Histological Analysis of Term Placentas from Hyperimmune Globulin-Treated and Untreated Mothers with Primary Cytomegalovirus Infection.

Background: The Congenital Human Cytomegalovirus Infection Prevention (CHIP) study, a randomized, blinded, placebo-controlled trial, demonstrated that the efficacy of hyperimmune globulin (HIG) was not different from that of placebo regarding transmission of cytomegalovirus (CMV) from mothers to newborns. Our aim was to analyze histologically HIG effects on placentas collected for the CHIP study.

Materials And Methods: Virological and histological analyses were performed on 40 placentas from transmitter and nontransmitter HIG-treated and untreated mothers by assessing the number of CMV-positive cells, tissue viral load, tissue damage, and compensatory mechanisms.

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development.

Between the 1980s and 1990s, three assays were developed for diagnosis of human cytomegalovirus (HCMV) infections: leuko (L)-antigenemia, l-viremia and l-DNAemia, detecting viral protein pp65, infectious virus and viral DNA, respectively, in circulating leukocytes Repeated initial attempts to reproduce the three assays in vitro using laboratory-adapted strains and infected cell cultures were consistently unsuccessful. Results were totally reversed when wild-type HCMV strains were used to infect either fibroblasts or endothelial cells. Careful analysis and sequencing of plaque-purified viruses from recent clinical isolates drew attention to the ULb' region of the HCMV genome.

Assessing Immunity to Rubella Virus: a Plea for Standardization of IgG (Immuno)assays.

Immunity to rubella virus (RV) is commonly determined by measuring specific immunoglobulin G (RV IgG). However, RV IgG results and their interpretation may vary, depending on the immunoassay, even though most commercial immunoassays (CIAs) have been calibrated against an international standard and results are reported in international units per milliliter. A panel of 322 sera collected from pregnant women that tested negative or equivocal for RV IgG in a prior test (routine screening) was selected.

Prevention of Primary Cytomegalovirus Infection in Pregnancy.

Background: Cytomegalovirus (CMV) is the leading infectious agent causing congenital sensorineural hearing loss and psychomotor retardation. CMV vaccine is currently unavailable and treatment options in pregnancy are limited. Susceptible pregnant women caring for children are at high risk for primary infection.

Cytomegalovirus DNAemia in pregnant women.

Background: Cytomegalovirus (CMV) transmission from mother to fetus occurs at a much greater rate following primary rather than reactivated infections and CMV dissemination in the mother is considered a key step in the pathogenesis of fetal infection. However, knowledge of CMV DNAemia in CMV-seropositive pregnant women is very limited.

Objective: Major objective of this study was to assess the prevalence and diagnostic value of CMV DNAemia in a large population of seropositive pregnant women.

Role of human cytomegalovirus (HCMV)-specific antibody in HCMV-infected pregnant women.

Maternal preconception immunity confers substantial protection against HCMV infection and disease to the unborn child. However, the protective role played by single components of virus-specific humoral and cellular immunity is poorly defined. Recently, it was discovered that UL128-131 gene products are essential for the virus to exert endothelial/epithelial cell tropism during natural infection.

A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus.

Background: Congenital infection with human cytomegalovirus (CMV) is a major cause of morbidity and mortality. In an uncontrolled study published in 2005, administration of CMV-specific hyperimmune globulin to pregnant women with primary CMV infection significantly reduced the rate of intrauterine transmission, from 40% to 16%.

Methods: We evaluated the efficacy of hyperimmune globulin in a phase 2, randomized, placebo-controlled, double-blind study.

Evaluation of fully automated assays for the detection of Rubella IgM and IgG antibodies by the Elecsys(®) immunoassay system.

Screening for acute rubella infection in pregnancy is an important element of antenatal care. This study compared the sensitivity, specificity and reproducibility of two new, fully automated Elecsys(®) Rubella IgM and IgG immunoassays designed for the Elecsys 2010, Modular Analytics E170, COBAS e-411 and COBAS e-601 and e602 analytical platforms, with current assays using serum from patients with primary rubella infections, vaccinated patients, patients with potentially cross-reacting infections and on routine samples in clinical laboratories in France, Germany and Italy. Both assays showed good within-run and within-laboratory precision.

Slow increase in IgG avidity correlates with prevention of human cytomegalovirus transmission to the fetus.

Following primary human cytomegalovirus (HCMV) infection, virus-specific IgG antibody shift from low to high avidity with individual variations in the rate of avidity maturation. The kinetics of the avidity maturation of IgG specific for HCMV nuclear antigen in pregnant women with primary infection was investigated. Absorbance values used for avidity index calculation of 286 sequential sera collected from 69 pregnant women with primary HCMV infection were retrieved.

Fetal human cytomegalovirus transmission correlates with delayed maternal antibodies to gH/gL/pUL128-130-131 complex during primary infection.

Primary human cytomegalovirus (HCMV) infections during pregnancy are associated with a high risk of virus transmission to the fetus. To identify correlates of intrauterine HCMV transmission, serial serum samples from HCMV transmitter and non-transmitter pregnant women with primary HCMV infection were analyzed for the presence of neutralizing antibodies against different glycoproteins and glycoprotein complexes, which are known to mediate entry into distinct types of host cells. Neutralizing activity was detected in the sera early after primary infection; absorption with a soluble pentameric complex formed by gH/gL/pUL128-131, but not with gH/gL dimer or with gB, abolished the capacity of sera to neutralize infection of epithelial cells.

Role of prenatal diagnosis and counseling in the management of 735 pregnancies complicated by primary human cytomegalovirus infection: a 20-year experience.

Background: The burden of congenital human cytomegalovirus (HCMV) infection is well recognized. However, screening for maternal infection remains controversial in view of diagnostic challenges, counseling difficulties, and absence of medical treatment.

Objective: To assess the role of prenatal diagnosis and counseling in the management of pregnancy complicated by primary HCMV infection.

Comparative evaluation of eight commercial human cytomegalovirus IgG avidity assays.

Background: The interpretation of a positive IgM antibody result to human cytomegalovirus (HCMV) in a pregnant woman is of major importance for the correct management of the pregnancy. Determination of HCMV-specific IgG avidity is considered an useful approach for distinguishing IgM antibody due to primary HCMV infection from IgM antibody elicited during non-primary infection.

Objective: Comparative evaluation of eight commercial HCMV IgG avidity assays currently available in Europe.

Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex.

Human cytomegalovirus (HCMV) is a widely circulating pathogen that causes severe disease in immunocompromised patients and infected fetuses. By immortalizing memory B cells from HCMV-immune donors, we isolated a panel of human monoclonal antibodies that neutralized at extremely low concentrations (90% inhibitory concentration [IC(90)] values ranging from 5 to 200 pM) HCMV infection of endothelial, epithelial, and myeloid cells. With the single exception of an antibody that bound to a conserved epitope in the UL128 gene product, all other antibodies bound to conformational epitopes that required expression of two or more proteins of the gH/gL/UL128-131A complex.

Human cytomegalovirus-specific CD4+ and CD8+ T cell responses in primary infection of the immunocompetent and the immunocompromised host.

The kinetics of primary human cytomegalovirus (HCMV) infection and specific T-cell responses were investigated in 16 immunocompetent pregnant women and 8 solid-organ transplant recipients (SOTR). T-cell responses to whole HCMV and to pp65 and IE-1 peptides were determined by flow cytometry evaluation of IFNgamma production. HCMV-specific CD4(+) and CD8(+) T-cells appeared earlier and simultaneously in immunocompetent subjects, whereas specific CD8(+) T-cells preceded CD4(+) T-cells in half of the SOTR examined.

Human cytomegalovirus-specific memory CD8+ and CD4+ T cell differentiation after primary infection.

Background: The development of human cytomegalovirus (HCMV)-specific T cell immunity after primary infection and its correlation with virus transmission to the fetus were investigated.

Methods: The membrane phenotype (CCR7 and CD45RA expression) of and intracellular cytokine (interferon [IFN]-gamma and interleukin-2) production by HCMV-specific T cells (stimulated with HCMV-infected dendritic cells) were investigated in 21 immunocompetent pregnant women (12 transmitters and 9 nontransmitters) and in 5 nonpregnant subjects during the first year after infection.

Results: IFN-gamma-producing CD4+ and CD8+ T cells were readily detected during the first month, and their levels did not significantly change with time.

Molecular epidemiology of primary human cytomegalovirus infection in pregnant women and their families.

The source of human cytomegalovirus (HCMV) infection was investigated in 29 pregnant women with primary HCMV infection by comparing DNA sequences of UL146, UL144 and a portion of UL55 gene of HCMV strains circulating within each family. Thirteen families were identified in which the pregnant woman, the husband and/or a child were shedding HCMV. In three of these families, both the woman and the husband suffered from a concomitant primary HCMV infection.

Maternal, fetal and neonatal diagnosis of congenital human cytomegalovirus infection.

Background: The socio-economic burden associated with congenital human cytomegalovirus (HCMV) infection is well recognized. Nevertheless, women are neither informed nor tested for HCMV antibody, and in the absence of screening, HCMV infections proceed mostly undiagnosed during pregnancy.

Methods: Knowledge has accumulated concerning both the natural history of HCMV infection and the availability of diagnostic tests.

Human cytomegalovirus (HCMV) DNAemia in the mother at amniocentesis as a risk factor for iatrogenic HCMV infection of the fetus.

To investigate whether invasive procedures performed in the presence of human cytomegalovirus (HCMV) DNA in maternal peripheral blood (HCMV DNAemia) represent a risk for iatrogenic transmission of HCMV infection to the fetus, 194 pregnant women undergoing prenatal diagnosis because of a primary HCMV infection and their 199 fetuses were investigated. Overall, 27 (37%) of 73 mothers of uninfected fetuses and 22 (37%) of 59 mothers of infected fetuses were HCMV DNAemia-positive at amniocentesis. Of the 8 mothers of the 8 fetuses with false-negative amniocentesis results, 4 were DNAemia-positive and 4 were DNAemia-negative at amniocentesis.

Cytomegalovirus (CMV) IE1- and pp65-specific CD8+ T cell responses broaden over time after primary CMV infection in infants.

Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in young children. We have previously shown that CD8+ T cell responses to CMV pp65 or IE1 protein were readily detectable in children with congenital or postnatal CMV infection. Here, we have further characterized the evolution of the peptide specificity of these responses in 7 infants<6 months of age at the start of the study.

Development of human cytomegalovirus-specific T cell immunity during primary infection of pregnant women and its correlation with virus transmission to the fetus.

Objective: We sought to study the development of human cytomegalovirus (HCMV)-specific T cell-mediated immune responses during primary HCMV infection in pregnancy.

Methods: The HCMV-specific lymphoproliferative response (LPR) and intracellular cytokine (interferon [IFN]- gamma and interleukin [IL]-2) production were investigated during the first year after primary infection in 49 pregnant women and 9 nonpregnant control subjects. An HCMV-specific CD4(+) and CD8(+) T cell LPR was detected by the 5,6-carboxyfluorescein diacetate succinimidyl ester dilution method, and a cell-division index was calculated.

Preconceptional primary human cytomegalovirus infection and risk of congenital infection.

The risk of vertical transmission of human cytomegalovirus (HCMV) was investigated in 14 women who had primary HCMV infection 2-18 weeks before their last menstrual period during 2001-2004. One (8.3%) of 12 newborns examined at birth was found to be subclinically infected.

Lymphoproliferative response in primary human cytomegalovirus (HCMV) infection is delayed in HCMV transmitter mothers.

Background: The T cell-mediated immune response to human cytomegalovirus (HCMV) after primary infection, as well as the determinants of intrauterine transmission, are poorly understood.

Methods: Sequential peripheral blood leukocyte samples from 74 pregnant women and 29 nonpregnant individuals with primary infection were examined for HCMV-specific CD4+ T cells by cytokine flow cytometry (CFC) and lymphoproliferative response (LPR) analysis. Immunological results for 19 transmitter and 21 nontransmitter mothers were compared.