Cytomegalovirus Serostatus Research Articles

Cytomegalovirus-related Complications and Management in Facial Vascularized Composite Allotransplantation: An International Multicenter Retrospective Cohort Study.

There is a paucity of data on the impact of cytomegalovirus (CMV) serostatus and CMV infection on outcomes in facial vascularized composite allotransplantation. This international, multicenter, retrospective cohort study presents data on CMV and basic transplant-related demographics, including pretransplant viral D/R serostatus, and duration of antiviral prophylaxis. CMV-related complications (viremia, disease), allograft-related complications (rejection episodes, loss), and mortality were analyzed. We included 19 patients, 4 of whom received CMV high-risk transplants (D+/R-). CMV viremia was noted in 6 patients (all 4 D+/R- patients and 2 D-/R+), mostly within the first-year posttransplant, shortly after discontinuation of antiviral prophylaxis (median 2 mo). CMV disease occurred in 2 D+/R- patients. The high-risk group experienced relatively more rejection episodes per month follow-up. None of D+/R- patients suffered allograft loss due to rejection (longest follow-up: 121 mo). D+/R- patients were at increased risk of CMV-related complications. Although a higher number of rejections was noted in this group, none of the D+/R- patients lost their allograft or died because of CMV or rejection. Thus, CMV D+/R- face transplantation can likely be safely performed with prophylaxis, active surveillance, and prompt treatment.

Impact Of Recipient CMV Serological Status On Outcomes After Heart Transplantation In Contemporary Prophylactic Treatment Era

Background Cytomegalovirus (CMV) infection can limit the long term success of heart transplantation (HT) by promoting cardiac allograft vasculopathy (CAV). Moreover, prophylactic treatment of HT recipients with ganciclovir and/or CMV hyperimmune globulin reduces the incidence of CAV. We aimed to determine the prognostic impact of CMV serostatus of the donor and recipient and its effect on survival, graft failure and drug treated rejection in the contemporary prophylactic treatment era. Methods We identified adult patients who underwent HT between 2000 and 2018 in the Scientific Registry of Transplant Recipients. These patients were categorized as per recipient and donor CMV serological status. We compared survival with the Kaplan-Meier method. We constructed Cox proportional hazards regression models to determine the risk-adjusted influence of CMV serostatus on survival. Results Out of 34,279 HT recipients, 46.3 % had dissimilar (8028 with -/+ and 7840 with +/-) and 53.7% had similar (n=5417 with -/- and 12,994 with+/+) CMV serostatus. Compared to dual negative CMV serostatus, recipients with other CMV serostatuses had significantly higher 1-, 3- and 5-year mortality (Figure & Table 1). Surprisingly, while CMV +/- had an increased prevalence of graft failure, CMV -/+ had a decreased prevalence of graft failure when compared to the dual negative serotype. There was no significant difference for drug treated rejection between groups (Table 2). Conclusion Recipient and donor CMV seronegative status is associated with best post-HT survival and decreased graft failure. Despite prophylactic treatment CMV positive serostatus impacts post HT outcomes. This observation warrants further investigation into developing strategies to improve outcomes in this large HT cohort. Cytomegalovirus (CMV) infection can limit the long term success of heart transplantation (HT) by promoting cardiac allograft vasculopathy (CAV). Moreover, prophylactic treatment of HT recipients with ganciclovir and/or CMV hyperimmune globulin reduces the incidence of CAV. We aimed to determine the prognostic impact of CMV serostatus of the donor and recipient and its effect on survival, graft failure and drug treated rejection in the contemporary prophylactic treatment era. We identified adult patients who underwent HT between 2000 and 2018 in the Scientific Registry of Transplant Recipients. These patients were categorized as per recipient and donor CMV serological status. We compared survival with the Kaplan-Meier method. We constructed Cox proportional hazards regression models to determine the risk-adjusted influence of CMV serostatus on survival. Out of 34,279 HT recipients, 46.3 % had dissimilar (8028 with -/+ and 7840 with +/-) and 53.7% had similar (n=5417 with -/- and 12,994 with+/+) CMV serostatus. Compared to dual negative CMV serostatus, recipients with other CMV serostatuses had significantly higher 1-, 3- and 5-year mortality (Figure & Table 1). Surprisingly, while CMV +/- had an increased prevalence of graft failure, CMV -/+ had a decreased prevalence of graft failure when compared to the dual negative serotype. There was no significant difference for drug treated rejection between groups (Table 2). Recipient and donor CMV seronegative status is associated with best post-HT survival and decreased graft failure. Despite prophylactic treatment CMV positive serostatus impacts post HT outcomes. This observation warrants further investigation into developing strategies to improve outcomes in this large HT cohort.

Invasive Cytomegalovirus Disease in a Low Risk CMV Serostatus, D-/R- Lung Transplant Recipient

<h3>Introduction</h3> Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality among transplant patients. Here, we report a case of lung transplant patient with low risk CMV serostatus (D-/R-) who developed invasive CMV disease. <h3>Case Report</h3> A 64-year-old lady with COPD underwent bilateral lung transplant. CMV serostatus was donor IgG negative / recipient IgG negative. Basiliximab was used for induction and was maintained on tacrolimus, mycophenolate and prednisone. Intraoperatively, she received 2 leucoreduced PRBC's. 15 days post-transplant she developed CMV viremia and was started on treatment dose valganciclovir. No mutations noted on the resistance panel. 2 weeks on therapy, there was no reduction in the CMV PCR. Chest CT showed a right pleural effusion which was exudative in nature. Microbiology testing was negative. Fluid cytology showed CMV cytopathic changes. Valganciclovir was changed to iv ganciclovir because of her GI absorption concerns. With 6 weeks of iv ganciclovir and monthly CMV Immune globulin, CMV PCR log values steadily declined. <h3>Summary</h3> Lung transplant patients with low risk CMV serostatus can have a minor risk of transfusion acquired (TA) or community acquired (CA) CMV infection. A single center retrospective study of low-risk organ transplant patients did not identify any cases of TA CMV infection in patients receiving leucoreduced PRBC. Another study showed 2.4% risk of TA CMV infection in patients receiving non-leucoreduced PRBC. CA CMV risk is greater than TA CMV, with the incidence being higher in children (3/100 patient years) compared to adults (0.46/100 patient years). Currently no guidelines exist to recommend CMV prophylaxis in low risk CMV serostatus transplant patients. Hence measures need to be taken to monitor such patients who are at increased risk for TA or CA CMV. Recipients whose IgG was negative during transplant work up should be retested at the time of transplant. CMV PCR monitoring should be considered if the donor or recipient received extensive transfusions.

Association Between Cytomegalovirus Serostatus, Antiviral Therapy, and Allograft Survival in Pediatric Heart Transplantation.

Background: Cytomegalovirus (CMV) is an important complication of heart transplantation and has been associated with graft loss in adults. The data in pediatric transplantation, however, is limited and conflicting. We conducted a large-scale cohort study to better characterize the relationship between CMV serostatus, CMV antiviral use, and graft survival in pediatric heart transplantation. Methods: 4,968 pediatric recipients of solitary heart transplants from the Scientific Registry of Transplant Recipients were stratified into three groups based on donor or recipient seropositivity and antiviral use: CMV seronegative (CMV-) transplants, CMV seropositive (CMV+) transplants without antiviral therapy, and CMV+ transplants with antiviral therapy. The primary endpoint was retransplantation or death. Results: CMV+ transplants without antiviral therapy experienced worse graft survival than CMV+ transplants with antiviral therapy (10-year: 57 vs 65%). CMV+ transplants with antiviral therapy experienced similar survival as CMV- transplants. Compared to CMV seronegativity, CMV seropositivity without antiviral therapy had a hazard ratio of 1.21 (1.07–1.37 95% CI, p-value = .003). Amongst CMV+ transplants, antiviral therapy had a hazard ratio of .82 (0.74–.92 95% CI, p-value < .001). During the first year after transplantation, these hazard ratios were 1.32 (1.06–1.64 95% CI, p-value .014) and .59 (.48–.73 95% CI, p-value < .001), respectively. Conclusions: CMV seropositivity is associated with an increased risk of graft loss in pediatric heart transplant recipients, which occurs early after transplantation and may be mitigated by antiviral therapy.

Cytomegalovirus infection in liver-transplanted children.

Cytomegalovirus (CMV) infection is a common complication of liver trans-plantation in children. The CMV serostatus of recipients and donors is the primary risk factor, and prophylaxis or pre-emptive strategies are recommended for high-risk patients. Graft rejection, coinfection and Epstein-Bar virus reactivation, which can lead to post-transplant lymphoproliferative disease, are indirect effects of CMV infection. Assessment of CMV infection viral load should be routinely performed upon clinical suspicion. However, tissue-invasive CMV disease is not associated with CMV viraemia and requires confirmation by tissue pathology. Oral valganciclovir and intravenous ganciclovir are equivalent treatments, and the duration of treatment depends on factors including CMV viral load, tissue pathology, and clinical response. Risk stratification by donor and recipient status prior to transplantation and post-transplantation antiviral prophylaxis or pre-emptive therapy are recommended. Adult guidelines have been established but additional study of the effectiveness of the preventive guidelines in children is needed. This review summarizes the burden, risk factors, clinical manifestations, laboratory evaluation, treatment, and prevention of CMV infection in children after liver transplantation.

Does the cytomegalovirus infection cause kidney transplant rejection in Erbil city patients, Kurdistan region of Iraq?

Does the cytomegalovirus infection cause kidney transplant rejection in Erbil city patients, Kurdistan region of Iraq?

Abstract P1-04-10: Breast cancer survivors exhibit an accumulation of CD4+ central memory T cells, a fall in CD8+ naïve T cells and higher activation of CD4+/CD8+ memory T cells in blood, which is positively correlated with age and fat mass index

Abstract Introduction: T cells are important for tumour control and surveillance, but it is not well known how breast cancer treatment impacts their characteristics in blood. Methods: Healthy women (n=38, age 45 ± 11 y), breast cancer survivors (n=27, age 56 ± 6 y) and breast cancer patients (n=5, age 44 ± 9 y) took part. Survivors comprised women who had received any form of treatment for breast cancer within 1-2 years and were considered free from disease by their oncologist. Patients were recently diagnosed women scheduled to undergo neoadjuvant chemotherapy within 2 weeks. Using flow cytometry, CD4+ and CD8+ T cell subsets, including Naïve (NA), Central memory (CM) and Effector cells (EM and EMRA) were identified using CD27/CD45RA. Activation was measured by HLA-DR expression. Age, Cytomegalovirus (CMV) serostatus, cardiorespiratory fitness and body composition were assessed. Statistical analyses were conducted between healthy women and survivors. Data for patients enabled a qualitative interpretation of immune profiles at the time of diagnosis. Results: Lymphocyte, monocyte and neutrophil counts were not different between groups. However, compared to healthy women, CD4+ CM T cells were +Δ21% higher among survivors (cells/l: 417 ± 110 vs 346 ± 161, p=0.028) and CD8+ NA T cells were −Δ25% lower (cells/l: 106 ± 46 vs 142 ± 83, p=0.034). The proportion of activated (HLA-DR+) CD4+ and CD8+ T cell subsets was +Δ31% higher among survivors compared to healthy women: CD4+ CM (+Δ25%: 35 ± 16 % vs 28 ± 6 %), CD4+ EM (+Δ32%: 54 ± 17 % vs 41 ± 9 %) and CD4+ EMRA (+Δ43%: 53 ± 21 % vs 37 ± 11 %), total CD8+ (+Δ30%: 43 ± 18 % vs 33 ± 9 %), CD8+ EM (+Δ30%: 57 ± 18 % vs 44 ± 13 %) and CD8+ EMRA T cells (+Δ25%: 55 ± 21 % vs 44 ± 12 %) (p&amp;lt;0.046). Compared to healthy women, survivors were older (56 ± 6 y vs 45 ± 11 y), had lower cardiorespiratory fitness (VO2max mL•kg-1•min-1: 29.0 ± 5.1 vs 36.2 ± 8.5), had lower lean mass (42.3 ± 5.1 kg vs 48.4 ± 15.8 kg), had higher body fat (36.2 ± 5.4 % vs 32.7 ± 6.4 %) and higher fat mass index (FMI kg/m2: 9.5 ± 2.3 vs 8.1 ± 2.7) (all p&amp;lt;0.034). Among all participants, age positively correlated with activation levels of CD4+ EMRA and CD8+ EMRA T cells and FMI positively correlated with the proportion of activated CD4+ EMRA and CD8+ EM and EMRA T cells (Pearson r&amp;gt;0.277 p&amp;lt;0.036). CMV serostatus was not different between groups and did not influence results. Compared to healthy women and survivors, patients were younger (44 ± 9 y), had lower cardiorespiratory fitness (VO2max 27.3 ± 2.2 mL•kg-1•min-1), higher body fat (40 ± 5.8%) and higher FMI (11.2 ± 3.8 kg/m2). Lean mass (44.3 ± 4.4 kg) was higher than survivors but lower than healthy women. Patterns exhibited by survivors (compared to healthy women) tended to be present among patients (e.g. an accumulation of memory T cells and a decline in NA T cells). T cell activation was closer to the levels exhibited by healthy women. Conclusion: Breast cancer survivors exhibited signs of immunosenescence, including a decline in naïve T cells and accumulations of memory T cells, which exhibited higher activation levels. Among all participants, T cell activation was positively correlated with age and fat mass index, potentially contributing to systemic inflammation and a decline in immune competency. Citation Format: Ainhoa Arana Echarri, Lauren Struszczak, Mark Beresford, John P Campbell, Robert H Jones, Rachel Butler, Dylan Thompson, James E Turner. Breast cancer survivors exhibit an accumulation of CD4+ central memory T cells, a fall in CD8+ naïve T cells and higher activation of CD4+/CD8+ memory T cells in blood, which is positively correlated with age and fat mass index [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-04-10.

Effect of Exercise on Acute Senescent Lymphocyte Counts: A Systematic Review and Meta-Analysis

Background: Highly differentiated, senescent lymphocytes are pro-inflammatory and contribute to age-related systemic inflammation, called inflammageing. There are several reports of acute changes in senescent lymphocyte counts post exercise, which potentially have consequences for systemic inflammation. However, there is little consensus since the studies differ with respect to participants, exercise protocols, cellular markers assessed, and the time point of assessment post exercise. Objective: We performed a systematic review and meta-analysis to assess the impact of exercise on senescent lymphocyte counts in blood immediately, 1 h and 2 h post exercise. Methods: The search was performed in PubMed (MEDLINE), Web of Science, Embase, Scopus, and Cochrane, on January 11, 2021. The 13 studies selected tested aerobic exercise effects, mainly in young men. They assessed the counts of lymphocytes (CD4 T cells, CD8 T cells, and NK cells), with the following immune cell marker combinations: KLRG1+, CD57+ (only NK cells), EMRA T cells (CD45RA+CCR7−CD28−CD27−), CD28−CD27−, KLRG1+CD28−, and CD28−. Independent extraction of articles was done by 2 researchers. Results: Standardized mean difference (SMD) and 95% confidence interval between baseline and post exercise showed significant increase (SMD >0.9, p < 0.003) in all types of senescent lymphocytes counts immediately post exercise. At 1 h post exercise, senescent CD4 T cells returned to baseline values (p = 0.74), CD8 T cells were reduced (−0.26 [−0.41; −0.11], p = 0.001), and senescent NK cells were raised (0.62 [0.14; 1.10], p = 0.01) above baseline. By 2 h post exercise, senescent CD4 T cells were reduced (−0.94 [−1.40; −0.48], p < 0.001), CD8 T cells remained below baseline (−0.53 [−1.04; −0.009], p = 0.04), and NK cells had returned to baseline values (−0.29 [−0.64; 0.07], p = 0.11). The main determinants of heterogeneity between studies were cytomegalovirus (CMV) serostatus and the characteristics of exercise protocols. CMV+ individuals had a higher immediate lymphocytosis and 1 h post lymphopenia than CMV− individuals. Exercise performed at higher intensities and shorter durations led to higher magnitude of change in senescent lymphocyte counts at all time-points. Conclusion: The differing effects of exercise on senescent NK cells and CD4 and CD8 T cells suggest differing susceptibility to factors modulating lymphocyte extravasation such as adrenaline and exercise intensity.

Current Tolerance-Associated Peripheral Blood Gene Expression Profiles After Liver Transplantation Are Influenced by Immunosuppressive Drugs and Prior Cytomegalovirus Infection

Spontaneous operational tolerance to the allograft develops in a proportion of liver transplant (LTx) recipients weaned off immunosuppressive drugs (IS). Several previous studies have investigated whether peripheral blood gene expression profiles could identify operational tolerance in LTx recipients. However, the reported gene expression profiles differed greatly amongst studies, which could be caused by inadequate matching of clinical parameters of study groups. Therefore, the purpose of this study was to validate differentially expressed immune system related genes described in previous studies that identified tolerant LTx recipients after IS weaning. Blood was collected of tolerant LTx recipients (TOL), a control group of LTx recipients with regular IS regimen (CTRL), a group of LTx recipients with minimal IS regimen (MIN) and healthy controls (HC), and groups were matched on age, sex, primary disease, time after LTx, and cytomegalovirus serostatus after LTx. Quantitative Polymerase Chain Reaction was used to determine expression of twenty selected genes and transcript variants in PBMCs. Several genes were differentially expressed between TOL and CTRL groups, but none of the selected genes were differentially expressed between HC and TOL. Principal component analysis revealed an IS drug dosage effect on the expression profile of these genes. These data suggest that use of IS profoundly affects gene expression in peripheral blood, and that these genes are not associated with operational tolerance. In addition, expression levels of SLAMF7 and NKG7 were affected by prior cytomegalovirus infection in LTx recipients. In conclusion, we found confounding effects of IS regimen and prior cytomegalovirus infection, on peripheral blood expression of several selected genes that were described as tolerance-associated genes by previous studies.

Characterization of Cytomegalovirus Viremia in Renal Transplant Recipients.

Kidney transplantation, while improving outcomes for patients with end-stage renal disease, comes with a risk of potentially life-threatening infections such as infection with cytomegalovirus (CMV), a virus associated with allograft rejection, organ dysfunction, and increased mortality. To characterize whether the choice and dose of immunosuppressant therapy and the duration of antiviral prophylaxis after transplant are associated with the incidence of CMV viremia. This study was a retrospective review of all kidney-only transplant recipients at the authors' centre from 2012 to 2016, with a minimum 1 year of follow-up. Patients with CMV viremia (defined as serum CMV viral load greater than 1000 IU/mL) were compared with patients who did not have viremia to investigate potential demographic and treatment-related risk factors. A total of 653 patients were included in the study, of whom 161 (25%) met the criteria for CMV viremia. In univariate analysis, patients with CMV viremia had older age (55 versus 53 years, p = 0.038) and lower mean body weight (75 versus 79 kg, p = 0.015); in addition, the CMV viremia group included larger proportions of patients with Asian descent (40% [64/161] versus 21% [104/492]) and donor-positive/recipient-negative CMV serostatus (29% [47/161] versus 14% [70/492]). With respect to immunosuppressant therapy, patients with CMV viremia more frequently received antithymocyte globulin (ATG) induction (50% [80/161] versus 28% [138/492], p < 0.001) and received a higher weight-based cumulative ATG dose (mean 4.5 versus 4.1 mg/kg, p = 0.038). The multivariate analysis retained use of ATG, cumulative dose of ATG, Asian descent, and CMV serostatus as risk factors for CMV viremia. No statistically significant differences were found for the maintenance immunosuppressant dosing or duration of antiviral prophylaxis. Use of ATG for induction and higher weight-based dose of ATG were associated with an increased risk of CMV viremia. In addition, a component of race may also be involved, with patients of Asian descent being at higher risk. No differences were found in the maintenance dose of immunosuppression or the duration of antiviral prophylaxis.

Detection of Cytomegalovirus Antibodies in the Serum of Hemodialysis Patients.

The infection with Cytomegalovirus (CMV) is one of the main causes of morbidity and mortality in hemodialysis patients. This study aims to investigate CMV serostatus in renal failure patients undergoing hemodialysis. The study included a total of 134 cases (55 females and 79 males) with an age range of 35 - 68 years (mean age 37.43 ± 13.42 years). HCMV-IgG and IgM were determined in subjects' sera. Eighty-seven out of 134 (65%) were undergoing hemodialysis, while 47 (35%) had normal kidney functions without HCV infection. Sixty-eight (78.2%) and 31 (35.6%) cases out 87 hemodialysis patients were positive for CMV-IgG and IgM antibodies, respectively. No significant differences were noted between females and males in terms of seroprevalence rates. High rate of positive CMV-IgG was observed among hemodialysis patients who were 48 - 64 years old. Our data suggest that seroprevalence of CMV antibodies among hemodialysis cases is high and causes complications for these patients.

Risk Factors for Early Cytomegalovirus Reactivation and Impact of Early Cytomegalovirus Reactivation on Clinical Outcomes after T Cell-Replete Haploidentical Transplantation with Post-Transplantation Cyclophosphamide

Risk factors for cytomegalovirus (CMV) reactivation and the impact of CMV reactivation on patient outcomes have been extensively investigated after matched related or unrelated donor transplantation, but little is known in the setting of haploidentical stem cell transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PT-Cy), in which recipients are considered more severely immunocompromised. We retrospectively analyzed a cohort of 554 consecutive patients undergoing Haplo-SCT with PT-Cy at 3 different centers. Early CMV reactivation (occurring within the first 120 days post-transplantation) occurred in 242 patients, for an estimated cumulative incidence of 44%. Among those patients, 74 (30%) had recurrent CMV and 20 (8%) had CMV disease. On multivariable analysis, positive recipient CMV serostatus (hazard ratio [HR] >2.5; P < .001), disease histology (lymphoid versus myeloid: HR, 0.66; P=.003) and increasing recipient age (HR, 1.01; P=.015) were independent predictors of CMV reactivation. At a 4-month landmark analysis, CMV reactivation was associated with higher 1-year and 5-year cumulative incidence of nonrelapse mortality (NRM) relative to patients without reactivation: 13% versus 5% and 22% versus 9%, respectively (P < .001). On multivariable analysis, CMV reactivation was an independent negative predictor of NRM (HR, 2.69; P < .001) and was close to statistically significant for overall survival (HR, 1.38; P=.062). Our results suggest that CMV reactivation plays an important role at determining NRM. Because patient CMV serostatus is the main predictor of CMV reactivation, it should be considered when evaluating strategies for preventing CMV reactivation. 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Chronic lung allograft dysfunction phenotype and prognosis by machine learning CT analysis.

Chronic lung allograft dysfunction (CLAD) is the principal cause of graft failure in lung transplant recipients and prognosis depends on CLAD phenotype. We used a machine learning computed tomography (CT) lung texture analysis tool at CLAD diagnosis for phenotyping and prognostication compared with radiologist scoring. This retrospective study included all adult first double lung transplant patients (January 2010-December 2015) with CLAD (censored December 2019) and inspiratory CT near CLAD diagnosis. The machine learning tool quantified ground-glass opacity, reticulation, hyperlucent lung and pulmonary vessel volume (PVV). Two radiologists scored for ground-glass opacity, reticulation, consolidation, pleural effusion, air trapping and bronchiectasis. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance of machine learning and radiologist for CLAD phenotype. Multivariable Cox proportional hazards regression analysis for allograft survival controlled for age, sex, native lung disease, cytomegalovirus serostatus and CLAD phenotype. 88 patients were included (57 bronchiolitis obliterans syndrome (BOS), 20 restrictive allograft syndrome (RAS)/mixed and 11 unclassified/undefined) with CT a median 9.5 days from CLAD onset. Radiologist and machine learning parameters phenotyped RAS/mixed with PVV as the strongest indicator (area under the curve (AUC) 0.85). Machine learning hyperlucent lung phenotyped BOS using only inspiratory CT (AUC 0.76). Radiologist and machine learning parameters predicted graft failure in the multivariable analysis, best with PVV (hazard ratio 1.23, 95% CI 1.05-1.44; p=0.01). Machine learning discriminated between CLAD phenotypes on CT. Both radiologist and machine learning scoring were associated with graft failure, independent of CLAD phenotype. PVV, unique to machine learning, was the strongest in phenotyping and prognostication.

Circulating CD4+ TEMRA and CD4+ CD28- T cells and incident diabetes among persons with and without HIV.

A higher proportion of circulating memory CD4+ T cells is associated with prevalent diabetes mellitus in persons with HIV (PWH) and HIV-negative persons. We assessed whether circulating T-cell subsets could also identify individuals who will subsequently develop diabetes. This is a longitudinal follow-up study of PWH and similar HIV-negative individuals from the Veterans Aging Cohort Study who provided peripheral mononuclear blood cells between 2005 and 2007. We quantified T-cell subsets using flow cytometry and functional assays to identify CD4+ and CD8+ naive, activated, senescent, memory (central, effector, and effector RA+), and TH1, TH2, and TH17-phenotype cells. The occurrence of an incident diabetes diagnosis (i.e. after baseline blood draw) was adjudicated by a two-physician chart review. Cox proportional hazards models adjusted for traditional risk factors, cytomegalovirus serostatus, and plasma inflammatory biomarkers assessed the relationship between T-cell subsets and incident diabetes. One thousand, eight hundred and thirty-seven participants (1259 PWH) without diabetes at baseline were included; 69% were black, 95% were men, and median follow-up was 8.6 years. Higher baseline frequencies of CD4+ T effector memory RA+ (TEMRA) cells defined as CD45RA+ CD27- (P = 0.04) and senescent T cells defined as CD4+ CD28- (P = 0.04) were associated with incident diabetes in PWH only. Higher frequencies of CD4+ TEMRA and CD4+ CD28- T cells were associated with incident diabetes in PWH only after adjustment for other factors. Additional studies are necessary to assess whether these cells act in blood via inflammatory mediators or reflect T-cell populations in metabolically active tissues.

Combined Analysis of Early CD4+ T Cell Counts and CMV Serostatus May Improve CMV Risk Assessment after Allogeneic Hematopoietic Cell Transplantation.

The incidence and severity of viral complications after cellular therapy are highly variable. Recent publications describe relevant interactions between the human Cytomegalovirus (CMV) and host immunity in recipients of allogeneic hematopoietic cell transplantation (HCT). Although immune monitoring is routinely performed in HCT patients, validated cut-off levels correlating with transplant outcomes such as survival or CMV reactivation are mostly limited to day +100, which is later than the median time for CMV reactivation in the absence of medical prophylaxis. To address this gap in early risk assessment, we applied an unsupervised machine learning technique based on clustering of day +30 CD4+ helper T cell count data, and identified relevant cut-off levels within the diverse spectrum of early CD4+ reconstitution. These clusters were stratified for CMV recipient serostatus to identify early risk groups that predict clinical HCT outcome. Indeed, the new risk groups predicted subsequent clinical events such as NRM, OS, and high CMV peak titers better than the most established predictor, i.e., the positive CMV recipient serostatus (R+). More specifically, patients from the R+/low CD4+ subgroup strongly associated with high CMV peak titers and increased 3-year NRM (subdistribution hazard ratio (SHR) 10.1, 95% CI 1.38–73.8, p = 0.023), while patients from the R-/very high CD4+ subgroup showed comparable NRM risks (SHR 9.57, 95% CI 1.12–81.9, p = 0.039) without such an association. In short, our study established novel cut-off levels for early CD4+ T cells via unsupervised learning and supports the integration of host cellular immunity into clinical risk-assessment after HCT in the context of CMV reactivation.

High Rate of Cytomegalovirus Detection in Cholestatic Preterm Infants.

Objectives: To evaluate the prevalence of cytomegalovirus (CMV) infection in preterm infants with cholestasis.Study design: Preterm infants (<37 weeks gestational age) with cholestasis were tested for CMV DNA using Taqman PCR in blood cells from sedimented whole blood, plasma, and urine. Infants were regarded as positive for CMV if any sample was tested positive. Their mothers were tested for CMV serostatus simultaneously. A control group of non-cholestatic preterm infants, and their mothers, were tested at a similar age.Results: A total of 69 preterm infants with a median gestational age of 26 weeks and 5 days were included, 45 cholestatic and 24 non-cholestatic. Of the cholestatic infants, 31/45 (69%) were CMV positive vs. 3/24 (13%) of the non-cholestatic infants (p < 0.001). Cholestatic infants were equally preterm as the non-cholestatic ones, but were more severely ill. After adjusting for the risk factors necrotizing enterocolitis, prolonged parenteral nutrition, and gestational age, being CMV positive remained significantly associated with cholestasis in a multivariable logistic regression model. Characteristics of CMV-positive and -negative cholestatic infants showed differences only for necrotizing enterocolitis, occurring in 55% (17/31) of CMV positive vs. 21% (3/14) of CMV negative (p = 0.054), and mortality. Eight cholestatic CMV-positive infants died (26%) vs. none of the CMV-negative infants (p = 0.044).Conclusions: CMV DNA was detected in two out of three cholestatic preterm infants, by far more often than in the non-cholestatic control group. Cholestasis with simultaneous detection of CMV DNA may be associated with increased mortality.

Changes in T and B cell subsets in end stage renal disease patients before and after kidney transplantation

BackgroundThe incidence of kidney transplantation performed in elderly patients has increased steadily recently. Higher risk of infection and mortality, but lower rate of rejection, are reported in older kidney transplant patients. This study aims to analyze the effect of transplantation on aging of T and B cells in kidney transplant patients, with the emphasis on age and Cytomegalovirus (CMV) latency.ResultsWe included 36 patients before and after (median 2.7 years) kidney transplantation and 27 age- and sex-matched healthy controls (HC). T and B cell subsets were measured by flow cytometry, with a focus on aged T cells (CD28-), and age associated B cells (ABCs, CD19 + CD21-CD11c+). Three years after transplantation a significant increase of total T cells among the lymphocytes was found compared to pre-transplantation and HC. Among the T cells CD4+ cells were decreased, especially naïve CD4+ cells and regulatory T cells. Total CD8+ cell proportions were increased, and proportions of naïve CD8+ cells were significantly decreased after transplantation, while CD8+ effector memory T cells re-expressing CD45RA were increased. CD28− T cells were significantly higher compared to HC after transplantation, especially in CMV seropositive patients. B cells were significantly decreased, while among B cells memory B cells and especially ABCs were increased after transplantation.ConclusionsAfter transplantation T and B cell subsets change towards more terminally differentiated memory cells compared to age-matched HC. Proportions of aged T cells and ABCs were associated with CMV serostatus.

HLA-B Leader Dimorphism Impacts on Outcomes of HLA-Matched Related/Unrelated Transplantation: Analysis of the Japanese Society for Transplantation and Cellular Therapy

HLA-B Leader Dimorphism Impacts on Outcomes of HLA-Matched Related/Unrelated Transplantation: Analysis of the Japanese Society for Transplantation and Cellular Therapy

Letermovir Is Effective for Prevention of Cytomegalovirus Reactivation in HLA-Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide

[Introduction] Cytomegalovirus (CMV) infection is a common viral infection in recipients of allogeneic hematopoietic stem cell transplantation (allo-SCT). Early CMV reactivation after allo-SCT is associated with worse non-relapse mortality (NRM) and overall survival (OS). Recently, T-cell replete HLA-haploidentical SCT using post-transplant cyclophosphamide (PTCy-haplo SCT) has been developed and spread rapidly worldwide. Rationale of this strategy is assumed to be selective and cytotoxic depletion of alloreactive T cells which are responsible for graft-versus-host disease (GVHD), while preserving non-alloreactive T cells which can contribute to fight infections. However, recent studies showed that PTCy-haplo SCT was associated with the increased incidence of CMV infection. Letermovir (LET), a novel anti-CMV agent, which inhibits the CMV DNA terminase complex, was approved for the prevention of CMV reactivation in allo-SCT recipients in 2018 in some countries including Japan based on the result of a phase 3 trial. Our facility performs LET prophylaxis in allo-SCT recipient if either donor or recipient is seropositive CMV. Although LET is effective for the prevention of CMV reactivation in allo-SCT recipients, the clinical effectiveness of LET prophylaxis in PTCy-haplo SCT is not well elucidated. Based on these things, we retrospectively evaluated the efficacy of LET prophylaxis in PTCy-haplo SCT.[Methods] We retrospectively analyzed consecutive 99 recipients who received PTCy-haplo SCT at Hokkaido University Hospital from March 2013 to March 2021. We compared the cumulative incidence of CMV reactivation between the LET prophylaxis group (LET group, 33 patients) and LET non-prophylaxis group (non-LET group, 66 patients). LET was initiated on the day 0 at a dosage of 480mg daily. All patients were monitored for CMV reactivation by using the anti-CMV pp65 monoclonal antibody HRP-C7 assay at least once a week from the time of engraftment. CMV reactivation was defined as the detection of CMV antigen positive cells per 50000 white blood cells, whereas CMV disease was defined by organ dysfunction attributable to CMV.[Results] As baseline patient's characteristics were summarized in Table1, there were no difference between LET and non-LET group in terms of age, sex, underlying disease, disease risk at transplantation, prior transplantation, conditioning intensity, and CMV serostatus. All patients received peripheral blood stem cell transplantation. GVHD prophylaxis consisted of Cy (40-50 mg/kg on day 3 and 4), tacrolimus (from day 5), and mycophenolate mofetil (from day 5). The cumulative incidence of CMV reactivation at 150 days after transplantation in LET group was significantly lower than that in non-LET group (30.3% versus 69.7%; P <.001, Figure1A). Importantly, CMV disease were occurred in three patients without LET prophylaxis (gastritis, enteritis, and retinitis), but not in the patients with LET prophylaxis. The cumulative incidence of NRM at 1 year was similar between the patients with and without LET prophylaxis (17.6% versus 9.2%; P=0.366, Figure1B), as was OS at 1 year (71.5% versus 69.4%; P=0.801, Figure1C). Neutrophil engraftment was achieved in 32 patients (97%) at a median of 15 days in LET group and 64 patients (97%) at a median of 14.5 days in non-LET group (P=0.243). Furthermore, platelet engraftment was achieved in 26 patients (79%) at a median of 34 days in LET group and 57 patients (86%) at a median of 31 days in non-LET group (P=0.282). These findings suggest that LET does not affect engraftment. Interestingly, the length of hospitalization in the LET group was significantly shorter than that in non-LET group (the median, 59.5 days versus 71 days; P=0.0488), suggesting that LET suppresses CMV reactivation leading to early discharge.[Conclusion] To our best knowledge, this is the largest retrospective study about the efficacy of LET in PTCy-Haplo SCT. LET is effective for prevention of CMV reactivation in PTCy-haplo SCT. Further studies focused on the long term effect of LET prophylaxis in PTCy-haplo SCT, such as the incidence of relapse and chronic GVHD, is warranted. [Display omitted] DisclosuresNakagawa: AbbVie GK: Research Funding; Takeda Pharmaceutical Company: Research Funding. Teshima: Gentium/Jazz Pharmaceuticals: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Honoraria; Nippon Shinyaku Co., Ltd.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Fuji pharma CO.,Ltd: Research Funding; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; TEIJIN PHARMA Limited: Research Funding; Astellas Pharma Inc.: Research Funding; Bristol Myers Squibb: Honoraria; Janssen Pharmaceutical K.K.: Other; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; Sanofi S.A.: Research Funding.

Graft-Vs-Host Disease (GvHD) Prophylaxis with Post-Transplant Cyclophosphamide (PTCy) and Thymoglobulin (ATG) Are More Important Determinants of Cytomegalovirus (CMV) Reactivation after Allogeneic Hematopoietic Cell Transplantation (HCT) Than Ex-Vivo T-Cell Depletion in the Era of Pre-Emptive Therapy

Background:Cytomegalovirus (CMV) is a common cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) despite major advances in diagnostic techniques and antiviral prophylactic strategies. The relative impacts of donor/recipient CMV serologic status, disease-specific and transplant-related prognostic factors on the risk of CMV reactivation and survival are undefined.Methods:We studied the outcome of 199 patients (median age, 46 years; range 17-71 years) receiving allogeneic HCT at National University Cancer Institute of Singapore (NCIS) between January 2016 and December 2020. Their hematologic diseases included AML (n=92), ALL (n=46), MDS (n=19), lymphomas (n=19), MPN (n=7) and others (n=16) such as refractory myelomas and aplastic anemias. The conditioning regimens used were either myeloablative (n=80) or reduced intensity conditioning (n=119) prior to an allograft from different donor sources. T-cell depletion (TCD) was used for GVHD prophylaxis in 124 patients; and this included post-transplant cyclophosphamide (PTCy, n=31), ex-vivo T-cell receptor alpha-beta / CD45RA depletion (TCRab/CD45RA) (ex-vivo TCD, n=31) for haploidentical HCT, or thymoglobulin (ATG, n=62) for matched unrelated donor (MUD) HCT.Results:With a median follow-up duration of 15.6 months (range, 0.2-63.6 months), 136 (68.3%) patients had CMV reactivation (median onset, 27.5 days) while 6 (3.0 %) patients developed clinically significant CMV disease, such as colitis, retinitis and encephalitis. The cumulative incidences of CMV reactivation within the first 100 days among the recipients of matched unrelated donor (MUD) (n=60), mismatched related donor or unrelated donor (MMRD/MMUD) (n=60), umbilical cord blood (UCB) (n=18) and matched related donor (MRD) (n=61) HCT were 71.6 %, 61.7 %, 50.0 % and 32.7 %, respectively (p<0.001).There were no statistically significant differences in overall survival (OS, p=0.830) and disease-free survival (DFS, p=0.983) at 5 years between CMV-seropositive (D+/R+ or D-/R+, n=181) and CMV-seronegative recipients (D-/R- or D+/R-, n=18). There were also no significant differences in the cumulative incidences of CMV reactivation within 100 days (p=0.879), CMV end-organ disease (p=0.522) and non-relapse mortality (NRM, p=0.202), respectively. HCT-CI score of ≥1 (p=0.005) and the use of reduced intensity conditioning regimen (p<0.001) were associated with a higher NRM at 2 years. There was also a trend towards higher NRM among patients with peak CMV DNA titers of above 1000 IU/ml, but this did not reach statistical significance (p=0.188).The secondary objective of this study was to determine the risk factors associated with CMV reactivation within the first 100 days post-transplant. There was no statistically significant impact of the donor or recipient CMV serostatus (p=0.790) on the risk of CMV reactivation. In multivariable analysis, the use of any T-cell depletion (p<0.001) was a significant predictor of CMV reactivation. In a subset analysis comparing the 3 different methods of TCD, the use of ATG (p=0.004) and PTCy (p=0.005) was found to be associated with an increased risk of CMV reactivation, but not in patients receiving ex-vivo TCD (p=0.184) (Figure 1). Notably, patients receiving ex-vivo TCD haploidentical HCT was not associated with a higher risk of CMV reactivation as compared to the recipients of MRD HCT without any TCD.Conclusions:Our study concluded that CMV serologic status did not affect the incidence of CMV reactivation, NRM, OS and DFS in patients undergoing allogeneic HCT. The use of PTCy and ATG for GVHD prophylaxis, remains the most important risk factor for CMV reactivation in the era of pre-emptive therapy and hence, the need for aggressive prevention strategies in this vulnerable group of patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.