Cytomegalovirus Serological Status Research Articles

Sicilian semi- and supercentenarians: identification of age-related T-cell immunophenotype to define longevity trait.

The immunophenotype of oldest centenarians, i.e. semi- and supercentenarians, could provide important information about their ability to adapt to factors associated with immune changes, including ageing per se and chronic Cytomegalovirus infection. We investigated, by flow cytometry, variations in percentages and absolute numbers of immune cell subsets, focusing on T cells, and pro-inflammatory parameters in a cohort of 28 women and 26 men (age range 19-110 years). We observed variability in hallmarks of immunosenescence related to age and Cytomegalovirus serological status. The eight oldest centenarians showed the lowest percentages of naïve T cells, due to their age, and the highest percentages of T-effector memory cells re-expressing CD45RA (TEMRA), according to their cytomegalovirus status, and high levels of serum pro-inflammatory parameters, although their means were lower than that of remaining 90+ donors. Some of them showed CD8 naïve and TEMRA percentages, and exhaustion/pro-inflammatory markers comparable to the younger ones. Our study supports the suggestion that immune ageing, especially of oldest centenarians, exhibits great variability that is not only attributable to a single contributor but should also be the full result of a combination of several factors. Everyone ages differently because he/she is unique in genetics and experience of life and this applies even more to the immune system; everybody has had a different immunological history. Furthermore, our findings on inflammatory markers, TEMRA and CMV seropositivity in centenarians, discussed in the light of the most recent literature, suggest that these changes might be not unfavourable for centenarians, and in particular for the oldest ones.

#5296 CYTOMEGALOVIRUS INFECTION AFTER COVID-19 IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE CENTER EXPERIENCE

Abstract Background and Aims Kidney transplant recipients (KTR) have adverse COVID-19 outcomes due to the immunosuppressed status and multiple comorbidities. Cytomegalovirus (CMV) is one of the most frequent opportunistic infections after kidney transplantation. However, data concerning its reactivation after COVID-19 is scarce. Herein, we present a single-center cohort of KRT presenting with CMV infection after COVID-19 and its clinical outcomes. Method Single-center cross-sectional study including 22 KTR with CMV viraemia detected by quantitative polymerase chain reaction up to 6 months after COVID-19, between 2020 and 2022. Demographic and clinical data were collected from the electronic records. Results A total of 22 KTR (13 male) were included with a mean age of 55.5±15.5 years and a median Charlson score of 4 (IQR 3-6). Median time after transplantation was 65 months (IQR 12.5-174.5; 3 KTR with <6 months) and only one patient had been submitted to living-donor transplantation. Eight patients received induction therapy with antithymocyte globulin (ATG). At transplantation time, CMV serologic status had been: 50% D+/R+, 13.6% D+/R- and 4.5% D-/R+. CMV infection prior to COVID-19 had been documented in 6 patients. Concerning COVID-19, severe or critical disease had been reported in 8 patients. Specific therapy had been used in 4 patients: 2 with remdesivir/baricitinib, one with remdesivir and one with molnupiravir. Moreover, immunosuppressive therapy had been adjusted in 11 patients, namely by withdrawing the antimetabolite and increasing steroids (7 patients). Median maximum steroid dose (expressed as equivalents of prednisone dose) had been 40 mg (IQR 20-40) and mean cumulative steroid dose had been 416±317 mg. CMV disease was documented in 8 patients (4 with gastrointestinal involvement) and the mean time of diagnosis after COVID-19 was 10±6 weeks. Maintenance immunosuppression included tacrolimus, antimetabolite and steroid in 12 patients; 6 patients had supratherapeutic levels of tacrolimus at CMV infection diagnosis. Median initial viraemia was 770 copies/mL (IQR 288-4106). Valganciclovir was used in 14 patients (one was already taking it as prophylaxis), ganciclovir in 4 patients and CMV enriched human intravenous immunoglobulin was used in one patient. Nine patients required hospitalization and 2 were transferred to an intensive care unit; one of these 2 patients died. Induction therapy with ATG, CMV serologic status at transplantation time, previous CMV infection, COVID-19 severity or supratherapeutic immunosuppressive drug levels were not associated with CMV infection severity or hospitalization. However, higher maximum steroid dose during COVID-19 was associated with CMV disease (p = 0.038), higher viraemia at diagnosis (p = 0.032) and hospitalization (p = 0.018). Conclusion CMV infection is a common and clinically relevant complication in KTR. Altered immunologic status after COVID-19 may predispose to this infection. In addition, immunosuppressive therapy adjustments, namely the increase in steroid dosing may be very relevant to favor reactivation of CMV. Larger studies are warranted, but careful monitoring could help identifying risk patients earlier and prophylaxis may be considered when increased corticosteroids are prescribed.

Evaluation of T-Cell Immune Status of Reduced-Dose Cyclosporine and Everolimus Combination Therapy in Kidney Transplant Patients

Kidney transplantation (KT) outcomes have significantly improved with calcineurin inhibitors (CNIs) administration. In recent years, the dose of CNIs has been reduced, and everolimus (EVR) has been used in combination with CNIs to avoid complications from the long-term use of CNIs. However, T-cell immune responses to these protocols have not been fully evaluated. This study evaluated the anti-donor T-cell responses to our CNI-sparing regimen. Fifty-five de novo KT patients were enrolled. Three months after KT, the patients were randomly assigned to either the EVR group, which received low-dose cyclosporine (CsA) (n=28), or the standard-exposure CsA control group (n=27), which was treated with both mycophenolate mofetil and methylprednisolone. Graft function, adverse events, and immunologic status were evaluated 3 years after KT. Mixed lymphocyte reaction (MLR) assays were performed to evaluate anti-donor T-cell responses in KT patients. Both groups maintained graft function well, but total cholesterol levels tended to increase annually in the EVR group. The incidence of cytomegalovirus (CMV) infection tended to be lower in the EVR group, regardless of the CMV serologic status. Immunologic evaluation by MLR assay showed that anti-donor T-cell responses were adequately maintained in both groups. EVR starting 3 months after KT can reduce the trough levels of CsA without affecting graft function or compromising the immunosuppressive effects. The EVR combination protocol is expected to reduce CNI toxicity and improve long-term prognosis after KT.

Knowledge of cytomegalovirus and available prevention strategies in pregnancy: a cross-sectional study in Portugal

Objective Maternal and fetal congenital infection by cytomegalovirus (CMV) during pregnancy is the leading infectious cause of neurologic impairment and hearing loss. Efforts at limiting CMV exposure are based on hygienic measures. This study assessed the relationship between CMV knowledge and pregnant women’s time perspective as per the Zimbardo Time Perspective Inventory (ZTPI) scale. Methods We conducted a prospective descriptive study at a secondary-care Portuguese hospital between October to November 2021. All consecutive pregnant women in antenatal third-trimester appointments were included. The questionnaire included: sociodemographic data, knowledge about CMV, and the ZTPI scale, validated to our population. The number of correct answers in the knowledge section of the questionnaire was tallied to determine the individual knowledge score (KS). We investigated patients subjective perceptions of CMV infection during pregnancy, CMV knowledge, and CMV serologic status of pregnant women. Results We enrolled 96 pregnant women. 81.0% had not previously heard about CMV and only 8.8% had heard about it through their obstetrician. No significant association between awareness of CMV and education level was detected. 16.0% of pregnant women declared that they were aware of the hygienic measures for CMV. The CMV serology was performed in 21.3% of those enrolled in the preconception assessment, and 13.8% proved to be immune. From the time perspective, half of the women displayed a future-oriented attitude. Future-oriented women had significantly higher KS. No significant association was found between KS and education level, age, or previous pregnancy. There was a significant association between KS and women that work in health care. Conclusions Most patients had no knowledge of CMV. Being a medical professional and having a future-oriented outlook increases knowledge about CMV. Primary health care and obstetrics doctors may play a crucial role in informing pregnant women of antenatal appointments. The CMV serology coverage is scarce in this sample. This study constitutes a first step toward raising the awareness of the general population about CMV.

Cytomegalovirus Donor Seropositivity Negatively Affects Survival After Heart Transplantation.

Prior studies have shown that cytomegalovirus (CMV) infection is a risk factor for the development of cardiac allograft vasculopathy (CAV) and is associated with reduced long-term survival after heart transplantation (HTx). The aim of this International Society for Heart and Lung Transplantation Transplant Registry study was to compare posttransplant survival in different CMV donor:recipient serologic combinations. We performed a retrospective cohort study, using the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, on 15 885 adult primary heart transplant recipients with known CMV serologic status between July 2004 and June 2014. Posttransplant survival and risk of developing CAV were compared across 4 groups: CMV-seronegative recipients (R-) receiving CMV-positive grafts (D+), intermediate-risk patients (D+R+ and D-R+), and low-risk patients (D-R-). Baseline characteristics (donor/recipient age, body mass index, recipient serum creatinine, blood group, donor cause of death, recipient diagnosis, and ischemic time) were mostly balanced between the groups. Kaplan-Meier survival analyses over a follow-up of 10 y revealed significantly worse survival for both D+ groups as compared to the CMV low-risk group (D+R+: 56.61% [95% confidence interval, 53.94-59.41] versus D-R-: 63.09% [59.74-66.64] P < 0.01 and D+R-: 57.69% [56.03-59.39] versus D-R-; P < 0.001), whereas recipient seropositivity alone was not associated with reduced survival (D-R+ versus D-R-P = 0.178). The risk of developing CAV after HTx was not significantly increased in D+ as compared to D- groups. In a large contemporary cohort, CMV status at the time of HTx was not associated with CAV development. However, there was a significant association between donor CMV seropositivity and reduced short- and long-term survival after HTx. Approaches to mitigate the impact of CMV on posttransplant survival are needed.

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.

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.

Determinants of Long-Term Survival Following Allogeneic Stem Cell Transplantation for Multiple Myeloma: A Multi-Centre Analysis Across the United Kingdom and Australia

IntroductionDespite the accepted utility of autologous stem cell transplantation for multiple myeloma, the role of allogeneic stem cell transplantation (alloSCT) remains controversial (Dhakal et al., 2016). The differences in practices across centres in patient selection, conditioning regimens and post-transplant care clouds the comparison of available studies. Moreover, the high rates of non-relapse mortality despite disease eradication demand an understanding of pre-allograft determinants of long-term survival. Included within these determinants is the appropriate timing for alloSCT, an important variable given the growing list of available myeloma therapies. We sought to identify the variables, including the influence of transplant centre and timing that govern long term survival following alloSCT for myeloma within integrated data in a large group of patients across three centres.MethodsA retrospective analysis of 93 patients undergoing alloSCT for multiple myeloma between January 2000 and June 2017 at three tertiary transplant centres - the Royal Melbourne Hospital, Australia and The Christie and Central Manchester NHS Foundation Trusts, United Kingdom. We collected: demographic data; disease-specific data, including previous treatment, disease status prior to alloSCT, and time from autologous SCT to alloSCT; and peri-transplant data including donor source and gender, stem cell dose, conditioning regime, and donor and recipient cytomegalovirus serological status. We measured overall survival, cause of death, acute and chronic graft versus host disease and progression free survival. Log-rank testing and cox regression analysis was performed with a multivariate regression model established on the basis of significant univariate associations.ResultsMedian age for the 93 patients at transplant was 49 years old (range 28 to 66 years). 65% of patients were male (n=60). 51 patients underwent alloSCT at the Royal Melbourne Hospital, 18 and 24 patients at the Christie and Central Manchester NHS Foundation Trusts, respectively. Patients received a median number of 2 lines of treatments prior to alloSCT (range 0-6). 51% (n=47) patients received stem cells from voluntary unrelated donors (VUD), and 49% from siblings (n=46). 78% (n=72) received a reduced intensity conditioning consisting of either 25mg/m2 fludarabine, 60mg/kg cyclophosphamide or 30mg/m2 fludarabine with 2Gy total body irradiation; 20% (n=18) received non-myeloablative conditioning with 30mg/m2 fludarabine and 750mg/m2 cyclophosphamide, 2% (n=3) underwent myeloablative conditioning with 60mg/kg cyclophosphamide and 4Gy total body irradiation.Median overall survival (OS) for the whole group was 8.1 years (interquartile range = 1.3 to 12.7 years). No difference was observed in OS across the three centres (log rank p=0.84) or across country (log-rank p=0.56). Conditioning regimens containing total body irradiation showed no association with relapse post allo SCT (odds ratio 0.68, 95% CI 0.30-1.55) and did not affect OS (hazard ratio, HR =1.00, 95% CI = 0.51-2.00).In accordance with previous findings (Dhakal et al., 2016), age over 40 at alloSCT was associated with a poorer survival (HR = 2.47, 95%CI 1.20 to 5.09). Patients who had stable or progressive disease at allograft showed poorer OS, even when controlling for number of lines of therapy and previous relapse (HR = 3.03, 95% CI 1.31-6.97).Patients who underwent alloSCT over one year following autologous SCT showed 3.4 times increased risk of death (95% CI 1.52-7.09) and 2.16 times increased risk of relapse (95% CI 1.18-3.93) even when controlling for age, prior relapse history, number of lines of treatment, disease status prior to alloSCT and transplanting hospital (Figure 1).ConclusionThis large multi-centre multivariate analysis demonstrates that transplant centre and low dose total body irradiation does not influence OS following alloSCT for multiple myeloma. Importantly, the time between autologous SCT and alloSCT of greater than one year is a strong predictor of poor OS. This remains true when controlling for several established risk factors. Our results demonstrate the importance of patient selection and timing in order to maximise OS for patients undergoing alloSCT for multiple myeloma.ReferenceDhakal B, et al. 2016. Allogeneic stem cell transplantation for multiple myeloma: is there a future? Bone Marrow Transplant, 51, 492-500. [Display omitted] DisclosuresRoutledge:Gilead: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Harrison:Celgene: Consultancy, Research Funding, Speakers Bureau. Cavet:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Speaker, Research Funding. Tholouli:Pfizer: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Ritchie:Amgen Inc.: Honoraria.

The effect of donor cytomegalovirus serological status on the outcome of allogeneic stem cell transplantation

Objective: Donor cytomegalovirus (CMV) serological negative status may have an adverse effect on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT), while there is inadequate data for Chinese people. This study is to explore the impact of donor CMV serological status on the outcome of CMV seropositive patients receiving allo-HSCT. Methods: Our study retrospectively analyzed 16 CMV seropositive patients with hematological malignancies receiving allogeneic grafts from CMV seronegative donors (antibody IgG negative) at Peking University People's Hospital from March 2013 to March 2020, which was defined as D-/R+ group. The other 64 CMV seropositive patients receiving grafts from CMV seropositive donors at the same period of time were selected as matched controls through a propensity score with 1∶4 depending on age, disease state and donor-recipient relationship (D+/R+ group). Results: Patients in D-/R+ group developed CMV DNAemia later than patients in the D+/R+ group (+37 days vs. +31 days after allo-HSCT, P=0.011), but the duration of CMV DNAemia in D-/R+ group was longer than that of D+/R+ group (99 days vs. 34 days, P=0.012). The rate of CMV reactivation 4 times or more in D-/R+ group was 4/16, significantly higher than that of D+/R+ group (4.7%, 3/64, P=0.01). The incidences of refractory CMV DNAemia (14/16 vs. 56.3%, P=0.021) and CMV disease (4/16 vs. 4.7%, P=0.01) in D-/R+ group were both higher than those in D+/R+ group. In addition, the application of CMV-CTL as the second-line antiviral treatment in D-/R+ group was more than that in D+/R+ group. Univariate analysis and multivariate analysis suggested that CMV serological negativity is an independent risk factor for refractory CMV DNAemia and the duration of CMV infection. The cumulative incidence of aGVHDⅡ-Ⅳ, cGVHD, 3-year probability of NRM, overall survival, and the cumulative incidence of relapse were all comparable in two groups. Conclusions: Although there is no significant effect on OS and NRM, the incidence of refractory CMV DNAemia, the frequency of virus reactivation, and the development of CMV disease in D-/R+ group are higher than those in controls. Therefore, CMV seropositive donors are preferred for CMV seropositive patients.

Cytomegalovirus seroconversion in pregnant army personnel of the Israel Defense Forces: Trends and risk factors.

Cytomegalovirus (CMV) seroconversion in pregnancy is a major health issue with potentially devastating fetal consequences. We opted to determine rates and trends of CMV seroconversion in pregnant army personnel and to isolate risk factors. In this retrospective cohort study, all pregnancies of army personnel between 2009 and 2019 were evaluated (n=10409) and all pregnancies with CMV laboratory records were included. Seroconversion rate was calculated overall and per year. Demographic and obstetrical characteristics were compared between exposed and unexposed women. Independent predictors of seroconversion were further investigated using logistic regression models. Cytomegalovirus serology status was available in 7665 pregnancies. Seroconversion was evident in 66 women (4.15%) among the seronegative pregnancies. Women in the seroconversion group were significantly more likely to belong to a higher social class. In the regression models, adjusted for age, place of residence, and education, higher parity (adjusted odds ratio [aOR] 2, P<0.001) and residing in a central district (aOR 2.67, P=0.002) were significantly associated with seroconversion. Higher social class appears to be a significant risk factor for CMV seroconversion during pregnancy. Residing in a central district and higher parity appear to be independently associated with an increased risk for seroconversion during pregnancy among army personnel.

Impact of cytomegalovirus serologic status on heart transplantation.

Cytomegalovirus (CMV) infection has been associated with increased risk of mortality, cardiac allograft vasculopathy, and de novo malignancy following heart transplantation in prior institutional reports. This study examines the impact of the recipient and donor CMV status on heart recipients in the United States. Adult heart transplant recipients were identified in the OPTN registry between 2005-2016. Recipients were stratified based on the recipient (R) and donor (D) CMV serologic status (+/-). The primary endpoint was survival 5-years after transplantation. The secondary endpoint was cardiac allograft vasculopathy 5-years after transplantation. Separate Cox proportional hazards regression models were developed to evaluate independent associations between CMV status and each of the study endpoints. A total of 21 878 recipients met the inclusion criteria. The breakdown of study arms by CMV serologic status was R-/D- = 3412, R+/D- = 4939; R-/D+ = 5230, and R+/D+ = 8,297. Five-year survival estimates were similar across groups (77-79%). CMV status was associated with increased mortality at 5-years (23%-41% increased risk) which was most evident in the first 3 months. The use of valganciclovir was associated with decreased risk of mortality (HR 0.56; 95% CI, 0.52-0.60). The cumulative incidence of cardiac allograft vasculopathy (R-/D- = 31%, R+/D- = 30%, R-/D+ = 31%, and R+/D+ = 30%) was similar across groups. CMV seropositivity at the time of transplantation is associated with increased long-term risk of mortality. Chemoprophylaxis with antivirals seems to mitigate this risk. There was no association with an increased risk of allograft vasculopathy.

Drug-resistant cytomegalovirus infection after lung transplantation: Incidence, characteristics, and clinical outcomes.

Cytomegalovirus (CMV) infection and development of CMV drug resistance can cause significant morbidity and mortality in patients with lung transplantation (LTX). We investigated the incidence of CMV drug resistance in adult patients with LTX and characterized this patient group and its outcomes. We analyzed a single-center retrospective cohort of 735 patients who received LTX between January 2012 and October 2017. We assessed the incidences of CMV UL97 and UL54 genotyping for clinically suspected drug resistance and confirmed drug resistance. Case-matched controls (3 control patients for each resistant patient) were identified by matching for CMV serological status, development of CMV disease or significant viremia (≥3,000 IU/ml), and transplantation date. The incidence of drug-resistant CMV was 1.98% (11/556) in donor and/or recipient CMV-positive patients and 4.7% (7/150) in donor-positive/recipient-negative patients. Altogether, 27 patients were tested for drug resistance, and 11 strains were resistant, 8 sensitive, and 8 inconclusive. No differences in immunosuppression, acute rejection, or pre-transplant sensitization were seen between case-matched groups. The peak CMV viral load and mean duration of viremia were significantly higher in the resistant group (324,000 vs. 117,000 mean IU/ml, p = 0.048 and 140 vs. 55 days, p < 0.001, respectively). The resistant group had increased overall mortality after onset of viremia compared with controls (3-year mortality 70% vs. 30%; p = 0.01). Drug-resistant CMV infection is rare, but patients who develop it have decreased overall survival. Peak CMV viral load and duration of CMV viremia were associated with development of resistant CMV infection.

Impact of Cytomegalovirus Infection on the Outcome of Patients With Cirrhosis: A Preliminary Study.

The aims of this study were to evaluate whether cytomegalovirus (CMV) infection is associated with hepatocellular carcinoma (HCC) and liver-related mortality in cirrhotic patients. In cirrhotic patients, the determinants of HCC and liver-related death are imperfectly known. CMV infection, by its prooncogenic and proinflammatory properties, may favor both the development of HCC and deleterious systemic inflammation. In the 1178 patients included between June 2008 and December 2012 in the CIrrhose et Risque de Carcinome Hépatocellulaire dans le grand-Est (CIRCE) study, a French multicenter case-control study designed to identify risk factors of HCC among cirrhotic patients, we identified 432 patients with interpretable CMV serological status at baseline. They included 159 cases with HCC and 273 controls. We measured factors associated with HCC at baseline and subsequent HCC in controls, and predictors of overall and liver-related death in the whole study population. During a median follow-up of 31 months, 25 cases of HCC developed in controls, and 209 deaths (163 liver-related) were recorded. There were 247 (57.2%) CMV-seropositive patients. CMV seropositivity was not associated with more frequent HCC at baseline or during follow-up, but among CMV-positive patients with HCC, the proportion of multinodular, infiltrative, or metastatic tumors at diagnosis was higher (73.8% vs. 57.3%; P=0.029), inducing higher mortality (74% vs. 52% at 3 years; P=0.004). By Cox-regression adjusted for age, gender, Model for End-stage Liver Disease (MELD) score, HCC at baseline, and diabetes, CMV seropositivity independently predicted all-cause (hazard ratio=1.45; 95% confidence interval, 1.08-1.94; P=0.013) and liver-related mortality (hazard ratio=1.56; 95% confidence interval, 1.04-2.30; P=0.031). In this preliminary study, CMV-seropositive cirrhotic patients were at higher risk of liver-related death caused by more aggressive HCCs or severe cirrhosis complications. These findings warrant confirmation.

Long-Term Impact of Cytomegalovirus Serologic Status on Lung Transplantation in the United States

Cytomegalovirus (CMV) infection has been associated with poor outcomes after solid organ transplantation. The long-term impact of donor and recipient CMV serological status on lung transplant outcomes remains unclear. Accordingly, we evaluated the impact of donor and recipient CMV status on long-term patients as well as allograft survival after single (SLT) and double lung transplantation (BLT). The Scientific Registry of Transplant Recipients was used to track all adult lung transplants in United States from May 2005 to June 2016. Patient mortality and bronchiolitis obliterans syndrome were determined up to 5 years using Cox proportional hazards modeling. Additionally, landmark analysis was performed conditional on survival at 1 year. Compared with donor negative-recipient CMV-IgG negative (D-R-), donor positive-recipient negative (D+R-) and donor positive-recipient positive (D+R+) groups had increased mortality at 1 and 5 years after BLT, with the former demonstrating highest risk. Although mortality was not increased with CMV seropositive donors after SLT at 1 year, both D+R- and D+R+ groups demonstrated greater mortality at 5 years. Risk of bronchiolitis obliterans syndrome was not affected by CMV serological status. Conditional landmark analysis confirmed that lungs from CMV seropositive donors conferred highest risk for long-term mortality. CMV seronegative recipients undergoing either BLT or SLT from CMV seropositive donors have the highest risk of long-term mortality that extends beyond the first year. Further studies are needed to determine the causes of higher mortality observed in the CMV seronegative recipients and risks and benefits of extension of CMV prophylaxis, particularly in the high-risk group.

Streamlining a blood center and hospital transfusion service supply chain with an informatics vendor-managed inventory solution: development, implementation, and 3-month follow-up.

The ordering process at Stanford Health Care involved twice-daily shipments predicated upon current stock levels from the blood center to the hospital transfusion service. Manual census determination is time consuming and error prone. We aimed to enhance inventory management by developing an informatics platform to streamline the ordering process and reallocate staff productivity. The general inventory accounts for more than 50 product categories based on characteristics including component, blood type, irradiation status, and cytomegalovirus serology status. Over a 5-month calibration period, inventory levels were determined algorithmically and electronically. An in-house software program was created to determine inventory levels, optimize the electronic ordering process, and reduce labor time. A 3-month pilot period was implemented using this program. This system showed noninferiority while saving labor time. The average weekly transfused:stocked ratios for cryoprecipitate, plasma, and red blood cells, respectively, were 1.03, 1.21, and 1.48 before the pilot period, compared with 0.88, 1.17, and 1.40 during (p = 0.28). There were 27 (before) and 31 (during) average STAT units ordered per week (p = 0.86). The number of monthly wasted products due to expiration was 226 (before) and 196 (during) units, respectively (p = 0.28). An estimated 7 hours per week of technologist time was reallocated to other tasks. An in-house electronic ordering system can enhance information fidelity, reallocate and optimize valuable staff productivity, and further standardize ordering. This system showed noninferiority to the labor-intensive manual system while freeing up over 360 hours of staff time per year.

Prevalence and Associated Factors of HIV and CMV Co-Infection in Tianjin, China

The prevalence and associated factors of human immunodeficiency virus (HIV) and cytomegalovirus (CMV) coinfection in patients starting antiretroviral therapy (ART) in Tianjin, China are under-studied. We measured CMV DNA in plasma specimens of 1347 HIV-infected patients. T-cell dynamics were measured by flow cytometry. A total of 1347 patients participated in this study. 1288 (95.6%) were male. The median age was 36. Both CMV positive and CMV negative groups were similar apart from the higher proportion of homosexual/bisexual HIV transmission in CMV negative group and the older age in CMV positive group. According to the duration of first-line ART, we did not observe a significant difference between CMV positive and CMV negative groups. CD4 counts and CD4 nadir counts are independent risk factors for the prevalence of CMV in HIV infected patients. We found a high prevalence of CMV (12.8%) in Tianjin HIV-infected patients starting ART. CMV serological status should be taken into account when measuring the effectiveness of antiretroviral therapy on immune restoration.

Myeloablative Versus Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Secondary Acute Myeloid Leukemia in Patients with Prior Myelodysplastic Syndrome/ Myeloproliferative Disorders: An ALWP of EBMT Study

▪Secondary acute myeloid leukemia (sAML) includes a heterogeneous group of diseases evolved from myelodysplasia, myeloproliferative disorders (MDS/ MPN), bone marrow failure syndrome or after exposure to leukemogenic agents such as chemotherapy and/or radiation therapy for malignant hematological (other malignant hematological diseases) or solid tumors.Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy but relapse is a frequent cause of failure after HCT occurring in more than 50% of patients. No systematic large analysis of HCT for sAML has evaluated risk factors and outcome based on a prior diagnosis of MDS or MPN. Therefore, the EBMT Acute Leukemia Working Party (ALWP) performed a multicenter retrospective registry study on patients undergoing HCT for sAML following MDS/MPN comparing myeloablative (MAC) to reduced intensity conditioning (RIC). ALWP-EBMT supplemental data forms were used to establish the occurrence of any prior hematological disorder or non-hematological malignancy as well as details of cytogenetic data and therapy.We studied 811 patients with a previous diagnosis of MDS/ MPD and available cytogenetic data who had received HCT for sAML from an HLA-identical sibling (MRD, n=344 [42.4%]) or unrelated donor transplant (URD- 9/10 or 10/10) during 2000-16. Median time from diagnosis (sAML) to transplant was 137 days (IQR 94-204). Median age at HCT was 59.57 years (IQR 52-65). sAML with adverse cytogenetics accounted for 269 (33.2%) patients. At the time of HCT, 401 (49.5%) patients were in CR1 and 367 (45.3%) had active disease. Median follow-up of surviving patients was 32 months (IQR, 11-62).Regimen intensity was assessed by EBMT criteria. MAC regimens were used in 326 (40.2%) patients while 485 (59.8%) received RIC. Older patients were more likely to receive RIC than MAC regimens (p<0.001). Most patients received peripheral blood stem cell grafts (n=731 [90.3%]; MAC 85.6% vs RIC 93.4%, p<0.001). A total of 534 (67.9%) patients were cytomegalovirus (CMV) seropositive pre-HCT. There were no significant differences in disease characteristics (e.g. disease status at transplant, cytogenetic risk category), donor source, year of transplant or CMV serology status between MAC and RIC cohorts. All patients received a calcineurin inhibitor-based combination as prophylaxis against graft versus host disease (GVHD) and 516 (63%) received in vivo T-cell depletion (rATG 474 (58%).A total of 667 (95.2%) patients engrafted (MAC 94.5% vs. RIC 95.6%; p=0.596). Acute GVHD (grade II-IV) within 100 days of HCT occurred in 24% (95% CI, 21-27; MAC vs. RIC, p=0.126) and 2-year cumulative incidence of chronic GVHD was 33% (95% CI 30-37; MAC vs. RIC, p=0.150). Three-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 41% (95% CI, 38-45; MAC 37% [31-42] vs. RIC 45% [40-49], p=0.029) and 25% (95% CI, 22-28%, MAC 25% [20-30] vs. RIC 25% [21-29], p=0.959), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia free survival (LFS) at 3 years were 40% (95% CI, 37-44; MAC 44% [38-50] vs. RIC 38% [33-43], p=0.041) and 34% (95% CI, 31-38; MAC 38% [33-45] vs. RIC 31% [27-36], p=0.032), respectively (Figure 1).In multivariate analysis by Cox Regression, a higher RI was seen after RIC regimens (HR 1.72 [1.16-2.55]; p=0.0063). Patients receiving RIC regimens had a higher risk of chronic GVHD (HR 1.37 [1.02-1.84], p=0.0389). Non-relapse mortality (NRM) was equivalent in MAC and RIC groups.MAC regimens were associated with superior OS (HR 1.46, 95% CI 1.1-1.94; p=0.0085) and LFS (HR 1.37, 95% CI 1.02-1.85; p=0.0387). High risk cytogenetics and older age contributed significantly to inferior outcomes.In summary, this EBMT registry study of HCT for sAML after MDS/MPN is the largest cohort reported. Myeloablative conditioning regimens were associated with a lower relapse risk and superior survival. Given that NRM after HCT has declined in the current era, these data indicate that the outcome of HCT for sAML may be improved by careful patient selection for MAC regimens. Survival may be further enhanced by effective pre-HCT disease control (also associated with decreased NRM) and post-HCT pre-emptive therapy to decrease RI. [Display omitted] DisclosuresSavani:Jazz Pharmaceuticals: Speakers Bureau. Ciceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Schmid:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees; MoilMed: Membership on an entity's Board of Directors or advisory committees. Mohty:Sanofi: Honoraria, Speakers Bureau.

Immunosenescence in persons with spinal cord injury in relation to urinary tract infections -a cross-sectional study-

BackgroundIndividuals with a spinal cord injury (SCI), despite specialized rehabilitation and good health care, have a reduced life expectancy. Infectious diseases, such as pneumonias, infected pressure sores and urinary tract infections (UTI) have been identified as the leading causes of mortality. We hypothesise that a premature onset of immune frailty occurs in SCI, possibly caused also by recurrent urinary tract infections.A cross sectional study was performed comparing blood and urine samples between able bodied controls (n = 84) and persons with spinal cord injury (n = 85). The results were grouped according to age (below and above 60 years). Assessed were the abundancies of immune cells, the concentration of soluble biomarkers, the in vitro functioning of lymphocytes as well as phenotypic exhaustion of T-cells in blood and urine. Further, the leucocyte telomere length and the cytomegalovirus (CMV) serological status were compared between the groups.ResultsWe observed in people with SCI lower proportions of naïve T-cells, more memory T-cells, reduced T-cell proliferation and higher CMV prevalence compared to age-matched controls. SCI participants older than 60 years had a higher prevalence of UTI compared with SCI persons younger than 60 years.ConclusionThe immune system of people with SCI shows traits of an increased immunological strain and a premature onset of immune frailty. The role of UTI in the onset of immune frailty remains to be elucidated as we did not see significantly higher abundancies of circulating UTI-bacteria specific T-cell clones in persons with SCI. We assume that any impact of UTI on the immune system might be compartmentalized and locally restricted to the urinary tract.

Periconceptional CMV infection prevention in Portugal: population subgroup study in a tertiary perinatal care center

Currently in Portugal, universal screening of pregnant women for Cytomegalovirus (CMV) infection is not performed. However, it is recommended to screen all women attending preconception care. We aimed to assess women’s attendance to preconception care and if their serologic status regarding CMV was known and/or investigated in that consultation. In this cross-sectional study, we interviewed 240 women admitted to the obstetrical ward of a hospital in the Metropolitan Area of Porto (Portugal) about their adherence to preconception care and collected data regarding their CMV serologic status and its investigation. We found that 71.3% of the women who attended preconception care were not screened for CMV infection. Among primigravida, the screening rate was only of 30.4% (upper limit of CI 95%: 44.8%). There were no statistically significant differences between the private and public sectors of healthcare. We observed attendance to preconception care is high (73.1%). For the population subgroup of the metropolitan area of Porto, attendance to preconception care is at least 66%, with a 95% confidence level. Portuguese guidelines stating a woman’s serologic status regarding CMV should be investigated in preconception care are not properly implemented. This suggests guidelines should assure the screening of previously non-screened women during pregnancy.

Cytomegalovirus and cancer after kidney transplantation: Role of the human leukocyte antigen system?

The role of cytomegalovirus (CMV) in cancer development after transplantation remains uncertain. We aimed to determine the association between donor and recipient CMV serological status and the risk of cancer development after kidney transplantation. Using data from the Australian and New Zealand Dialysis and Transplant (ANZDATA) Registry, we assessed the association between CMV donor/recipient (D/R) serological status and the risk of solid organ cancers in primary adult deceased-donor kidney transplant patients between 1990 and 2012. Of 8140 recipients, a total of 895 (11%) recipients developed incident cancers during a follow-up time of 51555 person-years. Human leukocyte antigen (HLA) mismatches was an effect modifier between CMV serological status and cancer (P=.03 for interaction). In recipients who have received 0-2 HLA-ABDR mismatched kidneys, the adjusted hazard ratios for cancer incidence among those with CMV D-/R-, CMV D-/R+, and CMV D+/R- were 0.47 (95% confidence interval [CI]: 0.24-0.91), 1.42 (95% CI: 0.97-2.07), and 1.02 (95% CI: 0.67-1.57), respectively compared with the reference of CMV D+/R+. A similar association was not observed in those with >2 HLA-ABDR mismatches. CMV D-/R- status was associated with a reduced risk of cancer in kidney transplant recipients who have received well-matched renal allografts, suggesting a potential role of HLA matching in cancer development.