Late-onset Cytomegalovirus Infection Research Articles

The effect of late-onset CMV infection on the outcome of renal allograft considering initial graft function.

Delayed graft function (DGF) increases the renal allograft failure risk. Late-onset Cytomegalovirus (CMV) infection's effect on the association between DGF and allograft failure has not been determined. In this retrospective cohort, we included all renal allograft recipients at London Health Sciences Centre from January 1, 2014 to December 30, 2017, and continued clinical follow-up until February 28, 2020. We determined whether late-onset CMV infection affects the association between DGF and allograft failure in stratified and Cox proportional hazard analyses. Of 384 patients (median age [interquartile range]: 55 [43.3-63]; 38.7% female), 57 recipients (14.8%) were diagnosed with DGF. Patients with DGF were at a greater risk of CMV infection than patients without DGF (22.8% vs. 11.3%, p = .017). Late-onset CMV infection (odds ratio [OR]: 4.7, 95% CI: 2.07-10.68) and rejection (OR: 9.59, 95% CI: 4.15-22.16) significantly increased the risk of allograft failure in recipients with DGF. Patients with DGF had a significantly greater risk of graft failure than those without DGF (17.5% vs. 6.1%, p = .007). In the adjusted Cox hazard model, CMV infection significantly increased the risk of allograft failure (aHR: 3.19, 95% CI: 1.49-6.84). Late-onset CMV infection considerably increased the risk of graft failure in patients with DGF. A hybrid preventive model including prophylaxis followed by CMV-specific cell-mediated immunity monitoring may decrease the risk of allograft failure in recipients with DGF.

P8.146: Early and Late-Onset Cytomegalovirus Infection Following Universal Prophylaxis in Kidney Transplant Recipients: Risk Factors and Outcome

P8.146: Early and Late-Onset Cytomegalovirus Infection Following Universal Prophylaxis in Kidney Transplant Recipients: Risk Factors and Outcome

Human Cytomegalovirus-Specific T-Cell Reconstitution and Late-Onset Cytomegalovirus Infection in Hematopoietic Stem Cell Transplantation Recipients following Letermovir Prophylaxis

Letermovir (LTV), recently approved for the prophylaxis of human cytomegalovirus (HCMV) reactivation after hematopoietic stem cell transplantation (HSCT), has been shown to decrease the rate of infection in the first months post-transplantation. The aim of this study was to evaluate the impact of LTV prophylaxis on immune reconstitution and late-onset infection. We studied HCMV infection and HCMV-specific T cell reconstitution in 2 matched groups of HSCT recipients, those treated with LTV prophylaxis (n=30; LTV group) and those receiving preemptive therapy (n=31; PET group). We analyzed the rates of graft-versus-host disease (GVHD), neutropenia, baseline disease recurrence, and overall survival in the 2 groups. Clinically significant infections necessitating preemptive therapy showed a similar rate in the 2 groups (PET: 21 of 31 [68%]; LTV: 17 of 30 [57%]; P=.434) but occurred significantly later (after prophylaxis discontinuation) in the LTV group. There was no between-group difference in peak HCMV DNAemia level (P=.232). HCMV-specific T cell recovery was delayed by approximately 100 days in the LTV group. HCMV-specific CD4 and CD8 T cell counts were significantly lower in the LTV group at days 120 to 360 and days 90 to 120, respectively. A lower rate of chronic GVHD (P=.024) was seen in the LTV group. Time to engraftment, rate of disease relapse, and 1-year survival were not different between the 2 groups, whereas trends toward a lower rate of neutropenia (P=.124) and a higher rate of acute GVHD grade III-IV (P=.103) were observed in the LTV group. Because LTV prophylaxis delays HCMV infection and HCMV-specific immune reconstitution, immunologic and virologic monitoring should be implemented after discontinuation of prophylaxis. The potential effect of LTV prophylaxis in reducing chronic GVHD should be evaluated in prospective studies.

Clinical Characteristics of Late-Onset Cytomegalovirus Infection After Kidney Transplantation

Late-onset cytomegalovirus (CMV) infection (LCI) has been emerging mong solid-organ transplant recipients. We explored clinical characteristics, risk factors, and outcomes of LCI in kidney transplantation (KT) recipients. A retrospective study of all adult KT recipients with LCIs (that occurred >6 months after transplant) from 2016 to 2018 was conducted. Clinical characteristics and outcomes were extracted. Risk factors of LCI were analyzed using Cox proportional hazards models. A total of 518 KT recipients were included. Ninety-eight percent had donor CMV-seropositive and recipient CMV-seropositive status (D+/R+). Ten (2%) KT recipients developed LCI with a median onset of 14 (interquartile range, 8-15) months. Those included asymptomatic CMV infection (40%) and tissue-invasive disease (60%). CMV D+/R- serostatus and a prior episode of rejection within 6 months were associated with LCI (hazard ratio, 17.35; 95% confidence interval, 3.60-83.63; P < .001) and (hazard ratio, 38.15; 95% confidence interval, 6.15-236.72; P < .001), respectively. There was no difference in the rate of allograft failure and mortality in those with LCI compared with those with early-onset CMV infection. LCI is uncommon after KT. Those with CMV seromismatch and a prior episode of rejection were more likely to develop LCI. Clinical and allograft outcomes were not different among each group.

Late-onset allograft rejection, cytomegalovirus infection, and renal allograft loss: Is anti-CMV prophylaxis required following late-onset allograft rejection?

Renal transplant recipients remain at risk of delayed-onset cytomegalovirus (CMV) infection occurring beyond a complete course of prophylaxis. In this retrospective cohort, all 278 patients who received renal allografts from deceased donors from 2014 to 2016 were followed until September 1, 2019. We determined the effect of early-vs late-onset acute rejection (EAR vs LAR [ie, occurring beyond 12months after transplantation]) on CMV infection and subsequently long-term allograft outcome. Median (IQR) duration of follow-up was 1186.0 (904.7-1531.2) days. Seventy patients including 49 patients with EAR and 21 with LAR received augmented immunosuppression. In the same interval, 40 patients developed CMV infection (36 patients beyond 90days after transplantation [90%]). In logistic regression analysis, D+/R- CMV serostatus (OR: 5.5, 95% CI: 2.5-12.2) and LAR (OR: 7.9, 95% CI: 2.8-22.2) significantly increased the risk of CMV infection. In Cox proportional hazard model, delayed-onset CMV infection (HR: 2.51, 95% CI: 1.08-5.86) and LAR (HR: 5.46, 95% CI: 2.26-13.14) significantly increased the risk of allograft loss. Patients with LAR are at risk of late-onset CMV infection. Post-LAR, targeted prophylaxis may reduce the risk of CMV infection and subsequently allograft loss. Further studies are required to demonstrate the effect of targeted prophylaxis following LAR.

The NFKB1 Promoter Polymorphism (-94ins/delATTG) Is Associated with Susceptibility to Cytomegalovirus Infection after Kidney Transplantation and Should Have Implications on CMV Prophylaxis Regimens.

Infections with cytomegalovirus (CMV) are one of the most frequent opportunistic infections in kidney transplant recipients. Current risk-adapted CMV chemoprophylaxis regimens are based almost solely on the donor and recipient CMV serostatus. Of note, the NFKB1 -94ins/delATTG promoter polymorphism was recently associated with a higher risk of CMV infection. Since single genetic association studies suffer from poor reliability for drawing therapeutic implications, we performed this confirmatory study and included 256 kidney transplant recipients from 2007 to 2014 in this retrospective study. Patients were genotyped for the -94ins/delATTG NFKB1 promoter polymorphism and followed up for 12 months. The incidence of CMV infection within 12 months after kidney transplantation was 37.5% (33/88) for the ins/ins, 21.5% (28/130) for the ins/del, and 23.7% (9/38) for the del/del genotypes (p = 0.023). Moreover, we evaluated the time of CMV infection onset. Ins/ins carriers had primarily late-onset CMV infection (median 194 days; interquartile range (IQR) 117–267 days) compared with heterozygous (ins/del; median 158 days; IQR 82–195 days) and homozygous deletion allele carriers (del/del; median 95 days; 84–123 days). Multivariate-restricted Cox regression model confirmed the ins/ins genotype to be an independent risk factor for the development of late-onset CMV infections. These findings should have an impact on post-kidney transplantation CMV chemoprophylaxis regimens.

Late-onset Cytomegalovirus Infection Associated With Gastric Outlet Obstruction in a Preterm Twin

The infant was born at a gestational age of 28 + 2 weeks as second twin to a 26-year-old woman, G1/P0, due to eclampsia. The patient developed well and was on full oral feeds when he started to develop nonbilious vomiting at 5 weeks. He was diagnosed with pyloric hypertrophy and underwent pylorotomy, but the condition did not improve and the patient was referred to our hospital. Here, esophagogastroduodenoscopy showed severely inflamed esophageal and gastric mucosa which was found to be due to cytomegaly virus (CMV) infection and a nonpassable pylorus. The patient underwent pyloroplasty revealing a fibrous pyloric ring. Histology showed giant cells suggestive of CMV infection which was confirmed by polymerase chain reaction. He was started on valganciclovir and discharged 4 weeks later on full enteral feeds. To our knowledge, this is the first case of gastric outlet obstruction due to CMV infection in a premature infant.

Impact of late-onset cytomegalovirus infection in the development of cardiac allograft vasculopathy in heart transplant recipients.

The impact of late-onset cytomegalovirus (CMV) infection (LOCI) on cardiac allograft vasculopathy (CAV) has yet to be established. A retrospective study was performed for patients who had undergone heart transplantation (HT) between January 1995 and October 2017 to analyze epidemiology of LOCI (any positive level of CMV pp65 antigenemia or DNAemia after 100days, without previous CMV replication) and its association with CAV. Our main hypothesis was that LOCI causes less direct and indirect effects compared to early onset infection (EOCI). Late-onset cytomegalovirus infection developed in 57 of 410 patients (13.9%) in a median time of 4.7months post-transplant. CAV at 10years was diagnosed in 31.6% of patients with LOCI, 34.6% with EOCI, and in 19.3% of CMV-uninfected patients. In the multivariate analysis, EOCI was an independent variable for developing CAV (HR 1.8, 95% CI 1.13-2.82, P=.01). Patients with LOCI showed a trend toward a higher risk of CAV, but the difference was not statistically significant (HR 1.7, 95% CI 0.95-3.08, P=.07). In the complementary log-log model, LOCI and EOCI had a similar CAV-free survival, and a higher probability of developing CAV than CMV-uninfected patients (P=.02). Cytomegalovirus infection after HT may result in the same long-term events regardless of its onset, with a higher risk of developing CAV at 10years than patients without CMV.

Late onset CMV disease presenting as a colonic stricture in a liver transplant recipient

Cytomegalovirus (CMV) is a common opportunistic infection in solid organ transplant (SOT) recipients in the first 6months after transplant. Late onset CMV infection or disease outside the classical risk period is uncommon and can present with atypical signs and symptoms. Here, we report a case of late onset CMV presenting as a colonic stricture more than 10years after liver transplantation in the absence of traditional CMV risk factors. We also briefly review CMV colitis presenting as a mass or stricture in SOT recipients.

Management of cytomegalovirus infection after hematopoietic stem cell transplantation

In a highly immunodeficient state following allogeneic hematopoietic stem cell transplantation (HSCT), the reactivation of cytomegalovirus (CMV) is occasionally uncontrollable, which leads to various clinical symptoms, such as pneumonia, enteritis, and hepatitis and finally to lethal outcomes. Although preemptive anti-CMV therapy based on monitoring of CMV infection by quantitative polymerase chain reaction and CMV antigenemia assays has reduced lethal CMV disease, CMV infection is associated with increased non-relapse mortality and reduced survival. A new antiviral drug, letermovir, which exhibited high tolerability and preventive effect on CMV infection, was approved as a prophylactic agent for CMV infection. In the future, it is expected that survival after allogeneic HSCT will be improved by preventing CMV infection. However, further investigations are warranted to solve problems, such as the establishment of the appropriate prophylaxis for CMV infection and the management of late-onset and drug-resistant CMV infection.

SUN-029 PREVENTIVE STRATEGIES FOR CYTOMEGALOVIRUS DISEASE IN RISK-STRATIFIED PATIENTS WITH GLOMERULONEPHRITIS AND RENAL VASCULITIS TREATED WITH POTENT IMMUNOSUPPRESSION

Cytomegalovirus (CMV) disease in immunocompromised individuals is associated with significant morbidity and mortality. Anti-viral prophylaxis effectively reduced CMV disease in solid organ transplant but have not been evaluated among patients with glomerulonephritis at-risk for CMV disease after immunosuppressive therapy. In this proof-of-concept study, we evaluated the utility and outcomes of a risk-stratified approach to anti-viral prophylaxis for adults with glomerulonephritis treated with potent immunosuppressants. Single-center retrospective cohort study of adults with glomerulonephritis prescribed methylprednisolone, cyclophosphamide or rituximab between July 2015 and June 2017. A risk-stratified approach to anti-viral prophylaxis versus surveillance, according to clinical and pharmacotherapy criteria (Figure 1), was implemented since March 2015. The outcome of CMV disease was defined by detection of CMV infection by virus isolation, culture or histopathologic testing of tissue samples. Data was censored at death, last visit to our institution before 30th October 2017. We studied 34 at-risk adults with glomerulonephritis prescribed methylprednisolone, cyclophosphamide or rituximab over 25 months. Median age was 46.5 (29.7, 67.2) years, 16 (45.7%) were male and 4 (11.4%) had diabetes. The most common diagnoses were renal vasculitis (28.6%), lupus nephritis (25.7%) and IgA nephropathy (14.3%). Median eGFR was 20.0 (IQR: 9.0, 45.2) ml/min/1.73 m2 and urine protein-to-creatinine ratio was 5.9 (4.1, 10.1) g/g. Immunosuppressive therapy during the first 3 months after kidney biopsy were methylprednisolone (88.6%), prednisolone (100%), cyclophosphamide (65.7%), mycophenolate (42.9%), rituximab (5.7%), plasma exchange (28.6%) and others (26.4%). Median follow up was 14.8 (6.5, 20.4) months. By criteria (Figure 1), 21 satisfied criteria for anti-viral prophylaxis but among them, only 9 received prophylaxis, 8 were on surveillance and the remaining 4 were not on any preventive strategy. Only 1 patient satisfied criteria for surveillance while the remaining 12 did not require any preventive strategy. In practice, 10 patients received anti-viral prophylaxis (9 according to recommendation and 1 who satisfied criteria for surveillance but physician opted for prophylaxis) for median duration of 9.1 (6.8, 14.1) weeks. Surveillance was performed in 9 patients, among whom 8 satisfied criteria for prophylaxis but their physicians opted for surveillance instead; 3 (8.8%) subsequently required pre-emptive therapy and another 1 patient (2.9%) developed CMV intestinal ulcers) despite CMV titer below action-able criterion within days preceding CMV disease. None of those on prophylaxis or pre-emptive therapy developed CMV disease although 1 patient developed late-onset CMV infection without organ-invasive disease 4 weeks after completing anti-viral prophylaxis. Adverse events (AE) related to anti-viral prophylaxis occurred in 4 patients: 3 patients had 1 AE of leucopenia, thrombocytopenia and transaminitis each and 1 patient had all 3 AE. A risk-stratified approach to anti-viral prophylaxis can be considered for glomerulonephritis treated with potent immunosuppressants but adverse events due to anti-viral prophylaxis were common. Prospective trials and cost-effectiveness studies are required to determine appropriate preventive measures to reduce CMV disease.

CMV-specific Cell-mediated Immunity at 3-month Prophylaxis Withdrawal Discriminates D+/R+ Kidney Transplants at Risk of Late-onset CMV Infection Regardless the Type of Induction Therapy.

Whether cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) at prophylaxis cessation predicts D+/R+ kidney transplants at risk of late-onset CMV infection after receiving distinct induction therapies is still not well characterized. We prospectively assessed CMV-specific CMI predicting late-onset CMV infection at prophylaxis withdrawal and at earlier time-points, in 96 consecutive D+/R+ patients receiving either anti-interleukin 2-receptor antibody (anti-IL2RA; n = 50) or rabbit antithymoglobulin (n = 46). CMV-specific CMI was evaluated against CMV antigens (IE-1, pp65) using an IFN-γ ELISpot assay. Fourteen (14.6%) of 96 patients developed late-onset CMV infection and 2 (2.1%) of 96 displayed disease. At 3 months, CMV-specific CMI frequencies were significantly lower in patients developing late-onset CMV infection (P < 0.001 for IE-1, P = 0.030 for pp65), regardless the type of induction therapy. Receiver operating characteristic curve analyses showed accurate CMV-specific CMI cutoffs (25 and 130 IFN-γ spots for IE-1 and pp65, respectively) classifying patients into high risk, intermediate risk, or low risk (log-rank = 0.006; hazard ratio, 4.084; 95% confidence interval, 1.431-11.651; P = 0.009), being IE-1 CMI the strongest predictor (odds ratio, 5.554; 95% confidence interval, 1.486-20.766; P = 0.011). Although the profound posttransplant CMV-specific CMI inhibition among rabbit antithymocyte globulin-treated patients precludes its use for risk stratification both before and early after kidney transplant, a similar proportion of at-risk patients could be identified before month 3 within anti-interleukin 2-receptor antibody-treated patients. Monitoring CMV-specific CMI at 3-month prophylaxis cessation discriminates kidney transplant recipient at risk of late-onset CMV infection, regardless the type of induction therapy.

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients

ABSTRACTIntroduction: Cornerstone immunosuppressive therapy currently relies on immediate-release tacrolimus, a calcineurin inhibitor (CNI) that is potentially nephrotoxic and is more diabetogenic than cyclosporine A. Two new formulations of tacrolimus have been launched: an extended-release formulation (Advagraf®/Astagraf XL®, Astellas company) and a long-lasting formulation (Envarsus®, Veloxis company).Area covered: Herein, we assess the efficacy of an extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) used in conjunction with or without an induction therapy (i.e., basiliximab) in de novo kidney-transplant recipients. To achieve this, we searched for suitable articles through PubMed.Expert commentary: Phases-III and -IV studies comparing Advagraf®/Astagraf XL® to Prograf® in association with mycophenolate mofetil (more than 2,500 patients) have demonstrated overall similar results with regards to patient/graft survival, biopsy-proven acute-rejection rate, and renal function (p > 0.05). A randomized controlled study in maintenance kidney transplant patients has shown (using electronic monitoring) that, as compared to Prograf®, Advagraf® significantly improved adherence to medication. Other studies report that Advagraf®-treated patients receiving a mTOR-inhibitor agent (sirolimus or everolimus) instead of MMF: this was associated with good allograft outcome, and might also prevent late-onset cytomegalovirus infection. Advagraf®-based immunosuppression given to de novo kidney-transplant recipients, with or without an induction therapy, provided excellent results compared to Prograf®; it also increased patients’ adherence to treatment.

Clinical values of preemptive therapy versus universal prophylaxis in the prevention of cytomegalovirus infection post kidney transplantation: a systematic review and Meta-analysis

Objective To evaluate the clinical efficacy of preemptive therapy versus universal prophylaxis in prevention of cytomegalovirus(CMV) infection post kidney transplantation. Methods Databases including the PubMed, EMbase, sinoMed, Web of Knowledge, the Cochrane Central Register of Controlled Trails (CENTRAL) and other databases were searched up to December 2016 for controlled clinical studies which involved preemptive therapy and universal prophylaxis. Odds ratio (OR) and mean difference (MD) with 95% confidence interval (CI) was performed using Review Manager 5.3 software to synthesize the results. Results 11 studies with a total of 2 560 patients were included in this Meta-analysis. Results showed that universal prophylaxis was superior to preemptive therapy in the total CMV infection and CMV disease(OR=3.38, 95%CI 2.13-5.36, P<0.001; OR=1.69, 95%CI 1.14-2.48, P=0.008), otherwise it was on the contrary in the late onset CMV infection and CMV disease (OR=0.07, 95%CI 0.02~0.19, P<0.001; OR=0.08, 95%CI 0.01-0.60, P=0.01). However, there was no significance in the short outcomes between the two groups including 1-year recipient and graft survival and renal function. In addition, preemptive therapy was superior to universal prophylaxis in the adverse events (OR=0.33, 95%CI 0.15-0.72, P=0.006). Conclusions There was no significant difference between the two prophylaxis in the prevention of CMV infection, but preemptive therapy was superior to universal prophylaxis in the prevention of anti-virus adverse effects. Key words: Kidney transplantation; Cytomegalovirus infection; Preemptive therapy; Universal prophylaxis; Meta-analysis

Prevention of Late-Onset Cytomegalovirus Infection and Disease in Donor-Positive/Recipient-Negative Kidney Transplant Recipients Using Low-Dose Valganciclovir

BackgroundThe main challenge with cytomegalovirus (CMV) prophylaxis in IgG donor-positive/recipient-negative (D+/R–) kidney transplant recipients is late-onset CMV disease. We evaluated a novel protocol for the prevention of late-onset CMV infection and disease in D+/R− organ recipients. MethodsOur prospective, observational, cohort study included 100 adult kidney transplant recipients. Prophylaxis with low-dose valganciclovir (450 mg/d, 3 times a week for 6 months) was administered to D+/R− recipients. Risk factors for CMV infection and disease were identified. Renal function and the outcomes of CMV infection and disease were compared between D+/R− (n = 15) and recipient-positive (R+; n = 81) organ recipients. ResultsD+/R− recipients showed significant independent risk factors with high hazard ratios for CMV infection (2.04) and disease (10.3). The proportion of CMV infection in D+/R− and R+ recipients was 80% and 46% (P = .023), and that of CMV disease was 33% and 6.2% (P = .008), repectively. D+/R− recipients developed CMV infection and disease within 6 months after transplantation. However, both CMV infection- and disease-free survival rates beyond 1 year post-transplantation defined as late-onset were stable in D+/R− recipients. Moreover, serum creatinine levels at 1 year post-transplantation were comparable between D+/R− and R+ recipients (1.45 ± 0.71 vs 1.16 ± 0.35 mg/dL, P = .26). ConclusionOur novel protocol prevented late-onset CMV infection and disease beyond 1 year post-transplantation in D+/R− recipients.

Clinical Outcomes with Antiviral Prophylaxis or Preemptive Therapy for Cytomegalovirus Disease after Liver Transplantation: A Systematic Review and Meta-Analysis

A literature search of PubMed, Cochrane, Embase was conducted up to June 1, 2016. References of the retrieved articles were also reviewed and relevant studies were included. The primary outcomes were incidence of CMV infection, incidence of CMV disease, mortality and opportunistic infection. The second outcomes were the mean time to CMV infection and CMV disease, adverse drug reaction (ADR). Sensitivity analysis and publication bias were evaluated. 6 cohort studies involving 1091 liver-transplant recipients (LTRs) were included. All studies were with high quality according to Newcastle-Ottawa Scales (NOS). Incidence of CMV infection and CMV disease showed significant difference between the AP and PT in high-risk patients. There was no significant difference of CMV-related mortality (725 patients, OR 1.27, 95%CI 0.12-13.47, p=0.84) and other opportunistic infections (311 patients, OR 0.85, 95%CI 0.49-1.45, p=0.55) in all "at-risk" patients between the two strategies, whereas late-onset CMV infection and CMV disease were found in patients receiving AP. We recommended the use of AP instead of PT in the high risk patients, and PT could be used in moderate or low risk patients for the similar clinical outcomes in preventing CMV disease. RCTs comparing the two strategies are warranted.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Risk Factors for Late-Onset Cytomegalovirus Infection or Disease in Kidney Transplant Recipients

CMV-D+/R- serostatus is the only well-established risk factor for late-onset cytomegalovirus (CMV) infection/disease (i.e., incident CMV infection/disease after cessation of prophylactic antiviral therapy). This study aimed to explore other potential risk factors for late-onset CMV infection/disease in kidney transplant recipients. We conducted a retrospective cohort study of 641 kidney transplant recipients in Toronto, Canada, from January 1, 2003, to December 31, 2010. The cumulative incidence of late-onset CMV infection/disease was assessed using the Kaplan-Meier product-limit method. Potential risk factors for late-onset CMV infection/disease were examined using Cox proportional hazards regression models. Cumulative incidence estimates for CMV infection/disease after prophylaxis cessation in D+/R- versus D+/R+ versus D-/R+ patients were 26.2% versus 7.4% versus 3.1% at 6 months and 30.0% versus 7.7% versus 3.7% at 1 year, respectively. D+/R- serostatus (vs. R+ serostatus) and an estimated glomerular filtration rate of less than 45 mL/min (vs. ≥ 60 mL/min) at prophylaxis cessation were independently associated with late-onset CMV infection/disease (hazard ratio, 4.04 [95% confidence interval, 2.39-6.83]; and hazard ratio, 2.03 [95% confidence interval, 1.07-3.88], respectively). Patients with lower estimated glomerular filtration rate at prophylaxis cessation may be at an increased risk of late-onset CMV infection/disease and should be considered for more intensive CMV viral load monitoring, particularly within the first year after prophylaxis cessation.

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.

Retrospective review of the incidence of cytomegalovirus infection and disease after liver transplantation in pediatric patients: Comparison of prophylactic oral ganciclovir and oral valganciclovir

Cytomegalovirus (CMV) is the most common viral infection after solid organ transplantation (SOT). Safe and effective prophylactic regimens that decrease its incidence after SOT are essential for long-term graft survival. Although valganciclovir is not Food and Drug Administration-approved for CMV prophylaxis in liver transplant recipients, postmarketing studies have shown valganciclovir to be as effective as ganciclovir in high-risk adult patients undergoing SOT. Currently, data are lacking for pediatric liver transplantation. The purpose of this study was to compare the efficacy and safety of valganciclovir and ganciclovir for CMV infection prophylaxis in pediatric liver transplant recipients. This was a retrospective study of 56 pediatric liver transplant recipients who were prescribed either oral ganciclovir (n = 37) or valganciclovir (n = 19). Patients were followed until 200 days after transplantation or death. The primary outcome measure compared the rates of early-onset CMV infection and CMV disease in the 2 medication groups. Secondary outcome measures identified patient-specific factors that contributed to CMV acquisition and the incidence of late-onset CMV infection or disease. The rates of adverse drug effects and discontinuation were also evaluated. Early-onset CMV disease was documented in 0% of valganciclovir patients and in 5.4% of ganciclovir patients (P = 0.54). There were no statistically significant differences in the secondary outcomes. An increased incidence of late-onset CMV disease was seen in the valganciclovir group versus the ganciclovir group (22.2% versus 8.1%, P = 0.23). No differences in adverse events were reported. In conclusion, no statistically significant differences were found in the incidence of CMV infection or disease between patients receiving oral valganciclovir and patients receiving oral ganciclovir.

Primary CMV Infections Are Common in Kidney Transplant Recipients After 6 Months Valganciclovir Prophylaxis

Prolonging cytomegalovirus (CMV) prophylaxis in CMV seronegative recipients of a kidney from CMV seropositive donor (D+/R-) may reduce the incidence of late infections. We analyzed late-onset primary CMV infections after 6 months valganciclovir prophylaxis. Data from all CMV D+/R- kidney transplant recipients between January 2004 and December 2008 at our center were analyzed. Patients with a functioning graft at 6 months after transplantation who received 6 months of valganciclovir prophylaxis 900 mg once daily were included (N = 127). CMV was diagnosed with quantitative PCR. Prophylaxis was completed in 119 patients. Prophylaxis was stopped at 3-5 months due to leukopenia or gastrointestinal side effects in eight patients. Late-onset primary CMV infection developed in 47/127 (37%) patients median 244 days after transplantation (range 150-655) and median 67 days after the cessation of prophylaxis (range 1-475). Four infections were asymptomatic. In others, symptoms included fever (N = 28), gastrointestinal symptoms (nausea, vomiting, diarrhea) (N = 24), respiratory tract symptoms (N = 12), and hepatopathy (N = 6). Median peak viral load was 13500 copies/mL (range 400-2,831,000). Recurrent CMV infection developed in 9/47 (19%) patients. No significant risk factors for CMV infection were identified. Symptomatic primary CMV infections were commonly detected also after prolonged valganciclovir prophylaxis.