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      Congenital Cytomegalovirus infection: advances and challenges in diagnosis, prevention and treatment

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          Abstract

          Cytomegalovirus (CMV) is the most frequent cause of congenital infection worldwide, with an estimated incidence in developing countries of 0.6–0.7% of all live births. The burden of disease related to congenital CMV in substantial, as it is the leading non-genetic cause of sensorineural hearing loss and an important cause of neurodevelopmental disabilities in children. Despite its clinical significance, congenital CMV infection often goes undetected because the majority of infected infants are asymptomatic at birth and screening programs have not been substantially implemented. Other than behavioral measures, effective interventions aimed at the prevention of maternal infection and of mother-to-child transmission are lacking. Due to a convergence of recent advances in both diagnostic and therapeutic strategies in infants with congenital CMV, though, the field likely will be changing rapidly over just the next few years. Specifically, a highly-sensitive screening test with high throughput potential has been developed, and treatment of infants symptomatically infected with congenital CMV has proven to be well-tolerated and effective in improving long-term hearing and neurodevelopmental outcomes.

          This review highlights the clinical importance of congenital CMV infection, the developments in laboratory diagnostics, and the benefits of antiviral therapy. It also identifies the global efforts still required in the prevention of maternal infection and in the optimization of antiviral therapy to further reduce the burden of congenital CMV disease.

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          Most cited references27

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          Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004.

          BACKGROUND. Congenital cytomegalovirus (CMV) infection causes permanent disabilities in more than 5500 children each year in the United States. The likelihood of congenital infection and disability is highest for infants whose mothers were CMV seronegative before conception and who acquire infection during pregnancy. METHODS. To provide a current, nationally representative estimate of the seroprevalence of CMV in the United States and to investigate trends in CMV infection, serum samples from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 were tested for CMV-specific immunoglobulin G antibody, and results were compared with those from NHANES III (1988-1994). Individuals aged 6-49 years (21,639 for NHANES III and 15,310 for NHANES 1999-2004) were included. RESULTS. For NHANES 1999-2004, the overall age-adjusted CMV seroprevalence was 50.4%. CMV seroprevalence was higher among non-Hispanic black and Mexican American children compared with non-Hispanic white children and increased more quickly in subsequent age groups. CMV seropositivity was independently associated with older age, female sex, foreign birthplace, low household income, high household crowding, and low household education. Compared with NHANES 1988-1994, the overall age-adjusted CMV seroprevalence for NHANES 1999-2004 was not significantly different. CONCLUSIONS. Many women of reproductive age in the United States are still at risk of primary CMV infection during pregnancy. There is an urgent need for vaccine development and other interventions to prevent and treat congenital CMV. The substantial disparities in CMV risk among seronegative women suggest that prevention strategies should include an emphasis on reaching racial or ethnic minorities and women of low socioeconomic status.
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            Vaccine prevention of maternal cytomegalovirus infection.

            Congenital infection with cytomegalovirus (CMV) is an important cause of hearing, cognitive, and motor impairments in newborns. In this phase 2, placebo-controlled, randomized, double-blind trial, we evaluated a vaccine consisting of recombinant CMV envelope glycoprotein B with MF59 adjuvant, as compared with placebo. Three doses of the CMV vaccine or placebo were given at 0, 1, and 6 months to CMV-seronegative women within 1 year after they had given birth. We tested for CMV infection in the women in quarterly tests during a 42-month period, using an assay for IgG antibodies against CMV proteins other than glycoprotein B. Infection was confirmed by virus culture or immunoblotting. The primary end point was the time until the detection of CMV infection. We randomly assigned 234 subjects to receive the CMV vaccine and 230 subjects to receive placebo. A scheduled interim analysis led to a stopping recommendation because of vaccine efficacy. After a minimum of 1 year of follow-up, there were 49 confirmed infections, 18 in the vaccine group and 31 in the placebo group. Kaplan-Meier analysis showed that the vaccine group was more likely to remain uninfected during a 42-month period than the placebo group (P=0.02). Vaccine efficacy was 50% (95% confidence interval, 7 to 73) on the basis of infection rates per 100 person-years. One congenital infection among infants of the subjects occurred in the vaccine group, and three infections occurred in the placebo group. There were more local reactions (pain, erythema, induration, and warmth) and systemic reactions (chills, arthralgias, and myalgias) in the vaccine group than in the placebo group. CMV glycoprotein B vaccine has the potential to decrease incident cases of maternal and congenital CMV infection. (ClinicalTrials.gov number, NCT00125502.) 2009 Massachusetts Medical Society
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              Passive immunization during pregnancy for congenital cytomegalovirus infection.

              Currently, there is no effective intervention for a primary cytomegalovirus (CMV) infection during pregnancy. We studied pregnant women with a primary CMV infection. The therapy group comprised women whose amniotic fluid contained either CMV or CMV DNA and who were offered intravenous CMV hyperimmune globulin at a dose of 200 U per kilogram of maternal weight. A prevention group, consisting of women with a recent primary infection before 21 weeks' gestation or who declined amniocentesis, was offered monthly hyperimmune globulin (100 U per kilogram intravenously). In the therapy group, 31 women received hyperimmune globulin, only 1 (3 percent) of whom gave birth to an infant with CMV disease (symptomatic at birth and handicapped at two or more years of age), as compared with 7 of 14 women who did not receive hyperimmune globulin (50 percent). Thus, hyperimmune globulin therapy was associated with a significantly lower risk of congenital CMV disease (adjusted odds ratio, 0.02; 95 percent confidence interval, -infinity to 0.15; P<0.001). In the prevention group, 37 women received hyperimmune globulin, 6 (16 percent) of whom had infants with congenital CMV infection, as compared with 19 of 47 women (40 percent) who did not receive hyperimmune globulin. Thus, hyperimmune globulin therapy was associated with a significantly lower risk of congenital CMV infection (adjusted odds ratio, 0.32; 95 percent confidence interval, 0.10 to 0.94; P=0.04). Hyperimmune globulin therapy significantly (P<0.001) increased CMV-specific IgG concentrations and avidity and decreased natural killer cells and HLA-DR+ cells and had no adverse effects. Treatment of pregnant women with CMV-specific hyperimmune globulin is safe, and the findings of this nonrandomized study suggest that it may be effective in the treatment and prevention of congenital CMV infection. A controlled trial of this agent may now be appropriate. Copyright 2005 Massachusetts Medical Society.
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                Author and article information

                Contributors
                +39.051.342754 , conce.marsico@gmail.com
                dkimberlin@peds.uab.edu
                Journal
                Ital J Pediatr
                Ital J Pediatr
                Italian Journal of Pediatrics
                BioMed Central (London )
                1824-7288
                17 April 2017
                17 April 2017
                2017
                : 43
                : 38
                Affiliations
                [1 ]Department of Medical and Surgical Sciences, Neonatology and Neonatal Intensive Care Unit, St.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 11, 40138 Bologna, Italy
                [2 ]ISNI 0000000106344187, GRID grid.265892.2, Department of Pediatrics, Division of Pediatric Infectious Diseases, , University of Alabama at Birmingham, ; Children’s Harbor Building 303, 1600 7th Avenue South, Birmingham, AL 35233 USA
                Author information
                http://orcid.org/0000-0001-5258-9417
                Article
                358
                10.1186/s13052-017-0358-8
                5393008
                28416012
                05ebbc61-2cbe-4c00-a821-9806769e92cd
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 27 March 2017
                : 8 April 2017
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases, National Institutes of Health
                Award ID: N01-AI-30025
                Funded by: National Institute of Allergy and Infectious Diseases, National Institutes of Health
                Award ID: HHSN272201100035C
                Funded by: National Institute of Allergy and Infectious Diseases, National Institutes of Health
                Award ID: HHSN2722016000017C
                Categories
                Review
                Custom metadata
                © The Author(s) 2017

                Pediatrics
                congenital cytomegalovirus,hearing loss,mother-to-child transmission,neonatal screening,antiviral therapy

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