Congenital cytomegalovirus (CMV) infections is the leading infectious cause of brain damage and the lading cause of sensorineural hearing loss (SNHL) in children in the U.S. The pathogenic factors that contribute to sequelae in children with congenital CMV infection are poorly understood. The objective of the proposed studies to delineate the mechanism of neurologic damage from this intrauterine infection. SNHL offers a convenient, readily available and important endpoint that can be objectively measured in the studies of pathogenesis and intervention. The fact that the majority of children with SNHL from congenital CMV infection exhibit postnatal progression of the deficit suggests that pathogenic events affecting hearing are occurring during early childhood. We propose that increased CMV viral burden contributes significantly to the development of sequelae such as SNHL. We also postulate that children with delayed onset and progressive hearing loss have an increased virus burden and higher levels of viral replication in the postnatal period. This hypothesis will be tested by investigating the association between measures of systemic viral burden and outcome in children with congenital CMV infection. More specifically, the role of viral load in progressive herring loss will be examined. The study subjects include children born at The University of Alabama Hospital who will screen positive for CMV on newborn virologic screening and those infants with congenital CMV infection who will be evaluated by the investigators. The enrolled subjects will be followed for a period of 3 years with regular audio-logic evaluations and samples collected (urine and blood) for viral load measurements. The virus burden will be measured by titering viruria and quantitating CMV DNA in serial peripheral blood samples from the study children. Alternatively, an immune mediated injury to highly specialized cells of the inner ear could result in SNHL. An analysis of the systemic measures of antiviral antibody and cellular immune responses in serial samples from the study children will examine this possibility. The association between viral load and virus specific immune responses will also be examined. An antiviral therapy protocol using 2 weeks of IV gangiclovir followed by 6 months of oral ganciclovir is proposed to further investigate the pathogenesis of congenital CMV infection during years 4 and 5. This protocol will allow us to test the hypothesis of increased viral load contributing to progressive SNHL by determining the effect of prolonged antiviral therapy on viral load and outcome. The results of the pathogenesis studies during the first three years could permit a better selection of children at increased risk for sequelae. Project 3 contributes to the overall goals of the program by providing knowledge of the pathogenesis of congenital CMV infection which is essential for formulation of strategies to prevent long-term neurologic morbidity associated with congenital CMV infection and thus, could provide significant public health benefit.

Project Start
1999-09-01
Project End
2000-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Pinninti, Swetha G; Rodgers, Mackenzie D; Novak, Zdenek et al. (2016) Clinical Predictors of Sensorineural Hearing Loss and Cognitive Outcome in Infants with Symptomatic Congenital Cytomegalovirus Infection. Pediatr Infect Dis J 35:924-6
Dreher, A Mackenzie; Arora, Nitin; Fowler, Karen B et al. (2014) Spectrum of disease and outcome in children with symptomatic congenital cytomegalovirus infection. J Pediatr 164:855-9
Hackett, Daniel J; Zhang, Changpin; Stefanescu, Carla et al. (2010) Enzyme-linked immunosorbent assay for measurement of cytomegalovirus glycoprotein B antibody in serum. Clin Vaccine Immunol 17:836-9
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Ross, Shannon A; Novak, Zdenek; Fowler, Karen B et al. (2009) Cytomegalovirus blood viral load and hearing loss in young children with congenital infection. Pediatr Infect Dis J 28:588-92
Ross, Shannon A; Novak, Zdenek; Kumbla, Rekha A et al. (2007) GJB2 and GJB6 mutations in children with congenital cytomegalovirus infection. Pediatr Res 61:687-91
Pass, Robert F; Fowler, Karen B; Boppana, Suresh B et al. (2006) Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome. J Clin Virol 35:216-20
Fowler, Karen B; Boppana, Suresh B (2006) Congenital cytomegalovirus (CMV) infection and hearing deficit. J Clin Virol 35:226-31
Zhang, Changpin; Buchanan, Hannah; Andrews, William et al. (2006) Detection of cytomegalovirus infection during a vaccine clinical trial in healthy young women: seroconversion and viral shedding. J Clin Virol 35:338-42

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