Congenital cytomegalovirus infection: patterns of fetal brain damage

Gabrielli, Liliana; Bonasoni, Maria Paola; Santini, Donatella; Piccirilli, Giulia; Chiereghin, Angela; Petrisli, Evangelia; Dolcetti, Riccardo; Guerra, Brunella; Piccioli, Milena; Lanari, Marcello; Landini, Maria Paola; Lazzarotto, Tiziana

doi:10.1111/j.1469-0691.2012.03983.x

Cited by 105 publications

(126 citation statements)

References 27 publications

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“…Viral load in placentas was determined as described previously. 15 CD3+, CD4+, CD8+, CD56+, and CD19+ lymphocyte counts were determined at each study visit. Surface phenotype (in the case of CD4+ and CD8+ lymphocytes) as well as interferon-γ-producing CMV-specific T cells were determined retrospectively by means of flow cytometry, as described previously.…”

Section: Laboratory Testsmentioning

confidence: 99%

A Randomized Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus

Revello¹,

et al. 2014

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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\ud 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. A total of 124 pregnant women with primary\ud CMV infection at 5 to 26 weeks of gestation were randomly assigned within 6 weeks after the presumed onset of infection to receive hyperimmune globulin or placebo every 4 weeks until 36 weeks of gestation or until detection of CMV in amniotic fluid. The primary end point was congenital infection diagnosed at birth\ud or by means of amniocentesis. Results: A total of 123 women could be evaluated in the efficacy analysis (1 woman in the\ud placebo group withdrew). The rate of congenital infection was 30% (18 fetuses or infants of 61 women) in the hyperimmune globulin group and 44% (27 fetuses or infants of 62 women) in the placebo group (a difference of 14 percentage points; 95% confidence interval, −3 to 31; P = 0.13). There was no significant difference\ud between the two groups or, within each group, between the women who transmitted the virus and those who did not, with respect to levels of virus-specific antibodies, T-cell–mediated immune response, or viral DNA in the blood. The clinical\ud outcome of congenital infection at birth was similar in the two groups. The number of obstetrical adverse events was higher in the hyperimmune globulin group than in the placebo group (13% vs. 2%). Conclusions: In this study involving 123 women who could be evaluated, treatment with hyperimmune globulin did not significantly modify the course of primary CMV infection during pregnancy. (Funded by Agenzia Italiana del Farmaco; CHIP ClinicalTrials.gov number, NCT00881517; EudraCT no. 2008-006560-11.

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Section: Laboratory Testsmentioning

confidence: 99%

A Randomized Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus

Revello¹,

et al. 2014

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“…Histological studies of tissue from fetuses and infants with fatal congenital HCMV have demonstrated mononuclear cell (MNC) infiltrates in the CNS, suggesting that host inflammatory responses contribute to the pathogenesis of infection (11,(23)(24)(25). Moreover, these studies also described a limited number of virus-infected cells within the CNS, indicating that virus-induced cellular cytopathology cannot account for the global and, importantly, the symmetric involvement of the brain in congenitally infected infants (11,(23)(24)(25).…”

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confidence: 99%

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

Seleme

Kosmac

Jonjić³

et al. 2017

J Virol

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Congenital human cytomegalovirus (HCMV) infection is a significant cause of abnormal neurodevelopment and long-term neurological sequelae in infants and children. Resident cell populations of the developing brain have been suggested to be more susceptible to virus-induced cytopathology, a pathway thought to contribute to the clinical outcomes following intrauterine HCMV infection. However, recent findings in a newborn mouse model of the infection in the developing brain have indicated that elevated levels of proinflammatory mediators leading to mononuclear cell activation and recruitment could underlie the abnormal neurodevelopment. In this study, we demonstrate that treatment with tumor necrosis factor alpha (TNF-␣)-neutralizing antibodies decreased the frequency of CD45 ϩ Ly6C hi CD11b ϩ CCR2 ϩ activated myeloid mononuclear cells (MMCs) and the levels of proinflammatory cytokines in the blood and the brains of murine CMVinfected mice. This treatment also normalized neurodevelopment in infected mice without significantly impacting the level of virus replication. These results indicate that TNF-␣ is a major component of the inflammatory response associated with altered neurodevelopment that follows murine CMV infection of the developing brain and that a subset of peripheral blood myeloid mononuclear cells represent a key effector cell population in this model of virus-induced inflammatory disease of the developing brain.IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the most common viral infection of the developing human fetus and can result in neurodevelopmental sequelae. Mechanisms of disease leading to neurodevelopmental deficits in infected infants remain undefined, but postulated pathways include loss of neuronal progenitor cells, damage to the developing vascular system of the brain, and altered cellular positioning. Direct virus-mediated cytopathic effects cannot explain the phenotypes of brain damage in most infected infants. Using a mouse model that recapitulates characteristics of the brain infection described in human infants, we have shown that TNF-␣ plays a key role in brain inflammation, including recruitment of inflammatory mononuclear cells. Neutralization of TNF-␣ normalized neurodevelopmental abnormalities in infected mice, providing evidence that virus-induced inflammation is a major component of disease in the developing brain. These results suggest that interventions limiting inflammation associated with the infection could potentially improve the neurologic outcome of infants infected in utero with HCMV.

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“…In the present study, hearing problems was not detected among neurological manifestations in symptomatic HCMV infected neonates. A large number of hearing problems that result from HCMV infection was detected at school age (39) , which may be attributed to misdiagnosis of hearing problems among neonates in this study. Petechial rash was described in 20% of the symptomatic HCMV infected neonates, which was found to be lower than those recorded by others: 33.3% and 32% (40) .…”

Section: Discussionmentioning

confidence: 95%

Human Cytomegalovirus Infection Among Neonates With Symptomatic Congenital Infections and Birth Defects

علوان¹,

عارف²,

الصفار³

et al. 2016

IJMS

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Congenital cytomegalovirus infection: patterns of fetal brain damage

Cited by 105 publications

References 27 publications

A Randomized Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus

A Randomized Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

Human Cytomegalovirus Infection Among Neonates With Symptomatic Congenital Infections and Birth Defects

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