be useful for predicting posttransplant risk of CMV infection, thus potentially guiding decision-making regarding CMV preventive treatment.

Late-Onset Cytomegalovirus (CMV) in Lung Transplant Recipients: Can CMV Serostatus Guide the Duration of Prophylaxis?

Evidence supports the use of 12 months of cytomegalovirus prophylaxis in all at-risk lung transplants; whether cytomegalovirus serostatus can be used to further optimize this duration remains to be determined. The purpose of this retrospective study was to determine if cytomegalovirus serostatus of both donor and recipient were associated with late-onset cytomegalovirus. The primary outcome was the proportion of lung transplants that developed cytomegalovirus infection or disease during the 180-day period following 6 months of prophylaxis in each at-risk serotype. Two hundred forty-four consecutive lung transplants were evaluated, 131 were included. The proportion of recipients with cytomegalovirus differed significantly between serotypes (20 of 41 [48.8%] D+/R- vs. 19 of 56 [33.9%] D+/R+ vs. 2 of 34 [5.9%] D-/R+; p < 0.001). In a multivariate model, older age (odds ratio [OR], 1.05, 95% confidence interval [CI] 1.004-1.099; p = 0.03) and D+/R- serostatus (OR, 3.83; 95% CI 1.674-8.770; p = 0.002) were associated with cytomegalovirus. Among R+ lung transplants, D- serostatus was associated with the absence of cytomegalovirus (OR, 0.12; 95% CI 0.0263-0.563; p = 0.007). These findings suggest that in the valganciclovir era, cytomegalovirus serostatus of both donor and recipient may identify lung transplants at heightened risk for late-onset cytomegalovirus.

The Effects of Preemptive Therapy Using a Very Low Threshold of pp65 Antigenemia to Prevent Cytomegalovirus Disease in Kidney Transplant Recipients: A Single-Center Experience

BackgroundPreemptive therapy is a valid option for cytomegalovirus (CMV) disease prevention in kidney transplant recipients. However, there are controversies regarding the appropriate threshold value to be reached before starting antiviral drugs. The aim of this study was to evaluate the benefit of a low threshold of the CMV pp65 antigenemia test as a guide to initiate the therapy. MethodsWe performed a prospective study on 47 consecutive kidney recipients. The CMV pp65 antigenemia test was performed over 6 months posttransplantation; patients who displayed ≥2/200,000 CMV antigen-positive leukocytes were treated for 2 months with valgancyclovir (450 mg twice a day). ResultsTwenty-five patients developed CMV infections, which were initially diagnosed at 55 ± 25 days posttransplantation. The number of CMV antigen-positive cells/200,000 leukocytes on the first positive test was 17 ± 22. The test first became negative at 17 ± 8 days after the diagnosis. A positive correlation was observed between the number of CMV antigen-positive cells and the time to obtain the first negative test (P = .01). At the end of follow-up (35.3 ± 16.4 months), none of the patients had developed CMV syndrome. Among the CMV-positive recipients, the creatinine levels showed no differences from the values before the CMV infection. No difference in creatinine levels was noted between CMV infection positive versus negative patients. ConclusionOur data suggested that a CMV antigenemia titer ≥ 2/200.000 leucocytes can be considered to be an appropriate threshold to start anti-CMV preemptive therapy.

Cytomegalovirus Infection and Lymphopenia Are Associated with Increased Mortality Post Autologous Stem Cell Transplantation

AbstractAbstract 4208 Introduction:Despite preventive and therapeutic antiviral medication cytomegalovirus (CMV) infection is still a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (SCT). Only limited data on CMV infection and disease are available in autologous SCT recipients. Previous studies have demonstrated that the probability of CMV infection is nearly 60% in seropositive patients and 23% in seronegative patients undergoing autologous SCT, but its impact in mortality is unclear. Methods:We retrospectively reviewed the medical records of 101 patients undergoing autologous SCT at Hospital Israelita Albert Einstein from January, 2005 to July, 2012. CMV infection was defined as a quantitative real time PCR assay showing greater than 165 copies and/or positive CMV pp65 antigenemia assay. Lymphocyte count was registered at 15th day after SCT and lymphopenia was defined as an absolute lymphocytes count (ALC) < 500 at that time point. Overall survival (OS) was estimated from the time of transplant until death, with surviving patients censored at last follow-up. Variables entered into the multivariate Cox analysis were those with a p-value <0.10 in the univariate analysis. CMV infection was analyzed as a time-dependent covariate, considering the time to CMV infection. Statistical analysis was performed with STATA (v11.0) and alfa error was defined as 5%. Results:The majority of patients were male (62.4%) and the median age was 58 years old (range: 3–76). Peripheral stem cell harvest was the main source of cells (92%). A positive serological CMV status was found in 93.75% of patients. Most common indications for autologous SCT were multiple myeloma (34%), non-Hodgkin’s lymphoma (40%) and Hodgkin’s lymphoma (6%). After a median follow-up of 2 years, the OS for the whole cohort was 61% (95% confidence interval [CI] 48–72%). CMV infection post SCT was seen in 26% of patients. In the univariate analysis, development of CMV infection and presence of D15 lymphopenia were associated with a higher mortality (CMV infection-hazard ratio [HR] 3.32 [95%IC 1.61–6.84]; p= 0.001; D15 lymphopenia- HR 2.37 [95% IC 1.11–5.05]; p= 0.024). Patients who developed CMV infection in the setting of D15 lymphopenia had the worse outcome (2-years OS 19%; 95% CI 9–43%; figure 1). D15 lymphopenia was not associated with a higher rates of CMV infection (p=0.41). In Cox multivariate analysis, lower overall survival was demonstrated in female patients (HR= 2.23, 95%IC 1.08–4.58; p= 0.029), in the presence of D15 lymphopenia (HR= 2.56, 95%IC 1.19–5.51; p= 0.016) and CMV infection (HR: 3.33, 95% IC1.61–46.86; p= 0.001). Conclusion:CMV infection post-autologous SCT is associated with a decreased survival, and in the concomitant presence of D15 lymphopenia appears to indicate a subgroup of patients with very poor outcome. It is possible that CMV infection does not lead directly to increased mortality, but is rather a surrogate marker of decreased immune function post-ASCT. Future studies should prospectively evaluate the incidence and prognostic impact of CMV infection post-ASCT and correlate with markers of immune recovery. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Replacement of Mycophenolic Acid by Everolimus in Patients Who Become Neutropenic after Renal Transplantation

The presence of neutropenia after kidney transplantation represents a frequent adverse event (AE) that is usually treated with lowering of mycophenolic acid (MPA) dose. This leads to an increased incidence of acute rejection episodes and potential loss of renal allograft. This study evaluated the efficacy and safety of everolimus when used instead of MPA in patients who developed neutropenia (absolute neutrophil count < 2000/μL). We studied 17 patients, 12 men and 5 women, aged 40 ± 12 years old, who developed neutropenia after kidney transplantation. Five of them were patients with high immunological risk (high titer of cytotoxic antibodies, second or third transplant). All patients treated with MPA (1912 ± 196mg/day), calcineurin inhibitor (cyclosporine n=1, tacrolimus n=16) and methylprednisolone. Neutropenia occurred in 15 patients during the first 3 months after transplantation and in 2 patients between the 3rd and 6th month post-transplantation (59 ± 38 days). The 15 patients who developed neutropenia during the first 3 months after transplantation were still on valgancyclovir as prophylaxis against cytomegalovirus (CMV) infection. A total of 118 episodes of neutropenia were recorded, originally treated by reduction of MPA dose and administration of granulocyte colony-stimulating factor (G-CSF). Three patients experienced acute rejection (Banff 1A) 5 to 10 days after the reduction of MPA dose (0-1000mg/day) which was successfully treated with IV pulse of methylprednisolone. Five patients developed CMV infection, 108 ± 65 days after the onset of neutropenia and 5.5±1.5 months after transplantation. The replacement of MPA (765 ± 390mg/day) by everolimus was performed 1 to 23 months after transplantation and 5 days up to 48 months from the onset of neutropenia. After the induction of everolimus, 50 episodes of neutropenia were observed in 6 patients. In one of them discontinuation of everolimus was necessary 1.5 month later and in the rest 5 (who developed CMV infection and treated by valgancyclovir), neutropenia of less severity was observed up to the end of treatment for CMV infection. In the remaining 11 patients, no episode of neutropenia was observed. No episode of acute rejection occurred and the renal function remained stable 6 months after initiation of everolimus and during the whole follow up period of 47±30months [eGFRMDRD6: 45±14ml/min/1.73m2 → (6months):51±16ml/min/1.73m2 → (47±30months): 47±22ml/min/1.73m2]. Conclusion: The replacement of MPA by everolimus because of neutropenia in renal transplant recipients on triple immunosuppressive regimen appears to be safe and effective alternative treatment. Although neutropenia also occurred after administration of everolimus, it was less serious and possibly due to a different mechanism of action. Further research with more prospective randomized studies is necessary in order to confirm these findings.

A Prospective Randomized Trial Aimed to Reduce the Incidence of Cytomegalovirus (CMV) Infection in Kidney Transplant Recipients

Introduction: CMV viremia and disease is frequent and is associated with inferior long-term patient and graft survival. This single center prospective study compares the effect of 3 immunosuppressive regimens on the incidence of CMV infection in kidney transplant recipients. Methods: Low immunological risk recipients of first kidney transplant were randomized (stratified according to donor source, living or deceased donors) to one of the following groups (G1) single 3 mg/kg dose of antithymocyte globulin, reduced exposure tacrolimus (TAC 4 ng/ml), everolimus (EVR 4-8 ng/mL) and prednisone or (G2) basiliximab, reduced exposure tacrolimus (TAC 6 ng/ml), everolimus (EVR 4-8 ng/mL) and prednisone or (G3) basiliximab, reduced exposure tacrolimus (TAC 8 ng/ml), mycophenolate and prednisone. The primary outcome in this study is the incidence of CMV infection or disease during the first year of transplantation. None of the patients received CMV prophylaxis. CMV infection is monitored weekly using concomitant PCR viral load and antigenemia test during the first 6 months of transplant. Here we show preliminary results of the first 63 out of 300 patients. Results: The mean age of this population was 44.5±12.3 years with 52.3% Caucasian, 62 % male and 76.2% recipients from deceased donor. Mean donor age was 43.6±10.9 years and among deceased donors transplants, the mean cold ischemia time was 22.9 ± 5 hours. This analysis includes 15 patients in G1, 19 in G2 and 29 in G3. Donor positive/recipient negative CMV was observed in 1 patient in G1 and 1 patient in G3, only. Overall, 12 (19%) episodes of acute rejection were diagnosed, 7 were biopsy confirmed (G1=0; G2=4; G3=3), 4 borderline changes (G1=2; G2=1; G3=1) and 1 interstitial nephritis (G3). Two patients in G2 and one patient in G3 required thymoglobulin to treat acute rejection (for 2A; 2B and 2A rejections, respectively). At time of acute rejection diagnosis tacrolimus trough blood concentrations were 3.8 ± 1.3 ng/mL for G1; 5.8 ± 1.2 ng/mL for G2 and 8.0 ± 3.1 ng/mL for G3. Mean serum creatinine at 3 months was 1.5 ± 0.5 mg/dL in G1, 1.5 ± 0.2mg/dL in G2 and 1.2 ± 0.3mg/dL in G3. Eight episodes of CMV infection were diagnosed (7 viremia and 1 disease; 2 recurrences) at mean time of 55.1 ± 32.9 days after transplant, all in G3 patients. Two patients had received previous treatment with thymoglobulin for acute rejection. Conclusions: This preliminary analysis indicates that patients receiving everolimus, with or without thymoglobulin, are at lower risk to develop CMV infection. These regimens also appear to provide comparable efficacy for the prevention of acute rejection and similar renal function.

Six-Month Low-Dose Valganciclovir Prophylaxis in Cytomegalovirus D+/R− Kidney Transplant Patients Receiving Thymoglobulin Induction

BackgroundThe use of T-cell-depleting antibody, such as thymoglobulin, is a risk factor for cytomegalovirus (CMV) infection. We studied the effectiveness of 6 months of low-dose valganciclovir prophylaxis in CMV-naive kidney transplant recipients of CMV-positive donor kidney (D+/R−) receiving thymoglobulin induction. MethodsWe included all D+/R− kidney transplant patients between October 2005 and December 2010 who received valganciclovir 450 mg daily for 6 months as per center protocol. CMV infection was confirmed by positive viremia. Kaplan-Meier and multivariate Cox proportional regression analyses were employed to compare the risk of CMV infection between patients with and without the use of thymoglobulin induction. ResultsOut of 170 D+/R− kidney transplant patients, 42 cases of CMV infection (24.6%) were diagnosed after a median follow-up of 3.2 years: six patients from the noninduction (9.4%) and 36 from the induction cohort (34.0%). The induction with thymoglobulin was associated with four times greater risk of developing CMV infection (adjusted hazard ratio: AHR 4.15, 95% 1.75, 9.86, P = .001). The use of thymoglobulin was associated with leukopenia but not neutropenia. ConclusionsAdditional measures are needed to reduce the elevated incidence of CMV infection in D+/R− kidney transplant patients receiving induction with thymoglobulin.

Assessment of Cytomegalovirus Hybrid Preventative Strategy in Pediatric Heart Transplant Patients.

Prevention strategies for cytomegalovirus (CMV) in pediatric transplant recipients are sparsely reported. A hybrid strategy that combines prophylaxis with preemptive therapy using serial CMV viral load monitoring is an emerging option. We report our clinical outcomes with a hybrid strategy in pediatric heart transplant recipients. A retrospective chart review was performed for pediatric heart transplant recipients who received a hybrid strategy of 2-4 weeks intravenous ganciclovir followed by serial whole blood CMV monitoring from 2002 to 2010. Subject demographics, medications, drug levels, serial CMV viral loads, intravascular ultrasound and angiography reports, and histopathology were collected. Descriptive statistics and patient groups were compared using χ(2), Fisher's exact, and Wilcoxon rank-sum tests. Twelve females and 13 males, ranging from 4 months to 19 years of age, underwent 26 heart transplants. Mean follow-up was 39 months (range, 5-94 months). Fourteen (54%) subjects were CMV donor (D)+/recipient (R)-, 8 (31%) were D+/R+, and 4 (15%) were D-/R+. Six subjects (23%) died of complications unrelated to CMV. Median prophylaxis duration was 25 days (range, 7-70 days). Ten (38%) subjects developed CMV infection: 1 subject had 2 episodes of CMV syndrome, and 1 subject had 2 episodes CMV. Although 6 of 14 patients with coronary artery vasculopathy had prior CMV, no association was found (P=.81). Median time to first CMV DNAemia was 2.3 months (range, 9 days to 24.8 months). Median time to viral load clearance was 29 days (range, 4-233 days). In addition, 25 D-/R- patients were transplanted and received no prophylaxis; 2 (8%) patients developed CMV infection. Pediatric heart transplant recipients who were at risk for CMV and treated with a novel preventative hybrid strategy developed CMV infection, syndrome, and disease at rates similar to those reported in literature for prophylactic strategies.

Simultaneous Monitoring of Cytomegalovirus-Specific Antibody and T-cell levels in Seropositive Heart Transplant Recipients

Human cytomegalovirus (CMV) active infection (CMV infection) poses serious risks to CMV-seropositive heart transplant recipients. We evaluated the usefulness of simultaneous assessment of CMV-specific values for parameters of the humoral (antibodies) and cellular (CD4+ and CD8+ T-cells) immune responses in the identification of heart recipients at risk of developing CMV infection after transplantation. We prospectively studied 38 CMV-seropositive heart recipients. Anti-CMV antibody titers were assessed using enzyme-linked immunosorbent assays. CD4+ and CD8+ T-cell responses to overlapping peptide pools of the CMV proteins pp65 and immediate early protein-1 (IE1) were evaluated by flow cytometry. Immunological studies were performed before transplantation and at 30days after transplantation. Patients with CMV infection were compared with heart recipients without CMV infection. During the 6-month follow-up period, 13 (34.2%) patients developed CMV infection. At baseline, the mean anti-CMV-IgG antibody titer was lower in patients who developed CMV infection. This difference remained at 30days after transplantation. One month after transplantation, the mean percentage of IE1-specific CD8+ T cells that are IFNg-positive (CD8/IFNg + IE1) was lower in CMV-infected patients. The predictive value of these variables at 30days was increased when they were combined. Cox regression analysis revealed an association between the risk of developing CMV infection and the combination marker (low anti-CMV titer [<16,100] and low CD8/IFNg + IE1 percentages [<0.40%], relative hazard, 6.07; p = 0.019). The combination marker remained significant after adjustment for clinical variables. This novel approach of a simultaneous assessment of specific anti-CMV antibody titers and CD8/IFNg + IE1 percentages might help identify heart transplant recipients with an increased risk of developing CMV infection.

Cytomegalovirus Infection after Prophylactic Valganciclovir Therapy Post–Kidney Transplantation: Case Reports

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

Cytomegalovirus infection and disease after allogeneic hematopoietic stem cell transplantation: experience in a center with a high seroprevalence of both CMV and hepatitis B virus

Cytomegalovirus (CMV) infection and disease are important concerns after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The similarity of hepatitis B virus (HBV) and CMV with regards to their chronic viral persistence and potential reactivation at the time of impaired cellular immunity has raised clinicians' interest in the occurrence and association between them among patients receiving allo-HSCT; however, only limited data have been obtained from a high seroprevalence region of both CMV and HBV. We monitored 117 adult allo-HSCT patients with both CMV polymerase chain reaction and pp65 antigenemia assay weekly until day 100. In 91.8% of our cases, donors and recipients were both CMV seropositive, and 13.7% of the patients were positive for HBV surface antigen. The incidences of CMV infection and disease were 45.3% and 6.8%, respectively. Grade II-IV acute graft-versus-host disease and anti-thymocyte globulin-containing conditioning regimen were associated with an increased risk of CMV infection in a multivariate analysis (hazard ratio 3.02, 95% CI 1.68-5.42, p < 0.001 and hazard ratio 5.29, 95% CI 2.57-10.8, p < 0.001). No survival disadvantage was found in patients who developed CMV infection (p = 0.699) and CMV disease (p = 0.093). No clinically significant HBV reactivation was found, and the underlying HBV infection in donors or recipients before allo-HSCT did not increase the risk of CMV infection and CMV disease and did not influence survival after allo-HSCT.

CMV Infection after Transplant from Cord Blood Compared to Other Alternative Donors: The Importance of Donor-Negative CMV Serostatus

Cytomegalovirus (CMV) infection and disease are important complications after hematopoietic stem cell transplant, particularly after transplant from alternative donors. Allogeneic cord blood transplantation (CBT) is being increasingly used, but immune recovery may be delayed. The aim of this study was to compare CMV infection in CBT with transplants from unrelated or mismatched related donors, from now on defined as alternative donors. A total of 165 consecutive transplants were divided in 2 groups: (1) alternative donors transplants (n = 85) and (2) CBT recipients (n = 80). Donor and recipient (D/R) CMV serostatus were recorded. The incidence of CMV infection, its severity, timing, and outcome were compared. Median follow-up was 257 days (1-1328). CMV infection was monitored by CMV antigenemia and expressed as CMV Ag positive cell/2 × 10(5) polymorphonuclear blood cells. There was a trend toward a higher cumulative incidence of CMV infection among CBT than alternative donor transplant recipients (64% vs 51%, P = .12). The median time to CMV reactivation was 35 days, and was comparable in the 2 groups (P = .8). The maximum number of CMV-positive cells was similar in the 2 groups (11 versus 16, P = .2). The time interval between the first and the last positive CMV antigenemia was almost 4 times longer in CBT compared with alternative donor transplants (109 vs 29 days, respectively, P = .008). The incidence of late CMV infection was also higher in CBT (62% vs 24%, P < .001). The incidence of early and late CMV infection in CBT was similar to D-/R+ alternative transplants, and higher than in D+/R+ alternative transplants: early infection, 72% in CBT versus 69% in D-/R+ alternative versus 55% in D+/R+ alternative (P = .21); and late infection, 67% in CBT versus 60% in D-/R+ alternative versus 7% in D+/R+ alternative (P < .001). Transplant-related mortality and overall survival were similar between the groups: 34% versus 36% (P = .6) and 54% versus 46% (P = .3) for alternative transplant and CBT, respectively. Longer duration and higher incidence of late CMV infection was seen in CBT patients, when compared with alternative donor transplants, whereas no difference in mortality was observed. The duration and incidence of late CMV infection were similar when D-/R+ CBT were compared with D-/R+ alternative donor transplants.