Incidence Of Cytomegalovirus Infection Research Articles

Post-transplant absolute lymphocyte count predicts early cytomegalovirus infection after heart transplantation

Immunosuppressive therapy can decrease rejection episodes and increase the risk of severe and fatal infections in heart transplantation (HT) recipients. Immunosuppressive therapy can also decrease the absolute lymphocyte count (ALC), but the relationship between early post-transplant ALC and early cytomegalovirus (CMV) infection is largely unknown, especially in HT. We retrospectively analyzed 58 HT recipients who tested positive for CMV IgG antibody and received basiliximab induction therapy. We collected preoperative and 2-month postoperative data on ALC and CMV load. The CMV load > 1200 IU/mL was used as the cutoff value to define early CMV infection. Post-transplant lymphopenia was defined as an ALC of < 500 cells/μL at postoperative day (POD) #7. On POD #7, 29 (50.0%) patients had post-transplant lymphopenia and 29 (50.0%) patients did not. The incidence of CMV infection within 1 or 2 months of HT was higher in the post-transplant lymphopenia group than in the non-lymphopenia group (82.8% vs. 48.3%, P = 0.013; 89.7% vs. 65.5%, P = 0.028, respectively). ALC < 500 cells/μL on POD #7 was an independent risk factor for early CMV infection within 1 month of HT (odds ratio, 4.14; 95% confidence interval, 1.16–14.77; P = 0.029). A low ALC after HT was associated with a high risk of early CMV infection. Post-transplant ALC monitoring is simple and inexpensive and can help identify patients at high risk of early CMV infection.

INCIDENCE OF CYTOMEGALOVIRUS DISEASE IN KIDNEY TRANSPLANT RECIPIENTS RECEIVING EVEROLIMUS AND REDUCED TACROLIMUS DOSES: A COHORT RETROSPECTIVE ANALYSIS

Introduction: Cytomegalovirus (CMV) is the most common viral pathogen occurring in postrenal transplantation. CMV infection usually develops during the first few months after transplantation. The success of CMV prophylaxis with antivirals has resulted in a decrease in the incidence of CMV infection. However, CMV remains a significant pathogen, associated with allograft rejection and loss, mortality, interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsies, and increased post-transplant costs. Purpose: To determine the incidence of cytomegalovirus disease in kidney transplant recipients receiving Everolimus and reduced Tacrolimus doses. Material and Methods: All low immunological risk patients, >18 years old whom received kidney transplantation at Santa Casa de Misericordia de Juiz de Fora between January 2013 and February 2017 were retrospectively assessed. The first group received induction therapy with Basiliximab, and the post-operative maintenance regimen included Tacrolimus, Mycophenolic acid and Prednisone (BAS/MPS), and the second group received Polyclonal antilymphocyte globulins (2,25mg/kg) as induction therapy, and then low dose of Tacrolimus (2mg/10kg/day), Everolimus and Prednisone as maintenance regimen (r-ATG/EVR). None of the patients received pharmacological prophylaxis or preemptive therapy against CMV. Results: Patients receiving EVR showed a lower incidence of CMV when compared to those receiving MPS (4.2% x 17.5%, p=0.005). There was an important difference in the time of hospitalization to treat CMV disease. Patients of the MPS stayed hospitalized for about 20 days more than the EVR group (p=0.005). There was no difference as to the incidence of rejection, delayed graft function or graft survival. Conclusion: Results from this trial conducted in low immunological risk kidney transplant recipients receiving no CMV prophylaxis demonstrated that EVR was associated to a decrease in CMV disease incidence when compared to MPS. These data suggest that kidney transplant recipients receiving EVR may not need CMV prophylaxis.

1198. Measurement of Pre-transplant Anti-cytomegalovirus (CMV) Immunoglobulin G Titer to Predict Risk of CMV Infection in CMV-seropositive Kidney Transplant Recipients

BackgroundAlthough cytomegalovirus (CMV)-seropositive solid organ transplant recipients have a lower risk of CMV infection compared with CMV-seronegative recipients, some patients remain at risk of CMV infection after transplant. Low pre-transplant anti-CMV immunoglobulin G (IgG) titer has been reported as a predictor of CMV infection in CMV-seropositive liver and heart transplant recipients, but this association in CMV-seropositive kidney transplant (KT) recipients has not been explored. We investigated the pre-transplant anti-CMV IgG titer and other CMV infection risk factors in CMV-seropositive KT recipients.MethodsThis retrospective study was conducted on CMV-seropositive KT recipients aged >18 years old at Ramathibodi Hospital during 2017 and 2018. The cumulative incidence of CMV infection was estimated with Kaplan–Meier methodology. The pre-transplant anti-CMV IgG titer was measured with an enzyme-linked fluorescent immunoassay. Risk factors for CMV infection were analyzed with Cox proportional hazards models.ResultsOf the 340 included CMV-seropositive KT recipients (37% female; age [mean±SD]: 43±11 years), 69% and 64% received deceased-donor allograft and induction therapy, respectively. The anti-CMV IgG titer was < 20 and >20 AU/ml in 7.1% and 92.9% of patients, respectively. During a mean follow-up of 14 months, the cumulative incidence of CMV infection was 14.8%, including both asymptomatic CMV infection (69%) and tissue-invasive disease (31%). A pre-transplant anti-CMV IgG titer of < 20 AU/ml was significantly associated with CMV infection in both the univariate analysis (HR, 2.70; 95%CI, 1.21–6.05, [p=0.02]) and the multivariate analysis (HR, 2.98; 95% CI, 1.31–6.77, [p=0.009]). Other significant risk factors of CMV infection included older donor age (HR, 1.03; 95% CI, 1.01–1.06, [p=0.005]), anti-thymocyte induction therapy (HR, 2.90; 95% CI 1.09–7.74, [p=0.033]), and prolonged cold ischemic time (HR, 1.06; 95% CI, 1.02–1.10, [p=0.002]).ConclusionA low pre-transplant CMV-specific humoral immunity is independently associated with post-transplant CMV infection in CMV-seropositive KT recipients. The universally available anti-CMV IgG titer test could potentially stratify those at risk and target preventive strategy appropriately.Disclosures All Authors: No reported disclosures

Letermovir for Prevention of Cytomegalovirus Reactivation in Haploidentical and Mismatched Adult Donor Allogeneic Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide for Graft-versus-Host Disease Prophylaxis

Cytomegalovirus (CMV) is serious viral infection in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. November 2017, the novel CMV DNA terminase complex inhibitor letermovir was approved for prophylaxis of CMV infection in CMV-seropositive allo-HCT recipients. Here we sought to determine the effectiveness of letermovir in preventing CMV infection in CMV-seropositive patients undergoing haploidentical or mismatched adult unrelated donor allo-HCT using post-transplantation cyclophosphamide-based graft-versus host-disease prophylaxis. Sixty-four patients underwent transplantation between 2014 and 2019, of whom 32 received letermovir and 32 did not receive letermovir. The day 180 cumulative incidence of CMV infection requiring therapy was 45.3% (95% confidence interval [CI], 32.7% to 57.1%) in the entire cohort, 68.8% (95% CI, 48.9% to 82.2%) in the patients who did not receive letermovir, and 21.9% (95% CI, 9.5% to 37.6%; P < .001) in patients who received letermovir. Adjusting for regimen intensity, disease histology, and age, the hazard ratio for CMV infection was .19 (95% CI, .08 to .47; P < .001) in patients who received primary prophylaxis with letermovir. The 1-year cumulative incidence of treatment- related mortality was similar between patients with and without letermovir treatment (16.9% versus 18.9%), as was overall survival (64.0% versus 49.0%). Persistent CMV infection requiring >28 days of therapy was more common in patients who did not receive letermovir (31.2% versus 6.2%; P=.02). In summary, letermovir was effective in preventing CMV infection in this high-risk population of HLA-mismatched allo-HCT recipients.

Antithymocyte induction dosing and incidence of opportunistic viral infections using steroid-free maintenance immunosuppression.

Currently, there is limited literature evaluating rATG induction dosing and incidence of opportunistic viral infections when using steroid-free maintenance immunosuppression. This single-center, retrospective, study compared high rATG (>4.5mg/kg) versus low (<4.5mg/kg) induction dosing and the overall incidence of early opportunistic viral infection at 180days in the setting of maintenance immunosuppression consisting of tacrolimus, mycophenolate, rapid steroid withdrawal, and a tiered antiviral prevention strategy based on donor-recipient Cytomegalovirus (CMV) serostatus. A total of 209 patients were included; 76 patients received low-dose and 133 patients received high-dose rATG. Incidence of overall opportunistic viral infection occurred more frequently in patients who received high compared to low dose (29.8% vs 25% p=.030). Incidence of CMV infection was also significantly increased in the high-dose group (31.6% vs 18.4% p=.039). In a multivariable model, rATG dose, as a continuous variable, remained a significant independent predictor of infection along with CMV risk (OR 1.46, 95% CI 1.02-2.09) controlling for age and CMV risk. There were no differences in graft-related outcomes at 180days. Higher cumulative rATG induction dose was associated with increased incidence of opportunistic viral infections, in the setting of a steroid-free maintenance immunosuppression in the early post-transplant period.

Cytomegalovirus retinitis after allogeneic hematopoietic stem cell transplantation under cytomegalovirus antigenemia-guided active screening.

Although cytomegalovirus (CMV) remains a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), the incidence of CMV retinitis is considered to be lower than the incidence of CMV infection in other organs following allogeneic HSCT. In this study, the incidence and characteristics of CMV retinitis were retrospectively evaluated in recipients of allogeneic HSCT. Ophthalmological screening was performed at the development of ocular symptoms or positive CMV infection using peripheral blood evaluated by pp65 antigenemia or polymerase chain reaction. Of the 514 patients, 13 patients developed CMV retinitis. The median onset of CMV retinitis was day 34 (range, 21-118) post transplant, and the cumulative incidence was 2.5% (95% CI, 1.6-4.2) at 6 months after transplantation. Five patients presented ocular symptoms at the onset. In the remaining eight asymptomatic patients, the diagnosis of CMV retinitis was made by the screening guided by positive CMV infection. All evaluable patients responded to antiviral treatment but three showed incomplete improvement with ocular sequela. Our results suggest that the incidence of CMV retinitis after allogeneic HSCT is not negligible and active ophthalmological screening based not only on symptoms but also positive CMV infection monitoring contributes to the early diagnosis of CMV retinitis.

Unknown cytomegalovirus serostatus in primary immunodeficiency disorders: A new category of transplant recipients.

Cytomegalovirus (CMV) serostatus of recipient (R) and donor (D) influences hematopoietic stem cell transplant (HSCT) outcome. However, it is not a reliable indicator of CMV infection in primary immunodeficiency disorder (PIDD) recipients who are unable to make adequate antigen-specific immunoglobulin (Ig) or who receive intravenous Ig (IVIg) prior to testing. Since no data exist on PIDD with unknown CMV serostatus, we aimed to evaluate the relationship between pre-HSCT recipient and donor serostatus and incidence of CMV infection in recipients with unknown serostatus. A retrospective analysis of all pediatric PIDD HSCTs (2007-2018) was performed at University of California San Francisco. Recipients were separated into categories based on pre-transplant serostatus: 1) seropositive (R(+)), 2) seronegative (R(-)), and 3) unknown serostatus (R(x)). Patients with pre-HSCT active CMV viremia were excluded. A total of 90 patients were included, 69% male. The overall incidence of CMV infection was 20%, but varied in R(+), R(-), and R(x) at 80%, 0%, and 14%, (P-value=.0001). Similarly, 5-year survival differed among groups, 60% R(+), 100% R(-), and 90% of R(x) (P-value=.0045). There was no difference in CMV reactivation by donor serostatus (P-value=.29), however, faster time to clearance of CMV was observed for R(x)/D(+) group (median 9.5days (IQR 2.5-18), P-value=.024). We identify a novel group of recipients, R(x), with an intermediate level of survival and CMV incidence post-HSCT, when compared to seropositive and seronegative recipients. No evidence of CMV transmission from D(+) in R(-) and R(x) was observed. We believe R(x) should be considered as a separate category in future studies to better delineate recipient risk status.

Comparison of clinical outcomes between ABO-incompatible and ABO-compatible pediatric liver transplantation: a systematic literature review and meta-analysis.

ABO-incompatible (ABO-i) liver transplantation (LT) is a life-saving method for pediatric patients in emergency situations that has the potential to expand the pool of liver donors. However, the risks of ABO-i compared to ABO-compatible (ABO-c) LT are unclear. To address this clinical uncertainty, we conducted a systematic review and meta-analysis to compare clinical outcomes between ABO-i and ABO-c LT in pediatric patients. A systematic search for studies comparing outcomes between ABO-i and ABO-c LT was performed in the MEDLINE (PubMed), EMBASE, and Cochrane Library databases through May 2020. Outcomes evaluated included graft survival rate, patient survival rate, rejection, infection, biliary complications, and vascular complications. Quality of evidence was assessed using the Newcastle-Ottawa scale. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using RevMan 5.3. A total of 12 studies involving 7461 patients were included in the review. Meta-analysis of these studies showed significantly lower 1year, 3year, and 5year graft survival rates for ABO-i vs. ABO-c LT (1year: OR = 0.46, 95% CI 0.35-0.59, P < 0.00001; 3years: OR = 0.47, 95% CI 0.36-0.63, P < 0.00001; 5year: OR = 0.48, 95% CI 0.37-0.63, P < 0.00001) as well as significantly lower 1year, 3year, 5year, and 10year patient survival rates for ABO-i vs. ABO-c (1year: OR = 0.34, 95% CI 0.24-0.49, P < 0.00001; 3years: OR = 0.24, 95% CI 0.14-0.40, P < 0.00001; 5years: OR = 0.47, 95% CI 0.35-0.64, P < 0.00001; 10years: OR = 0.59, 95% CI 0.38-0.90, P = 0.02). No significant differences were observed between the groups in incidence of cytomegalovirus infection, acute cellular rejection, acute rejection, biliary complications, or hepatic artery thrombosis. Our systematic review and meta-analysis showed consistently lower patient survival and graft survival in pediatric ABO-i LT compared to ABO-c LT. However, ABO-i LT is still a life-saving emergency option for pediatric patients waiting for a suitable liver source.

A single-centre observational study comparing the impact of different cytomegalovirus prophylaxis strategies on cytomegalovirus infections in kidney transplant recipients

Background/objective: Prevention of cytomegalovirus (CMV) infection is an important component of post kidney transplant care. We aimed to evaluate the impact of two different CMV prophylaxis protocols on the epidemiology and outcomes of CMV infections at our centre. Methods: This is a single-centre retrospective before/after observational study. Kidney transplant recipients who received Protocol 1, a valacyclovir- or valganciclovir-based regimen prescribed for one to three months based on the CMV risk status between 2004 and 2008, were compared to those who received Protocol 2, a valganciclovir-based regimen prescribed for three months and six months for those at moderate and high risk, respectively, between 2010 and 2014. The impact of different prophylaxis regimens on the incidence of CMV infections, disease, recurrent infections and onset of CMV infection at 24 months were reviewed. Results: There were 192 patients included; 106 patients received Protocol 1, 86 received Protocol 2. At 24 months, the incidence of CMV infection was 53.8% and 55.8% in Protocols 1 and 2, respectively ( p=0.884). The incidence rates of CMV disease and recurrent CMV infections were higher in Protocol 1, but this was not statistically significant. The median time to first CMV infection was significantly shorter in patients who received Protocol 1: 132 days (interquartile range (IQR) 125–139 days) versus 185 days (IQR 178–192 days), p=0.001. Both prophylaxis protocols were well tolerated. Conclusion: The incidence of CMV infection was similar in both protocols. Where valganciclovir is not available, valacyclovir may be considered over no prophylaxis. Post-prophylaxis CMV infections are not uncommon, and vigilance for it should be advocated.

One Year of Preemptive Valganciclovir Administration in Children After Liver Transplantation

ObjectivesValganciclovir (VGCV) is used as prophylaxis against cytomegalovirus (CMV) infection after pediatric living donor liver transplantation (LDLT). The purpose of this study was to examine the efficacy of 1 year of preemptive VGCV administration compared with a shorter administration after pediatric LDLT. MethodsVGCV was administered to 56 children who underwent LDLT. CMV and Epstein-Barr virus (EBV) antibody status, pp65 antigenemia, and other laboratory data were assessed at 1 year after LDLT. Patients were divided into the 1-year group (n = 32) (patients who had 1 year of VGCV administration) and the <1-year group (n = 24) (patients who had less than 1 year of VGCV administration). ResultsStudy participants consisted of 34 females and 22 males, with a mean age of 4.2 years at transplant. Regarding pretransplant donor (D)/recipient (R) CMV antibody status, 13 were D positive (+)/R negative (-), 27 were D+/R+, 8 were D-/R+, and 8 were D-/R-. For EBV, 22 were D+/R+, 32 were D+/R-, and 2 were D-/R-. In the 1-year group, only 2 patients (6.5%) developed CMV infection, whereas 8 patients (33.3%) developed CMV infection in the <1-year group. The CMV pp65 antigenemia assay was positive in 2 patients. CMV IgM was positive in 7 patients. One year of preemptive VGCV administration was associated with a lower incidence of CMV infection (P = .008), but not EBV infection. No adverse effects were observed. ConclusionsOne year of preemptive VGCV administration after LDLT is safe and suppresses CMV infection. It was useful after pediatric LDLT.

The Aquaporin3 Promoter Polymorphism -1431 A/G is Associated with Acute Graft Rejection and Cytomegalovirus Infection in Kidney Recipients Due to Altered Immune Cell Migration.

Major complications after kidney transplantation are graft rejection and cytomegalovirus (CMV) infection, which are related to T-cell function, which depends on aquaporin 3 (AQP3) expression. The impact of the AQP3 A(−1431)G promoter polymorphism in kidney transplant recipients was unelucidated and we explored the effect of AQP3 polymorphism on immune cell function and its association with graft rejection and CMV infection in 237 adult patients within 12 months after transplantation. AQP3 promoter polymorphism was molecular and functional characterized. Kaplan–Meier plots evaluated the relationship between genotypes and the incidence of CMV infection and graft rejection. AQP3 A(−1431)G A-allele was associated with enhanced immune cell migration and AQP3 expression in T-cells. The incidences of rejection were 45.4% for the A-allele and 27.1% for G-allele carriers (p = 0.005) and the A-allele was a strong risk factor (hazard ratio (HR): 1.95; 95% CI: 1.216 to 3.127; p = 0.006). The incidences for CMV infection were 21% for A-allele and 35% for G-allele carriers (p = 0.013) and G-allele was an independent risk factor (p = 0.023), with a doubled risk for CMV infection (HR: 1.9; 95% CI: 1.154 to 3.128; p = 0.012). Hence, A-allele confers more resistance against CMV infection, but susceptibility to graft rejection mediated by T-cells. Thus, AQP3-genotype adapted management of immunosuppression and antiviral prophylaxis after kidney transplantation seems prudent.

Association Between Polymorphisms in Cytokine Gene and Viral Infections in Renal and Liver Transplant Recipients: A Systematic Review.

Although transplantations are associated with an increased risk of post-transplantation infections, they greatly improve life expectancy and patients' quality of life. Cytokine genes play an important role in the success of transplants due to their immunological functions. A systematic review was conducted to evaluate cytokine gene polymorphisms and risk of cytomegalovirus (CMV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in kidney and liver transplant recipients. A systematic search was conducted using PubMed, EMBASE, Medline and Google Scholar from their inception until January 28, 2019 using appropriate key words. Review articles, case reports or series, studies conducted on non-human subjects and published in languages other than English were excluded. Data were abstracted using a standardized form. The quality of the studies included was assessed using "Risk of Bias Assessment tool for Non-randomized Studies (RoBANS)". Thirty-one studies met our inclusion criteria; populations studied were diverse with a sample ranging from 20 to 1,671. Nineteen studies evaluated Interleukin (IL)-28B polymorphism, while six studies evaluated interferon lambda (IFN-λ) gene polymorphisms and their impact on CMV, HCV, and HBV progression. Polymorphisms in IL-10 gene were investigated in six studies. Polymorphisms in IL-12B and IL-1B gene were associated with a higher risk of developing CMV infections while polymorphisms in IL-28B were associated with a lower incidence of CMV infection in renal transplant recipients. Similarly, polymorphisms in IL-28B were associated with higher liver dysfunction from HBV infection in liver transplant recipients. Studies included had low risk of bias. Cytokine gene polymorphisms IL-12B and IL-1B were found to be associated with an increased risk of infection in kidney transplants and IL-28B in liver transplant recipients. However, the small number and heterogeneity of studies limits the generalization of our results. Further research may lead to finding these associations in larger studies which perhaps improve the use of genetic testing and targeted antiviral therapy. This will further reduce the risk of viral infections associated with cytokine gene polymorphisms in post renal and liver transplant recipients.

Delayed vs initial cytomegalovirus prophylaxis after kidney transplantation.

It is recommended to start cytomegalovirus (CMV) prophylaxis within 10days of solid organ transplant, if indicated. Our center underwent a cost-savings initiative to delay CMV prophylaxis initiation from postoperative day zero to postoperative day 7 or upon discharge, hypothesizing this would not affect clinical outcomes but could impact costs. The purpose of this retrospective study was to determine the effects of early vs delayed (<72 vs >72hours after transplant) CMV prophylaxis in kidney and kidney/pancreas transplant recipients transplanted between June 2014 and January 2017. The primary endpoint was incidence of CMV infection within 1year. Secondary endpoints included CMV disease, CMV testing, and valganciclovir cost during index hospitalization. A total of 173 patients (114 early, 59 delayed) were included. CMV infection occurred in 61% vs 54% in the early vs delayed group (P=.5). Excluding low-level DNAemia (QNAT<200IU/mL), infection occurred in 30% vs 22% in the early vs late group (P=.4). The median days to starting prophylaxis were 0 and 6 in the early and delayed group (P<.05), which led to a median cost savings of $497.00 per patient during index hospitalization (P<.05). Delaying prophylaxis initiation did not impact CMV outcomes in this cohort and decreased costs.

Effectiveness of valacyclovir prophylaxis against the occurrence of cytomegalovirus infection in kidney transplant recipients.

BackgroundCytomegalovirus (CMV) infection is a crucial infection in kidney transplant recipients (KTRs) despite advancements in diagnostic and treatment methods. There are still many controversies about the ways to prevent CMV infection.MethodsWe retrospectively analyzed 153 KTRs who underwent kidney transplantation (KT) between September 2013 and January 2016. We classified KTRs into two groups: valacyclovir prophylaxis group (intravenous ganciclovir for 2 weeks after KT, followed by oral valacyclovir for 3 months) and historical control group (only intravenous ganciclovir for 2 weeks after KT). We evaluated the incidence of CMV infection, clinical outcomes, CMV-free survival rate between the two groups and risk factors for the development of CMV infection.ResultsMean time between KT and diagnosis of CMV infection was 4.5±3.3 months. The valacyclovir prophylaxis group showed lower incidence of CMV infection than the historical control group (21.7% vs. 43.9%, P=0.011). The valacyclovir prophylaxis group showed higher CMV-free survival rate than the control group (P=0.011). In multivariable-adjusted analysis, independent risk factors for the development of CMV infection were no valacyclovir prophylaxis, older age at KT, thymoglobulin induction, and delayed graft function.ConclusionsValacyclovir prophylaxis for 3 months showed significant reduction in the incidence of CMV infection in KTRs. Therefore, we suggest valacyclovir prophylaxis for 3 months in KTRs with risk factors such as old age, thymoglobulin induction, and delayed graft function.

Targeting Latent Human Cytomegalovirus (CMV) with a Novel Fusion Toxin Protein during Ex Vivo Lung Perfusion

Donor to recipient CMV mismatch leads to high incidence of CMV infection post lung transplant leading to inferior long-term patient outcomes. CMV latently infected cells ubiquitously express a surface marker, US28. We aimed to evaluate the therapeutic effects of a novel fusion toxin protein (F49A-FTP) that targets US28 in human lungs during EVLP, with the ultimate goal of minimizing or preventing CMV reactivation post transplantation. Human lungs rejected for transplantation were randomly placed on EVLP alone or EVLP+1mg/L of F49A-FTP (n=6 each) for 6 hours. Biopsies were collected to evaluate viral reactivation using an in vitro assay that induces latent CMV to reactivate to an infectious phase. Since US28 has 38% homology to the human CX3CR1 chemokine receptor, potential off-target effects of the toxin were studied using flow cytometry for cell death assessment of CD34+ and CD14+ cells. Lung function on EVLP was evaluated as a safety endpoint. F49A-FTP was delivered through the PA on EVLP with no acute toxic events based on physiological parameters (Figure 1A). We performed an in vitro assay using tissue samples obtained after EVLP to stimulate CMV to reactivate in order to assess efficacy of the drug. After primary culture from lung tissue samples, relative reactivation events (assessed with IFF staining for IE protein of lytic CMV, Figure 1B) occurred in 100% of controls vs. only 0.04±0.02% of treated lungs. For off-target analysis, we performed flow cytometry and calculated the ratio of post:pre perfusion CD34+ and CD14+ cells (Figure 1C). There were no changes in number of cells for both groups: CD34+ ratio 0.8±0.5 vs. 0.6±0.5 (control and F49A-FTP, respectively, p=0.4974); CD14+ ratio 1.54±0.74 vs. 1.66±1.13 (control and F49A-FTP, respectively, p=0.8660). Our study demonstrates that ex vivo F49A-FTP treatment of human lungs on EVLP markedly attenuates CMV reactivation. Ongoing ex vivo and in vivo reactivation experiments will confirm these findings.

Extending cytomegalovirus prophylaxis in high-risk (D+/R-) lung transplant recipients from 6 to 9 months reduces cytomegalovirus disease: A retrospective study.

Cytomegalovirus (CMV)-seronegative recipients receiving a seropositive allograft (D+/R-) are at a high risk of developing CMV disease. Our program increased the duration of CMV prophylaxis from 6 to 9months in May 2013. Here, we present the impact on the incidence of CMV infection, disease, side effects, rejection, and other factors. Retrospective cohort of 241 CMV (D+/R-) patients transplanted between January 1, 2008, and December 31, 2017. Blood CMV testing was done according to protocol. All patients received ganciclovir/valganciclovir as prophylaxis. We compared the incidence and timing of CMV infection and disease up to 6months after cessation of prophylaxis between patients who received 9months (May 2013 onwards) and a historical control group who received 6months of prophylaxis (prior to May 2013). CMV infection was defined as detectable CMV viremia in the absence of symptoms. CMV disease was defined as CMV syndrome or tissue-invasive disease. Side effects of prophylaxis and CMV resistance were recorded. A total of 116 patients were included in the 6-month group and 125 in the 9-month group. The extended 9-month CMV prophylaxis delayed the onset of CMV infection (median time to CMV infection after lung transplantation 295 vs 353days, P<.01) but did not significantly reduce the incidence of CMV infection (65% vs 64%, P=.06, log-rank). The 9-month prophylaxis delayed the onset and decreased the incidence of CMV disease from 50% in the 6-month group to 42% (P=.02 log-rank). There was no difference in the rate of adverse effects (leukopenia in 32% in both groups, P=.53) or development of CMV resistance between the two groups (4 cases in both groups, P=.92). There were no significant differences in overall survival or the rate of chronic lung allograft dysfunction between the groups. Extending duration of CMV prophylaxis from 6 to 9months resulted in a delayed and decreased incidence of CMV disease in our lung transplant population. The absolute risk reduction achieved by extended CMV prophylaxis was 8%. The incidence of CMV infection, and ganciclovir resistance and side effects were similar between the two groups. Our results suggest that extending CMV prophylaxis in the highest risk CMV D+/R- group is effective in reducing CMV disease.

The Influence of Antithymocyte Globulin Dose on the Incidence of CMV Infection in High-risk Kidney Transplant Recipients Without Pharmacological Prophylaxis.

Optimizing antithymocyte globulin (ATG) dosage is critical, particularly for high-risk kidney transplant (KT) recipients without cytomegalovirus (CMV) prophylaxis. We studied 630 KT recipients with expanded criteria donors or panel reactive antibody ≥50% at Hospital do Rim, Brazil (January 1, 2013 to May 21, 2015) to determine whether a single ATG dose was safe and effective in patients without CMV prophylaxis. Patients received ≥4 doses (1-1.5 mg/kg/per dose) until June 17, 2014, when the induction protocol changed to a single ATG dose (3 mg/kg). We used Cox regression to compare the risk of CMV infection and acute rejection (AR) among KT recipients by ATG dose. Adjusting for clinical and transplant factors, a single ATG dose was associated with a lower risk of CMV infection (adjusted hazard ratio [aHR]: 0.63; 95% confidence interval [CI], 0.42-0.93; P = 0.02) and a similar risk of AR (aHR: 1.16; 95% CI, 0.47-2.83; P = 0.8), compared to multiple doses. We found no differences in death-censored graft loss (5.0% versus 4.8%, aHR: 1.06; 95% CI, 0.51-2.23; P = 0.9) or mortality (4.7% versus 3.4%; aHR: 1.42; 95% CI, 0.62-3.24; P = 0.4) at 1-year post-KT by ATG dose. In our study of high-risk KT recipients without CMV prophylaxis, a single ATG dose decreased the risk of CMV infection without increasing the risk of AR or compromising graft or patient survival.

The incidence of cytomegalovirus infection after deceased-donor kidney transplantation from hepatitis-C antibody positive donors to hepatitis-C antibody negative recipients

Background Deceased-donor kidney transplantation (KT) from hepatitis C (HCV)-infected donors into HCV-uninfected recipients (HCV D+/R−) could become standard care in the near future. However, HCV viral replication by viral transmission might lead to a higher incidence of cytomegalovirus (CMV) infection in these recipients. Methods A national-registry-based retrospective cohort study was conducted using the Scientific Registry of Transplant Recipients (SRTR) data set. We assessed the incidence of CMV infection in HCV antibody (Ab) negative recipients receiving kidneys from HCV Ab positive (HCVAb D+/R−) and negative (HCVAb D−/R−) donors. The risk of CMV infection was analyzed by Cox regression analysis in a propensity score (PS) matched-cohort of HCVAb D+/R− (n = 950) versus HCVAb D−/R− (n = 950). Sensitivity analysis was also conducted in the entire cohort (n = 181 082). Results The mean age at baseline was 54 years, 75% were male, and 55% of the patients were African American in PS-matched cohort. Compared to the HCVAb D−/R − patients, recipients with HCVAb D+/R − showed identical probability for the incidence of CMV infection (Hazard Ratio (HR) = 1.00, 95% Confidence Interval (CI): 0.82–1.22). In the sensitivity analysis, compared to the HCVAb D−/R − patients, the HCVAb D+/R − group had a significantly lower risk of CMV infection in the unadjusted analysis (HR = 0.75, 95%CI: 0.65–0.85), while this risk difference disappeared after the adjusted analysis (HR = 0.99, 95%CI: 0.87–1.14). Conclusion The incidence of CMV infection was similar in recipients who received HCVAb D + and HCVAb D − KT. Further studies are needed to assess this association in KT from HCV nucleic acid positive donors.

Surveillance of viral infections in renal transplant recipients – A prospective observational study

Background: There has been significant advancement in the field of renal transplantation in the last few decades. However, the long-term graft survival has not dramatically increased. Among all the infections, viral infections continue to be a major contributor to graft failure as well as severe mortality and morbidity in renal transplant recipients. Materials and Methods: It was a prospective, nonrandomized, observational study of the duration of 1 year that was conducted in live donor renal transplant recipients (n = 96). Blood samples were collected from all live renal allograft recipients at specified intervals and investigated for the viral infections. Glomerular filtration rate (GFR) and tacrolimus levels were measured at follow-ups. Results: Prior to renal transplant, the hepatitis C prevalence was the highest accounting for viral infection in 7.3% of the total study population. The study had pretransplant cytomegalovirus (CMV) and BK virus (BKV) infection rates of 1.04% each. CMV infection had the highest incidence rate occurring in 29.1% of the total population posttransplantation. There was significant incidence of CMV infection (CMV+) after rejection (P = 0.016). The incidence of BKV infection in our study through 1 year was 8.3%. The incidence of CMV infection correlated well with mean tacrolimus trough level of 10.58 ± 1.25 ng/mL. The mean estimated GFR (eGFR) at 12 months in infected patients was 65.12 ± 5.31 ml/min/1.73 m2 which was significantly lower compared to controls which was 75.53 ± 2.24 ml/min/1.73 m2 though they had comparable mean eGFR at baseline (P = 0.008). Conclusions: Hepatitis C was the dominant infection among all pretransplant viral infections. The highest incidence of CMV and BKV infection was after 6 months' posttransplant. Rejection was associated with CMV infection. All patients with BKV viremia had viruria. High level of tacrolimus was associated with CMV incidence. CMV infection was associated with lower eGFR at 1-year postrenal transplant.

Pretransplant adaptive NKG2C+ NK cells protect against cytomegalovirus infection in kidney transplant recipients.

Cytomegalovirus (CMV) infection constitutes a complication for kidney transplant recipients (KTR) and CMV-specific T cells reduce the risk of viral replication in seropositive patients. CMV promotes the adaptive differentiation and expansion of an NK cell subset, hallmarked by expression of the CD94/NKG2C receptor with additional characteristic features. We previously reported an association of pretransplant NKG2C+ NK cells with a reduced incidence of CMV infection. We have strengthened the analysis in cryopreserved peripheral blood mononuclear cells from an enlarged KTR cohort (n=145) with homogeneous immunosuppression, excluding cases at low risk of infection (ie, CMV D-R-) or receiving antiviral prophylaxis. Moreover, adaptive NKG2C+ NK cell-associated markers (ie, NKG2A, CD57, Immunoglobulin-like transcript 2 [LIR1 or LILRB1], FcεRI γ chain, and Prolymphocytic Leukemia Zinc Finger transcription factor) as well as T lymphocyte subsets were assessed by multicolor flow cytometry. The relation of NKG2C+ NK cells with T cells specific for CMV antigens was analyzed in pretransplant patients (n=29) and healthy controls (n=28). Multivariate Cox regression and Kaplan-Meier analyses supported that NKG2C+ NK cells bearing adaptive markers were specifically associated with a reduced incidence of posttransplant symptomatic CMV infection; no correlation between NKG2C+ NK cells and CMV-specific T cells was observed. These results support that adaptive NKG2C+ NK cells contribute to control CMV infection in KTR.