Prevention Of CMV Disease Research Articles

Cytomegalovirus immunity in high-risk liver transplant recipients following preemptive antiviral therapy versus prophylaxis.

CMV-specific T cells, NK cells, and neutralizing antibodies (nAbs) were assessed in a randomized trial of CMV prevention with preemptive antiviral therapy (PET) versus prophylactic antiviral therapy (PRO) in donor-seropositive/recipient-seronegative (D+R-) liver transplant recipients (LTxR) at 100 days (end of intervention) and at 6 and 12 months after transplant. The PET group had significantly increased numbers of circulating polyfunctional T cells, NK cells, and nAbs compared with the PRO group at day 100, and several CMV immune parameters remained significantly higher by 12 months after transplant. Among PET recipients, preceding CMV viremia (vs. no preceding viremia) was associated with significantly higher levels of most CMV immune parameters at day 100. Higher numbers of CMV-specific polyfunctional T cells and NKG2C+ NK cells at day 100 were associated with a decreased incidence of CMV disease in multivariable Cox regression. The strongest associations with protection against CMV disease were with increased numbers of CMV-specific polyfunctional CD4+ T cells, CD3negCD56dimCD57negNKG2Cpos cells, and CD3negCD56dimCD57posNKG2Cpos NK cells. Our results suggest that PET is superior to PRO for CMV disease prevention by allowing low-level CMV replication and associated antigen exposure that is promptly controlled by antiviral therapy and facilitates enhanced CMV protective immunity in D+R- LTxR.

Late CMV Disease after Hematopoietic Cell Transplantation: Significance of Post-Transplant Cyclophosphamide, Steroid Treatment and CMV Viral Load

Introduction: Pre-emptive therapy (PET) and letermovir prophylaxis are effective in preventing CMV disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT), and are widely used worldwide. However, both strategies are associated with late-onset CMV disease. The goal of this study was to determine the period of risk, clinical manifestations, risk factors for initial and recurrent late CMV disease at key landmark time points, and its impact on mortality. Patients and Methods: We retrospectively analyzed CMV seropositive allogeneic HCT recipients transplanted between 2001 and 2017 who survived more than 100 days post HCT. All patients underwent PCR monitoring and PET before day 100 and for patients deemed at high risk for late CMV complications continuation of PCR monitoring and PET was recommended. Data were collected via medical record review of CMV disease and viremia, PET, transplant variables such as lymphopenia, corticosteroid use, donor type, stem cell source, type of underlying disease, and outcomes for 2 years post-transplantation. Cumulative incidence curves and Cox proportional hazards models were used to evaluate time to event and risk factors for late CMV disease and mortality. Results: Among 2155 day 100 survivors, 166 episodes of late CMV disease were observed in 144 (6.7%, 95% CI 5.7%-7.8%) patients. Most of the cases were diagnosed between day 100 and 1 year (126 cases), 40 episodes occurred within the second year (1.6% 95%CI 1.2%-2.3%) post HCT (Figure 1). CMV gastrointestinal (GI) disease (3.4%, 95% CI 2.7%-4.2%) was the most common manifestation of late CMV disease, followed by CMV pneumonia (2.9%, 95% CI 2.2%-3.7%), occurring at a median of 196 days after HCT for first GI disease episode (range 104-685) and 211 days (range 105-574) for first late pneumonia. Twenty-nine patients (10.5%, 95% CI 7%-14.7%) developed recurrent CMV disease. Most recurrences involved the same anatomical site as the first episode with a median of 126 days (range 52-444) after the initial event. Five patients developed a third episode, with a median of 145 (range 85-350) days after their second episode. Prolonged CMV surveillance was recommended in 1787 (83%) cases. High risk patients included: cord blood recipients , in vivo T-cell depletion, acute or chronic GvHD requiring steroid treatment, or those who were treated due to CMV infection before day 100. Based on day 100 risk stratification, cumulative incidence of late CMV disease occurred in 7.6% (95% CI 6.4%-8.9%) and 2.8% (95% Ci 1.4%-4.8%) in high and low risk groups, respectively. In a subgroup analysis (HCT 2001-2011), adherence to late CMV surveillance recommendations was reduced: by week 20 post-HCT, approximately 6 weeks post-discharge, only 65% of patients had CMV PCR tests performed. By 1-year post-HCT, only 40% of patients were still being tested. In multivariable analyses, steroid treatment after day 100 at a dose of ≥1mg/kg, post-transplant cyclophosphamide, GvHD prior day 100, and CMV viremia before day 100 were associated with increased risk of late CMV disease. (Figure 2). The only factors contributing to recurrence of CMV disease were HLA mismatched donor status (aHR 2.92, 95% CI 1.03-8.28) and treatment with high dose steroids ≥1mg/kg after day 100 (as time dependent variable) (aHR 7.60, 95% CI 3.32-17.4). In a landmark analysis of 1-year survivors, the risk of late CMV disease was increased in chronic GvHD patients (aHR 2.11, 95% CI 0.99-4.51, p=0.054) and those with a CMV disease episode prior to 1 year (aHR 2.80, 95% CI 1.23-6.40). Among 144 patients with late CMV disease, 32 (22%) died within 6 weeks of diagnosis of the last episode. Patients who developed late CMV pneumonia were at the highest risk of death by year 2 after HCT (aHR 4.08, 95% CI 2.62-6.35), while GI disease was associated with a somewhat lower risk (aHR 1.62, 95% CI 1.05-2.5). Conclusion: In a large cohort for which late surveillance and PET was recommended, late CMV disease occurred frequently, and was associated with the use of high dose steroids, post-transplant cyclophosphamide, and CMV reactivation before day 100. Late CMV pneumonia and GI disease were associated with overall mortality. Improved strategies to prevent late CMV disease are needed in high-risk patients, including continued antiviral prophylaxis or surveillance strategies that are more suitable for the late setting, such as home-based CMV testing.

Association of Cytomegalovirus (CMV) DNAemia With Long-Term Mortality in a Randomized Trial of Preemptive Therapy and Antiviral Prophylaxis for Prevention of CMV Disease in High-Risk Donor Seropositive, Recipient Seronegative Liver Transplant Recipients.

In a post-hoc analysis of the association of CMV DNAemia with long-term mortality in a randomized trial of CMV preemptive therapy vs. antiviral prophylaxis in D+R- liver transplant recipients, post-intervention CMV DNAemia was associated with increased mortality after adjusting for study arm.

A Systematic Review and Meta-analysis of Optimized CMV Preemptive Therapy and Antiviral Prophylaxis for CMV Disease Prevention in CMV High-Risk (D+R-) Kidney Transplant Recipients.

We conducted a systematic review and meta-analysis of PET with weekly CMV polymerase chain reaction monitoring for ≥3 mo and UP with 6 mo of valganciclovir. PubMed and Embase databases were reviewed from January 1, 2010, to April 1, 2022. Risk of bias was assessed with 3 instruments (Cochrane RoB, Cochrane RoBINS-I, and an instrument for assessing risk in observational studies). The primary outcome was CMV disease incidence by 1-y posttransplant. Secondary outcomes by 1-y were graft loss, acute allograft rejection, and mortality. Results were synthesized using generalized linear mixed model meta-analysis. PET studies were stratified into low-threshold (LT) and high-threshold (HT) PET based on the viral load threshold for initiation of antiviral therapy. Twenty-five studies met inclusion criteria (6 PET, 19 UP). CMV disease incidence was significantly higher in HT (0.30 [95% confidence interval (CI), 0.22-0.39]) versus LT PET (0.06 [95% CI, 0.03-0.12]). LT PET was associated with a significantly lower CMV disease incidence (0.06 [95% CI, 0.03-0.12]) versus UP (0.21 [95% CI, 0.17-0.27]). Incidence of graft loss, acute allograft rejection, or mortality was not significantly different between LT PET and UP (P > 0.05 for all comparisons). Receipt of lymphocyte-depleting antibodies was not associated with a significant difference in CMV disease incidence (odds ratio = 1.34 [95% CI, 0.80-2.25]). LT PET is associated with a significantly lower incidence of CMV disease compared to UP with similar rates of other clinical outcomes. These findings provide rationale and preliminary data for a randomized superiority trial of optimized LT-PET versus UP in donor seropositive recipient seronegative kidney transplant recipients.

Seropositivity for Viral Infectious Diseases in Leukemia Patients and Its Relationship with Cytogenetic Changes

Introduction: Leukemias are involving the bone marrow and the soft tissues in the inner parts of the bones. This malignancy is the most common pediatric cancer, and its etiologic causes are not well understood. This multifactorial disease is believed to be linked to genetic and non-hereditary environmental factors. Cytogenic analyses of chromosomal abnormalities provide diagnostic and prognostic values in leukemia patients. Given the high prevalence of viral diseases and clinical suspicions of the relationship between certain viral infections and leukemia, it is necessary to investigate this possible relationship, especially in third-world countries. The present study recruited 65 children with leukemia (AML, CML, or ALL) who were presented to two tertiary hospitals. At first, all the patients underwent testing for HBV, HCV, CMV, EBV, and HIV. Bone marrow specimens were studied for identifying possible chromosomal abnormalities in cytogenic investigations. According to our findings, there was a relationship between the incidence of leukemia, the 12:21 chromosomal translocation, and CMV infection. Therefore, preventing CMV infection can lead to a reduced incidence of leukemia. It is expected that the findings of this study enlighten scientists to conduct more extensive research on the relationship between viral diseases and leukemia in third-world countries.
 Materials and Methods: The present study recruited 65 children with leukemia (AML, CML, or ALL) who were presented to two tertiary hospitals. At first, all the patients underwent testing for HBV, HCV, CMV, EBV, and HIV. Bone marrow specimens were studied for identifying possible chromosomal abnormalities in cytogenic investigations.
 Results: According to our findings, there was a relationship between the incidence of leukemia, the 12:21 chromosomal translocation, and CMV infection. Thus, CMV infection is highly suspected to cause a chromosomal abnormality and predispose children to leukemia . Therefore, preventing CMV infection can lead to a reduced incidence of leukemia.
 Conclusion: In this study, we demonstrated that acute Lymphoblastic Leukemia is relevant to the 12:21 chromosomal translocation and CMV virus infections, So the reduction in leukemia prevalence is dependent on the prevention of CMV disease. It is expected that the findings of this study enlighten scientists to conduct more extensive research on the relationship between viral diseases and leukemia in third-world countries.

572. Antiviral Toxicities Among Pediatric Solid Organ Transplant Recipients

BackgroundGanciclovir (GCV) and valganciclovir (VGCV) are used for prophylaxis (PPX) and treatment for CMV in pediatric solid organ transplant (SOT) recipients, but the frequency and impact of toxicities from these medications are not well described.MethodsRetrospective cohort study of children undergoing SOT at Children’s Hospital of Philadelphia from Jan 2012 - Jun 2018. EMR were reviewed to identify laboratory-based toxicities between 15 days and 1 year post-transplant; medication management within 14 days of toxicity onset was recorded. Toxicities were defined as GCV or VGCV-associated if a patient was on the antiviral at toxicity onset. We defined acute kidney injury (AKI) as ≥50% change in creatinine (Cr) from 30 days prior, leukopenia as WBC < 3500/µL, neutropenia as ANC < 1000/µL, and thrombocytopenia as < 100K/µL. Incidence rates of toxicities on PPX and treatment were compared to rates during no antiviral using univariate Poisson regression.Results285 children received 299 SOTs: 108 liver, 91 kidney, 69 heart, 31 lung. Nearly half (46%) of toxicities during the first year after transplant occurred while on GCV or VGCV PPX or treatment, but their use accounted for only 23% of all follow-up time. Receipt of VGCV and GCV PPX and treatment were associated with significantly higher incidence rates of toxicities compared to no antiviral (Fig 1). Of 259 GCV or VGCV-associated toxicities, 44% (n=113) were leukopenia, 26% (66) neutropenia, 26% (66) AKI, and 6% (15) thrombocytopenia (Table 1). Most recipients of VGCV PPX (64%) sustained at least one toxicity while on PPX. AKI during VGCV PPX led to stopping/dose-adjusting of VGCV in 43% and of immunosuppression in 57% of cases. Neutropenia during VGCV PPX resulted in stopping/dose-adjusting of VGCV in 63%, of immunosuppression in 36%, and of TMPX/SMX PPX in 36% of cases. During VGCV PPX, 81% of AKI was stage II/III (≥100% change in Cr) and 65% of neutropenia was severe (< 500/µL); 11% of both AKI (n=6) and neutropenia (n=7) during VGCV PPX resulted in hospitalization.Figure 1. Incidence Rates of Toxicities from Day 15 through 1 Year After Transplant Table 1. Antiviral Use and Toxicity 2 Weeks to 1 Year After Transplant ConclusionGCV and VGCV use was associated with significant renal and hematological toxicities in pediatric SOT recipients. While VGCV and GCV are effective at preventing CMV disease in pediatric SOT, clinicians should consider risk of toxicity when evaluating CMV prevention strategies.DisclosuresKevin J. Downes, MD, Merck, Inc. (Grant/Research Support)

Clinical outcomes of allogeneic hematopoietic stem cell transplant recipients developing Cytomegalovirus DNAemia prior to engraftment.

There is limited information on the impact of CMV DNAemia episodes developing prior to engraftment (pre-CMV DNAemia) on clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). This issue was addressed in the current retrospective multicenter study including 878 patients. All participant centers used preemptive antiviral therapy strategies for prevention of CMV disease. CMV DNA load in blood was monitored by real-time PCR assays. A total of 144 patients (cumulative incidence 16.5%, 95% CI, 14%-19%) had an episode of pre-CMV DNAemia at a median of 10 days after allo-HSCT. Patients who developed pre-CMV DNAemia had a significantly higher (P = < 0.001) probability of recurrent episodes (50%) than those who experienced post-CMV DNAemia (32.9%); Nevertheless, the incidence of CMV disease was comparable (P = 0.52). Cumulative incidences of overall mortality (OM) and non-relapse mortality (NRM) at 1-year after allo-HSCT were 32% (95% CI, 29-35%) and 23% (95% CI 20-26%), respectively. The risk of OM and NRM in adjusted models appeared comparable in patients developing a single episode of CMV DNAemia, regardless of whether it occurred before or after engraftment, in patients with pre- and post-engraftment CMV DNAemia episodes or in those without CMV DNAemia.

The Role of the Human Cytomegalovirus UL133-UL138 Gene Locus in Latency and Reactivation.

Human cytomegalovirus (HCMV) latency, the means by which the virus persists indefinitely in an infected individual, is a major frontier of current research efforts in the field. Towards developing a comprehensive understanding of HCMV latency and its reactivation from latency, viral determinants of latency and reactivation and their host interactions that govern the latent state and reactivation from latency have been identified. The polycistronic UL133-UL138 locus encodes determinants of both latency and reactivation. In this review, we survey the model systems used to investigate latency and new findings from these systems. Particular focus is given to the roles of the UL133, UL135, UL136 and UL138 proteins in regulating viral latency and how their known host interactions contribute to regulating host signaling pathways towards the establishment of or exit from latency. Understanding the mechanisms underlying viral latency and reactivation is important in developing strategies to block reactivation and prevent CMV disease in immunocompromised individuals, such as transplant patients.

Impact of standardized protocols for cytomegalovirus disease prevention in pediatric solid organ transplant recipients.

End-organ disease caused by CMV is a significant cause of morbidity and mortality in pediatric SOT recipients. Pediatric transplant centers have adopted various approaches for CMV disease prevention in this patient population. We observed significant practice variation in CMV testing, prophylaxis, and surveillance across SOT groups in our center. To address this, we implemented evidence-based standardized protocols and measured outcomes pre- and post-implementation of these protocols. We performed retrospective chart review for SOT recipients from 2009 to 2014 at Boston Children's Hospital. Using descriptive statistics, we measured practice improvement in provision of appropriate prophylaxis, occurrence of neutropenia and associated complications, and occurrence of CMV DNAemia and CMV disease pre- and post-intervention. The pre- and post-intervention periods included 141 and 109 patients, respectively. With the exception of kidney transplant recipients, provision of appropriate valganciclovir prophylaxis improved across SOT groups post-intervention (P<.01). Occurrence of >1 episode of neutropenia was greater in the preintervention period (30% vs 10%, P<.001). In both periods, neutropenia was associated with few episodes of invasive infections. The occurrence of CMV disease did not differ and was overall low. However, due to routine surveillance a significantly greater number of asymptomatic CMV DNAemia episodes were identified and treated in the post-intervention period. Implementation of standardized prevention protocols helped to improve the provision of appropriate prophylaxis to patients at risk for CMV acquisition, increased the diagnosis and treatment of asymptomatic CMV DNAemia, and decreased episodes of recurrent neutropenia in patients receiving prophylaxis.

Management and prevention of cytomegalovirus infection in paediatric hematopoietic stem cell transplant (HSCT) recipients: A binational survey.

CMV infection is an important cause of morbidity and mortality among HSCT recipients. Optimal strategies for prevention and management of CMV disease following haematopoietic stem cell transplantation remain uncertain. We conducted an online survey of Australasian paediatric allogeneic HSCT centres on management and prevention of CMV disease in this patient group. We asked for one response from a representative of the HSCT team and one from a representative of the ID team at each centre. All Australasian paediatric HSCT centres responded to our survey. Management of CMV in pre-transplant setting was consistent between centres. All centres used a pre-emptive strategy to prevent CMV disease, guided by quantitative CMV PCR. In the post-transplant post engraftment setting, all centres recommended using ganciclovir (5mg/kg/dose twice daily) as a first-line therapy for CMV reactivation or disease, with treatment duration of 14days, provided declining CMV quantitative PCR. There was substantial variability of practice between centres in post-transplant management of CMV reactivation, especially during the pre-engraftment phase. Similarly, there was lack of uniformity in indication, dosing and duration of maintenance therapy. Divergence was noted between responses from HSCT and ID physicians within centres. This study identifies areas of uniformity and others of great variability in prevention and management strategies for CMV in paediatric HSCT. Data on CMV infection and management in HSCT patients should be routinely collected as part of prospective trials to inform guidelines and improve prevention and treatment of this important complication.

1579. Evaluation of MATCH: an Electronic Individual Patient-Focused Management System Aimed at Preventing Cytomegalovirus Disease Following Solid Organ Transplantation

BackgroundCytomegalovirus (CMV) infection is common among solid-organ transplant (SOT) recipients and may cause CMV disease, if not promptly treated. Strategies to prevent CMV disease include chemoprophylaxis and pre-emptive monitoring and treatment of emerging subclinical infection. To optimize the implementation of these strategies as part of routine care, we developed and implemented a proactive and patient-tailored CMV management system for SOT patients (the MATCH program) in our center. Two key performance characteristics of success of MATCH are diagnosing CMV at low levels and avoiding CMV disease at diagnosis; these characteristics are assessed here before (2007–2010), during (2011–2012) and after (2013–2015) the implementation of the MATCH program.MethodsIn MATCH, SOT recipients follow a personalized, yet standardized, plan for monitoring, prophylaxis and pre-emptive therapy depending on underlying risk for CMV infection. The plan is composed in accordance with the recipient’s a priori risk as to CMV IgG serostatus and is continually updated during the post-transplant course according to patient′s current situation. Each individual patient plan is produced and implemented by a rule-based artificial intelligence (AI) platform, harvesting relevant real-time data from electronic medical records. Via predefined algorithms, plans and revisions are created and alerts are generated in case of missed planned monitoring for or molecular detection of CMV infection. Prior to its implementation, prevention of CMV disease was left at the discretion of the individual physician.ResultsA total of 603, 357, and 531 patients received an SOT before, during and after implementing MATCH, resp., of whom 88 (14.6%), 56 (15.7%) and 119 (22.4%) developed CMV infection within the first year of transplantation (Table 1). Among those with CMV infection, the % with high viral load decreased as did the % with CMV disease at the time of diagnosis of CMV infection during and after the implementation of MATCH relative to before (Figure 1). ConclusionThe implementation of a rule-based AI platform guiding routine prevention of CMV disease among SOT recipients was associated with improved CMV-specific outcome, indicating its ability to identify the CMV infection sooner after onset and before causing disease.Disclosures All authors: No reported disclosures.

1590. A Hybrid CMV Prevention Strategy Is Effective in Preventing CMV Disease Outcomes in Pediatric Solid Organ Transplant Patients

BackgroundOptimal CMV prevention strategies for pediatric solid-organ transplant (SOT) patients have not been clearly defined for early and late post-transplant periods.MethodsWe analyzed CMV prevention strategies in liver, kidney, heart, lung and intestinal SOT patients from 2005 to 2015 in our institution. A hybrid strategy was defined as prophylaxis for ≤6 months post-transplant and then transition to a pre-emptive strategy.ResultsOf 833 patients, 769 were prophylaxis and 62 were hybrid strategies. Compared with prophylaxis, hybrid patients were more likely to have a D−/R− CMV serology status, be ≤1 year old and have a heart transplant (P < 0.001). We found no significant differences in CMV disease frequency, rejection or mortality between hybrid and prophylaxis groups. In total, we found 13 cases of CMV disease, of which 1 was a hybrid and the rest a prophylaxis strategy. The median time to CMV disease was 1.5 years from transplant. We found more allograft rejection (n = 9) in patients with CMV disease compared with patients with CMV infection or no Infection. For the same comparisons, no significant difference was found for age or type of organ transplant. Late rejection was frequent (n = 6/13, 67%) in patients with CMV disease, and the majority were not started on empiric anti-virals with the rejection episode. In contrast, no CMV disease was found in patients who had late rejection and received empiric anti-viral with the rejection episode, even though these patients had increasing CMV DNAemia (P = 0.04).ConclusionIn the early post-transplant period, a hybrid CMV prevention strategy is effective with similar clinical outcomes compared with a prophylaxis strategy, even in younger CMV naïve patients and relatively more immune suppressed heart transplant patients. A hybrid strategy may provide effective long-term control of intermittent CMV replication as suggested by the low frequency of CMV disease in this group compared with prophylaxis. In the late post-transplant period, administering episodic empiric anti-virals with a rejection diagnosis may be necessary to prevent CMV disease associated with late rejection episodes.Disclosures All authors: No reported disclosures.

CMV seronegative donors: Effect on clinical severity of CMV infection and reconstitution of CMV-specific immunity

BackgroundCytomegalovirus (CMV)-specific T-cells are crucial to prevent CMV disease. CMV seropositive recipients transplanted with stem cells from a CMV seronegative allogeneic donor (R+D−) may be at risk for CMV disease due to absence of donor CMV-specific memory T-cells in the graft. MethodsWe analyzed the duration of CMV reactivations and the incidence of CMV disease in R+D− and R+D+ patients after alemtuzumab-based T-cell depleted allogeneic stem cell transplantation (TCD alloSCT). To determine the presence of donor-derived primary CMV-specific T-cell responses we analyzed the origin of CMV-specific T-cells in R+D− patients. ResultsThe duration of CMV reactivations (54 versus 38 days, respectively, p = 0.048) and the incidence of CMV disease (0.14 versus 0.02, p = 0.003 at 1 year after alloSCT) were higher in R+D− patients compared to R+D+ patients. In R+D− patients, CMV-specific CD4+ and CD8+ T-cells were mainly of recipient origin. However, in 53% of R+D− patients donor-derived CMV-specific T-cells were detected within the first year. ConclusionsIn R+D− patients, immunity against CMV was predominantly mediated by recipient T-cells. Nevertheless, donor CMV serostatus significantly influenced the clinical severity of CMV reactivations indicating the role of CMV-specific memory T-cells transferred with the graft, despite the ultimate formation of primary donor-derived CMV-specific T-cell responses in R+D− patients.

96 - A Modified Intensive Strategy to Prevent CMV Disease in Seropositive Umbilical Cord Blood Transplant Recipients

Abstract We previously demonstrated a lower rate of CMV reactivation and disease among seropositive umbilical cord blood transplant (CBT) recipients receiving an intensive prophylaxis strategy consisting of ganciclovir on days -8 to -2 pre-transplant, high-dose valacyclovir post-transplant, and twice-weekly serum CMV PCR testing. We hypothesized that a modified intensive strategy excluding pre-transplant ganciclovir would be similarly effective. We compared the risk of CMV reactivation, occurrence of CMV disease, and duration of anti-CMV therapy by day 100 post-CBT in patients receiving the modified intensive and intensive strategies. Forty patients received the modified intensive strategy, and 43 received the intensive strategy. There was no difference in the hazard for CMV reactivation (HR, 1.1; p = 0.77). No patients developed CMV disease in the modified intensive cohort compared to 2 patients in the intensive cohort ( p = .53). There was no difference in the hazard for early (≤30 days post-CBT; p = .76) or high-level (>1000 IU/ml; p = .37) CMV reactivation. Patients in the modified intensive cohort had marginally higher CMV viral loads and percentages of days of CMV detection and treatment, although the contribution of pre-transplant ganciclovir to these changes is unclear. The overall percentage of treatment days was 32% in both cohorts after accounting for pre-transplant ganciclovir. In conclusion, exclusion of prophylactic ganciclovir before CBT did not impact the risk for CMV reactivation or disease, although CMV kinetics appeared to differ by prevention strategy. Best practices for CMV prevention will need further study as new prophylactic strategies become available.

Impact of antiviral prophylaxis in adults Epstein-Barr Virus-seronegative kidney recipients on early and late post-transplantation lymphoproliferative disorder onset: a retrospective cohort study.

Post-transplantation lymphoproliferative disorder (PTLD) pathogenesis is related to EBV infection. Mismatch with the donor (EBV D+/R-) is the main risk factor for both early PTLD (<1 year post-transplantation) and late (>1 year). In these at-risk patients, the role of antiviral prophylaxis for preventing PTLD remains controversial. We analyzed the impact of antiviral drugs given to prevent CMV disease in a monocentric retrospective cohort of 73 adult kidney or kidney-pancreas EBV-seronegative recipients, transplanted between 01/01/2000 and 01/01/2016. Thirty-seven (50.7%, prophylaxis group) received (val-)aciclovir or (val-)ganciclovir for 3-6 months and 36 (49.3%, no-prophylaxis group) received no-prophylaxis. Mean follow-up was 69 ± 7.2 months in the prophylaxis group and 91 ± 10.3 months in the no-prophylaxis group. Monitoring of EBV PCR revealed that prophylaxis delayed primary infection at 100 days (43% vs. 84%, P = 0.02). Early PTLD incidence was not different between groups (4/37 vs. 4/36, P = 0.99). Concerning late events, EBV-related neoplasia incidence was significantly lower in treated patients among whom no cases were observed, while in the no-prophylaxis group 6 cases were reported (P = 0.02). Despite a weak level of evidence our study suggests that antiviral prophylaxis could prevent late onset PTLD.

Low-dose valganciclovir prophylaxis for cytomegalovirus in intermediate-risk (R+) renal transplant recipients: Single-center experience.

Renal transplant recipients (RTR) who are seropositive for CMV (R+) are considered to be at intermediate risk for CMV disease. Current guidelines recommend high-dose valganciclovir (VGCV) prophylaxis because of limited data on the efficacy of low-dose VGCV. We describe our experience with using low-dose VGCV in R+ RTR. We retrospectively reviewed a cohort of 316 R+ RTR at our institution between 2002 and 2006. The primary endpoint was CMV disease at 1 year post transplant. The incidence of CMV disease at 12 months after transplantation was only 3% (6/221) in the D+R+ and 4% (4/95) in the D-R+ RTR. Low-dose VGCV was effective at preventing CMV disease in intermediate-risk (R+) RTR.

Human Cytomegalovirus Particles Treated with Specific Antibodies Induce Intrinsic and Adaptive but Not Innate Immune Responses.

Human cytomegalovirus (HCMV) persistently infects 40% to 100% of the human population worldwide. Experimental and clinical evidence indicates that humoral immunity to HCMV plays an important role in restricting virus dissemination and protecting the infected host from disease. Specific immunoglobulin preparations from pooled plasma of adults selected for high titers of HCMV antibodies have been used for the prevention of CMV disease in transplant recipients and pregnant women. Even though incubation of HCMV particles with these preparations leads to the neutralization of viral infectivity, it is still unclear whether the antibody-treated HCMV particles (referred to here as HCMV-Ab) enter the cells and modulate antiviral immune responses. Here we demonstrate that HCMV-Ab did enter macrophages. HCMV-Ab did not initiate the expression of immediate early antigens (IEAs) in macrophages, but they induced an antiviral state and rendered the cells less susceptible to HCMV infection upon challenge. Resistance to HCMV infection seemed to be due to the activation of intrinsic restriction factors and was independent of interferons. In contrast to actively infected cells, autologous NK cells did not degranulate against HCMV-Ab-treated macrophages, suggesting that these cells may not be eliminated by innate effector cells. Interestingly, HCMV-Ab-treated macrophages stimulated the proliferation of autologous adaptive CD4+ and CD8+ T cells. Our findings not only expand the current knowledge on virus-antibody immunity but may also be relevant for future vaccination strategies.IMPORTANCE Human cytomegalovirus (HCMV), a common herpesvirus, establishes benign but persistent infections in immunocompetent hosts. However, in subjects with an immature or dysfunctional immune system, HCMV is a major cause of morbidity and mortality. Passive immunization has been used in different clinical settings with variable clinical results. Intravenous hyperimmune globulin preparations (IVIg) are obtained from pooled adult human plasma selected for high anti-CMV antibody titers. While HCMV neutralization can be shown in vitro using different systems, data are lacking regarding the cross-influence of IVIg administration on the cellular immune responses. The aim of this study was to evaluate the effects of IVIg on distinct components of the immune response against HCMV, including antigen presentation by macrophages, degranulation of innate natural killer cells, and proliferation of adaptive CD4+ and CD8+ T cells.

25 Pre-emptive therapy for cmv viremia in living donor liver transplant recipients: a single centre experience

Background CMV infection is among the most common complication after liver transplantation which may result in graft loss, survival and increased cost. There are two major strategies for CMV disease prevention after transplantation: preemptive therapy and universal prophylaxis. We present our cohort of recipients of Living Donor Liver Transplant (LDLT) with non-detectable CMV DNA pre-transplant, with moderate risk of CMV viremia (D+/R+, d-/R+), who were preemptively treated. Aim To determine whether preemptive strategy may be feasible approach in patients with moderate risk for CMV viremia in LDLT and its appropriateness for Acute Cellular Rejection(ACR), length of hospital stay and risk of developing other infection and all-cause mortality. Method In this retrospective cohort, 225 adults with moderate risk for CMV viremia who underwent LDLT at Shifa International Hospital from 29/4/2011 to 26/4/2016 were included. All recipients were checked for CMV viremia at day 7, patients with significant viremia (DNA >137 IU/ml) were treated for CMV preemptively. Non-viremic patients on day 7 were only re-checked if had deranged LFT on follow up. Results Out of 225 patients, 83 (36.8%) patients had detectable CMV DNA at day 7. Patients with higher pre-transplant MELD >18 had more chances of developing CMV viremia n=42 (50.6) than those with MELD Conclusions Pre-emptive CMV strategy may be an acceptable approach in patients with moderate risk of CMV viremia in resource constraint setting; however, this needs prospective randomised trials for validation.

CMV in Hematopoietic Stem Cell Transplantation.

Due to its negative impact on the outcome of stem cell transplant (SCT) and solid organ transplant patients (SOT) CMV has been called “the troll of transplantation”. One of the greatest advances in the management of SCT has been the introduction of the preemptive strategy. Since its introduction, the incidence of the viremia, as expected, remains unchanged but there has been a marked decline in the incidence of early CMV disease. However, in spite of the advances in prevention of CMV disease, CMV is still today an important cause of morbidity and mortality. Late CMV disease is still occurring in a significant proportion of patients and the so-called indirect effects of CMV are causing significant morbidity and mortality. Fortunately there have been several advances in the development of new antivirals, adoptive immunotherapy and DNA-CMV vaccines that might transform the management of CMV in the near future.

Cytomegalovirus post kidney transplantation: prophylaxis versus pre-emptive therapy?

Cytomegalovirus is the most important pathogen causing opportunistic infections in kidney allograft recipients. The occurrence of CMV disease is associated with higher morbidity, higher incidence of other opportunistic infections, allograft loss and death. Therefore, an efficient strategy to prevent CMV disease after kidney transplantation is required. Two options are currently available: pre-emptive therapy based on regular CMV PCR monitoring and generalized antiviral prophylaxis during a defined period. In this review, we describe those two approaches, highlight the distinct advantages and risks of each strategy and summarize the four randomized controlled trials performed in this field so far. Taken this evidence together, pre-emptive therapy and anti-CMV prophylaxis are both equally potent in preventing CMV-associated complications; however, the pre-emptive approach may have distinct advantages in allowing for development of long-term anti-CMV immunity. We propose a risk-adapted use of these approaches based on serostatus, immunosuppressive therapy and availability of resources at a particular transplant centre.