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Background: In kidney transplantation, concerns have been raised regarding increased incidence of viral opportunistic infections in hepatitis C virus (HCV) nucleic acid test (NAT)-negative (-) recipients who received HCV NAT-positive (+) donor kidneys, specifically BK polyomavirus (BKPyV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). The purpose of this study was to determine the incidence of these three viral opportunistic infections in HCV NAT- recipients who have undergone kidney transplantation with HCV NAT+ donor kidneys at our institution., Methods: This was an Institutional Review Board-approved, single-center, retrospective case-control study of HCV NAT- kidney transplant recipients with HCV NAT+ donors from 2018 to 2021. The primary outcome was the cumulative incidence of viral infections of BKPyV, CMV, and/or EBV within 1 year following kidney transplantation., Results: A total of 231 patients were included, 77 in the exposed (donor HCV NAT+) group and 154 in the control (donor HCV NAT-) group. The adjusted cumulative incidence of viremia within 1 year did not statistically differ between groups (77% exposed group versus 66% for the control group, hazard ratio 1.34, 95% confidence interval 0.95-1.89). In addition, no statistically significant differences were observed for secondary outcomes with the exception of CMV viremia (62% exposed versus 49% control, p = 0.021). However, there were more patients in the exposed group at high risk for CMV viremia based on serostatus (CMV Donor+/Recipient-, D+/R-)., Conclusion: Among patients who received HCV NAT+ donor kidneys, no clear association was observed between exposure to HCV NAT+ donor kidneys and viral infections of BKPyV, CMV, or EBV., (© 2024 Wiley Periodicals LLC.)

Background: Alemtuzumab is a lymphocyte depleting agent used for induction in kidney transplant, but long-term information on its use in pediatric recipients remains sparse., Methods: We performed a single-center retrospective cohort study of 57 pediatric kidney transplant recipients receiving alemtuzumab 20 mg/m 2 /dose ×2 doses for induction immunosuppression. All patients underwent surveillance biopsies, and 91.3% underwent steroid withdrawal by day 4 post-transplant. Outcomes of interest included graft survival, development of donor specific antibodies (DSA), incidence of viremia and PTLD, and duration of lymphopenia., Results: Median follow-up time was 7.9 years (IQR 5-13.6 years). Median graft survival was 16.5 years (95% CI 11.6-unknown). DSA developed in 36.5% at a median of 944 days (IQR 252-2113 days). Incidences of BK polyomavirus DNAemia (BKPyV-DNAemia), CMV DNAemia, and EBV DNAemia were 38.6%, 22.8%, and 14%, respectively; one patient developed PTLD at 13.3 years post-transplant. Median duration of lymphopenia was 365 days (IQR 168-713 days); 19.3% of patients remained lymphopenic at 3 years post-transplant. There was no association between duration of lymphopenia and graft survival, rejection, DSA detection, or viremia., Conclusions: A two-dose alemtuzumab induction protocol can have excellent outcomes with a steroid-free maintenance immunosuppression regimen. More comprehensive, multicenter, comparative studies of pediatric kidney transplant are needed to improve long-term outcomes., (© 2024 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Background: Recent studies suggest the transplantation of Hepatitis C (HCV) hearts from viremic donors is associated with comparable 1 year survival to nonviremic donors. Though HCV viremia is a known risk factor for accelerated atherosclerosis, data on cardiac allograft vasculopathy (CAV) outcomes are limited. We compared the incidence of CAV in heart transplant recipients from HCV viremic donors (nucleic acid amplification test positive; NAT+) compared to non-HCV infected donors (NAT-)., Methods: We retrospectively reviewed annual coronary angiograms with intravascular ultrasound from April 2017 to August 2020 at two large cardiac transplant centers. CAV was graded according to ISHLT guidelines. Maximal intimal thickness (MIT) ≥ 0.5 mm was considered significant for subclinical disease., Results: Among 270 heart transplant recipients (mean age 54; 77% male), 62 patients were transplanted from NAT+ donors. CAV ≥ grade 1 was present in 8.8% of the NAT+ versus 16.8% of the NAT- group at 1 year, 20% versus 28.8% at 2 years, and 33.3% versus 41.5% at 3 years. After adjusting for donor age, donor smoking history, recipient BMI, recipient, hypertension, and recipient diabetes, NAT+ status did not confer increased risk of CAV (HR.80; 95% CI.45-1.40, p = 0.43) or subclinical IVUS disease (HR.87; 95% CI.58-1.30, p = 0.49). Additionally, there was no difference in the presence of rapidly progressive lesions on IVUS., Conclusion: Our data show that NAT+ donors conferred no increased risk for early CAV or subclinical IVUS disease following transplantation in a cohort of heart transplant patients who were treated for HCV, suggesting the short-term safety of this strategy to maximize the pool of available donor hearts., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Cytomegalovirus (CMV) infection is the most common infection following pediatric liver transplantation (LT). Preemptive therapy (PET) is an approach to initiate antiviral treatment for asymptomatic early CMV viremia detected by surveillance testing. However, data on CMV infection after PET are scarce, and the optimal cut-off remains controversial. This study aimed to evaluate the incidence, risk factors, and consequences of CMV infection in pediatric LT using 2 different viral load (VL) cut-offs., Methods: We retrospectively reviewed patients aged 0-18 years who underwent LT at Ramathibodi Hospital between March 2001 and August 2020. Demographic data, CMV infection, CMV treatment, and consequences of CMV infection were collected. CMV viremia was monitored by a quantitative nucleic acid amplification test. Clinical outcomes were compared after starting antiviral therapy at a low (>400 but <2000 IU/mL) and a high VL cut-off (≥2000 IU/mL)., Results: A total of 126 patients were included. CMV infection was 71% (90/126), with an incidence rate of 5.5 per 1000 patient-day. Higher tacrolimus and prednisolone dosages were associated with CMV infection with an adjusted hazard ratio of 1.2 (95%CI 1.0-1.4, p = .02) and 2.4 (95%CI 1.9-3.4, p < .001), respectively. The consequences of CMV infection did not differ significantly for the low and high CMV VL cut-off groups., Conclusion: CMV infection in LT recipients is common and is associated with higher tacrolimus and corticosteroid dosage. Additionally, using the CMV VL cut-off at 2000 IU/mL to initiate antiviral therapy is practical and effective in preventing CMV disease., (© 2023 Wiley Periodicals LLC.)

BK viremia is endemic among kidney transplant recipients (KTRs). Incidence, risk factors, outcomes, and clinical management of detectable versus high BK viremia have not been considered previously in KTR in the modern era. This observational study examined KTR transplanted between January 1, 2009 and December 31, 2016. Any BK viral load in the serum constituted detectable BK viremia and ≥10 3 copies/ml constituted high viremia. Among 1193 KTRs, the cumulative probability of developing detectable and high BK viremia within 2 years posttransplant were 27.8% and 19.6%, respectively. Significant risk factors for detectable BK viremia included recipient age (HR 1.02 [95% CI: 1.01, 1.03]) and donor age (HR 1.01 [95% CI: 1.00, 1.02]). Recipient age also predicted high BK viremia (HR 1.02 [95% CI: 1.01, 1.03]), whereas White race (HR 0.70 [95% CI: 0.52, 0.95]), nondepleting induction therapy (HR 0.61 [95% CI: 0.42, 0.89]), and delayed graft function (HR 0.61 [95% CI: 0.42, 0.88]) were protective. Mean estimated glomerular filtration rates were 4.28 ml/min/1.72 m 2 (95% CI: 2.71, 5.84) lower with detectable BK viremia. Although low viral load was usually not acted upon at first presentation, antiproliferative dose reductions were the most common initial management. BK viremia remains a common early complication in a modern cohort of KTRs. These findings highlight the benefit of early BKV monitoring in addition to intensive clinical management. Clinical responses beyond first positive BK viremia tests, and their implications for graft outcomes, merit further investigation., (© 2022 Wiley Periodicals LLC.)

Background: Cytomegalovirus infection represents a significant cause of morbidity and mortality after hematopoietic stem cell transplantation. This study aimed to evaluate the incidence of viremia and disease due to cytomegalovirus and the risk factors in pediatric patients with hematopoietic stem cell transplantation in our institution., Methods: This was a retrospective cohort of patients under 19 years of age who underwent allogeneic hematopoietic stem cell transplantation due to any indication between 2012 and 2019. The analysis included the diagnosis of cytomegalovirus viremia or disease during post-transplant follow-up, evaluation of risk factors, and outcomes. The statistical analysis included univariate and multivariate analyses, and the cumulative incidence of cytomegalovirus viremia was determined by the Kaplan-Meier method using STATA 14 statistical software., Results: A total of 182 transplants were included. At 100 days, the cumulative incidence of cytomegalovirus viremia was 70.5%, and that of cytomegalovirus disease was 4.7%. Overall survival at 2 years was 74%, and event-free survival was 64%. The remaining demographic characteristics were not predictors of infection. There was no association between viremia and relapse or survival of the patients. Higher mortality was noted in cytomegalovirus disease., Conclusions: During the study period, the incidence of cytomegalovirus disease was similar to that of other pediatric reports, but the incidence of viremia was higher. Pre-emptive therapy has diminished disease rates and death due to infection. Viral load cutoff points should be standardized to guide treatment and avoid myelotoxicity., (© 2022 Wiley Periodicals LLC.)

Background: Improved short- and long-term outcomes of kidney transplantation have been achieved over the past decades due to improved immunosuppression. This may have increased the risk for infections and, particularly, for the viral infections: cytomegalovirus (CMV), Epstein-Barr virus (EBV), and polyoma BK virus (BKV)., Methods: A retrospective review of viremic CMV, EBV, and BKV infections in pediatric renal transplant recipients treated and followed by a national referral center over a 10-year period., Results: Sixty-seven patients (68% males) received 68 kidney grafts (62% from living donors) during the study period; the mean follow-up period was 5.2 ± 2.4 years. Twenty-seven viremic episodes were documented (CMV: 13, EBV: 6, BKV: 8) in 24 patients (35.2%). The median time (interquartile range) to viremia post-transplant was 11 (4-38) months. The viral infection rate was significantly higher in the years 2014-2015 than in previous years (61% vs. 29%, p = .017). Compared to patients who did not develop viremia, patients with viremias were younger at the time of transplantation, were more likely to receive thymoglobulin induction pre-transplant and to develop an acute rejection. Multiple logistic regression modeling identified transplant year and recipient's age as significant risk factors for viremia. Graft outcome and eGFR at the last follow-up was similar between patients who did and did not develop viremia., Conclusions: Viral infections continue to be a major cause of morbidity in pediatric kidney transplant recipients. However, with close monitoring and prompt intervention, patient and renal outcomes remain favorable., (© 2021 Wiley Periodicals LLC.)

Introduction: BK polyomavirus (BKV) is a common infection among kidney transplant recipients (KTR). Risk factors and outcomes based on donor characteristics remain largely unknown., Methods: In this study, we aimed to analyze the impact of donor factors through a paired kidney analysis. We included 289 pairs of adult deceased donor transplants (578 KTRs total); each pair had received kidneys from the same donor. Recipient pairs were divided into three groups: "no BK group" if neither KTR developed BK viremia (n = 336), "discordant" if the only one did (n = 176), and "concordant" if both did (n = 66). Acute rejection (AR), graft failure, and BK nephropathy (BKN) were outcomes of interest., Results: Donors in the concordant group were younger, had lower kidney donor profile index (KDPI), and were less likely to be donor after circulatory death (DCD). In multivariate analyses, KTRs who had a donor with a higher body mass index (BMI) (hazard ratio (HR): 0.97; 95% confidence interval (CI): 0.95-0.99; p = .009) were less likely to develop BKV. Concordance was not associated with AR (HR: 0.83; 95% CI: 0.51-1.34; p = .45), graft failure (HR: 1.77; 95% CI: 0.42-7.50; p = .43), or BKN (HR: 1.02; 95% CI: 0.51-2.03; p = .96)., Discussion: Our study suggests lower donor BMI is associated with BKV infection, and concordance or discordance between paired kidney recipients is not associated with poor outcomes., (© 2021 Wiley Periodicals LLC.)

Background: Immunomodulatory effects attributable to cytomegalovirus (CMV) would predispose to BK polyomavirus (BKPyV) infection after kidney transplantation (KT), although available evidence is conflicting. It has been suggested that (val)ganciclovir therapy may increase the risk of BKPyV viremia and BKPyV-associated nephropathy (BKPyVAN) as a result of drug-induced T-cell impairment., Methods: We investigated whether CMV replication and/or (val)ganciclovir exposure (either as prophylaxis or treatment) were associated with the development of BKPyV viremia or BKPyVAN in a prospective cohort of 399 KT recipients. CMV infection (any level or high-level viremia and area under the curve of DNAemia) and (val)ganciclovir exposure (any duration of therapy and cumulative days of treatment) during the first post-transplant year were explored through separate landmark survival analyses., Results: Cumulative incidence of BKPyV viremia and BKPyVAN after a median follow-up of 551 days was 23.1% and 2.5%, respectively. One-year rates of CMV infection and (val)ganciclovir therapy were 47.4% and 54.1%, respectively. No differences were observed in BKPyV viremia- or BKPyVAN-free survival according to previous CMV infection or (val)ganciclovir exposure in any of the landmark analyses. Adjusted Cox models confirmed this lack of association., Conclusion: Our findings do not confirm the existence of a relevant impact of CMV infection or (val)ganciclovir therapy on the risk of post-transplant BKPyV events., (© 2021 Wiley Periodicals LLC.)

Introduction: Viral infections pose a serious risk for children undergoing hematopoietic stem cell transplant (HSCT). There are few published case series of prevalence, risk factors, and outcomes examining multiple viruses simultaneously, and no pediatric Australasian data published to date. We describe the real-life experience of viremia in pediatric HSCT in a single tertiary center., Methods: All episodes of viremia in children undergoing HSCT between 2000 and 2018 were identified by matching HSCT patients' unique identification numbers with positive blood polymerase chain reaction (PCR) results for human adenovirus (HAdV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpes virus 6 (HHV-6). Paper or electronic charts and electronic pathology results were used to extract the study variables., Results: Viremia was detected in 177/445 (39.8%) HSCT episodes, of which 46% were allogeneic and 19% autologous transplants. Viremia was disseminated in 96 (21.6%) episodes, with 80 (18%) having more than one virus. HAdV was detected in 108 (24.3% of total episodes) and frequently in autologous transplants, CMV in 71 (16.0%), EBV in 60 (13.5%), and HHV-6 in 38 (8.5%). Of 174 children, 19 (10.9%) died of a viral-associated cause, with viral mortality highest in CMV (18.3%), lowest in HHV-6 (2.6%) with HAdV and EBV similar (6.6% and 6.7%). Adenoviral (but not other virus) dissemination was significantly associated with lower lymphocyte count at time of first detection. CMV dissemination and death were significantly associated with initial and highest CMV viral loads (copies/mL)., Conclusion: This study presents the first pediatric-specific Australasian data for viremia in HSCT. Findings may help guide clinicians in prophylaxis and treatment decisions., (© 2021 Wiley Periodicals LLC.)

Background: Adenovirus (AdV) is increasingly recognized as a threat to successful outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Guidelines have been developed to inform AdV screening and treatment practices, but the extent to which they are followed in clinical practice in the United States is still unknown. The incidence of AdV in the United States is also not well documented. The main objectives of the AdVance US study were thus to characterize current AdV screening and treatment practices in the United States and to estimate the incidence of AdV infection in allo-HCT recipients across multiple pediatric and adult transplant centers., Methods: Fifteen pediatric centers and 6 adult centers completed a practice patterns survey, and 15 pediatric centers and four adult centers completed an incidence survey., Results: The practice patterns survey results confirm that pediatric transplant centers are more likely than adult centers to routinely screen for AdV, and are also more likely to have a preemptive AdV treatment approach compared to adult centers. Perceived risk of AdV infection is a determining factor for whether routine screening and preemptive treatment are implemented. Most pediatric centers screen higher-risk patients for AdV weekly, in blood, and have a preemptive AdV treatment approach. The incidence survey results show that from 2015 to 2017, a total of 1230 patients underwent an allo-HCT at the 15 pediatric transplant centers, and 1815 patients underwent an allo-HCT at the 4 adult transplant centers. The incidences of AdV infection, AdV viremia, and AdV viremia ≥ 1000 copies/mL within 6 months after the first allo-HCT were 23%, 16%, and 9%, respectively, for patients at pediatric centers, and 5%, 3%, and 2%, respectively, for patients at adult centers., Conclusions: These findings provide a more recent estimate of the incidence of AdV infection in the United States, as well as a multicenter view of practice patterns around AdV infection screening and intervention criteria, in pediatric and adult allo-HCT recipients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The risk of subsequent cytomegalovirus infection (CMV) in kidney transplant recipients (KTR) after diagnosis of BK polyomavirus viremia (BKV) is unclear, and current evidence is conflicting. We reviewed all KTR transplanted at our institution between 1/1/2005 and 12/31/2015. Follow-up began 3 months after transplantation to avoid confounding effects of prophylaxis. Clinically significant BKV, defined as detectable BK viremia >1000 copies/mL via molecular diagnostic testing (PCR), was treated as a time-varying exposure with 1-year follow-up. This viral load cutoff was chosen to ensure a more homogenous population that would be considered to have clinically significant BK viremia that necessitated management via immunosuppressive modification. Patients were then screened for subsequent CMV infection. 2435 RTX recipients met inclusion criteria; of these, 314 developed BKV during follow-up (BK+). Lymphocyte depletion, tacrolimus maintenance, and biopsy-proven rejection were significantly higher in the BK+ group. BK+ was associated with lower risk of subsequent CMV infection (BK+ HR 0.45, 95% CI 0.22-0.94, P = .03, relative risk reduction 55%). When adjusted for significant confounding factors, CMV incidence remained reduced in the BK+ population (HR 0.47, 95% CI 0.22-0.98, P = .04). This large series of KTR demonstrates that BKV is associated with lower risk of subsequent CMV infection., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: We examined the burden of CMV DNAemia and time to such events among renal transplant patients receiving CMV prophylaxis. We targeted the first year after transplantation, with the primary focus being on the first 3 months., Methods: We conducted a retrospective review of renal transplant patients (<18 years) who were transplanted and followed at our center between January 2007, and December 2017. Clinical and laboratory data were obtained from the medical records and laboratory databases., Results: Among 141 patients, the median age at transplant was 12.7 years (range 0.87-17.83 years). CMV DNAemia was detected in 33 of 77 patients eligible for prophylaxis (42.9%; 95% CI 31.6-54.6) during the first post-transplant year. Proportionately more D+R- patients were present among patients with DNAemia compared with those without DNAemia (15/38, 39.5% vs 16/103, 15.5%, P = .005). Median time to first positivity was 134 days (range 0-304 days). Eight patients had a positive PCR during the first 3 months (5.7% of all patients). Among those eligible for prophylaxis, 6.5% had DNAemia during the first 3 months while on prophylaxis. Among patients whose first positive PCR was after 3 months post-transplant, the median time to positivity was 52 days (range 13-214 days) after the end of prophylaxis., Conclusions: Breakthrough CMV DNAemia was documented among children receiving antiviral prophylaxis. While routine monitoring while on prophylaxis might not be warranted for the majority of patients, studies are needed to determine the optimal indications for CMV PCR testing while on prophylaxis., (© 2019 Wiley Periodicals, Inc.)

The renal survival rate of pediatric renal transplant recipients (pRTR) has improved with the use of modern immunosuppressive agents; however, the incidence of post-transplantation viral infection has increased. This study investigated the incidence of BK viremia and BK viral-associated nephropathy (BKVAN) in pRTR. One-hundred-and-thirty-four pRTR were divided into two groups: group 1 (n = 20, 14.9%) comprised those who were prospectively followed with longitudinal analyses after renal transplantation in the time period from May 2007 to June 2008, while group 2 (n = 114, 85.1%) cross-sectional study of those who were transplanted from January 1994 to April 2007. The mean ages at transplantation in groups 1 and 2 were 10.6 ± 4.7 years and 7.8 ± 4.5 years, respectively. BK viremia was detected in four (20.0%) patients in group 1, and seven (6.1%) in group 2 (P = 0.04), with increased incidence associated with induction therapy. The median time to detection of BK viremia after transplantation was 44 days in group 1 and 142 days in group 2. BKVAN was diagnosed in three patients (two in group 1 and one in group 2). All three patients diagnosed with BKVAN were receiving tacrolimus, mycophenolate mofetil, and corticosteroids as maintenance immunosuppression. Reducing immunosuppression resulted in reduced BK viremia. Monitoring for BK viremia and BKVAN is important in pRTR being treated with the current immunosuppressive regimen. The first line of treatment for BK viremia remains careful reduction of immunosuppression and close monitoring of renal allograft function., (© 2019 Wiley Periodicals, Inc.)

Background: BKPyV is an important cause of premature graft failure after KT. Most clinical studies describe BKPyV infection in adult KT patients. We studied the prevalence of post-transplant BKPyV viremia, serology, and graft function in pediatric KT recipients., Methods: Forty-six pediatric patients transplanted between 2009 and 2014 were followed up for BKPyV DNAemia by plasma PCR for median 2.3 (range: 1-6) years. BKPyV-specific antibodies were retrospectively analyzed using virus-like particle ELISA. GFR was measured annually by 51 Cr-EDTA clearance, and serum samples were screened for DSAs by Luminex assay., Results: BKPyV viremia was demonstrated in nine patients at a median of 6 months post-KT. Early BKPyV viremia at 3 months post-KT associated with decreased concomitant GFR and tendency for decreased subsequent graft function. Three of nine patients with BKPyV viremia developed DSA, all against class II antigens. PyVAN developed to four patients and responded to judicious reduction in IS. One graft was lost later due to ABMR. BKPyV-IgG was found in 18 of 31 patients (58%) tested at transplantation, and seven recipients seroconverted after transplantation with a significant increase in IgG levels with IgM. Finally, BKPyV-IgG was detectable in 31 of 40 patients (78%) at the end of the study., Conclusions: Post-transplant BKPyV viremia in pediatric KT patients may alter graft function and contribute to progression of chronic allograft injury. BKPyV-IgG predicts past exposure. Low or absent BKPyV-specific antibody levels were seen pretransplant in 42% of tested patients, but were not predictive of prolonged replication or poor outcome., (© 2018 Wiley Periodicals, Inc.)

Background: There is a growing need for robust antimicrobial stewardship interventions in both ambulatory and solid organ transplant (SOT) populations., Methods: A retrospective quasi-experiment was conducted to evaluate the impact of a pharmacist-driven antimicrobial stewardship intervention targeting cytomegalovirus (CMV) viremia in ambulatory SOT recipients. The intervention consisted of (a) real-time CMV DNA surveillance and result notification conducted by the pharmacist and (b) recommendations for the optimization of drug therapy provided at the time of result notification. The intervention period was compared to a pre-intervention period of usual care. Of 431 adult SOT recipients who had an initial quantifiable CMV viral load in the ambulatory setting, 185 received antiviral induction therapy and were included for analysis., Results: Significantly fewer patients in the intervention period reached a CMV viral load >10 000 IU/mL immediately prior to treatment (10.6% vs 27.3%; P = 0.004), and a significantly greater proportion of patients in the intervention period achieved CMV eradication at 21 days (84.5% vs 71.7%; P = 0.038). Additional differences favoring the intervention period were antiviral initiation within 5 days of the first quantifiable CMV DNA (62.4% vs 55.0%; P = 0.02) and time-to-CMV eradication (25.5 vs 28.9 days; P = 0.003). Although not significant, there were also numerical reductions in CMV-related hospital admissions (11.9% vs 19.0%; P = 0.188) and CMV disease (5.9% vs 12.0%; P = 0.151) during the intervention period, as well as fewer episodes of CMV resistance at 1-year (2.3% vs 4.0%; P = 0.689)., Conclusion: Together, these findings suggest a potential role for pharmacist involvement in CMV surveillance and treatment optimization in ambulatory SOT recipients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is a consequence of BKPyV replication in the urinary tract in kidney transplant recipients (KTR)., Objectives: The objectives were to determine the prevalence of BKPyV replication and BKPyVAN, risk factors associated to sustained viremia and BKPyVAN, and viremia cut-off that best predict the occurrence of sustained viremia and nephropathy in KTR of a single University Hospital Kidney Transplant Center., Patients and Methods: All KTR undergoing transplantation from August 2010 to December 2011 were enrolled and monitored up to 2 years posttransplantation for BKPyV viruria by decoy cells shedding or polymerase chain reaction (PCR) and viremia by PCR. Kidney biopsy was indicated if sustained viremia (two or more viremia above 10 000 copies/mL) to confirm BKPyVAN diagnosis., Results: In this study, 326 transplants were performed and 246 patients were included. Prevalence of viruria was 36.9%, viremia 22.3% and nephropathy 3.2%. Male gender was the only risk factor associated to sustained viremia or nephropathy. Cut-off value of viremia that best discriminates the progression to sustained viremia and to BKPyVAN was 37 488 and 44 956 copies/mL, respectively., Conclusions: Prevalence of viruria, viremia, and nephropathy were similar to those reported in literature but the cut-off value of viremia that best discriminates the risk of progression to nephropathy was greater than the value usually reported, which is 10 000 copies/mL., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Most studies of post-transplant CMV infection have focused on either solid organ or hematopoietic cell transplant (HCT) recipients. A large prospective cohort study involving both lung and HCT recipients provided an opportunity to compare the epidemiology and outcomes of CMV infections in these 2 groups., Methods: Patients were followed up for 30 months in a 6-center prospective cohort study. Data on demographics, CMV infections, tissue-invasive disease, recurrences, rejection, and immunosuppression were recorded., Results: The overall incidence of CMV infection was 83/293 (28.3%) in the lung transplant group and 154/444 (34.7%) in the HCT group (P = .0706). Tissue-invasive CMV disease occurred in 8/83 (9.6%) of lung and 6/154 (3.9%) of HCT recipients with CMV infection, respectively (P = .087). Median time to CMV infection was longer in the lung transplant group (236 vs 40 days, P < .0001), likely reflecting the effects of prophylaxis vs preemptive therapy. Total IgG levels of < 350 mg/dL in lung recipients and graft vs host disease (GvHD) in HCT recipients were associated with increased CMV risk. HCT recipients had a higher mean number of CMV episodes (P = .008), although duration of viremia was not significantly different between the 2 groups. CMV infection was not associated with reduced overall survival in either group., Conclusions: Current CMV prevention strategies have resulted in a low incidence of tissue-invasive disease in both lung transplant and HCT, although CMV viremia is still relatively common. Differences between the lung and HCT groups in terms of time to CMV and recurrences of CMV viremia likely reflect differences in underlying host immunobiology and in CMV prevention strategies in the modern era., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: We sought to determine whether conversion from tacrolimus/mycophenolate mofetil (TAC-MMF) into tacrolimus/mTOR inhibitor (TAC-mTOR) immunosuppression would reduce the incidences of BK and CMV viremia after kidney/pancreas (KP) transplantation., Methods: In this single-center review, the TAC-mTOR cohort (n = 39) was converted at 1 month post-transplant to an mTOR inhibitor and reduced-dose tacrolimus. Outcomes were compared to a cohort of KP recipients (n = 40) maintained on TAC-MMF., Results: At 3 years post-transplant, KP survivals and incidences of kidney/pancreas rejection were equivalent between mTOR and MMF-treated cohorts. (P = ns). BK viremia-free survival was better for the mTOR vs MMF-treated group (P = .004). In multivariate analysis, MMF vs mTOR immunosuppression was an independent risk factor for BK viremia (hazard ratio 12.27, P = .02). Similarly, mTOR-treated recipients displayed better CMV infection-free survival compared to the MMF-treated cohort (P = .01). MMF vs mTOR immunosuppression (hazard ratio 18.77, P = .001) and older recipient age (hazard ratio 1.13 per year, P = .006) were independent risk factors for CMV viremia. Mean estimated GFR and HgbA1c levels were equivalent between groups at 1, 2, and 3 years post-transplantation., Conclusion: Conversion from TAC/MMF into TAC/mTOR immunosuppression after KP transplantation reduced the incidences of BK and CMV viremia with an equivalent risk of acute rejection and similar renal/pancreas function., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: There is a paucity of data available about BK polyomavirus (BKPyV) infection after renal transplantation (RTX) in resource-limited countries with a predominantly living-donor, ABO-compatible RTX program. We aimed to assess BKPyV infection in such patients in a public hospital in India., Methods: We prospectively evaluated plasma BKPyV replication in 62 patients at 1, 3, 6, 9, and 12 months after RTX. Sustained significant BK viremia (SSBKV) was defined as significant viremia (≥10 000 copies/mL) detected ≥2 times, and BKPyV-associated nephropathy (BKVAN) as histologic changes of BKVAN with BK viremia with/without graft dysfunction., Results: All patients underwent RTX without requiring desensitization. Incidence of BK viremia was: 17.7%, 41.9%, 16.1%, 25.8%, and 17.7% at 1, 3, 6, 9, and 12 months, respectively. Of 62 patients, 64.5% had BKPyV viremia during the study, 32.2% had significant viremia, all except one detected in the first 6 months. Nine (14.5%) patients had SSBKV. There was no biopsy-proven BKVAN. At the end of 1 year, mean serum creatinine was higher and graft dysfunction was significantly more common in patients with SSBKV compared to those without SSBKV., Conclusion: Transient BK viremia is common in low/intermediate immunologic risk RTX recipients in India, with a peak occurring at 3-6 months. Most clear their viremia by 12 months. Graft dysfunction seems to be more frequent in patients with SSBKV, although BKVAN is uncommon on biopsy in these patients., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Epstein-Barr virus (EBV) poses a significant threat to patient and graft survival post-transplant. We hypothesized that recipients who shed EBV at transplant had less immunologic control of the virus and hence were more likely to have active EBV infection and disease post-transplant. To test this hypothesis, we conducted a 5-year prospective study in primary solid organ transplant recipients. We measured EBV DNA in oral washes and blood samples by quantitative PCR before transplant and periodically thereafter for up to 4 years. Pre-transplant samples were available from 98 subjects. EBV DNA was detected pre-transplant in 32 of 95 (34%) and 5 of 93 subjects (5%) in oral wash and blood, respectively. Recipients with and without detectable pre-transplant EBV DNA were not significantly different demographically and had no significant difference in patient and graft survival (P = .6 for both comparisons) or post-transplant EBV viremia-free survival (P = .8). There were no cases of EBV-related disease or post-transplant lymphoproliferative disorder (PTLD) in any of the patients with detectable EBV DNA pre-transplant. In conclusion, detectable EBV DNA pre-transplant was not associated with differences in patient/graft survival, post-transplant EBV viremia, or EBV-related diseases including PTLD., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: While screening for asymptomatic BK viremia (BKV) has been well studied in isolated kidney transplant recipients, there is a paucity of published outcomes in simultaneous pancreas-kidney (SPK) transplant recipients who underwent BKV screening followed by pre-emptive reduction in immunosuppression., Methods: This is a single-center, retrospective review of 31 consecutive SPK recipients who were transplanted over a 5-year period following the initiation of a serum BKV screening protocol., Results: BK viremia developed in 11 (35.5%) patients, and all patients achieved complete viral clearance following reduction in immunosuppression. Two patients (6.5%) developed BK virus nephropathy, but both had preserved allograft function. One patient developed mild rejection of the kidney allograft following clearance of BKV, and two patients developed mild rejection of the pancreas allograft after reduction in immunosuppression, but there were no kidney or pancreas allograft losses due to rejection. The development of BK viremia did not impact overall patient survival or kidney and pancreas allograft survival., Conclusion: Screening asymptomatic SPK recipients for BKV followed by reduction in maintenance immunosuppression appears to be an effective strategy to prevent kidney allograft dysfunction and graft loss due to BK virus nephropathy, without compromising pancreas allograft outcomes., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pediatric patients requiring kidney transplant after hematopoietic cell transplant receive multiple courses of immunosuppression placing them at risk for infection. To elucidate potential risk factors for infection, we compared the immunosuppressive regimens and infectious complications of pediatric kidney transplant recipients at a single institution who had previously undergone hematopoietic cell transplant from different donors to similar patients reported in the literature. Among the initial four post-hematopoietic cell transplant kidney transplant patients reviewed, viremia episodes were universal, including BK virus, Epstein-Barr virus, and human herpesvirus-6, with one death from presumed BK virus encephalitis. No viremia was reported in five similar cases in the literature. Risk factors for increased infection include use of lymphodepleting serotherapy in HCT conditioning, multiple HCTs, limited immune reconstitution time between transplants, increased pre-KTx viral burden, and use of T-cell-depleting versus -suppressive induction immunosuppression for KTx. These findings suggest that pediatric post-HCT KTx recipients are at increased risk for viral infections, likely benefitting from thorough pre-KTx evaluation of immune reconstitution and preferential use of non-T-cell-depleting induction therapy for KTx. We applied these recommendations to one subsequent post-HCT patient requiring KTx at our institution with excellent outcomes one year post-KTx., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: It remains unclear whether overall degree of immunosuppression or specific effects of individual immunosuppressive agents are causal for increased occurrence of BK polyomavirus (BKPyV) infection in renal transplant recipients (RTR)., Methods: A prospective, multicenter, open-label randomized controlled trial in 361 de novo RTR was performed. A total of 224 RTR were randomized at 6 months into three treatment groups with dual therapy consisting of prednisolone (Pred) plus either cyclosporine (CsA), mycophenolate sodium (MPS), or everolimus (EVL). Primary outcomes were incidence of BK viruria, BK viremia, and BKPyV-associated nephropathy (BKVAN)., Results: From 6 months, incidence of BK viruria in the MPS group (43.6%) was significantly higher than in the other groups (CsA: 16.9%, EVL: 19.8%) (P=.003). BKVAN was diagnosed in 3 patients, all treated with MPS (7.8%, P=.001). Longitudinal data analysis showed a lower BKPyV load and a significantly faster clearance of BK viruria in the CsA group compared to the MPS group (P=.03)., Conclusions: Treatment with MPS was associated with an increased incidence of BK viruria. Dual immunosuppressive therapy with CsA and Pred was associated with the lowest rate of BKPyV replication and the fastest clearance of the virus., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: BK polyomavirus virus (BKPyV) screening and immunosuppression reduction effectively prevent graft loss due to BKPyV-associated nephropathy (BKPVAN) during the first year after transplantation. The aim of our study was to evaluate the impact of this infection during longer follow-up periods., Methods: We reviewed the outcome of our screening and immunosuppression reduction protocol in 305 patients who received a kidney transplant between March 2008 and January 2013. Quantitative BKPyV DNA surveillance in plasma was performed at 1, 2, 3, 6, 9, and 12 months after transplantation. Patients with significant viremia and/or biopsy-proven BKPVAN were treated with immunosuppression reduction and leflunomide., Results: During the first post-transplant year, 24 patients (7.9%) developed significant viremia at a median time of 95 days, and 18 patients had BKPVAN; 23 of the 24 (7.5%) were treated according to our protocol (group BKV+); 225 patients (73.8%) did not develop any BK viremia (group BKV-). Allograft function was similar in both groups at 1 month post transplantation (P=.87), but significantly worse at 1 year in the BKV+ group (P=.002). Thereafter, kidney function stabilized in the BKV+ group and no differences in patient and graft survival were seen between the groups after a median follow-up of 4 years., Conclusions: We confirm the early occurrence of BKPyV replication after transplantation and the short-term decline in renal function. However, early detection of BKPyV replication, prompt diagnosis, and reduction in immunosuppression may offer long-term benefits for graft function., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: As immunosuppressive therapy and allograft survival have improved, the increased incidence of sepsis has become a major hurdle of disease-free survival after renal transplantation., Methods: We identified 112 of 957 kidney transplant recipients (KTRs) with sepsis. In all, 31 KTRs developed severe sepsis or septic shock, and 30 KTRs died from sepsis. KTRs without sepsis were used for comparison. CMV-specific and alloreactive T cells were measured using an interferon-γ Elispot assay. The extent of immunosuppression was quantified by lymphocyte subpopulations., Results: Five-year patient survival was 70.3% with sepsis compared to 88.2% without (P<.001). Five-year estimated glomerular filtration rate was lower in KTRs developing sepsis (P<.001). Upon multivariate analysis, diabetes, lymphocyte-depleting induction, donor age, CMV replication, and acute rejection increased the risk of sepsis (P<.05). Age, diabetes, underweight/obesity, and pneumonia as site of infection were predictive factors of mortality (P<.05). Early-onset sepsis was associated with decreased CD3+ and CD4+ T cells pre-transplantation (P<.05). Impaired CMV-specific cellular immunity pre-transplantation was associated with CMV replication and early-onset sepsis (P<.05). High frequencies of alloreactive T cells were associated with acute rejection, lymphocyte-depleting rejection treatment, and early-onset sepsis (P<.05)., Conclusion: KTRs developing sepsis show inferior patient survival and allograft function. Identified risk factors and differences in lymphocyte counts, CMV-specific immunity, and alloreactivity may prove useful to identify KTRs at increased risk., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

JC polyomavirus-associated nephropathy (JC-PVAN) is a rare but challenging cause of renal dysfunction. We report JC-PVAN in a renal allograft recipient and highlight the obstacles in definitive diagnosis of this disease entity. A deceased-donor renal transplant recipient was diagnosed with JC polyomavirus nephritis 4 years after transplantation. Immunosuppressive agents were subsequently reduced, resulting in an initial stabilization of renal function. We present this interesting case and discuss the challenges with diagnosing and treating this rare entity., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Ureteral stents are used in kidney transplantation (KTX) to decrease post-operative complications, but they are associated with BK polyomavirus viremia (BKV). Our primary outcome was to determine the association between ureteral stent duration and BKV. Secondary outcome measures were the association between bacteriuria and stent duration or use of ureteral stent strings., Methods: Between January 2010 and January 2015, 403 patients underwent KTX at the Virginia Mason Medical Center and met inclusion criteria. Stent duration was classified as short (<3 weeks) or long (>3 weeks). Multivariate logistic regression models were created to assess for factors associated with BKV. The covariates in the BKV model were chosen a priori based on stent duration and risk factors previously described in the literature., Results: Ureteral stents were placed in 304 (75.4%) transplants. Stent strings were left attached in 166 (54.6%) patients. On multivariate analyses, long stent duration was significantly associated with increased risk of BKV compared with no stent (odds ratio [OR] 1.92, P=.044, 95% confidence interval [CI] 1.04-3.74). Short stent duration was not associated with BKV. Sixty-two (15.4%) patients had bacteriuria. Bacteriuria was associated with female gender (OR 2.77, P<.001, 95% CI 1.58-4.95), and there was a dose-dependent effect with stent duration compared with no stent-short duration (OR 2.46, P=.049, 95% CI 1.05-6.49) and long duration (OR 3.58, P=.004, 95% CI 1.58-9.25). Stent strings were not associated with either complication., Conclusions: The association between ureteral stents and BKV may be dose dependent., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The use of T-cell replete haploidentical hematopoietic cell transplant (haplo-HCT) has increased substantially since the introduction of post-transplant cyclophosphamide (PTCy) regimens. Limited data exist concerning infectious complications of haplo-HCT utilizing mobilized peripheral blood (PB) hematopoietic cells., Methods: This retrospective cohort study included all adult patients at our institution undergoing PB haplo-HCT with PTCy between June 2009 and June 2015. Infections were microbiologically confirmed. Invasive fungal infections (IFI) classified as "proven" or "probable" by standard definitions were included., Results: In total, 104 patients were identified. Median follow-up was 218 days (range: 6-1576). A total of 322 episodes of infection were recorded. Eighty-nine percent of patients experienced at least one infection. Median time to first infection was 22 days. Patients experiencing at least one bacterial, viral, and IFI were 62%, 72%, and 6%, respectively. The majority (69%) of bacterial infections were caused by enteric organisms. Seven cases of Staphylococcus aureus infection were recorded, with one bacteremia case. Cytomegalovirus (CMV) viremia occurred in 54/71 (76%) at-risk patients at a median time of 24 days. Sixteen (15%) patients developed CMV disease. Nineteen percent (20/104) of patients developed BK polyomavirus-associated cystitis. Six (6%) patients experienced a total of seven IFI. Infection was the primary cause of death for 12% (6/51) of patients and was a secondary cause for 41%., Conclusion: In PB haplo-HCT patients, a high incidence of CMV viremia and disease was observed. Infections with enteric bacteria were common. Fungal and staphylococcal infections were uncommon. Further studies are needed to compare infectious complications in haplo-HCT with other transplant modalities., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: BK polyomavirus (BKV) infection and BKV nephropathy (BKVN) are risk factors for allograft function and survival., Methods: We retrospectively analyzed BK viremia and BKVN in 348 patients who received a kidney transplantation donated after brain death (n=232) or living donation (n=116) between 2008 and 2013. A total of 266 patients were treated with standard immunosuppression consisting of basiliximab induction, calcineurin inhibitor (CNI), and mycophenolic acid (MPA, n=219) or everolimus (n=47); 82 patients received more intense immunosuppression with lymphocyte depletion, CNI and MPA (n=38) or everolimus (n=44)., Results: BK viremia occurred in 33 (9.5%) patients in the first year and in 7 (2.0%) recipients in the second year after transplantation. BKVN occurred in 4 (1.1%) patients in the first year. Donor and recipient age, diabetes, previous transplantation, and type of transplantation (donated after brain death vs living donation) were not risk factors (P>.05). BK incidence did not differ depending on induction or maintenance immunosuppression., Conclusion: Incidence of BK viremia is independent of recipient characteristics, type of transplantation as well as induction and maintenance immunosuppression., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

BK virus-(BKV) associated nephropathy (BKVN) is a major cause of allograft injury in kidney transplant recipients. In such patients, subclinical reactivation of latent BKV infection can occur in the pre-transplant period. The purpose of this study was to determine whether urinary BKV shedding in the immediate pre-transplant period is associated with a higher incidence of viruria and viremia during the first year after kidney transplantation. We examined urine samples from 34 kidney transplant recipients, using real-time quantitative polymerase chain reaction to detect BKV. Urine samples were obtained in the immediate pre-transplant period and during the first year after transplant on a monthly basis. If BKV viruria was detected, blood samples were collected and screened for BKV viremia. In the immediate pre-transplant period, we detected BKV viruria in 11 (32.3%) of the 34 recipients. During the first year after transplantation, we detected BKV viruria in all 34 patients and viremia in eight (23.5%). We found no correlation between pre-transplant viruria and post-transplant viruria or viremia (p = 0.2). Although reactivation of latent BKV infection in the pre-transplant period is fairly common among kidney transplant recipients, it is not a risk factor for post-transplant BKV viruria or viremia., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We aimed to investigate the roles of cytokines during polyomavirus BK (BKV) reactivation in renal transplant patients. Forty-eight renal allograft recipients were enrolled, and their sera BKV viral load and mRNA expression levels of cytokines in peripheral blood mononuclear cells were measured by real-time polymerase chain reaction. Patient's age and gene expression levels of interleukin (IL)-2 (10.04 ± 2.63 vs. 8.70 ± 2.40, p = 0.049) and transforming growth factor (TGF)-β (12.58 ± 2.59 vs. 10.89 ± 1.91, p = 0.015) were significantly higher in BKV viremia (+) renal transplant patients. Multivariate logistic regression analysis revealed that age and mRNA expression levels of TGF-β, but not IL-2, significantly correlated with the presence of BKV viremia. Sera BKV viral loads showed a positive correlation with patient age and the levels of TGF-β and IL-6 mRNA. After adjusting for age and sex in the regression model, both age and TGF-β mRNA levels maintained a significant positive association with sera BKV viral loads. Serum TGF-β concentration tended to be higher in BKV viremia (+) patients (p = 0.079). In conclusion, expression levels of TGF-β were found to correlate with both BKV viremia positivity and sera BKV viral loads in renal transplant patients., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HHV-6 is an evolving pathogen in the field of AlloHCT. However, the impact of HHV-6 on AlloHCT outcomes remains to be elucidated. We studied the incidence and clinical impact of HHV-6 viremia in children following AlloHCT. One hundred consecutive children were monitored weekly by plasma PCR for the first 180 days following AlloHCT for HHV-6, CMV, EBV, and ADV. HHV-6 viremia was defined as plasma PCR >1000 viral copies/mL. The median age was nine yr. Following AlloHCT, 19% (95% CI 11.3-26.7%) of patients had HHV-6 viremia, with the highest incidence of reactivation (14/19, 73%) occurring during day +15-day +98. The proportion of platelet engraftment by day +180 was lower in patients with HHV-6 viremia (58%) than in those without HHV-6 viremia (82%), p = 0.028. Delay in neutrophil and platelet engraftment was not associated with HHV-6 viremia in multivariate analysis. Similarly, HHV-6 viremia was not associated with TRM in multivariate analysis (p = 0.15). In summary, HHV-6 viremia is prevalent in pediatric AlloHCT recipients. Based on our study results, we recommend that HHV-6 PCR should only be performed on clinical suspicion., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Up to 20% of renal transplant recipients (RTR) will develop human BK polyomavirus (BKPyV) viremia. BKPyV viremia is a pre-requisite of polyomavirus-associated nephropathy (PyVAN). Risk of BKPyV infections increases with immunosuppression. Currently, the only effective therapy against PyVAN is reductions in immunosuppression, but this may increase the risk of rejection. In vitro data have shown that pravastatin dramatically decreased caveolin-1 expression in human renal proximal tubular epithelial cells (HRPTEC) and suppressed BKPyV infection in these cells. Based on these data, we postulated that statin therapy may prevent the progression of BKPyV viremia to PyVAN., Patients and Methods: A multicenter, retrospective study was conducted in adult RTR transplanted between July 2005 and March 2012. All patients with documented BKPyV viremia (viral load >500 copies/mL on 2 consecutive tests) were included. Group I consisted of patients taking a statin before the BKPyV viremia diagnosis (n = 32), and Group II had no statin exposure before or after the BKPyV viremia diagnosis (n = 36). The primary endpoint was the incidence of PyVAN., Results: Demographic data, transplant characteristics, and the degree of immunosuppression (i.e., induction/maintenance therapies, rejection treatment) were similar between the groups, with the exception of more diabetics in Group I. The incidence of PyVAN was comparable between the 2 groups (Group I = 28.1% vs. Group II = 41.7%; P = 0.312)., Conclusions: Despite the proven in vitro effectiveness of pravastatin preventing BKPyV infection in HRPTEC, statins at doses maximized for cholesterol lowering, in RTR with BKPyV viremia, did not prevent progression to PyVAN., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Cytomegalovirus (CMV) is a common infection after myeloablative allogeneic hematopoietic stem cell transplant (M-alloHSCT). Achievement of complete donor T-cell chimerism (CDC-T) post transplant is a measure of immune reconstitution. We investigated the association between CDC-T post M-alloHSCT and the incidence of CMV viremia., Methods: We retrospectively reviewed all CMV and chimerism results of 47 patients for the first 6 months post M-alloHSCT. CDC-T was analyzed as a time-varying covariate for association with post M-alloHSCT CMV viremia., Results: CMV viremia occurred in 15 (32%) and CDC-T was achieved in 38 (81%) recipients within the first 6 months post M-alloHSCT. On univariable analysis, increased CMV viremia was seen among patients with CDC-T (hazard ratio 2.81 [P = 0.07, 95% confidence interval = 0.93-8.52]). A 30-day landmark analysis showed that the incidence of CMV viremia at 6 months (regardless of recipient CMV serostatus) was 50% among those who had achieved CDC-T by day 30, and 23% among those who had not (P = 0.06)., Conclusion: We conclude that shorter time to CDC-T may be associated with higher risk of CMV viremia. If confirmed in a larger cohort, this might be a marker for risk stratification in the management of CMV in this population., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: A correlation exists between polyomavirus BK (BKV) viremia in renal transplant recipients (RTR) and the degree of immunosuppression. However, the impact of pre-transplant desensitization on the incidence of BKV viremia is unknown., Methods: This retrospective study evaluated living-donor RTR between January 2004 and December 2008 receiving routine BKV viral load monitoring. Patients were divided into those who underwent pre-transplant desensitization (n = 20) and those who did not (n = 71). The primary endpoint was the incidence of BKV viremia at 1 year post transplant., Results: All demographic data were similar, except for more female patients (65% vs. 36.6%; P = 0.0392) in the desensitized group. More desensitized patients had a previous transplant (75% vs. 12.7%; P < 0.0001) and were more likely to be induced with basiliximab (75% vs. 35.2%; P = 0.0021). Following transplantation, antibody-mediated rejection (AMR) rates were highest in the desensitized group (55% vs. 1.4%; P < 0.0001). The incidence of BKV viremia at 1 year post transplant was significantly higher in desensitized patients (45% vs. 19.7%; P = 0.0385). Desensitization was also associated with a higher prevalence of BKV viremia at any time post transplant (50% vs. 22.5%; P = 0.0245), polyomavirus-associated nephropathy (20% vs. 2.8%; P = 0.0198) and BKV-related allograft loss (10% vs. 0%; P = 0.0464). Also of note, in a subgroup analysis of only our desensitized patients, it did not appear that development of AMR significantly impacted the incidence of BKV viremia in these individuals., Conclusions: This analysis reveals that pre-transplant desensitization significantly increases the risk for BKV viremia and nephropathy., (© 2013 John Wiley & Sons A/S.)

Aims and Methods: This study assessed incidence, predictive factors, and outcome of Epstein-Barr virus (EBV) DNAemia in 100 recipients of allogeneic hematopoietic stem cell transplant. A total of 68 patients received anti-thymocyte globulin before unrelated grafts., Results: Cumulative incidence of high-load EBV DNAemia defined by levels >10,000 copies/mL was 14% at 12 months. In multivariate analysis, a CD4+ T-lymphocyte count >50 μL at day +30 was the only factor significantly associated with a reduced risk of high-load EBV DNAemia. Thirteen of 16 patients with high viral loads were preemptively treated with rituximab and achieved EBV DNA negativity. Three patients had already developed post-transplant lymphoproliferative disorder (PTLD) at the time of detection of high EBV DNA loads, and they obtained complete response after rituximab infusions and chemotherapy. Patients with high EBV DNA load had a significantly higher transplant-related mortality (TRM) compared with patients with negative or low viral load (54% vs. 16%, P = 0.009) and a trend to lower overall survival (55% vs. 29%, P = 0.060)., Conclusion: We conclude that CD4+ cell count at day +30 is a predictive factor for EBV DNAemia and may help identify patients requiring closer monitoring. Although only 3% of patients progressed to PTLD and were all successfully managed, EBV reactivation was associated with higher TRM, mainly because of infections., (© 2013 John Wiley & Sons A/S.)

The incidence and clinical course of polyomavirus-associated nephropathy (PyVAN) in our well-HLA-matched kidney transplant population mainly on low-dose cyclosporine-based triple-drug immunosuppression has not been described in detail. We aimed to characterize our patients with PyVAN and BK virus (BKV) viremia. Among 166 kidney transplantations between January 2007 and February 2011 followed up at Helsinki University Hospital nephrology clinic, 136 were screened for BKV viremia by quantitative analysis of BKV DNA in plasma. PyVAN was diagnosed by biopsy histopathology and SV40 T-antigen detection. BKV viremia or PyVAN were treated by reducing immunosuppression. BKV viremia was detected in 12 (9%) patients. PyVAN was diagnosed in six patients (4%). In the six patients with no PyVAN, four had low-level viremia (<10,000 copies/mL) of short duration (<2 months), one had high-level viremia, and one had sustained low-level viremia. After reduction of immunosuppression, all except one patient were able to clear viremia. No grafts were lost due to PyVAN. Even in a low-risk population, BKV viremia and PyVAN occur, highlighting the importance of monitoring viral loads. Reduction of immunosuppression was successful, and no grafts were lost due to PyVAN., (© 2012 John Wiley & Sons A/S.)

Unlabelled: Induction immunosuppression has provided great advances in reducing the incidence of acute rejection (AR) following kidney transplantation. Despite this success, there has been recent concern over possible increased rates of viral complications when such powerful immunosuppressive therapy is used. This study was undertaken to determine the incidence of BK viral infection following kidney transplantation under alemtuzumab induction therapy., Methods: With institutional review board approval, a retrospective study was performed of all patients undergoing kidney transplantation under alemtuzumab induction at a single center. The incidence of BK viremia was determined, and univariate analysis was performed to determine factors associated with the development of BK viremia. Further analysis was undertaken, using standard statistical methods, to determine the rates of graft survival and hazard ratio (HR) for AR in patients with and without BK viremia., Results: There were 456 patients in the current study, with a mean age of 51 years. The majority of these (61.8%) were male, and 73.5% were Caucasian. The overall incidence of BK viremia identified on routine screening was 6.6%. Univariate analysis failed to identify any significant predictors of BK viremia. One-, 3-, and 5-year graft survival for patients who developed BK viremia was 96.6%, 91.7%, and 91.7%, respectively, compared with 94.1%, 87.8%, and 80.2% for patients without BK viremia (P = 0.860). BK viremia was associated with a significantly increased risk for AR (HR 3.48, 95% confidence interval 1.24-9.76; P = 0.018)., Conclusion: The incidence of BK viremia following alemtuzumab induction appears to be in concordance with the published literature, with satisfactory graft survival rates. BK viremia is, however, associated with an increased risk for AR., (© 2011 John Wiley & Sons A/S.)

After allogeneic hematopoietic stem-cell transplantation (allo-HSCT), EBV infections can be potentially dangerous and even life threatening. We evaluated the EBV viremia in 80 consecutive allo-HSCT with quantitative EBV-PCR every 2 weeks during the first 3 months and monthly thereafter until 1 yr after allo-HSCT or until death. We found a significantly more frequent viremia in patients who had in vivo T-cell depletion in which 23 out of 51 (45%) had EBV-PCR positivity. The EBV virus load was also significantly higher in the in vivo T-cell depleted group. Three patients developed clinical symptoms of EBV-PTLD and were treated with monoclonal anti-CD20 antibodies. No EBV- driven mortality was seen in this cohort. In our opinion EBV-PCR monitoring is mandatory after allo-HSCT. Most of the patients with EBV viremia had a good evolution after tapering the immune suppression, so this should be the first-line management of pediatric patients with EBV viremia. Monoclonal anti-CD20 antibodies should be reserved for those patients with early symptoms of EBV-PTLD., (© 2012 John Wiley & Sons A/S.)

Human herpesvirus-6 (HHV-6) is a major cause of limbic encephalitis with a dismal prognosis after allogeneic hematopoietic stem cell transplantation (SCT). Because our previous trial of preemptive therapy with foscarnet sodium (phosphonoformic acid; PFA) failed to prevent HHV-6 encephalitis, we conducted a prospective study to examine the safety of prophylactic PFA administration and elucidate the changes in the plasma HHV-6 DNA levels in the early post-SCT period. Plasma HHV-6 DNA was measured thrice weekly from day 6. PFA, 90 mg/kg/day, was administered from days 7 to 21 after bone marrow or peripheral blood SCT and to day 25 after umbilical cord blood transplantation. Of the 10 patients enrolled, 2 dropped out of the study, 1 because of early death, and 1 with a low glomerular filtration rate. Grade 3 or greater adverse events occurred in 9 of the 10 prophylactic PFA patients and in 7 of the 10 control patients who had clinical backgrounds similar to the study subjects and underwent SCT during the same period. Neurological disorders developed in none of the study subjects but in 4 of the 10 control patients, including 2 with HHV-6 encephalitis. HHV-6 reactivation occurred in 3 of the 10 study subjects. The prophylactic PFA regimen was thus safe and it may reduce the risk of limbic encephalitis, but is not considered to be potent enough to prevent HHV-6 reactivation., (© 2011 John Wiley & Sons A/S.)

Background: BK nephropathy (BKN) is an important complication of renal transplantation with a reported incidence between 1% and 10% in different parts of the world. Early diagnosis is important to plan early therapeutic strategies. The epidemiology and evolution of BKN is relatively unknown in India and hence, the present study has been designed to prospectively monitor the activation of BK virus (BKV) in renal transplant recipients in India., Patients and Methods: In this study, 32 renal allograft recipients were prospectively monitored with protocol biopsies of allografts, BKV DNA load in plasma, and viral particles in urine by electron microscopy (EM) on day 1, and at 1, 3, and 6 months. Additionally, the baseline BKV DNA load in plasma was quantitated in 21 corresponding donors., Results: On follow-up in 32 recipients, 9.7%, 23.8%, 19.2%, and 13.3% of patients showed viral profiles by EM at day 1, 1 month, 3 months, and 6 months, respectively. BKV DNA positivity in plasma was 25.8%, 42.9%, 15.4%, and 20% at day 1, 1 month, 3 months, and 6 months, respectively, with mean BKV copy number/mL plasma of 1796, 1029, 2611, and 3318, respectively. A total of 15.7% (17/108) urine samples of 32 renal recipients were positive by urine EM. Out of 100 protocol biopsies, none developed histologically demonstrable cytopathic effects of BKN, although 8% biopsies were SV-40 large T antigen (SV-40 T Ag) positive. By quantitative real-time polymerase chain reaction assay, 27/108 (25%) of recipients' plasma samples were positive for BKV. Peak viremia and viruria occurred at 1-3 months post transplantation. The baseline viremia in donors was predictive of viremia positivity in the post-transplantation period at 1 month. Twenty-four episodes of graft dysfunction were attributed mainly to rejection., Conclusion: The study shows a total of 15.7% and 25% urine and plasma samples were positive for BKV at any time during a 6-month follow-up. The highest incidence of BK viruria and viremia occurred at 1 month. In protocol biopsies, focal positivity of SV-40 T Ag was seen in 8% biopsies., (© 2011 John Wiley & Sons A/S.)

Background: Polyoma BK virus nephropathy (PVN) is a leading cause of renal allograft injury and loss. The mainstay of treatment, as there are no target therapies approved by the US Food & Drug Administration, is reduction in immunosuppression. However, current approaches are shifting to screening for viremia as an indicator of oncoming nephropathy, with subsequent reduction in immunotherapy. We attempted not only to replicate these data but also to evaluate the utility of polyoma viremia as a surrogate marker for overimmunosuppression in general, thus allowing prevention not only of PVN but also of other viral opportunistic infections such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV) disease., Patients and Methods: We conducted a retrospective cohort analysis of renal transplant recipients at our center. The historical controls (2003-2005, n = 134) had received their allograft before the institution of a monthly serum polymerase chain reaction (PCR) polyoma screening protocol. The screened cohort received their allograft afterwards (2006-2008, n=134). Screening was performed using PCR techniques with prompt reduction in immunosuppression for viremic patients. The patients were followed for the development of PVN, acute rejection, renal allograft function, and survival., Results: Polyoma viremia was noted in 16% of the screened population, with none developing PVN after prompt reduction of immunosuppression. Clearance of the viremia occurred by 6 months in 95% of the patients after reduction of immunotherapy. No patient in the screened group developed CMV or EBV disease. Of the controls, 7 (5%) developed PVN and 12 (9%) developed CMV or EBV disease, compared with none of the screened patients (P<0.05). The incidence of acute rejection was comparable between the groups (4% controls, 5% screened). No deleterious effects were noted on patient or allograft survival, allograft function (measured by serum creatinine), rates of fungal infection, or the rate of post-transplant lymphoproliferative disorder in the screened patients., Conclusions: Monthly PCR monitoring for BK viremia, together with a modest decrease in immunotherapy, is not only safe but also effectively prevents PVN and is associated with a significantly decreased rate of CMV and EBV disease in renal transplant patients. BK viremia may also serve as a surrogate marker for overimmunosuppression., (© 2010 John Wiley & Sons A/S.)

Background: Deficiencies in cytomegalovirus (CMV)-specific T lymphocytes impair the immunologic response against CMV reactivation after allogeneic hematopoietic stem cell transplantation (HSCT)., Methods: A time-dependent analysis was conducted to determine the association between the percentages and kinetics of interferon-gamma-producing CMV-specific CD4+ and CD8+ T lymphocytes and CMV viremia among 30 allogeneic HSCT recipients., Results: Higher percentages of CD4+ T lymphocytes activated with CMVpp65 (hazard ratio [HR]: 2.06; 95% confidence interval [95% CI]: 1.18-3.6; P=0.011) and CMV lysate (HR: 1.18; 95% CI: 0.99-1.42; P=0.072), and higher percentages of CD8+ T lymphocytes activated by CMV immediate early-1 (HR: 1.2; 95% CI: 1.01-1.43; P=0.038) and CMVpp65 (HR: 1.12; 95% CI: 1.0-1.27; P=0.060) were associated with time-to-CMV viremia. Furthermore, a higher degree in the decline of CMV lysate-activated CD4+ T lymphocytes (HR: 1.14; 95% CI: 0.96-1.36; P=0.125) and CMVpp65-activated CD8+ T lymphocytes (HR: 1.36; 95% CI: 1.03-1.78; P=0.031) was suggestive of or significantly associated with time-to-CMV viremia., Conclusions: Higher levels of CMV-specific CD4+ and CD8+ T lymphocytes were associated with subsequent CMV viremia after HSCT. The association between CMV viremia and the degree of decline in CMV-specific T lymphocytes suggests that severe disruption in homeostatic CMV-specific immune environment contributes to the immunopathogenesis of CMV after allogeneic HSCT.

Background: BK virus-associated nephropathy (BKVAN) can be diagnosed only with renal graft biopsy. Definitive diagnosis of BKVAN requires demonstration of BK virus (BKV) replication in renal allograft tissues. Non-invasive analysis of urine and blood is considered essential in screening renal transplant recipients., Patients and Methods: This study evaluated prospectively the replication of BKV in plasma and urine with qualitative and quantitative real-time polymerase chain reaction in 32 de novo (group A) and 34 chronic (group B) renal transplant recipients and the long-term impact on graft function., Results: In group A, 456 samples (228 plasma, 228 urine) were examined and BKV was detected in 31 (31/228, 14%) samples of plasma and 57 (57/228, 25%) samples of urine in 20 (20/32, 62.5%) and 23 (23/32, 72%) recipients, respectively. Incidence of viremia and viruria increased during the first 6 months presenting a peak the third postoperative month (viremia: 28% and viruria: 31%). Immune suppressive treatment with tacrolimus showed significant relation with viremia. Renal graft function in de novo renal transplant recipients remained stable throughout the follow-up period without influence of BKV replication. In group B, incidence of viremia and viruria were 3% (1/34) and 9% (3/34) correspondingly, indicating that after the first post-transplant year the risk of BKV re-activation is diminished., Conclusion: The highest incidence of BK viremia and viruria is observed the third post-transplantation month, confirming previously published studies in Europe and the United States, and long-term follow up shows that BKV replication decreases significantly after the third post-transplant month and even transient viremia or viruria does not have an impact on renal function.

Background: BK polyomavirus (BKV) infection has emerged as an important cause of renal allograft loss. There is no proven therapy, and much basic clinical information is still lacking., Methods: We serially enrolled 95 outpatient renal transplant recipients (43% of whom were African American) in a single center cross-sectional screening study to determine the prevalence of BKV infection by whole blood polymerase chain reaction, and the prevalence of decoy cells by urinalysis and cytology. We also investigated the demographic and clinical factors associated with BKV infection, and the performance of urinalysis for decoy cells as a screening test for BKV infection., Results: The point prevalence of active BKV viremia was 7.4%. When subjects without active viremia but with a history of viremia and/or nephropathy were included, the overall prevalence was 15.8%. Urinary decoy cells were common, present in 50% of subjects at study entry. Urinalysis for decoy cells as a screen for BKV viremia had a sensitivity of 86%, specificity of 52%, positive predictive value of 13% and negative predictive value of 98%., Conclusions: Decoy cells on urinalysis were the only factor independently associated with an increased risk of BKV infection on multivariate analysis. Although associated with BKV infection on univariate analysis, thymoglobulin, mycophenolate mofetil, and tacrolimus use were not independently associated with BKV infection on multivariate analysis, neither were history of acute rejection, gender, race, nor cause of end-stage renal disease.

Cytomegalovirus (CMV) remains a serious problem after hematopoietic stem cell transplantation (HSCT). To investigate the incidence of CMV infection and outcome we retrospectively analyzed 70 consecutive pediatric allogeneic HSCTs monitored by CMV polymerase chain reaction (PCR), with at least 1-year follow-up or until death. All patients at risk for CMV infection (CMV-seropositive patients and CMV-seronegative recipients transplanted from CMV-seropositive donors) received hyperimmune anti-CMV globulins whereas in the group of HSCT patients with both donor and recipient CMV negativity, polyvalent immunoglobulins were given, both at a dose of 400 mg/kg. All patients received acyclovir at prophylactic doses for at least 6 months. Patients were monitored twice a week by CMV PCR. Patients with 2 positive results for CMV DNAemia received ganciclovir for 14 days and continued until 2 consecutive negative results were obtained. The incidence of CMV DNAemia was 12.8% (9/70) in the whole group, with significant higher risk for patients with CMV-seropositive recipient status, 8 out of 22 (36%), vs. patients with seronegative status, 1 out of 48 (2%) (P=0.0002). Three out of 9 patients with DNAemia developed CMV disease despite adequate preemptive treatment. The transplant-related mortality was higher in the CMV-seropositive recipient group (P=0.05). Age, use of hyperimmune anti-CMV globulins at a high dose, and the low incidence of graft-versus-host disease might be contributing factors to this low incidence.

Post-transplant clinical disease with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) is a known risk factor for graft dysfunction and lymphoproliferation. We postulate that subclinical, asymptomatic viremia also adversely impacts outcomes, and may warrant re-assessment of current monitoring and antiviral prophylaxis protocols. A single-center study was conducted on 102 pediatric (51 steroid-free and 51 matched steroid-based historical controls). Quantitative viral loads were serially monitored and correlated with outcome measures. Overall, the incidence of CMV and EBV clinical disease was 5% (1% CMV and 4% EBV); however, the incidence of subclinical viremia was 44% (12.7% CMV, 38.2% EBV, 6.9% CMV + EBV). Risk factors for subclinical viremia were EBV naivety (p = 0.07), age less than five yr (p = 0.04), lack of prophylaxis (p = 0.01), and steroid usage (p = 0.0007). Subclinical viremia was associated with lower three-yr graft function (p = 0.03), increased risk of acute rejection (odds ratio 2.07; p = 0.025), hypertension (p = 0.04), and graft loss (p = 0.03). Subclinical asymptomatic CMV and EBV viremia is a risk factor for graft injury and loss. These findings support the need for aggressive, serial viral monitoring to better determine the appropriate length of post-transplant antiviral prophylaxis, and to determine the effect of immunosuppression protocols on the development of viremia.

Polyomavirus-induced nephropathy has emerged as an important cause of renal graft dysfunction. Limited pediatric data are available for this disease. We therefore reviewed the results of the first year of polyomavirus screening in our pediatric renal transplant recipients to determine the prevalence of polyomavirus viremia and urinary shedding. Screening included detection of polyomavirus in plasma by polymerase chain reaction (PCR) and in urine by electron microscopy (EM). In patients with a positive screening test, an assessment of graft dysfunction was made. Fifty-two patients met the inclusion criteria. Urinary EM was performed in 205 samples and polyomavirus was detected in 10 patients, representing 19% of the study population. PCR was performed on 222 samples and was positive for the BK virus in plasma from seven patients or 13.4% of the study population. Eight patients had a positive screening test and increased creatinine. All these patients underwent renal transplant biopsy. This revealed evidence of polyomavirus nephropathy in four patients. Our findings reveal a high prevalence of polyomavirus in both urine and plasma that is frequently associated with graft dysfunction. These findings support the routine screening of pediatric post-renal transplant patients for polyomavirus replication.

This study was performed to evaluate the incidence, risk factors, and outcome of cytomegalovirus (CMV) infection in autologous stem cell transplantation (ASCT), with the aim of performing preemptive therapy in patients with antigenemia. Starting from 2001, 171 consecutive ASCTs were performed in 136 patients; 102 of these patients were seropositive for CMV at the onset of hematological disease. In all these patients, a CMV pp65 antigenemia assay was determined weekly, starting from the day when the absolute neutrophil count went above 500/microL, and until day 60 after ASCT; subsequently, antigenemia was determined only when a CMV infection was suspected. Among the 136 transplanted patients, 40 (29.4%) presented a positive antigenemia; all of them were seropositive for CMV before ASCT; and no cases of primary infection were seen. The incidence of CMV infection in the seropositive population was 40/102 (39.3%); 6 patients (5 with multiple myeloma and 1 with non-Hodgkin's lymphoma) who received 2 ASCTs developed CMV infections after both transplantations, so that positive antigenemia developed after 46/171 (26.9%) transplantations. First positive antigenemia presented a median of 32 days (range 7-57) after stem cell reinfusion. The median antigenemia level at the first appearance was 2/200,000 (range 1-1000). No significant prognostic factors could be shown. Enteritis was present in 5 patients; 2 of them also had fever, and 1 of them also had thrombocytopenia. In 5 patients fever without any other clinical signs or symptoms was present; 30 patients were asymptomatic. Fourteen patients were treated with anti-CMV drugs. CMV reactivation was successfully treated in all patients, and no patient died from CMV disease.