Cytomegalovirus Seroconversion Research Articles

Prevalence and timing of prenatal ultrasound findings in cytomegalovirus‐infected pregnancies

AbstractIntroductionTo investigate the prevalence and timing of prenatal neurosonographic abnormalities after primary cytomegalovirus seroconversion by the first trimester of pregnancy. The additional value of magnetic resonance imaging (MRI) and the correlation between cytomegalovirus viral load in amniotic fluid and adverse neonatal outcomes were evaluated.Material and MethodsA retrospective study between 2006 and 2022 examined data from 440 women with amniocentesis for periconceptional and first‐trimester cytomegalovirus seroconversion. Cases with positive amniocentesis and subsequent follow‐up were included. Prenatal neurosonography, MRI, and clinical outcomes were analyzed.ResultsOut of 190 women included, 37% (n = 70) presented with a normal neurosonography. Patients exhibiting abnormal neurosonography findings showed higher viral loads in amniotic fluid compared to those with a normal neurosonography (p = 0.002). In 26% (n = 49) the first abnormal ultrasound sign was already picked up at amniocentesis, and the most common ones were echogenic bowels (49%) and periventricular echogenicity (43%). With increasing gestational age, the likelihood of a new abnormal neurosonography finding decreases. MRI discovered additional abnormalities in 14% (n = 10).ConclusionsThe results highlight the importance of combining diagnostic modalities, from amniocentesis to biweekly ultrasound monitoring and subsequent MRI evaluation, to capture the chronological progression and subsequent outcome of congenital cytomegalovirus.

Neonatal and short-term outcome after late vertical transmission in congenital CMV-infected fetuses following primary first-trimester maternal seroconversion

ObjectiveTo document the course of neonatal and short-term outcomes in pregnancies after first trimester CMV (cytomegalovirus) seroconversion and negative amniotic fluid (AF) CMV PCR.MethodsWe included 375 patients with a first-trimester...

Impact of cytomegalovirus (CMV) seroconversion pre-allogeneic hematopoietic cell transplantation on posttransplant outcomes.

Cytomegalovirus (CMV) reactivation post-allogeneic hematopoietic cell transplantation (post-alloHCT) increases morbidity and mortality. We sought to determine the frequency of CMV seroconversion in patients pre-alloHCT and to investigate the impact on posttransplant outcomes. We retrospectively investigated 752 adult patients who underwent alloHCT at our center from January 2015 to February 2020 before the adoption of letermovir prophylaxis. CMV serology was assessed at consult and pretransplant. The cohort was divided into four groups based on pretransplant CMV seroconversion: negative to positive (Group 1), positive to negative (Group 2), consistently negative (Group 3), and consistently positive (Group 4). Eighty-nine patients (12%) had seroconverted from negative to positive, 17 (2%) from positive to negative, 151 (20%) were consistently seronegative, and 495 (66%) were consistently seropositive pretransplant. For the four CMV serostatus groups, cumulative incidence of CMV reactivation at 6 months posttransplant was 4.5%, 47.1%, 6.6%, and 76.6% for Groups 1, 2, 3, and 4, respectively (p < .0001). No differences between groups were seen regarding Grade III-IV acute graft-versus-host disease (GVHD) (p = .91), moderate/severe chronic GVHD (p = .41), or graft failure (p = .28). On multivariable analysis, there was no impact of CMV serostatus group on overall survival (p = .67), cumulative incidence of relapse (p = .83) or non-relapse mortality. alloHCT patients who demonstrate CMV seroconversion pretransplant from negative to positive have a very low risk of CMV reactivation posttransplant. The observed seroconversion may be due to passive CMV immunity acquired through blood products. Quantitative CMV immunoglobulin G/immunoglobulin M pretransplant may help differentiate between true seroconversion and passively transmitted CMV immunoglobulin.

Cytomegalovirus infection in non-immunocompromised critically ill patients: A management perspective.

Critically ill patients are a vulnerable group at high risk of developing secondary infections. High disease severity, prolonged intensive care unit (ICU) stay, sepsis, and multiple drugs with immunosuppressive activity make these patients prone to immuneparesis and increase the risk of various opportunistic infections, including cytomegalovirus (CMV). CMV seroconversion has been reported in up to 33% of ICU patients, but its impact on patient outcomes remains a matter of debate. Even though there are guidelines regarding the management of CMV infection in immunosuppressive patients with human immunodeficiency virus/ acquired immuno deficiency syndrome, the need for treatment and therapeutic approaches in immunocompetent critically ill patients is still ambiguous. Even the diagnosis of CMV infection may be challenging in such patients due to non-specific symptoms and multiorgan involvement. Hence, a better understanding of the symptomatology, diagnostics, and treatment options may aid intensive care physicians in ensuring accurate diagnoses and instituting therapeutic interventions.

A Phase 2, Single-Arm, Multicohort, Open Label, Multicenter Trial of Off-the-Shelf Natural Killer Cells (SAR445419) in Patients with High-Risk Myeloid Malignancies Undergoing Allogeneic HSCT

Background and Significance: Relapse remains the leading cause of treatment failure for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the risk depends on parameters such as age and conditioning intensity, relapse is experienced in 30-50% of patients after conventional HSCT in high-risk AML/MDS. Initial safety and post-HSCT relapse risk reduction results were reported in a phase I study of haploidentical (haplo) donor-derived natural killer (NK) cells expanded ex vivo on feeder cells expressing IL-21 and 4-1BBL in conjunction with haplo-HSCT (Ciurea et al, Leukemia, 2022). This study supported exploring SAR445419 (SAR'419), an off-the-shelf (OTS) product, derived from universal donor NK cells and expanded ex vivo in a feeder cell-free system using plasma membrane particles bearing membrane-bound IL-21 and 4-1BBL. Here, we aim to test whether SAR'419 can mediate an effective anti-leukemia response and reduce post-transplant relapse rate when administered in the peri-transplant period. Study Design and Methods: In this multicenter, multicohort, phase 2, single-arm trial (NCT05726682), patients with high-risk AML/MDS planned for allo-HSCT from matched sibling, matched unrelated or haplo donors will be enrolled in 2 cohorts. Cohort A will comprise patients aged 18‒65 years undergoing myeloablative conditioning with hematopoietic cell transplantation comorbidity index ≤3 and cohort B will comprise patients aged 18‒75 years undergoing reduced intensity conditioning. Patients with prior allogeneic transplantation or AML beyond first complete remission will be excluded from the study. Patients will undergo HSCT conditioning starting on Day ‒7 and will receive a peripheral blood stem cell graft on Day 0. Prophylaxis for Graft-versus-host disease (GVHD) using cyclophosphamide, mycophenolate mofetil, and tacrolimus will start on Day +3. SAR'419 will be administered as adjunctive therapy to the HSCT on Day ‒2, Day +7, and Day +28. To confirm the anticipated safety profile of SAR'419, a safety run-in will be conducted in 6‒12 patients in each cohort prior to open enrollment. Patients will be enrolled until 51 and 44 patients in cohorts A and B, respectively, receive at least the first 2 doses of SAR'419 at the target dose confirmed during safety run-in. In total, approximately 107 patients will be enrolled. The primary endpoint, relapse free survival (RFS), will be assessed at 12 months post-HSCT. Additional primary endpoints include frequency of graft failure, life-threatening infusion-related reactions or cytokine release syndrome, tumor lysis syndrome, immune cell-associated neurotoxicity syndrome, acute GVHD, overall mortality at 100 days post-HSCT, non-relapse mortality, and cytomegalovirus reactivation/infection. Secondary endpoints are safety, tolerability, and the impact of SAR'419 on HSCT outcomes, stem cell engraftment, GVHD, infection, and quality of life. Exploratory assessments include evaluation of the impact of SAR'419 on immune reconstitution, cytomegalovirus seroconversion, minimal residual disease, resource utilization, SAR'419 immunogenicity and persistence and their impact on outcomes in whole blood (including serum and plasma) and bone marrow aspirates. RFS will be reported as the percentage of patients who are relapse free and alive at 12 months from the date of HSCT and who received at least the first 2 planned doses of SAR'419. Adverse events will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 and will be summarized using descriptive statistics.

Maternal cytomegalovirus infection and delayed language development in children at 3 years of age-a nested case-control study in a large population-based pregnancy cohort.

Maternal cytomegalovirus (CMV) infection in pregnancy may result in vertical transmission of CMV to the child. Long-term effects of congenital CMV infection include visual, cognitive as well as neurological impairment. The aim of this study was to estimate the odds ratios for CMV seropositivity and seroconversion in mothers, with and without delayed language development in 3 year old children, nested within a large cohort. The Norwegian Mother, Father and Child Cohort Study (MoBa) is a prospective population-based pregnancy cohort that includes 95 200 mothers and 114 500 children. Blood samples were obtained from mothers during pregnancy weeks 17 or 18 in pregnancy and after birth. We included 300 women from MoBa with children suffering from delayed language development at three years of age, based on validated questionnaires. Within the cohort, 1350 randomly selected women were included as controls to perform a nested case-control study. The cases and controls were tested for CMV IgG antibodies by an enzyme-linked immunosorbent assay. Among mothers of cases, 63.2% were CMV-IgG positive in the sample at birth, as compared to 55.9% among controls; OR 1.36, (95% CI; 1.05 to 1.76). Also, among case mothers, 8/118 (6.8%) initially seronegative cases, seroconverted. Among initially seronegative controls, seroconversion occurred in 23/618 (3.7%) mothers. The OR for seroconversion in cases as compared to control mothers was 1.88 (CI; 0.82 to 4.31), thus not statistically significant different. This study shows a higher risk of delayed language development at three years of age in children born by mothers seropositive for CMV, compared to children born from seronegative mothers.

Impact of Cytomegalovirus (CMV) Sero-Conversion Pre Allogeneic Stem Cell Transplant on Post-Transplant Outcomes

INTRODUCTION: The choice of an ideal allogeneic hematopoietic cell transplantation (allo-HCT) donor depends on numerous parameters, including cytomegalovirus (CMV) sero-status matching. We sought to determine the frequency of observed CMV seroconversions in patients pre allo-HCT and to investigate the impact on post-transplant CMV reactivation and survival outcomes. METHODS: We conducted a retrospective study that included 752 adult patients that underwent allo-HCT at the Princess Margaret Cancer Centre from January 2015 to February 2020, before the adoption of letermovir prophylaxis in high-risk patients. CMV serology was assessed for all patients at consult and pre-transplant assessment. The cohort was divided into 4 groups based on apparent pre-transplant seroconversion: 1) From negative to positive (group1), 2) From positive to negative (group2), 3) Consistently negative (group3), 4) Consistently positive (group 4). We documented the occurrence of CMV viremia in all 4 groups depending on CMV sero-status of the donor, and investigated post-transplant outcomes. Standard routine monitoring for CMV viremia post-transplant was performed using quantitative polymerase chain reaction (PCR). RESULTS: The minimum follow-up of survivors was 2 years. Eighty-nine patients (12%) had sero-converted from negative to positive, 17 (2%) from positive to negative, 151 (20%) were consistently sero-negative and 495 (66%) were consistently sero-positive pre-transplant. Transplant indications were acute myeloid leukemia (AML) in 50%, acute lymphoid leukemia (ALL) in 19% of patients. Median age of the entire cohort was 58 years (range: 18-76), 43% were female, 38% had hematopoietic cell transplant- comorbidity index (HCT-CI) ≥3, 20% had Karnofsky performance status (KPS) <90%, for 23% the disease risk index (DRI) was high or very high. Fully HLA matched donor were 78% of the donors. Haplo-identical donors were 14%, 58% of donors were unrelated and 28% were matched related. Reduced intensity conditioning (RIC) was given to 77% of patients, 89% underwent in-vivo T-cell depletion. No difference was shown between the four CMV sero-status groups regarding overall survival (OS) (p=0.46), cumulative incidence of relapse (CIR)(p=0.76), neutrophil recovery (p=0.20), platelet recovery (p=0.69), grade III-IV acute graft-versus-host disease (GVHD)(p=0.93), moderate/severe chronic GVHD (p=0.57) or graft failure (p=0.28). For the four groups, the cumulative incidence of CMV reactivation at 6 months was 5.6%, 47.1%, 7.9% and 79.4% for group 1,2,3 and 4 respectively (Figure). In multivariable analysis, recipient CMV sero-status pre-transplant was associated with CMV reactivation (Hazard ratio HR=20, 95% CI= 11-34, p<0.0001 for consistently positive CMV sero-status compared to consistently negative, irrespective of donor CMV sero-status). Other parameters influencing CMV reactivation included increasing CD34+ cell dose (HR=1.02, 95% CI=1.004-1.04, p=0.02) and haplo-identical donor status (HR=2.1 in comparison to matched related donors, 95% CI =1.55-2.84, p<0.0001). Considering both donor and recipient CMV sero-status, we separated the cohort into eight groups (Table). In 89 patients that converted CMV serology pre-transplant from negative to positive, 6 patients had CMV reactivation post-transplant (5 of them received stem cells from a CMV positive donor). In 17 patients that converted from positive to negative, 8 (47%) had CMV reactivation post-transplant. In the consistently CMV positive group, the incidence of CMV reactivation was high with either CMV negative (87.5%) or CMV positive (77.2%) donors (Table). CONCLUSION: Allo-HCT patients that demonstrate CMV sero-conversion pre-transplant from negative to positive have a very low risk of CMV reactivation post-transplant. The observed sero-conversion in these patients may be due to passive CMV immunity acquired through the administration of blood-derived products. Patients that sero-converted from positive to negative pre-transplant continue to demonstrate CMV reactivation risk even with a CMV negative donor. Quantitative CMV IgG/IgM pre-transplant may help to differentiate between true sero-conversion and passively transmitted CMV immunoglobulins, which in turn may facilitate determination of CMV reactivation risk as well as donor choice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune thrombocytopenia secondary to Cytomegalovirus infection during pregnancy: A case report and review of the literature

Background: Cytomegalovirus (CMV) is a rare cause of Immune Thrombocytopenic Purpura (ITP) and even rarer during pregnancy. Case: A 27-year-old pregnant woman presented with severe thrombocytopenia in the latent phase of labor. She was treated with dexamethasone and platelet transfusions and underwent a successful vaginal delivery. The neonate had severe thrombocytopenia as well. Serology assays of the mother revealed CMV seroconversion with a negative Polymerase Chain Reaction (PCR). The neonate had a positive PCR and was treated with Intravenous Immunoglobulin (IVIG), steroids, platelets and Valganciclovir with a good response. The mother’s platelet count normalized three months later. Conclusions: CMV infection should be considered as a potential cause for severe thrombocytopenia during pregnancy and can lead to early detection and treatment for Congenital CMV.

Congenital Infections: Priorities and Possibilities for Resource-limited Settings.

Congenital Infections: Priorities and Possibilities for Resource-limited Settings.

Impact of maternal cytomegalovirus seroconversion on newborn and childhood hearing loss.

Objectives/hypothesisThe objective of this study is to describe long‐term hearing outcomes in infants born to mothers with a known cytomegalovirus (CMV) positivity who were not tested for congenital CMV. Study typeClinical research study.DesignRetrospective cohort study.MethodsRetrospective chart review was performed for mothers seropositive to CMV. Mother–infant dyads (130) were identified between January 1, 2013 and January 1, 2017. Outcomes data was collected through June 1, 2020. Demographics, risk factors for hearing loss, evidence of CMV infection, other causes of hearing loss, need for speech therapy services, and results of all hearing tests were collected.ResultsAll 130 infants were asymptomatic and 5 were tested for congenital CMV. Five were negative for CMV and excluded from analyses. Of the remaining 125, only 1 had low‐viral avidity IgG antibodies. None had IgM antibodies. Four children (3.2%) had hearing loss at last audiogram and one child had delayed onset SNHL due to an enlarged vestibular aqueduct. Speech therapy for communication was required for 33 children (26.4%).ConclusionsKnowledge of maternal perinatal CMV status can allow for education about possible sequelae of cCMV, as well as trigger an alert for testing babies born to mothers with low‐viral avidity IgG during the first trimester, when the risk of vertical transmission is highest. Also, babies born to CMV positive mothers may be more at risk for communication delays necessitating intervention. Studies focusing on the impact of maternal CMV related to childhood communication deficits could elucidate any direct relationships.

Lower prevalence of congenital cytomegalovirus infection in Portugal: possible impact of COVID-19 lockdown?

Cytomegalovirus (CMV) is the most frequent cause of congenital infection all over the world. Its prevalence ranges from 0.2 to 2.2%. Transmission from children to their pregnant mothers is a well-known risk factor, particularly if they attend a childcare centre. This study aims to compare the prevalence of CMV congenital infection (CMV_CI) in Portugal (Lisbon) between two studies, performed respectively in 2019 and 2020. In the 2019 study, performed in two hospitals, we found a 0.67% CMV_CI prevalence, using a pool strategy previously tested with saliva samples. In the 2020 study, using the same pool approach in four hospitals (the previous and two additional), and based on 1277 samples, the prevalence was 0.078%.Conclusion: The close temporal coincidence with COVID-19 lockdown suggests that these measures may have had a significant impact on this reduction, although other explanations cannot be ruled-out. What is Known:• Cytomegalovirus is the leading cause of congenital infection.• Behavioural measures decrease cytomegalovirus seroconversion in pregnant women.What is New:• From 2019 to 2020 there was a significant reduction in the prevalence of congenital CMV infection.

Seroprevalence of Cytomegalovirus and Associated Factors Among Preconception Women: A Cross-Sectional Nationwide Study in China.

Background: Cytomegalovirus seroconversion during pregnancy is common and has a substantial risk of congenital infection with longterm sequale. Screening during pregnancy or vaccination have not been shown to be effective for eliminating congenital infections. Preconception screening policy has not been evaluated adequately in a large scale. This nationwide study aimed to investigate epidemiological features of cytomegalovirus seropositivity and its geographic variation among Chinese women planning a pregnancy to gather epidemiological evidence as an essential for developing novel prevention strategies.Method: This cross-sectional sero-epidemiological survey enrolled women intending to become pregnant within 6 months in mainland China during 2010–2012. The primary outcomes in this study were cytomegalovirus Immunoglobulin G and M seropositivity. Secondary outcomes were the associations between Immunoglobulin G and Immunoglobulin M, with socio-demographic characteristics, including age, occupation, education level, place of residence, and ethnicity. The overall seropositivity and regional disparity was analyzed on the individual and regional level, respectively.Results: This study included data from 1,564,649 women from 31 provinces in mainland China. Among participants, 38.6% (n = 603,511) were cytomegalovirus immunoglobulin G+, 0.4% (n = 6,747) were immunoglobulin M+, and 0.2% (n = 2,879) were immunoglobulin M+ and immunoglobulin G+. On individual level, participant's age, ethnicity, and residing region were significantly associated with IgG+, IgM+, and IgM+IgG+ (P < 0.001), while occupation, education level, and place of residence were not statistically significant (P > 0.05). On regional level, cytomegalovirus immunoglobulin G and immunoglobulin M seropositivity was highest in the eastern region (49.5 and 0.5%, respectively), and lowest in the western region (26.9 and 0.4%, respectively). This geographic variation was also noted at the provincial level, characterized by higher provincial immunoglobulin M+ and immunoglobulin G+ rates associated with higher immunoglobulin G seropositivity. In the subgroup analysis of immunoglobulin G seropositivity, areas of higher immunoglobulin G positivity had a higher rate of immunoglobulin M+, indicating an expected increased risk of reinfection and primary infection.Conclusions: A substantial proportion of women (>60%) were susceptible to cytomegalovirus in preconception period in China, and immunoglobulin G seropositivity was seen at a low-medium level with substantial geographic variation. Integration of cytomegalovirus antibody testing in preconception screening program based on regional immunoglobulin G seropositivity, should be considered to promote strategies directed toward preventing sero-conversion during pregnancy to reduce the risk of this congenital infection.

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

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

Impact of normothermic ex vivo lung perfusion on early post-transplantation cytomegalovirus infection.

BackgroundThe low acceptance rates in lung transplantation underline the importance to use every potential transplantable organ. With the use of normothermic ex vivo lung perfusion (EVLP) there is a potential to use more donor lungs for transplantation. Aim of this study was to evaluate if EVLP has an effect on cytomegalovirus (CMV) infection after lung transplantation.MethodsBetween May 2016 and October 2018, 57 lung transplants were performed. Out of these 21 extended criteria lungs were evaluated by EVLP and 16 transplanted. In a retrospective study, results of EVLP treated lungs were compared with lungs after cold storage preservation (CSP). Donor/recipient CMV IgG status and seroconversion rate was examined.ResultsDonors were CMV IgG+ in EVLP 69% and CSP 61% (n.s.). Best pO2 on procurement at FiO2 1.0 was in EVLP 278±76 versus CSP 413±96 mmHg (P≤0.05). Recipients were CMV IgG+ in EVLP 38% and CSP 63% (P<0.07). CMV seroconversion: EVLP 12%, CSP 20% (P<0.05), in the CSP group in 5% recipients with more than 1,000 copies/mL were diagnosed by PCR and treated for CMV infection. Procalcitonin (PCT) levels from day 1 to day 5 were significantly lower for CSP group (P<0.05). 30-day mortality was 12% for EVLP recipients.ConclusionsNormothermic EVLP did not influence CMV infection rate, however early PCT levels were higher in EVLP group. Short-term results were comparable to standard lung transplantation.

Single-nucleotide polymorphism-based chromosomal microarray analysis provides clues and insights into disease mechanisms.

Chromosomal microarray analysis (CMA) is the modality of choice for prenatal diagnosis in pregnancy with fetal malformation, as it has a high diagnostic yield for microdeletion/duplication syndromes. The aim of this study was to demonstrate the additional utility of single-nucleotide polymorphism (SNP)-based CMA in diagnosing monogenic diseases, imprinting disorders and uniparental disomy (UPD). CMA was performed using Affymetrix CytoScan array, for all indications in 6995 pregnancies, at a tertiary referral hospital from November 2013 to June 2018. We describe four cases that had a CMA result that provided a more comprehensive understanding of the complex genetic mechanisms underlying the clinical presentation. In the first fetus, CMA was performed due to intrauterine growth restriction and revealed a 75 kbp maternally inherited microdeletion encompassing the Bloom syndrome gene (BLM). A diagnosis of Bloom syndrome was made upon identifying a paternally inherited common Ashkenazi founder mutation. In the second case, CMA was performed due to severely abnormal maternal serum analytes and revealed a deletion in 14q32.2q32.31 on the maternally inherited copy, leading to a diagnosis of Kagami-Ogata syndrome, which is an imprinting disorder. In the third case, amniocentesis was performed because of late-onset fetal macrosomia and mild polyhydramnios. CMA detected a deletion encompassing the locus of Prader-Willi/Angelman syndrome. In the fourth case, amniocentesis was performed due to maternal cytomegalovirus seroconversion. Maternal UPD of the entire long arm of chromosome 11 was detected. Prenatal CMA, based on oligo and SNP platforms, increases the diagnostic yield and enables a wider spectrum of disorders to be detected through the identification of complex genetic etiologies beyond only copy number variants. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Prolonged Low-Dose Prophylaxis With Valganciclovir in Cytomegalovirus-Negative Recipients of Kidney Transplants From Cytomegalovirus-Positive Donors Allows Seroconversion and Prevents Cytomegalovirus Disease

BackgroundCytomegalovirus-negative recipients of kidneys from cytomegalovirus (CMV)-positive donors (D+/R−) are at high risk to develop severe clinical manifestations of CMV disease. Long-term data about incidence and timing of CMV seroconversion, CMV disease, and the influence of prolonged valganciclovir prophylaxis on the clinical course of CMV infection are missing. MethodsWe conducted a retrospective long-term study of 89 consecutive CMV D+/R− kidney transplant recipients transplanted between 2003 and 2012. All recipients received valganciclovir prophylaxis after transplantation (median 187 [126-261] days) with a median dose of 213 (181-338) mg/d. Long-term outcome was assessed over a maximum of 10 years post-transplant. ResultsDuring follow-up (median 62 months) 60 of 89 (67%) patients had CMV seroconversion, and 29 of 89 (33%) developed symptomatic CMV disease. In addition, in 38 of the 60 (63%), seroconversion occurred during prophylaxis (median 154 days post-transplant), and in 22 patients, after the end of prophylaxis (median 320 days after transplantation). Baseline characteristics of the 2 groups did not differ significantly. Seroconversion during prophylaxis vs seroconversion after the end of prophylaxis was associated with significantly lower incidence of CMV disease (34% vs 73%, P = .007), less severe CMV disease (16% vs 64%, P < .001), and fewer organ manifestations (26% vs 64%, P = .006). The risk of CMV disease was limited to the first 475 days after transplantation. Valganciclovir resistance occurred in just 1 case (1%). ConclusionsProlonged prophylaxis with low-dose valganciclovir allowed CMV seroconversion during prophylaxis in a high proportion of D+/R− patients. Seroconversion occurred after a median of 154 days and was associated with significantly lower incidence of CMV disease, less severe CMV disease, and fewer CMV complications.

Infection materno-fœtale à CMV : étude rétrospective dans un CPDPN sur une période de 14 ans

Cytomegalovirus (CMV) is the most frequent cause of congenital infection. The aim of this research was to describe the decision-process for parents to pursue gestation or to ask medical abortion after materno-fetal CMV infection. The primary objective of this study is to analyze the decision-process for parents after materno-fetal infection with positive PCR after amniocentesis, to ask or not a medical termination of pregnancy (TOP). The secondary objectives are to compare ours results with literature review (pronostics factors, ultrasonographic signs and neonatal symptomatology). This is a retrospective study, focused with a pluridisciplinary materno-fetal prenatal medical center, during a 14-year long period. Only 15patients have been included in the study. They have been divided in 2groups (the first group who decided to ask a TOP [n=8] and the second group who pursued the gestation [n=7]). We compare respectively their clinical, ultrasonographic, or other imagery and biological paths, before and after the birth. A total of 15/16patients had a CMV seroconversion before 20weeks of gestation. The only infection after 20SA did not have any sequelae. The ultrasonography and the cerebral fetal MRI appeared to be very complementary for the assesment of brain injury, which is more frequent in the group with a TOP (7/8versus 4/7). Three neonates out of 4who had a cord positive viral blood load at birth are presenting neonatal symptoms, 2of them will have severe brain and hearing injuries, the fourth one had no sequelae after 6months of life. Only the presence of ultrasonographic major brain damages, and confirmation with MRI, had a pejorative value as prognosis factor suggesting to patients to choose a TOP. Nevertheless, other ways of research are possible to assess the prognostic value in this difficult prenatal diagnosis process.

New diagnostics and methods of assessing pregnant women at risk of cytomegalovirus

Human cytomegalovirus (CMV) infection can occur in pregnant women by primary infection or by non-primary infection, namely by either reactivation of the latent virus or reinfection with a different strain1. In all cases the mother can transmit the virus to the fetus through the placenta2,3. In the diagnosis of primary CMV infection, the gold standard is maternal seroconversion to CMV-specific antibodies. Currently, women are not routinely screened for CMV before conception or during pregnancy, thus CMV seroconversion is infrequently documented1. Lastly, serological diagnosis of non-primary CMV infection is very difficult and very often unreliable since no optimal diagnostic methods are currently available. Today, the fetal compartment can be only studied by amniocentesis and ultrasound examination for the diagnosis and prognosis of CMV infection and generally, invasive diagnostic protocol can be only suggested to pregnant women with evidence of primary CMV infection acquired early in gestation and in case of abnormal findings suggestive of congenital infection1. Therefore, a correct maternal diagnosis makes so that invasive prenatal diagnosis is only offered in selected cases. This report points out how a CMV-screening program combined with an advanced diagnostic protocol performed on pregnant women could identify those at high risk of transmitting the virus to their fetus. Furthermore, we evaluated the possible role of soluble HLA-G (sHLA-G) molecules detected in maternal and fetal samples in order to more accurately assess a greater risk of CMV-transmission and fetal/neonatal injury.

Increased Incidence of Leucopenia With FDA Approved Valganciclovir Dosing for CMV Prophylaxis in Pediatric Kidney Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV) infection is a serious complication following kidney transplantation, and may lead to graft failure and loss, as well as increased mortality. Valganciclovir is used for CMV prophylaxis in pediatric kidney transplant recipients at high and moderate risk (CMV D+ and/or R+ serostatus). The dose recommendation in pediatric patients was previously determined through extrapolation from adult data, and varied from 10-12 mg/kg/day. Based on recent pediatric data, dose recommendations were changed in 2010 to 7 x BSA x CrCl, which was approved by the FDA. The newer dosing has led to a 2-3 fold increased dose as compared to traditional dosing for many patients. Concurrently we have observed a rise in the incidence of leucopenia post-transplant in the pediatric kidney transplant recipients at our center. OBJECTIVES: To identify whether increased dosing of valganciclovir in pediatric kidney transplant recipients is associated with increased incidence of leucopenia. METHODS: We conducted a retrospective cohort study of 95 pediatric kidney transplant recipients at our center from January 1, 2008 to December 31, 2013. The incidence of leucopenia (defined as WBC count <3000 cells/μL) was assessed, and compared between the patients receiving traditional vs. FDA approved dosing of valganciclovir. RESULTS: Seventy-nine incident pediatric kidney transplant recipients received valganciclovir for CMV prophylaxis, and 36 (45.6%) of these received valganciclovir per the FDA approved dosing recommendation. Twenty-eight (77.8%) of the patients who received the FDA approved valganciclovir dosing developed leucopenia, as compared to 23 (53.5%) of the 43 patients that received traditional dosing. The relative risk for development of leucopenia among the group receiving the FDA approved (vs. traditional) valganciclovir dosing was 1.45 (p = 0.0246). CONCLUSION: In this single center study, CMV prophylaxis with FDA approved dosing of oral valganciclovir following kidney transplantation in at-risk pediatric patients was associated with an increased incidence of leukopenia. Future studies are needed to examine the generalizability of these findings, as well as to weigh the risk-benefit ratio of higher valganciclovir dosing with its impact on CMV seroconversion.

Comparison of Cytomegalovirus (CMV) Enzyme-Linked Immunosorbent Spot and CMV Quantiferon Gamma Interferon-Releasing Assays in Assessing Risk of CMV Infection in Kidney Transplant Recipients

Assessing cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) represents an appealing strategy for identifying transplant recipients at risk of infection. In this study, we compared two gamma interferon-releasing assays (IGRAs), Quantiferon-CMV and CMV enzyme-linked immunosorbent spot (ELISPOT), to determine the ability of each test to predict protective CMV-specific T-cell responses. Two hundred twenty-one Quantiferon-CMV and ELISPOT tests were conducted on 120 adult kidney transplant recipients (KTRs), including 100 CMV-seropositive transplant recipients (R+) and 20 CMV-seronegative transplant recipients of a CMV-positive donor (D+/R-). As a control cohort, 39 healthy adult subjects (including 33 CMV-seropositive and 6 CMV-seronegative subjects) were enrolled. CMV IgG serology was used as a reference for both tests. In the CMV-seropositive individuals, the ELISPOT and Quantiferon-CMV assays provided 46% concordance with the serology, 12% discordance, 18% disagreement between ELISPOT or Quantiferon-CMV and the serology, and 24% gray areas when one or both tests resulted in weak positives. None of the CMV-seronegative subjects showed detectable responses in the ELISPOT or the Quantiferon-CMV test. In transplant recipients, both the ELISPOT and Quantiferon-CMV assays positively correlated with each other and negatively correlated with CMV DNAemia in a significant way (P<0.05). During the antiviral prophylaxis, all 20 D+/R- KTRs we examined displayed undetectable Quantiferon-CMV and ELISPOT results, and there was no evidence of CMV seroconversion. The receiving operator curve (ROC) statistical analysis revealed similar specificities and sensitivities in predicting detectable viremia (areas under the curve [AUC], 0.66 and 0.62 for Quantiferon-CMV and ELISPOT, respectively). ELISPOT and Quantiferon-CMV values of >150 spots/200,000 peripheral blood mononuclear cells (PBMCs) and >1 to 6 IU gamma interferon (IFN-γ) were associated with protection from CMV infection (odds ratios [OR], 5 and 8.75, respectively). In transplant recipients, the two tests displayed similar abilities for predicting CMV infection. Both the ELISPOT and Quantiferon-CMV assays require several ameliorations to avoid false-negative results.