Risk Of Cytomegalovirus Infection Research Articles

Different impact of rATG induction on CMV infection risk in D+R- and R+ KTRs.

Rabbit antithymocyte globulin (rATG) induction is associated with profound immunosuppression, leading to a higher risk of cytomegalovirus (CMV) infection compared with anti-interleukin 2 receptor antibody (anti-IL-2RA). However, this risk, depending on the baseline CMV serological recipient/donor status, is still controversial. The CMV DNAemia-free survival between rATG- and anti-IL-2RA-treated patients was analyzed in donor-positive/recipient-negative (D+R-) and recipient-positive (R+) patients in 1 discovery cohort of 559 kidney transplant recipients (KTRs) and 2 independent cohorts (351 and 135 kidney KTRs). The CMV-specific cell-mediated immunity (CMI) at baseline and at different time points after transplantation was assessed using an interferon γ enzyme-linked immunosorbent spot assay. rATG increased the risk of CMV DNAemia in R+ but not in D+R- KTRs. In R+ CMI-positive (CMI+) patients, the CMV DNAemia rate was higher in rATG-treated than in anti-IL-2RA-treated patients; no difference was observed among R+ CMI-negative (CMI-) patients. Longitudinal follow-up demonstrated a deeper depletion of preformed CMV CMI in R+ rATG-treated patients. D+R- KTRs have the highest risk of CMV DNAemia, but rATG adds no further risk. Among R+ KTRs, we described 3 groups, the least prone being R+CMI+ KTRs without rATG, then R+CMI+ KTRs with rATG, and finally R+CMI- KTRs. CMV serostatus, baseline CMV-specific CMI, and induction therapy may lead to personalized preventive therapy in further studies.

Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice.

Cytomegalovirus (CMV) is one of the most common opportunistic infections that affect the outcome of solid organ transplantation. This updated guideline from the American Society of Transplantation Infectious Diseases Community of Practice provides evidence-based and expert recommendations for screening, diagnosis, prevention, and treatment of CMV in solid organ transplant recipients. CMV serology to detect immunoglobulin G remains as the standard method for pretransplant screening of donors and transplant candidates. Antiviral prophylaxis and preemptive therapy are the mainstays of CMV prevention. The lack of a widely applicable viral load threshold for diagnosis and preemptive therapy is highlighted, as a result of variability of CMV nucleic acid testing, even in the contemporary era when calibrators are standardized. Valganciclovir and intravenous ganciclovir remain as drugs of choice for CMV management. Strategies for managing drug-resistant CMV infection are presented. There is an increasing use of CMV-specific cell-mediated immune assays to stratify the risk of CMV infection after solid organ transplantation, but their role in optimizing CMV prevention and treatment efforts has yet to be demonstrated. Specific issues related to pediatric transplant recipients are discussed.

A Longitudinal Study of γδ T Cell Subsets Post Lung Transplant: Potential Players in CMV Immunity

Purpose Cytomegalovirus (CMV) is the predominant opportunistic infection in lung transplant (LTx) recipients and there is a need to develop biomarkers that indicate CMV immunity. To this end, we have recently reported that natural killer (NK) cells expressing the activating receptor, CD94-NKG2C, may be important in the control of CMV following LTx. γδ T cells can also aid in CMV immunity, yet their role following LTx is unknown. In this study, we longitudinally assessed the phenotype of γδ T cells in the blood of LTx recipients with and without CMV reactivation. Methods Cryopreserved peripheral blood mononuclear cells (PBMC) from LTx recipients treated at the Alfred Hospital were examined by multicolour flow cytometry. Patients were stratified by risk of CMV infection into low risk (CMV donor (D) negative (-), CMV recipient (R) -, n=6), moderate risk (CMV R positive (+), n=13 (n=6 no CMV reactivation, n=7 with CMV reactivation) or high risk (CMV D+, R-) n=12 (n=5 no CMV reactivation, n=7 with CMV reactivation). CMV reactivation was classified as CMV PCR positive (>150 copies/ml) in blood and/or BAL within the first 12-months following LTx. The phenotype of γδ T cells from the LTx recipients was assessed at pre-LTx and 0.5, 1.5, 3, 6, 9, 12- and 18-months post-LTx (where available). We then compared γδ T cell phenotype between LTx recipients with and without CMV reactivation to healthy non-transplant donors (n=12). Results There was an increase in the proportion of γδ T cells expressing the Vδ1 receptor in LTx recipients compared to healthy controls, reaching significance in all CMV risk groups at 18-months post-LTx. At all time-points, there was a higher proportion of γδ T cells expressing NKG2C in moderate CMV risk recipients only without CMV reactivation compared to healthy controls. Conversely, in high CMV risk recipients with CMV, an increased proportion of γδ T cells expressed NKG2C at 18-months post-transplant compared to healthy controls. Conclusion Subsets of γδ T cells could be linked with control of CMV following LTx. Moreover, the NK cell receptor CD94-NKG2C is seemingly important in the control of CMV by multiple cell types. In conclusion, we have demonstrated that γδ T cells are an active and dynamic component of the LTx environment and may have utility as a biomarker following LTx, particularly when used in combination with NK cell analysis.

More Advanced Heart Failure Prior to Heart Transplant May Influence the Cytomegalovirus Specific T Cell Response in Cytomegalovirus Positive Recipients

Purpose Current assessment of risk of Cytomegalovirus (CMV) infection in CMV+ heart transplant (HT) recipients is poor. A diminished CMV-specific T cell response against 2 CMV antigens (IE-1 and pp65), using the IFN-γ ELISPOT, is associated with higher risk of developing CMV infection after HT. However we do not know the reasons for this diminished CMV-specific T cell response. We aimed to evaluate predictors of intermediate or high risk of developing CMV infection according to the IFN-γ ELISPOT at the time of HT. Methods We prospectively evaluated all CMV+ HT recipients in one institution from 2017 until present in whom we performed an IFN-γ ELISPOT on the day of HT. Patients were classified into low risk (IE-1>23 spots and pp65>79 spots) and not low risk: Intermediate (IE-1 Results We included 26 CMV+ HT recipients of which 14 had low risk ELISPOT and 12 not low risk ELISPOT (4 intermediate, 6 high and 2 anergic). Variables closer to HT according to the ELISPOT group are presented in the table. We included left ventricular ejection fraction (LVEF), MELD score and NTproBNP value in the multivariate analysis but none of them significantly predicted a not low risk ELISPOT. Conclusion More advanced heart failure before HT may be associated with a higher risk of CMV infection in CMV+ recipients. We need bigger numbers to confirm this tendency.

Evaluation of Cytomegalovirus-Specific T Cell Response Can Improve Risk Stratification of CMV Infection in Heart Transplant Recipients

Purpose Current assessment of risk of cytomegalovirus (CMV) infection in CMV+ heart transplant (HT) recipients is poor. This has led to universal prophylaxis, but this strategy has significant costs and side-effects. We aimed to evaluate the impact of determining CMV-specific T cell responses against 2 CMV antigens (IE-1 and pp65), using the IFN-γ ELISPOT on use of prophylaxis and the incidence of CMV infection in CMV+ HT recipients. Methods We prospectively evaluated all CMV+ HT recipients in 1 institution in whom we performed an IFN-γ ELISPOT prior to HT and 2 weeks post-HT. The ELISPOT result could be low risk (IE-1>23 spots and pp65>133 spots) or not low risk. This information plus clinical assessment led to deciding between pre-emptive therapy or prophylaxis with Valgancyclovir 900 mg daily for 3 months. We collected incidence of CMV viremia (any positive CMV PCR), CMV infection (CMV PCR>1500 IU/ml) and CMV disease and incidence of leucopenia ( Results We included 29 HT recipients with 26 IFN-γ ELISPOTs pre-HT and 28 IFN-γ ELISPOTs post-HT. Mean age was 56 years old, 24% female and 45% were emergency HT. Donor CMV serology was positive in 62% of cases. Induction therapy was given in 90% of patients. All received Tacrolimus + Mycophenolate mophetil + steroids. Figure 1 shows the main outcomes of the study. One patient died before the second IFN-γ ELISPOT determination and is not included. No patient with a low risk ELISPOT post-HT developed CMV infection, giving a positive predictive value of the test of 100%. The incidence of leucopenia was 7(39%) from 18 patients treated with prophylaxis. 2 needed G-CSF. Conclusion Evaluation of CMV-specific T cell response using the ELISPOT assay in CMV+ HT recipients can help stratify risk for CMV infection. Patients with a low risk ELISPOT 2 weeks post-HT may safely undergo pre-emptive therapy.

Human Cytomegaly Virus Immunoglobulin as an Early Adjunctive Therapy Increased CMV-Free Survival after Heart Transplantation

Purpose There is still an ongoing discussion whether a prophylactic or a preemptive therapy against cytomegalovirus (CMV) is superior to reduce the incidence of CMV viremia, acute rejections (AR) or cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). Thus, we evaluated different CMV treatment strategies in this setting. Methods HTx patients (n=56) were retrospectively studied regarding the end points of CMV-free survival viremia, AR, and CAV. The average follow-up was 4.15 years (355 days up to 7.5 years). Patients were classified into 3 groups according to their CMV therapy: preemptive therapy (PRE, n=19), prophylactic drug monotherapy (PROM, either valganciclovir for 3 months or early single dose of 1mg/kg/BW of CMV immunoglobulin, CMVIG, 2 weeks post-HTx, n=18) or prophylactic double drug therapy (PROD, valganciclovir for 3 months plus early single dose of CMVIG, n=19). For statistical analysis X2, X2-log-rank and T-Tests were used. Results Median patient survival was similar: PRE-group 2243 days, PROM-group 2417 days, and PROD-group 2410 days, respectively. However, the median CMV-viremia free survival was different among the groups: 1817 days in the PROD-group, 1459 days in the PROM-group and 1482 in the PRE-group (p=0.52). A subanalysis of patients with high risk for CMV infection (donor+/ recipient-CMV status) the CMV-free survival was significantly higher when patients received double prophylaxis therapy compared to the other two groups (p<0.01). Whether the incidence of AR nor of CAV was not significantly influenced by the choice of CMV treatment regimen. Antiviral medication was discontinuated in 10.5% PRE-group, 38.9% PROM-group, and 31.6% PROD-group, respectively. Conclusion Our study results suggest that early therapy with CMVIG as adjunct to antiviral treatment could prolong CMV-free survival in patients with CMV risk of infection. If a repetitive CMVIG dosing post-HTx will further reduce CMV infection needs to be explored in the future. There is still an ongoing discussion whether a prophylactic or a preemptive therapy against cytomegalovirus (CMV) is superior to reduce the incidence of CMV viremia, acute rejections (AR) or cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). Thus, we evaluated different CMV treatment strategies in this setting. HTx patients (n=56) were retrospectively studied regarding the end points of CMV-free survival viremia, AR, and CAV. The average follow-up was 4.15 years (355 days up to 7.5 years). Patients were classified into 3 groups according to their CMV therapy: preemptive therapy (PRE, n=19), prophylactic drug monotherapy (PROM, either valganciclovir for 3 months or early single dose of 1mg/kg/BW of CMV immunoglobulin, CMVIG, 2 weeks post-HTx, n=18) or prophylactic double drug therapy (PROD, valganciclovir for 3 months plus early single dose of CMVIG, n=19). For statistical analysis X2, X2-log-rank and T-Tests were used. Median patient survival was similar: PRE-group 2243 days, PROM-group 2417 days, and PROD-group 2410 days, respectively. However, the median CMV-viremia free survival was different among the groups: 1817 days in the PROD-group, 1459 days in the PROM-group and 1482 in the PRE-group (p=0.52). A subanalysis of patients with high risk for CMV infection (donor+/ recipient-CMV status) the CMV-free survival was significantly higher when patients received double prophylaxis therapy compared to the other two groups (p<0.01). Whether the incidence of AR nor of CAV was not significantly influenced by the choice of CMV treatment regimen. Antiviral medication was discontinuated in 10.5% PRE-group, 38.9% PROM-group, and 31.6% PROD-group, respectively. Our study results suggest that early therapy with CMVIG as adjunct to antiviral treatment could prolong CMV-free survival in patients with CMV risk of infection. If a repetitive CMVIG dosing post-HTx will further reduce CMV infection needs to be explored in the future.

Cytomegalovirus (CMV) Pentameric Complex (PC) Neutralizing Antibodies (nAb) from a Randomized, Controlled Trial of CMV-Specific Intravenous Immunoglobulin (IVIG) for the Prevention of Primary CMV Infection after Hematopoietic Cell Transplantation (HCT)

Prevention of CMV disease after HCT remains a challenge. In addition to antivirals, immune-based strategies such as active and passive immunization may have potential roles preventing infection. CMV entry into epithelial and endothelial cells requires distinct viral proteins including UL128, UL130, UL131A, gB and gH/gL that combine to form a PC. A nAb assay was developed by Gerna et al. that measures nAb activity against PC, although its clinical application in HCT patients has not been described. In 1991, Bowden et al. conducted a study where CMV IVIG was administered as prophylaxis to D+/R- patients early after allogenic HCT. Although it showed reduced CMV infection in CMV IVIG recipients, CMV disease was not reduced thus its use was never adopted. This impact on infection suggests the possibility that CMV IVIG inhibits infection via neutralization of an unidentified entry pathway that may include PC. From the original cohort, we tested 538 serum samples from 61 patients using CMV DNA polymerase chain reaction (PCR) to compare clinically significant viral load (≥ 4 log10 IU/ml) or histopathologically detected CMV between groups. We also used a CMV nAb assay to evaluate anti-PC neutralizing capacity. The assay uses retinal pigmented epithelial (ARPE-19) cells exposed to serial dilutions of serum combined with a laboratory CMV strain, BADrUL131-Y4, that contains a green fluorescent protein (GFP) cassette. After one hour incubation, cells are washed and incubated for one week. Fluorescence is measured and we construct curves that plot viral neutralization against serum dilution and from these we extrapolate an IC-50; that is the dilution where 50% virus neutralization is achieved. After excluding three patients infected prior to day 21 post-transplant, there were 27 CMV IVIG and 31 control patients. Neither cumulative incidence of CMV infection (Figure 1, p=0.55), nor IC-50 values (Figure 2, p=0.19) differed by study arm, though observed median IC-50 values were higher in the CMV IVIG arm (5.8) than in the control arm (4.8). We found no association between IC-50 and risk of CMV infection (HR=1.8, 95% CI 0.6-5.3, p=0.31). Using modern CMV detection methods, our study suggests CMV IVIG does not result in decreased CMV viral load. Although the PC nAb composition of the CMV IVIG used is unknown, it did not appear protective against CMV infection. We successfully evaluated CMV PC entry-specific neutralizing activity in the HCT setting using a nAb assay, however evaluation among larger cohorts is needed to determine its clinical utility.

Letermovir Prophylaxis Demonstrates High Efficacy in Adult Cytomegalovirus (CMV) Seropositive Cord Blood Transplant (CBT) Recipients: A Comparison with Pre-Letermovir Era CBT Controls

Background CMV seropositive CBT recipients have a high risk of CMV infection. Early pre-emptive therapy is required to avoid CMV disease but is associated with significant toxicities. Methods This analysis compares the day +100 incidence & severity of clinically significant CMV infection (viremia leading to pre-emptive treatment or disease) in CMV seropositive CBT adult patients (pts) who received letermovir prophylaxis transplanted 12/2017-6/2018 vs historic controls transplanted 3/2013-12/2017. Control pts received ganciclovir prophylaxis days -7 to -2 then standard dose acyclovir. Letermovir pts received standard dose acyclovir & started letermovir IV or PO on day +7 & continued beyond day +100. All pts received uniform intermediate intensity Cy 50 mg/kg / Flu 150 mg/m2/ Thio 5-10 mg/kg / TBI 400 cGy conditioning with CSA/ MMF. Pts were monitored by qPCR twice weekly from approximately day +14-60 & then 1-2 x/weekly days +60-100. Results 62 [median age 51 years (range 23-66), 46 leukemia, 7 MDS/ MPD, 9 NHL/ HL] historic control pts received double unit grafts with a median unit-recipient HLA-allele match of 5/8 (range 2-7). By day +100, 51 pts developed clinically significant CMV infection for a day +100 cumulative incidence of 82% (95%CI: 70-90). The median viremia onset was 34 days (range 5-74) & 5 pts developed CMV disease by day +100 (3 pulmonary, 2 GI). Initial therapy was with foscarnet in 28 pts & ganciclovir/ valganciclovir in 23. Clinically significant therapy toxicities (renal &/or myelosuppression) were observed in 38/51 (75%) pts (Table 1). By day +100, CMV caused or contributed to 3 pulmonary deaths. 10 pts [median age 48 years (range 24-59), 9 leukemia, 1 MDS/ MPD, median 5/8 (range 3-6) unit-recipient HLA-match] received letermovir prophylaxis (8 IV, 2 PO) (Table 2). All pts engrafted. The day +100 cumulative incidence of clinically significant CMV infection was 0% (p Conclusions This analysis suggests letermovir prophylaxis is highly effective at mitigating CMV disease, CMV-related mortality, & the need for toxic CMV therapies. Moreover, it has been well tolerated in CBT recipients. While further detailed investigation in a larger population is required, this data is very promising & the extent of the benefit suggests that letermovir could be a cost-effective new standard of care in adult CBT. The duration of needed prophylaxis beyond day +100 in CBT recipients also requires investigation.

PTX3 Polymorphisms Influence Cytomegalovirus Reactivation After Stem-Cell Transplantation.

Background: Reactivation of latent human cytomegalovirus (CMV) in patients undergoing allogeneic stem-cell transplantation (HSCT) predisposes to several clinical complications and is therefore a major cause of morbidity and mortality. Although pentraxin-3 (PTX3) has been previously described to bind both human and murine CMV and mediate several host antiviral mechanisms, whether genetic variation in the PTX3 locus influences the risk of CMV infection is currently unknown.Methods: To dissect the contribution of genetic variation within PTX3 to the development of CMV infection, we analyzed described loss-of-function variants at the PTX3 locus in 394 recipients of HSCT and their corresponding donors and assessed the associated risk of CMV reactivation.Results: We report that the donor, but not recipient, h2/h2 haplotype in PTX3 increased the risk of CMV reactivation after 24 months following transplantation, with a significant effect on survival. Among recipients with h2/h2 donors, CMV seropositive patients as well as those receiving grafts from unrelated donors, regardless of the CMV serostatus, were more prone to develop viral reactivation after transplantation. Most importantly, the h2/h2 haplotype was demonstrated to display an influence toward risk of CMV reactivation comparable to that conferred by the unrelated status of the donor alone.Conclusions: Our findings demonstrate the important contribution of genetic variation in donor PTX3 to the risk of CMV reactivation in patients undergoing HSCT, highlighting a promising prognostic value of donor PTX3 to predict risk of CMV reactivation in this clinical setting.

Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis

BackgroundInterleukin-2 (IL-2) antagonist has been used as an induction therapy in many centres in calcineurin inhibitor-sparing regimens. Tacrolimus has overwhelmingly replaced cyclosporine in the maintenance immunosuppressive protocols in many transplant centres. The aim of our study and meta-analysis is to explore the effect of IL-2 induction therapy on the rate of rejection and patient and graft survival in standard-risk renal transplant patients with tacrolimus-based maintenance immunotherapy. Secondary aims included assessment of the effect of IL-2 induction therapy on creatinine change and the risk of cytomegalovirus (CMV) infection.MethodsWe conducted a systematic review in different databases to identify studies and research work that assessed the effect of IL-2 antibody induction therapy on renal transplant outcomes. Inclusion criteria for our meta-analysis were all studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients on tacrolimus-based maintenance immunosuppressive therapy. Data collected were the name of the first author, journal title, year of publication, country where the study was conducted, number of patients in the IL-2 induction therapy arm and in the placebo arm, number of patients who had biopsy-proven rejection and graft survival in each arm. A random effects model was used for the meta-analysis.ResultsOf the 470 articles found in different databases, 7 were included in the meta-analysis. Forest plot analysis for rate of rejection during the follow-up period post-transplant showed no significant difference between the groups. There was no evidence of heterogenicity between included studies (I2 = 21.8%, P = 0.27). The overall risk difference was −0.02 [95% confidence interval (CI) −0.05–0.01]. A random effects meta-analysis for patient and graft survival was performed using forest plot analysis and showed no significant effect of IL-2 receptor (IL-2R) antibody induction on patient or graft survival compared with placebo. The overall risk difference was −0.01 (95% CI −0.04–0.01) and 0.00 (95% CI −0.00–0.01), respectively. Three of the included studies showed no effect of basiliximab on creatinine change, two showed no effect on risk of CMV infection and two showed less risk of post-transplant diabetes in the basiliximab group.ConclusionIL-2R antibody induction therapy has no significant effect on the rate of rejection or patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy. More randomized controlled studies are needed.

Current treatment modalities of immunocompromised patients with cytomegalovirus infection. I. Epidemiological and clinical perspectives

Human cytomegalovirus is a DNA virus with a global prevalence of 40-100%. In humans, primary infection is followed by a lifelong latent persistent phase. Even in individuals developing adequate specific immunity, interactions with the resident virus do probably occur. Clinically significant problems, however, appear primarily in immunocompromised hosts. As a result of an impaired T-cell mediated immunity, viral reactivation as well as a viral disease resulting in organ damage can develop. Most severely affected are HIV positive persons in AIDS stage and individuals undergoing solid organ or stem cell transplantation. As vital functions and survival may adversely be affected by cytomegalovirus reactivation and disease, it is of paramount significance to evaluate evident risk factors. Viral reactivation and organ specific disease can be detected by several methods based on conventional and molecular biological and histological diagnostic techniques. An up-to-date management of affected patient groups requires a meticulous assessment of the possible risk for cytomegalovirus infection and development of an adequate antiviral strategy. Orv Hetil. 2019; 160(3): 83-92.

Universal prophylaxis with valganciclovir versus preemptive therapy in minimizing the risk of cytomegalovirus infection and disease in high-risk and intermediate-risk kidney transplant recipients: a single-center experience

Objective Cytomegalovirus (CMV) is one of the most frequent viral pathogens that results in post-transplantation infection. Universal prophylaxis and preemptive therapy have long been used to prevent and treat CMV infection, respectively, in post-transplantation cases. The aim of this study was to compare the universal prophylaxis with valganciclovir versus preemptive therapy in minimizing the risk of CMV infection and disease in high-risk and intermediate-risk kidney transplant recipients. Patients and methods This single-center, retrospective cohort study enrolled 63 kidney transplant recipients between March 2017 and January 2018. The outcome variables were occurrence of CMV infection and CMV disease, 1-year estimated glomerular filtration rate (eGFR), allograft rejection, allograft loss, and mortality within the first year after transplantation in high-risk (D+/R−) patients managed with universal prophylaxis of oral valganciclovir and intermediate-risk (D+/R+ or D−/R+) patients receiving preemptive treatment. Results Of the 63 kidney transplant recipients, 19 (30.2%) were grouped as high risk for CMV infection/disease and 44 (69.8%) were intermediate risk for CMV infection/disease. The average duration of post-transplantation follow-up was 349 (SD 136) days in the high-risk cohort and 335 (SD 112) days in the intermediate-risk cohort (P=0.56). CMV infection was found in 15 (34.1%) of the 44 intermediate-risk patients receiving preemptive therapy and in four (21.1%) of the 19 high-risk patients receiving universal prophylaxis (P Conclusion Intermediate-risk (D+/R+ or D−/R+) kidney transplant recipients receiving preemptive therapy had significantly higher frequency of CMV infection/disease than high-risk (D+/R−) kidney transplant recipients receiving oral valganciclovir universal prophylaxis during early post-transplantation period. No statistically significant differences were found in relation to allograft rejection, allograft loss, eGFR, and mortality at 1 year in both the cohorts.

NFKB1 promoter polymorphism: A new predictive marker of cytomegalovirus infection after kidney transplantation.

Cytomegalovirus (CMV) infection represents a common cause of morbidity and mortality in kidney transplant recipients (KTR). The NF-kB signaling pathway is highly involved in the pathogenesis of CMV infection. The -94ins/delATTG functional polymorphism in the promoter of NFKB1 has been associated with low intracellular levels of the protein and high incidence of inflammatory and autoimmune disease. In this study, we evaluated the association of this NFKB1 polymorphism with the risk of CMV infection. CMV infection was defined as virus isolation or detection of viral antigens or nucleic acid in any body fluid or tissue specimen. Using Cox regression and survival analysis, we analyzed the association between the polymorphism and CMV infection as well as recurrence in the first 12months after transplantation. We analyzed the -94ins/delATTG NFKB1 polymorphism of 189 KTRs. The 65% of CMV infections occurred in ins/ins group. Survival free from CMV infection was 54.7% for ins/ins group and 79.4% for deletion carriers one year after transplantation (P<0.0001). At multivariate regression, deletion carriers showed a lower risk of CMV infection and recurrence with respect to ins/ins KTRs (HR=0.224 P=0.0002; HR=0.307, P=0.012, respectively). In conclusion, pretransplantation screening for NFKB1 -94ins/delATTG polymorphism may predict CMV infection and improve the management of patients at higher risk of infection in the post-transplant period.

Donor NKG2C Copy Number: An Independent Predictor for CMV Reactivation after Double Cord Blood Transplantation

Cytomegalovirus (CMV) is a member of the herpesviridae family and remains latent in the host cells after primary infection. The virus reactivates in the immunosuppressed host and is a leading cause of morbidity following allogeneic hematopoietic stem cell transplant (allo-HSCT). Natural killer (NK) cells provide the first-line defence against viruses and a subset of NK cells expressing NKG2C have been shown to play a role in the immune surveillance of human CMV. Deletion of the NKG2C gene has been reported as a risk factor for viral infections including CMV and HIV, but current data on the influence of NKG2C gene-copy number variations in the donor graft on the risk of CMV reactivation after allo-HSCT is limited. Following cord blood transplantation (CBT), where the T-cell compartment is functionally naïve, the NKG2C genotype may have an even more pronounced impact on the risk of CMV reactivation. Therefore, we studied NKG2C copy number in the donor graft and the risk of CMV reactivation after double umbilical cord blood transplantation (DUCBT) in 100 CMV seropositive DUCBT recipients and their corresponding cord blood grafts (n=200). The gene encoding NKG2C is present at different copy numbers in the genomes of different individuals, with possible genotypes including 2 copies (wt/wt), 1 copy due to heterozygous deletion (wt/del) or 0 copies due to homozygous deletion (del/del). Among the donor CB units, approximately 2/3 had both copies of the gene (wt/wt), 1/3 had only one copy (wt/del) and only a minority of units had 0 copies with both alleles deleted (del/del). In the setting of DUCBT, the combined graft may contain 0 to 4 functional copies of NKG2C gene. In our cohort, patients whose combined grafts contained only 1 or 2 NKG2C gene copies had a significantly higher probability of CMV reactivation than patients whose combined grafts had 3 or 4 NKG2C copies. The 6-month cumulative incidence of CMV reactivation for the 4 groups was 100%, 92.9%, 60.5% and 55.9% respectively (p=0.005). No patient received a graft with zero gene copies. For the rest of the analysis we divided the patients into two groups, namely the 84 patients who received a combined graft with 3 or 4 NKG2C copies and the 16 patients who received two units with 1 or 2 NKG2C copies. The 6-month cumulative incidence of CMV reactivation for the two groups was 58.4% and 93.7% respectively (p=0.0003). In a multivariate analysis, receiving a combined graft with low NKG2C copy number (1 or 2 copies) (HR=2.72, CI=1.59-4.64; p<0.0001) and reduced intensity conditioning (RIC) (HR=0.59, CI=0.35-0.99, p=0.046) were the only independent predictors for CMV reactivation. Interestingly, the NKG2C copy number of the dominant cord was not predictive for CMV reactivation, suggesting that both cord blood units contribute to the antiviral response early post-DUCBT. Our study points to an important role for donor NKG2C in protection against CMV reactivation after DUCBT. If confirmed in larger numbers of CBT recipients, NKG2C genotyping of the CB graft may be a useful biomarker for predicting the risk of CMV infection after CBT, thus guiding the intensity of CMV prophylaxis for individual patients. Moreover these novel findings may provide a compelling rationale for considering NKG2C genotype as a criterion in the algorithm of CB selection for DUCBT. DisclosuresOran:ASTEX: Research Funding; AROG pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding. Shpall:Affirmed GmbH: Research Funding.

Going beyond serology for stratifying the risk of CMV infection in transplant recipients.

Knowledge of donor and recipient (D/R) cytomegalovirus (CMV) serostatus is critical for risk stratification of CMV infection and disease in transplant recipients, particularly in the solid organ transplantation (SOT) setting. Despite its broad availability and the success of it use, the risk stratification based on the D/R serostatus is not free of limitations since there are a nondepreciable number of patients that are not accurately categorized by this approach. In fact, up to 20% of seropositive SOT recipients, classically considered at intermediate risk, develop episodes of CMV infection and disease after transplantation. Here, we provide an overview of additional donor and recipient factors that may have utility in identifying patients at risk for post-transplant CMV infection. Specifically, we summarize our current understanding regarding the potential use of use CMV-specific T-cell-mediated immunity, neutralizing antibodies and host genetics that may influence the risk of CMV infection and disease. We provide an overview of the benefits and limitations associated with using these immunological factors in risk stratification and propose specific variables that could be analyzed at the pretransplant evaluation to improve the identification of patients with increased individual susceptibility.

Incidence of cytomegalovirus in cardiac transplant recipients receiving induction immunosuppression with antithymocyte globulin.

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in cardiac transplant recipients. Use of induction immunosuppression in cardiac transplantation may have an impact on the incidence of CMV, but literature is limited. Single-center, retrospective cohort study comparing the risk of CMV infection and disease in cardiac transplant patients receiving antithymocyte globulin (ATG) induction therapy to those receiving no antibody induction. A total of 75 patients were included in our analysis, 50 who received ATG induction and 25 who did not. CMV infection occurred in 10 (20%) and 5 (20%) patients in the ATG and No ATG groups, respectively (P > 0.99). CMV disease occurred in 10 (20%) and 4 (16%) patients in the ATG and No ATG groups, respectively (P = 0.763). The median time from transplant to CMV infection was 200.0 [142.5, 364.5] days in the ATG group vs 221.0 [192.0, 299.0] days in the No ATG group (P = 0.723). The median time from end of CMV prophylaxis to CMV infection was 94.5 [66.5, 151.0] days in the ATG group vs 53.0 [41.0,149.5] days in the No ATG group (P = 0.202). Freedom from CMV infection was highest in the D+/R+ group and lowest in the D+/R- group. In cardiac transplant recipients, ATG induction was not associated with an increased incidence of CMV infection or disease in the setting of valganciclovir prophylaxis and an initial maintenance immunosuppression regimen of primarily steroids, mycophenolate mofetil, and tacrolimus.

Cytomegalovirus infection in day care centres: A systematic review and meta-analysis of prevalence of infection in children.

Maternofetal transmission of cytomegalovirus (CMV) is the most common infectious cause of congenital malformation in developed countries. Maternal infection often results from close contact with infected children, and this may occur in day care centres (DCCs). A systematic review of observational studies was conducted to examine the prevalence of CMV infection among children attending DCCs. Meta-analysis using the random effect model was performed for studies including controls. Sources included PubMed, EMBASE (until August 2018), and references from identified publications. Inclusion criteria were studies reporting CMV infection prevalence among childcare children aged less than 7years of age. Controls were children without childcare exposure. CMV infection was defined as viral excretion detected by culture, polymerase chain reaction, or CMV seropositivity. Twenty-eight publications including 8347 participants met the eligibility criteria. The pooled prevalence of CMV infection among children in childcare from all studies was 32% (95% CI 23-41). Within case-controlled studies, prevalence among children attending DCCs was 34% (95% CI 25-44), whereas prevalence among those without childcare exposure was 22% (95% CI 15-30). Meta-analysis showed a significant association between DCC attendance and CMV infection (odds ratio 2.69, 95% CI 1.68-4.30; heterogeneity χ2 /df=8; I2 =84%, P<0.00001). Attendance at DCCs is significantly associated with increased risk of childhood CMV infection. Prevention strategies to reduce risk of CMV infection of pregnant women and children should involve review of DCC exposure and consideration of preventative hygiene strategies.

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation

Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.

Incidence of Cytomegalovirus DNAemia in Pediatric Kidney Transplant Recipients After Cessation of Antiviral Prophylaxis.

Late cytomegalovirus (CMV) infection can occur after cessation of viral prophylaxis in kidney transplant recipients, yet, timing of infection is unclear and longer duration of prophylaxis may be warranted. We conducted a retrospective cohort study of 86 children (35 CMV donor seropositive, recipient seronegative [D + R-] and 51 CMV recipient seropositive [R+]) younger than 18 years who received a kidney transplant between January 2002 and June 2014 and were treated with antiviral prophylaxis for 3 months after transplantation. Incidence of CMV DNAemia and CMV disease was determined using Kaplan-Meier analyses and risk factors were assessed using Poisson regression. Of the 86 children, 61.6% were male and median age at transplant was 13.4 years (interquartile range [IQR], 8.9-15.6) with a median follow-up of 35.2 months (IQR, 18.0-54.5). Incidence of CMV DNAemia within the first 3 months after prophylaxis cessation in CMV D + R- and CMV R+ children was 22.9% and 23.5% and incidence of CMV disease was 11.4% and 0%, respectively. Cumulative incidence of CMV DNAemia in both groups was similar (31.4%). Children who received antithymocyte globulin were more likely to develop CMV DNAemia compared with those who received anti-IL-2 (IRR, 2.98; 95% confidence interval, 1.41-6.30) after controlling for age, sex, Epstein-Barr Virus serostatus and rejection. This study demonstrates a high incidence of CMV infection after cessation of antiviral prophylaxis. These results support extension of antiviral prophylaxis beyond 3 months and/or intensive viral load monitoring to reduce risk of CMV infection in D + R- and R+ children, especially those receiving antithymocyte globulin.

MRP2 24 CT is Associated with an Increased Risk of Cytomegalovirus Infection Among Renal Transplant Recipients

MRP2 24 CT is Associated with an Increased Risk of Cytomegalovirus Infection Among Renal Transplant Recipients