IGH Complementarity Determining Region-3-Cytomegalovirus Protein Chemical Complementarity Linked to Better Overall Survival Probabilities for Glioblastoma.

Cytomegalovirus (CMV) has long been thought to have an association with glioblastoma multiforme (GBM), although the exact role of CMV and any subsequent implications for treatment have yet to be fully understood. This study addressed whether IGH complementarity determining region-3 (CDR3)-CMV protein chemical complementarity, with IGH CDR3s representing both tumor resident and blood-sourced IGH recombinations, was associated with overall survival (OS) distinctions. IGH recombination sequencing reads were obtained from (a) the Clinical Proteomic Tumor Analysis Consortium, tumor RNAseq files; and (b) the cancer genome atlas, blood exome-derived files. The Adaptive Match web tool was used to calculate chemical complementarity scores (CSs) based on hydrophobic interactions, and those scores were used to group GBM cases and assess survival probabilities. We found a higher OS probability for cases whose hydrophobic IGH CDR3-CMV protein chemical complementarity scores (Hydro CSs) were in the upper 50th percentile for several CMV proteins, including UL99 and UL123, as well as for CSs based on known B cell epitopes representing these proteins. We also identified multiple immune signature genes, including CD79A and TNFRSF17, for which higher RNA expression was associated with higher Hydro CSs. Results were consistent with the idea that stronger immunoglobulin responses to CMV are associated with better OS probabilities for GBM.

Exploring the relationship between HCMV serostatus and outcomes in COVID-19 sepsis.

Background: Sepsis, a life-threatening condition caused by the dysregulated host response to infection, is a major global health concern. Understanding the impact of viral or bacterial pathogens in sepsis is crucial for improving patient outcomes. This study aimed to investigate the human cytomegalovirus (HCMV) seropositivity as a risk factor for development of sepsis in patients with COVID-19. Methods: A multicenter observational study enrolled 95 intensive care patients with COVID-19-induced sepsis and 80 post-surgery individuals as controls. HCMV serostatus was determined using an ELISA test. Comprehensive clinical data, including demographics, comorbidities, and 30-day mortality, were collected. Statistical analyses evaluated the association between HCMV seropositivity and COVID-19 induced sepsis. Results: The prevalence of HCMV seropositivity did not significantly differ between COVID-19-induced sepsis patients (78%) and controls (71%, p = 0.382) in the entire cohort. However, among patients aged ≤60 years, HCMV seropositivity was significantly higher in COVID-19 sepsis patients compared to controls (86% vs 61%, respectively; p = 0.030). Nevertheless, HCMV serostatus did not affect 30-day survival. Discussion: These findings confirm the association between HCMV seropositivity and COVID-19 sepsis in non-geriatric patients. However, the lack of an independent effect on 30-day survival can be explained by the cross-reactivity of HCMV specific CD8+ T-cells towards SARS-CoV-2 peptides, which might confer some protection to HCMV seropositive patients. The inclusion of a post-surgery control group strengthens the generalizability of the findings. Further research is needed to elucidate the underlying mechanisms of this association, explore different patient populations, and identify interventions for optimizing patient management. Conclusion: This study validates the association between HCMV seropositivity and severe COVID-19-induced sepsis in non-geriatric patients, contributing to the growing body of evidence on viral pathogens in sepsis. Although HCMV serostatus did not independently influence 30-day survival, future investigations should focus on unraveling the intricate interplay between HCMV, immune responses, and COVID-19. These insights will aid in risk stratification and the development of targeted interventions for viral sepsis.

Mortality in recipients of allogeneic haematopoietic cell transplantation in the era of cytomegalovirus primary prophylaxis: a single-centre retrospective experience.

OBJECTIVES: Allogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes. METHODS: We conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D-/R-, R+/LTV-, and R+/LTV+. Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, and relapse up to week 48 after allo-HCT. The D-/R- group served as the reference for comparisons in univariate, competing risk regression, and cumulative incidence functions. RESULTS: The analysis included 1071 consecutive allo-HCT recipients: 131 D-/R-, 557 R+/LTV-, and 383 R+/LTV+. All-cause mortality by day 100 was 6.1% for the D-/R- group, compared with 14.0% (p 0.024) and 7.8% (p 0.7) for the R+/LTV- and R+/LTV + groups, respectively. Non-relapse mortality by day 100 was 11.0%, 6.8% and 3.8% for R+/LTV-, R+/LTV+, and D-/R- groups, respectively, without significant difference. When including relapse as a competing event, the hazard ratio for non-relapse mortality was 1.83 (95% CI: 1.12-2.99, p 0.017) for R+/LTV- compared with D-/R- and 1.05 (95% CI 0.62-1.77, p 0.85) for R+/LTV + compared with D-/R-. DISCUSSION: CMV primary prophylaxis with LTV abrogated the mortality gap based on CMV serostatus, a protective effect that persisted after discontinuation of primary prophylaxis.

Cytomegalovirus infection in intensive care unit patients with hematological malignancies: Characteristics and clinical outcomes.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with poor outcome in ICU patients. However, data on immunocompromised patients are scarce. This study aims to describe characteristics and outcomes of critically ill hematological patients and CMV infection. CMV disease characteristics and relationship between CMV viral load, CMV disease, coinfections by other pathogens and outcomes are described. METHODS: Retrospective single center study (Jan 2010-Dec 2017). Adult patients, admitted to the ICU, having underlying hematological malignancy and CMV infection were included. Results are reported as median (interquartile) or n (%). Factors associated with hospital mortality or CMV disease were analysed using logistic regression. RESULTS: 178 patients were included (median age 55y [42-64], 69.1% male). Hospital mortality was 53% (n = 95). Median viral load was 2.7 Log [2.3-3.5]. CMV disease occurred in 44 (24.7%) patients. Coinfections concerned 159 patients (89.3%). After adjustment for confounders, need for vasopressors (OR 2.53; 95%CI 1.11-5.97) and viral load (OR 1.88 per Log; 95%CI 1.29-2.85) were associated with hospital mortality. However, neither CMV disease nor treatment were associated with outcomes. Allogeneic stem cell transplantation (OR 2.55; 95%CI 1.05-6.16), mechanical ventilation (OR 4.11; OR 1.77-10.54) and viral load (OR 1.77 per Log; 95%CI 1.23-2.61) were independently associated with CMV disease. Coinfections were not associated with CMV disease or hospital mortality. CONCLUSION: In critically-ill hematological patients, CMV viral load is independently associated with hospital mortality. Conversely, neither CMV disease nor treatment was associated with outcome suggesting viral load to be a surrogate for immune status rather than a cause of poor outcome.

Predictors of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: Insights from a real-world experience.

BACKGROUND: We aimed to investigate factors associated with cytomegalovirus (CMV) viremia and CMV disease and its impact on post-transplant outcomes including overall survival (OS) following allogeneic hematopoietic stem cell transplantation (Allo-SCT). METHODS: We conducted a single-center retrospective study including 452 Allo-SCT recipients (matched unrelated donor, MUD 61%; haploidentical, haplo 39%) from 2016 to 2021. Data were analyzed using SPSS v28. Descriptive (chi-square and t-test), Kaplan-Meier and regression analyses were conducted. RESULTS: The median age was 57 years. Sixty-one percent were males and 84.3% were Caucasians. CMV serostatus was positive in 59.1% of recipients. The median follow-up was 24.4 months. CMV viremia and CMV disease were observed in 181 (40%) and 32 (7%) patients, respectively. Among CMV seropositive recipients, 65% developed CMV viremia and 11% were noted to have CMV disease compared to 4% and 1% in seronegative recipients, respectively (p < 0.001). Patients with CMV disease had significantly lower OS than those without CMV disease (median 14.1 months vs. not reached, p = 0.024); however, OS was not associated with CMV viremia (median not reached in both groups, p = 0.640). Letermovir prophylaxis was used in 66% (n = 176/267) of CMV seropositive recipients, but no impact was observed on the incidence of CMV viremia or CMV disease and OS. CONCLUSIONS: CMV disease leads to significantly inferior survival after an allogeneic hematopoietic cell transplantation. Recipient CMV seropositive status was associated with the risk of CMV viremia and CMV disease, and this was not abrogated with the use of Letermovir prophylaxis.

Prior cytomegalovirus reactivation may lead to worse bacterial bloodstream infection outcomes in HSCT patients.

BACKGROUND: Cytomegalovirus (CMV) reactivation is common after transplantation, and may further augment natural killer (NK) cell activity, which has a protective role through both innate and adaptive immune responses. Bacterial bloodstream infections (BBSIs) are a common cause of morbidity and mortality in patients following allo-HSCT. Therefore, we hypothesized that CMV reactivation might play a role in the outcomes of patients with BBSI after allo-HSCT. OBJECTIVES: We investigated the role of CMV reactivation in the clinical outcomes of patients with BBSI after allo-HSCT. STUDY DESIGN: A total of 101 BBSI patients (45 non-CMV reactivation [NCR] and 56 CMV reactivation [CR]) were included in the study following allo-HSCT. Clinical and laboratory findings were reviewed, and differences were tested using the Chi-square (χ2) test. Multivariate Cox regression analysis was used to calculate hazard ratios for between-group comparisons of clinical outcomes. RESULTS: CMV reactivation had a negative prognostic impact on the clinical outcomes of BBSI patients following allo-HSCT with regard to the 1-year overall survival time (HR, 3.583; 95% CI, 1.347-9.533; P = 0.011). In 56 BBSI patients with CMV reactivation following allo-HSCT, the 1-year mortality among those in whom CMV was reactivated first (CRF) was significantly elevated (56.5% vs. 18.2%, P = 0.003) compared with patients in whom the BBSIs occurred first (BOF). CONCLUSIONS: CMV reactivation in BBSI patients is related to higher mortality 1-year after allo-HSCT. Further studies on a larger cohort are needed to better understanding the mechanism of CMV reactivation influence.

Monitoring Porcine Cytomegalovirus in Both Donors and Recipients is Crucial for Recipient's Survival in Pig-to-Cynomolgus Xenotransplantation.

BACKGROUND: Xenotransplantation, particularly when involving pig donors, presents challenges related to the transmission of porcine cytomegalovirus (pCMV) and its potential impact on recipient outcomes. This study aimed to investigate the relationship between pCMV positivity in both donors and recipients and the survival time of cynomolgus monkey recipients after xenogeneic kidney transplantation. METHODS: We conducted 20 cynomolgus xenotransplants using 18 transgenic pigs. On the surgery day, donor pig blood was sampled, and DNA was extracted from serum and peripheral blood mononuclear cells. Recipient DNA extraction followed the same protocol from pre-transplantation to post-transplantation. Porcine cytomegalovirus detection used real-time polymerase chain reaction (real-time PCR) with the ViroReal kit, achieving a sensitivity of 50 copies/reaction. A Ct value of 37.0 was the pCMV positivity threshold. RESULTS: Of 20 cynomolgus recipients, when donors tested negative for pCMV, recipients also showed negative results in 9 cases. In 4 cases where donors were negative, recipients tested positive. All 5 cases with pCMV-positive donors resulted in positive assessments for recipients. Detection of donor pCMV correlated with shorter recipient survival. Continuous recipient positivity during observation correlated with shorter survival, whereas transient detection showed no significant change in survival rates. However, donor pig phenotypes and transplantation protocols did not significantly impact survival. CONCLUSION: The detection of pCMV in both donors and recipients plays a crucial role in xenotransplantation outcomes. These findings suggest the importance of monitoring and managing pCMV in xenotransplantation to enhance long-term outcomes.

Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation.

Cytomegalovirus (CMV) causes significant morbidity and mortality in recipients of allogeneic hematopoietic cell transplantation (HCT). Whereas insights gained from mathematical modeling of other chronic viral infections such as HIV, hepatitis C, and herpes simplex virus-2 have aided in optimizing therapy, previous CMV modeling has been hindered by a lack of comprehensive quantitative PCR viral load data from untreated episodes of viremia in HCT recipients. We performed quantitative CMV DNA PCR on stored, frozen serum samples from the placebo group of participants in a historic randomized controlled trial of ganciclovir for the early treatment of CMV infection in bone marrow transplant recipients. We developed four main ordinary differential Equation mathematical models and used model selection theory to choose between 38 competing versions of these models. Models were fit using a population, nonlinear, mixed-effects approach. We found that CMV kinetics from untreated HCT recipients are highly variable. The models that recapitulated the observed patterns most parsimoniously included explicit, dynamic immune cell compartments and did not include dynamic target cell compartments, consistent with the large number of tissue and cell types that CMV infects. In addition, in our best-fitting models, viral clearance was extremely slow, suggesting severe impairment of the immune response after HCT. Parameters from our best model correlated well with participants' clinical risk factors and outcomes from the trial, further validating our model. Our models suggest that CMV dynamics in HCT recipients are determined by host immune response rather than target cell limitation in the absence of antiviral treatment.

Cytomegalovirus infection in malignant pleural mesothelioma.

Human cytomegalovirus (HCMV) is a highly prevalent herpes virus which persists as a latent infection and has been detected in several different tumor types. HCMV disease is rare but may occur in high-risk settings, often manifesting as a pulmonary infection. To date HCMV has not been investigated in malignant pleural mesothelioma (MPM). In a consecutive case series of 144 MPM patients we evaluated two biomarkers of HCMV: IgG serostatus (defined as positive and negative) and DNAemia (>100 copies/mL of cell free HCMV DNA in serum). Approximately half of the MPM patient population was HCMV IgG seropositive (51%). HCMV DNAemia was highly prevalent (79%) in MPM and independent of IgG serostatus. DNAemia levels consistent with high level current infection (>1000 copies/mL serum) were present in 41% of patients. Neither IgG serostatus nor DNAemia were associated with patient survival. In tissues, we observed that HCMV DNA was present in 48% of tumors (n = 40) and only 29% of normal pleural tissue obtained from individuals without malignancy (n = 21). Our results suggest nearly half of MPM patients have a high level current HCMV infection at the time of treatment and that pleural tissue may be a reservoir for latent HCMV infection. These findings warrant further investigation to determine the full spectrum of pulmonary infections in MPM patients, and whether treatment for high level current HCMV infection may improve patient outcomes.

Cytomegalovirus Serostatus and Functional Impairment in Liver Transplant Recipients in the Current Era.

BACKGROUND: Whether donor (D+) or recipient (R+) cytomegalovirus (CMV) seropositivity is associated with functional impairment in liver transplant recipients is not known. METHODS: Patients included adult liver transplant recipients in the Organ Procurement and Transplantation Network database transplanted over a five-year period from 1 January 2014-31 December 2018. Functional status in the database was assessed using Karnofsky performance scale. A logistic regression model that controlled for potential confounders was used to examine the association of CMV serostatus and functional status. Variables significantly associated with functional status (p < 0.05) were then used to develop propensity score and propensity score matched analysis was conducted where each patient was compared with a matched-control with the same propensity score. RESULTS: Among 30,267 adult liver transplant recipients, D+ or R+ patients had significantly lower functional status at last follow-up than the D-R- cohort (OR 0.88, 95% CI 0.80-0.96, p = 0.007). In propensity score matched model, D+ or R+ patients had significantly lower functional status than matched-controls (p = 0.009). D+ or R+ CMV serostatus (p = 0.018) and low functional level (p < 0.001) were also independently associated with infections as cause-of-death. CONCLUSIONS: D+ or R+ liver transplant recipients had lower functional status and higher risk of deaths due to infections. Future studies are warranted to examine the mechanistic basis of these findings in the setting of transplantation.

A Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus Infection.

BACKGROUND: Primary cytomegalovirus (CMV) infection during pregnancy carries a risk of congenital infection and possible severe sequelae. There is no established intervention for preventing congenital CMV infection. METHODS: In this multicenter, double-blind trial, pregnant women with primary CMV infection diagnosed before 24 weeks' gestation were randomly assigned to receive a monthly infusion of CMV hyperimmune globulin (at a dose of 100 mg per kilogram of body weight) or matching placebo until delivery. The primary outcome was a composite of congenital CMV infection or fetal or neonatal death if CMV testing of the fetus or neonate was not performed. RESULTS: From 2012 to 2018, a total of 206,082 pregnant women were screened for primary CMV infection before 23 weeks of gestation; of the 712 participants (0.35%) who tested positive, 399 (56%) underwent randomization. The trial was stopped early for futility. Data on the primary outcome were available for 394 participants; a primary outcome event occurred in the fetus or neonate of 46 of 203 women (22.7%) in the group that received hyperimmune globulin and of 37 of 191 women (19.4%) in the placebo group (relative risk, 1.17; 95% confidence interval [CI] 0.80 to 1.72; P = 0.42). Death occurred in 4.9% of fetuses or neonates in the hyperimmune globulin group and in 2.6% in the placebo group (relative risk, 1.88; 95% CI, 0.66 to 5.41), preterm birth occurred in 12.2% and 8.3%, respectively (relative risk, 1.47; 95% CI, 0.81 to 2.67), and birth weight below the 5th percentile occurred in 10.3% and 5.4% (relative risk, 1.92; 95% CI, 0.92 to 3.99). One participant in the hyperimmune globulin group had a severe allergic reaction to the first infusion. Participants who received hyperimmune globulin had a higher incidence of headaches and shaking chills while receiving infusions than participants who received placebo. CONCLUSIONS: Among pregnant women, administration of CMV hyperimmune globulin starting before 24 weeks' gestation did not result in a lower incidence of a composite of congenital CMV infection or perinatal death than placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences; ClinicalTrials.gov number, NCT01376778.).

Impact of antiviral treatment on long-term prognosis in non-immunocompromised patients with CMV reactivation.

BACKGROUND: Reactivation of human cytomegalovirus (CMV) occurs in non-immunocompromised patients with or without specific organ involvement, but it is still unknown whether it has a clinical implication on long-term prognosis or not. METHODS: A retrospective cohort study evaluating non-immunocompromised adult patients with CMV reactivation was conducted during the period between January 2010 and February 2018. Patients were divided into ganciclovir-treated and non-treated groups. Patients who died within 30 days from CMV reactivation were excluded as they died from complex causes of conditions. Survivors were followed for 30-months to evaluate long-term prognosis. RESULTS: A total of 136 patients with CMV reactivation was included, consisting of 66 ganciclovir-treated (48.5%) and 70 non-treated (51.5%) patients. Overall, patients were old-aged (median 70 years old) and most were treated with pneumonia of any cause (91.2%). More patients in ganciclovir-treated group were treated at intensive care unit (43.9% vs 24.3%, respectively) and had higher viral load over 5000 copies/ml (48.5% vs 22.9%) than non-treated group (all P < 0.05). Primary and secondary endpoints including 30-months survival (28.0 vs 38.9%, respectively) and 12-months survival (40.3% vs 49.2%) were not statistically different between the ganciclovir-treated and non-treated groups. In the multivariate analyses, ganciclovir treatment was not associated with 30-months survival (HR 1.307, 95% CI 0.759-2.251) and 12-months survival (HR 1.533, 95% CI 0.895-2.624). CONCLUSION: In a retrospective cohort study evaluating non-immunocompromised patients with CMV reactivation, ganciclovir treatment was not associated with long-term prognosis. Antiviral treatment in this condition would not be necessary unless organ involvement is suspected.

Cytomegalovirus Viral Load Kinetics Predict Cytomegalovirus End-Organ Disease and Mortality After Hematopoietic Cell Transplant.

BACKGROUND: We investigatedthe association between time-averaged area under the curve (AAUC) of cytomegalovirus (CMV) viral load (VL) by day 100 and overall survival (OS) at 1-year after hematopoietic cell transplantation (HCT). METHODS: In a retrospective cohort study, including patients receiving HCT between June 2010 and December 2017 from Memorial Sloan Kettering Cancer Center, AAUC was calculated for patients with detected VL. Patients were categorized into non-controllers (Q4) and controllers (Q1-Q3) using the highest AAUC quartile as cutoff. Cox models were used to estimate the association between AAUC and OS. Patients with non-detected CMV VL were categorized into elite-controllers (recipient+ [R+] or R-/donor+ [D+]) and R-/D-. RESULTS: The study (N = 952) included 282 controllers, 93 non-controllers, 275 elite-controllers, and 302 R-/D-. OS was 80.1% and 58.1% for controllers and non-controllers, respectively. In multivariable models, non-controllers had worse OS versus controllers (adjusted hazard ratio [HR] = 2.65; 95% confidence interval [CI], 1.71-4.12). In landmark analyses, controllers had similar OS as elite-controllers (HR = 1.26; 95% CI, .83-1.91) or R-/D- (HR = 0.98; 95% CI, .64-1.5). CONCLUSIONS: Non-controllers had worse OS 1-year post-HCT. Controllers had similar OS as elite-controllers or R-/D-. Future studies are needed to validate our AAUC cutoff across different cohorts and CMV management strategies.

Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis.

Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy [n = 545]: hazard ratio [HR], 50.3; SibCy [n = 279]: HR, 47.7; SibCNI [n = 1065]: HR, 24.4; P < .001). D+/R- patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.

Cytomegalovirus gastritis: Clinicopathological profile.

BACKGROUND: Cytomegalovirus (CMV) gastritis is occasionally reported in case reports and limited case series. Up to now, it is the largest and most comprehensive retrospective study of CMV gastritis. METHODS: All patients who were histologically diagnosed with CMV gastritis at Linkou Chang Gung Memorial Hospital between January 2000 and April 2020 were included. Patients were divided into two groups according to immunity. Between-group differences in characteristics, manifestations, endoscopic features, prognostic factors, and outcomes were analyzed. The main endpoint was 3-month mortality. RESULTS: A total of 54 patients (34 immunocompromised, 20 immunocompetent) were enrolled. Common presentations included gastrointestinal bleeding (35.2%), abdominal pain (33.3%) and fever (31.5%). The endoscopic features included ulcer (88.9%) and inflammation (11.1%). The 3-month mortality rate was 20.4% and overall mortality rate was 40.7%. Acute kidney injury was the only independent risk factor for 3-month mortality (OR 53.89, 95%CI 1.56-1861.73, p = 0.027). Anti-viral therapy and host immune status did not affect 3-month mortality. CONCLUSION: Both immunocompromised and immunocompetent patients with CMV gastritis have high mortality rates, without significant between-group differences. Acute kidney injury is the only independent predictive factor for 3-month mortality. Prevention of acute kidney injury may possibly improve the 3-month mortality rate.

Associations of Cytomegalovirus Infection With All-Cause and Cardiovascular Mortality in Multiple Observational Cohort Studies of Older Adults.

BACKGROUND: Whether latent cytomegalovirus (CMV) infection in older adults has any substantial health consequences is unclear. Here, we sought associations between CMV-seropositivity and IgG titer with all-cause and cardiovascular mortality in 5 longitudinal cohorts. METHODS: Leiden Longevity Study, Prospective Study of Pravastatin in the Elderly at Risk, Longitudinal Study of Aging Danish Twins, and Leiden 85-plus Study were assessed at median (2.8-11.4 years) follow-up . Cox regression and random effects meta-analysis were used to estimate mortality risk dependent on CMV serostatus and/or IgG antibody titer, in quartiles after adjusting for confounders. RESULTS: CMV-seropositivity was seen in 47%-79% of 10 122 white community-dwelling adults aged 59-93 years. Of these, 3519 had died on follow-up (579 from cardiovascular disease). CMV seropositivity was not associated with all-cause (hazard ratio [HR], 1.05; 95% confidence interval [CI], .97-1.14) or cardiovascular mortality (HR, 0.97; 95% CI, .83-1.13). Subjects in the highest CMV IgG quartile group had increased all-cause mortality relative to CMV-seronegatives (HR, 1.16; 95% CI, 1.04-1.29) but this association lost significance after adjustment for confounders (HR, 1.13; 95% CI, .99-1.29). The lack of increased mortality risk was confirmed in subanalyses. CONCLUSIONS: CMV infection is not associated with all-cause or cardiovascular mortality in white community-dwelling older adults.

Prognostic Factors on Graft Function in Pediatric Kidney Recipients.

BACKGROUND: Graft survival in pediatric kidney transplant recipients has increased in the last decades. Determining prognostic factors for graft function over time allows the identification of patients at risk for graft loss and could lead to improvement of current guidelines. METHODS: Data were collected among pediatric kidney transplant recipients in a single center during the first 5 years after transplantation. Mixed model analysis was used to indicate possible prognostic factors for the loss of graft function. RESULTS: A total of 100 pediatric kidney transplant recipients were analyzed. Negative prognostics of graft function are higher donor age and higher recipient age, presence of obstructive uropathology, re-transplant, and occurrence of BK viremia. The negative influence on graft function of both donor age and presence of obstructive uropathology increased over time. In this study, the factors that did not influence graft function over time were the number of HLA mismatches, pre-transplant dialysis, intra-abdominal graft placement, ischemia time, occurrence of acute rejection, presence of lower urinary tract dysfunction, occurrence of urinary tract infections, and infections with cytomegalovirus and Epstein-Barr virus. CONCLUSIONS: This study showed that a higher donor age and higher recipient age, presence of obstructive uropathology, a re-transplant, and the occurrence of BK viremia were negative prognostic factors of graft function over time, in the first 5 years after transplant. Graft function was comparable between steroid-sparing regimens (preferable in low-risk patients) and regimens including steroids (for special reasons).

CMV viral load kinetics as surrogate endpoints after allogeneic transplantation.

BACKGROUNDViral load (VL) surrogate endpoints transformed development of HIV and hepatitis C therapeutics. Surrogate endpoints for CMV-related morbidity and mortality could advance development of antiviral treatments. Although observational data support using CMV VL as a trial endpoint, randomized controlled trials (RCTs) demonstrating direct associations between virological markers and clinical endpoints are lacking.METHODSWe performed CMV DNA PCR on frozen serum samples from the only placebo-controlled RCT of ganciclovir for early treatment of CMV after hematopoietic cell transplantation (HCT). We used established criteria to assess VL kinetics as surrogates for CMV disease or death by weeks 8, 24, and 48 after randomization and quantified antiviral effects captured by each marker. We used ensemble-based machine learning to assess the predictive ability of VL kinetics and performed this analysis on a ganciclovir prophylaxis RCT for validation.RESULTSVL suppression with ganciclovir reduced cumulative incidence of CMV disease and death for 20 years after HCT. Mean VL, peak VL, and change in VL during the first 5 weeks of treatment fulfilled the Prentice definition for surrogacy, capturing more than 95% of ganciclovir's effect, and yielded highly sensitive and specific predictions by week 48. In the prophylaxis trial, the viral shedding rate satisfied the Prentice definition for CMV disease by week 24.CONCLUSIONSOur results support using CMV VL kinetics as surrogates for CMV disease, provide a framework for developing CMV preventative and therapeutic agents, and support reductions in VL as the mechanism through which antivirals reduce CMV disease.FUNDINGMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.