Longitudinal investigation of hearing disorders in children with congenital cytomegalovirus.

This investigation consisted of a longitudinal study of the effects of congenital cytomegalovirus (CMV) infection on hearing sensitivity in 860 children with documented asymptomatic or symptomatic congenital CMV infection. Of the 651 children with asymptomatic CMV infection, 48 (7.4%) developed sensorineural hearing loss (SNHL), compared to 85 (40.7%) of the children with symptomatic CMV infection. Children in both groups experienced latent effects consisting of delayed onset of loss, threshold fluctuations, and/or progressive loss of hearing. It can be concluded that congenital CMV infection is a leading cause of SNHL in children. The late onset and progression of loss necessitates continued monitoring of hearing sensitivity in this population.

Neuropsychological functioning in patients with asymptomatic congenital cytomegalovirus infection.

Congenital cytomegalovirus (CMV) infection has an affinity for the central nervous system and has been implicated in a variety of neurological impairments. Analysis of cognitive functioning in children with asymptomatic congenital CMV infection, however, has revealed no general intellectual deficits. The present study was designed to explore neuropsychological test performance in these children, compared with healthy control subjects, providing data from more sensitive measures of neurocognitive functioning. The sample consisted of 109 children diagnosed with asymptomatic congenital CMV infection and 173 control subjects who were compared on tests measuring various aspects of perceptual and motor functioning, memory, problem solving, and traditional intelligence measures. Young (41NDASH6 yr) control patients performed significantly better on the Full-Scale but not the Verbal or Performance intelligence quotient (IQ) measures than patients with asymptomatic congenital CMV infection, without accompanying consistent neuropsychological performance differences. However, no IQ or neuropsychological differences were found between groups of older children. The present study adds to the existing literature finding no reliable, lasting differences in IQ scores and adds to our knowledge by finding no reliable, lasting differences in neuropsychological test performance.

Effects of antigen dose and immunization regimens on antibody responses to a cytomegalovirus glycoprotein B subunit vaccine.

The purpose of this phase I study was to evaluate the safety and immunogenicity of 2 doses of cytomegalovirus glycoprotein B (CMV gB)/MF59 vaccine at 3 different immunization schedules. Ninety-five volunteers were randomized to 6 groups. Antibodies to gB represent the majority of the CMV-specific neutralizing response. Three groups received 5 microgram of gB antigen combined with MF59 (a proprietary adjuvant) and 3 groups received a 30-microgram dose at 0, 1, and 2 months; 0, 1, and 4 months; or 0, 1, and 6 months. The vaccine was well tolerated, and there was no significant difference in antibody production between the 2 doses. The vaccine induced highest antibody titers when given at 0, 1, and 6 months. A low dose of CMV gB/MF59 may be the preferred dose for future studies.

A subunit cytomegalovirus vaccine based on recombinant envelope glycoprotein B and a new adjuvant.

A phase I randomized, double-blind, placebo-controlled trial was done with a cytomegalovirus (CMV) vaccine based on the envelope glycoprotein, gB, combined with a novel adjuvant, MF59. Participants received CMV gB vaccine with MF59 or CMV gB with alum or placebo at 0, 1, and 6 months. A fourth vaccine was given at 12 months to a subgroup. Levels of neutralizing antibody and antibody to gB 2 weeks after the third dose of vaccine exceeded those in seropositive control subjects. the formulation with MF59 was more immunogenic than that with alum. The optimal dose of gB appeared to be between 5 and 30 microg. The fourth dose produced a prompt rise in antibody level. There were no serious adverse events associated with vaccine. Local and systemic reactions were generally mild and, except for pain at the injection site, occurred with similar frequency in recipients of placebo and CMV vaccine.

Asymptomatic primary cytomegalovirus infection: virologic and immunologic features.

We followed 45 seronegative adolescents for acquisition of cytomegalovirus (CMV); 6 (5 female, 1 male) seroconverted after a median of 7.5 months. All were free of signs and symptoms. CMV was isolated from 32 (59.2%) of 54 urines, 2-80 weeks after infection; viruria was less frequent after 6 months. CMV was isolated from saliva of 3 subjects, vaginal swabs of 2 of 5, and 1 white blood cell (WBC) sample. CMV DNA was detected by polymerase chain reaction in WBCs and plasma from all subjects tested. The proportion of WBC samples with CMV DNAemia was 75%-80% within 16 weeks of infection, declining to 0%-25% after 48 weeks. The rate of plasma DNAemia was 25%-40% at 8-16 weeks, declining with time. IgG antibody to CMV, glycoprotein B (gB), and neutralizing antibody were present after 6-8 weeks. Lymphocyte proliferative responses to CMV and to gB were low, compared with those of controls. CMV shedding was of shorter duration than expected. Although antibody response was prompt and vigorous, CMV DNA could be detected in blood for months.

Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus.

OBJECTIVES: To determine the frequency of symptomatic congenital cytomegalovirus (CMV) infection in the offspring of women with a recurrent maternal CMV infection and to characterize the demographic and newborn findings. METHODS: Study subjects consisted of infants with symptomatic congenital CMV infection identified by a newborn virologic screening program at the University of Alabama Hospital between 1991 and 1997 and were enrolled in a long-term follow-up study. Maternal infections were categorized by an analysis of archival serum specimens collected before pregnancy and at the time of delivery. Demographic data and clinical findings at birth were collected from maternal and newborn hospital records and from parents at the time of initial evaluation. RESULTS: Of the 47 infants with symptomatic congenital CMV infection identified during the study period, 8 were born to mothers with a confirmed nonprimary or recurrent CMV infection. The type of maternal infection could be ascertained in only approximately 43% (20/47) of the children with symptomatic congenital CMV infection born at the University of Alabama Hospital during the study period. There were no significant differences in demographic characteristics of the recurrent infection group and the infants who were born to mothers with either primary CMV infection during pregnancy or unclassified maternal infection. Similarly, the range of severity of clinical abnormalities during the newborn period did not differ in the two groups of children. Furthermore, there were no significant differences in the incidence of sequelae at long-term follow-up in the two groups of children. CONCLUSIONS: Symptomatic congenital CMV infection can occur after a nonprimary or recurrent maternal infection. However, the exact incidence of symptomatic congenital CMV infection among children born to women with preexisting immunity remains to be defined.

Newborn hearing screening: will children with hearing loss caused by congenital cytomegalovirus infection be missed?

OBJECTIVE: To predict whether universal newborn auditory screening will identify most infants with sensorineural hearing loss (SNHL) caused by congenital cytomegalovirus (CMV) infection. STUDY DESIGN: A cohort of 388 children born between 1980 and 1996 at one hospital and identified during the newborn period as having congenital CMV infection received repeated hearing evaluations to assess whether hearing loss had occurred. RESULTS: SNHL was detected in 5.2% of all infants at birth. Late-onset SNHL occurred among the children throughout the first 6 years of life. By the age of 72 months, the cumulative incidence of SNHL was 15.4% in the cohort. Children with clinically apparent disease at birth had significantly more SNHL than children without any apparent disease (22.8% vs 4.0% at 3 months and 36.4% vs 11.3% at 72 months of age). CONCLUSIONS: Universal screening of hearing in neonates will detect less than half of all SNHL caused by congenital CMV infection. Because most infants with congenital CMV infection are without symptoms at birth, these children are unlikely to be recognized as being at risk for SNHL and will not receive further hearing evaluations to detect late-onset hearing loss. A combined approach of universal screening of neonates for hearing, as well as for detection of congenital CMV infection, needs to be considered.

Intellectual assessment of children with asymptomatic congenital cytomegalovirus infection.

The findings of previous studies examining the neurocognitive development of children with clinically inapparent (asymptomatic) cytomegalovirus (CMV) infection have demonstrated mixed results. These studies have generally depended on small sample sizes (i.e., < 50). We examined the intellectual development of children with asymptomatic congenital CMV infection using a sample larger than previous studies. Two hundred and four cases aged 5 to 200 months were compared with 177 uninfected siblings ranging in age from 6 to 203 months. Parents were administered the Developmental Profile, a measure of developmental achievement. Children who were older than 30 months were administered an objective intelligence measure. Results of this study showed that children with asymptomatic congenital CMV infection do not demonstrate intellectual impairment, and that they perform similarly to uninfected siblings. Parents tended to overestimate their child's level of functioning regardless of whether the child had CMV infection.

Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.

Congenital cytomegalovirus (CMV) infection occurs in approximately 1% of newborns in the United States. A phase II evaluation was done of ganciclovir for the treatment of symptomatic congenital CMV infection. Daily doses of 8 or 12 mg/kg were administered in divided doses at 12-h intervals for 6 weeks. Clinical and laboratory evaluations sought evidence of toxicity, quantitative virologic responses in urine, plasma drug concentrations, and clinical outcome. A total of 14 and 28 babies received 8 and 12 mg/kg/day, respectively. Five additional babies received ganciclovir on a compassionate plea basis. Significant laboratory abnormalities included thrombocytopenia (< or = 50,000/mm3) in 37 babies and absolute neutropenia (< or = 500 mm3) in 29 babies. Quantitative excretion of CMV in the urine decreased; however, after cessation of therapy, viruria returned to near pretreatment levels. Hearing improvement or stabilization occurred in 5 (16%) of 30 babies at 6 months or later, indicating efficacy.

Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection.

OBJECTIVE: To determine the prevalence and temporal changes of sensorineural hearing loss (SNHL) among children with clinically inapparent (asymptomatic) congenital cytomegalovirus (CMV) infection identified from a cohort of newborn infants screened for congenital CMV infection. METHODS: The study population consisted of 307 children with documented asymptomatic congenital CMV infection, 76 uninfected siblings of children with asymptomatic congenital CMV infection, and 201 children whose neonatal screen for congenital CMV infection showed negative results. Audiologic evaluations were completed for all children to determine their hearing status. RESULTS: SNHL occurred only in children with congenital CMV infection. Of the children with asymptomatic congenital CMV infection, 22 (7.2%; 95% confidence interval, 4.5% to 10.6%) had SNHL. Among the children with hearing loss, further deterioration of hearing occurred in 50.0%, with the median age at first progression at 18 months (range, 2 to 70 months). Delayed-onset SNHL was observed in 18.2% of the children, with the median age of detection at 27 months (range, 25 to 62 months). Fluctuating SNHL was documented in 22.7% of the children with hearing loss. CONCLUSIONS: Asymptomatic congenital CMV infection is likely a leading cause of SNHL in young children. The continued deterioration of hearing and delayed onset of SNHL in these children emphasizes the need for continued monitoring of their hearing status.

Neuroradiographic findings in the newborn period and long-term outcome in children with symptomatic congenital cytomegalovirus infection.

OBJECTIVE: To determine whether newborn cranial computed tomographic (CT) scan abnormalities predict an adverse neurodevelopmental outcome in children with symptomatic congenital cytomegalovirus (CMV) infection and to examine the association between clinical findings at birth and imaging abnormalities. METHODS: The data from 56 children with symptomatic congenital CMV infection who underwent cranial CT scans as newborns and were enrolled in a long-term follow-up study were analyzed. The incidence of sequelae was compared between the groups of children with normal and abnormal imaging studies. The relationship between CT scan results and other newborn findings was also examined. RESULTS: Abnormal CT scans were noted in 70% of subjects; intracerebral calcification was the most frequent finding. Most of the children with an abnormal newborn CT scan (90%) developed at least one sequela, compared with 29% of those with a normal study. Only 1 child with a normal CT scan had an IQ < 70, in contrast to 59% of those with imaging abnormalities. In addition, almost half of the children with CT abnormalities had an IQ < 50 compared with none of those with a normal CT scan. Newborn CT abnormalities were also associated with an abnormal hearing screen at birth and hearing loss on follow-up. None of the neonatal neurologic findings were predictive of an abnormal CT scan. CONCLUSION: In neonates with symptomatic congenital CMV infection, a cranial CT scan is a good predictor of an adverse neurodevelopmental outcome. In addition, newborn clinical and laboratory findings did not predict neuroradiographic abnormalities in neonates with symptomatic congenital CMV infection.

Immunization strategy for prevention of congenital cytomegalovirus infection.

Women of childbearing age are a logical target for a vaccine aimed at prevention of congenital cytomegalovirus (CMV) infections. However, the impact of a CMV vaccine could likely be enhanced by considering the sources of maternal infection and characteristics of mothers of infected newborns. Contact with preschool-age children and sexual activity are important sources of CMV infection for young women. Approximately half of infants with congenital CMV infection in the U.S. are born to unmarried, adolescent mothers. To prevent CMV infection in those who are the sources of maternal infection as well as in young, unmarried mothers, universal immunization of toddlers and preteen children should be considered.

Hearing loss and congenital symptomatic cytomegalovirus infection: a case report of multidisciplinary longitudinal assessment and intervention.

More than 6000 children born annually in this country have hearing loss resulting from congenital cytomegalovirus (CMV) infection, the leading nonhereditary congenital cause of hearing loss in children. This exemplary congenital symptomatic CMV case focuses on the results of longitudinal audiologic, educational, medical, psychological, and visual evaluations and intervention. Decreased ocular motor control and visual acuity were observed as was bilateral deterioration of hearing from 3 days though 9 years of age. Treatment with dexamethasone and histamine resulted in almost complete reversal of the most recent progression of hearing loss in the left ear.

Infectious causes of hydrops fetalis.

A variety of infectious agents have been associated with nonimmune hydrops fetalis, most notably parvovirus B19, cytomegalovirus, herpes simplex virus, Toxoplasma gondii, and Treponema pallidum. These agents produce hydrops through effects on fetal bone marrow, myocardium, or vascular endothelium. Knowledge of the epidemiology and clinical characteristics of maternal and fetal infection can be used to select a diagnostic approach. Etiologic diagnosis will guide prognosis and the selection of specific chemotherapy.

Safety and immunogenicity of an inactivated hepatitis A vaccine in preschool children.

Young children in day care centers are an important source of hepatitis A virus (HAV) infection. The safety and immunogenicity of an inactivated HAV vaccine was evaluated in 57 children in day care centers. Nonimmune healthy children were given 0.5 mL of vaccine with subsequent doses: group A (28 children), second and third doses 1 and 2 months after the first; group B (29 children), second and third doses at 1 and 6 months. Antibody to HAV was measured before each dose and 8 months after the initial dose. All children developed antibody to HAV. Groups A and B had similar levels of antibody at 2 months; levels were lower in group B before the third dose and higher 8 months after the first dose. Local reactions after vaccination were reported in 17 children (29.8%). Minor systemic side effects that cleared spontaneously were observed in 27 children (47%).

Maternal age and congenital cytomegalovirus infection: screening of two diverse newborn populations, 1980-1990.

Cytomegalovirus (CMV) is the leading cause of congenital viral infection in the United States. To prevent damaging congenital CMV infections, it is necessary to have accurate population estimates of prevalence and to identify maternal factors associated with an elevated risk of congenital infection in the newborn. From 1980 through 1990, 17,163 offspring of predominantly low-income nonwhite women who delivered at a public hospital and 9892 newborns of predominantly mid- to upper-income white women who delivered at a private hospital were screened for congenital CMV infection. Women < 20 years old (adjusted prevalence odds ratio [POR], 4.8; 95% confidence interval [CI], 2.6-8.9) at the public hospital and all nonwhite women (adjusted POR, 1.6; 95% CI, 1.1-2.2) had an increased risk of delivering an infected newborn. Newborns of adolescent women in both populations had the highest prevalence of clinically apparent infection. Offspring of nonwhite low-income adolescents are at greatest risk for congenital CMV infection and more damaging sequelae.

Neonatal screening for congenital cytomegalovirus infection by detection of virus in saliva.

A rapid assay for detection of cytomegalovirus (CMV) in saliva was evaluated as a screening method for congenital infection. Samples of saliva were examined by detection of early antigen fluorescent foci (DEAFF) and standard tissue culture (TC). Results were compared with those from urine DEAFF. CMV was detected in saliva from 31 (1.7%) of 1870 newborns, 26 by DEAFF and TC, 1 by DEAFF alone, and 4 by TC alone. Urine DEAFF was positive in 28 of these 31 newborns. The sensitivities of various tests were saliva TC, 96.8%; saliva DEAFF, 87.1%; and urine DEAFF, 90.3%. A change in transport medium for 825 saliva samples resulted in improved sensitivities: saliva TC and saliva DEAFF, 100%; urine DEAFF, 92.3%. Screening saliva of newborns for CMV appears to be at least as sensitive a method for detecting congenital infection as detection of viruria; saliva can be collected with less difficulty and expense than urine.