Congenital and perinatal cytomegalovirus infections.
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Biomedical subjects
Publications and source records attributed to S Stagno.
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Of unselected postpartum women, 39% reactivated cytomegalovirus in breast milk, vaginal secretions, urine, and/or saliva. Consumption of infected breast milk led to infection of 69% of the infants. Although there was some milk secretory immune response to this virus, it prevented neither viral shedding nor viral transmission. All infected infants chronically shed cytomegalovirus. However, no infants have yet demonstrated chronic sequelae. Two preterm infants did develop a significantly acute problem, pneumonitis, which did resolve. The possibility that an unnecessary and perhaps more severe illness might occur in low-birth-weight seronegative infants fed banked human milk from sources other than the mother is disturbing and needs resolution.
A 10-year-old girl with a 1-year history of lower genitourinary tract symptoms suggestive of bacterial infection but with numerous negative urine cultures was referred to the University of Alabama urology clinic after empirical treatment with multiple antibiotics failed to resolve her symptoms. An extensive urologic evaluation revealed no structural or physiologic abnormalities, but an exudative vaginitis was noted and large numbers of Ureaplasma urealyticum and Mycoplasma hominis were isolated from the lower genital tract. Cultures for Chlamydia, viruses, and routine bacterial pathogens were negative. After initiation of tetracycline therapy, symptoms resolved and subsequent cultures for mycoplasmas were negative. In addition, a seroconversion was noted for M hominis but not for U urealyticum. Chlamydia serology was negative. It was later learned that the patient had been sexually molested just prior to the onset of symptoms. This case illustrates the necessity of early consideration of a mycoplasmal etiology in the patient with persistent genitourinary symptoms and no obvious bacterial pathogen, or in the patient whose condition is refractory to routine antibiotic therapy.
We studied the incidence of primary and recurrent cytomegalovirus infection in 3712 pregnant women--2698 of middle to high income and 1014 of low income--to determine whether there were differences in the effects on the fetus. In the higher-income group, 1203 women (45 per cent) did not have antibodies to cytomegalovirus and were therefore susceptible to primary infection, as compared with 179 women (18 per cent) of low income. Congenital infection occurred more often (1.6 vs. 0.6 per cent) in infants in the low-income group. In this group it was associated with recurrent maternal infection more often (in 82 per cent) than with primary maternal infection, whereas in the upper-income group, it was associated with primary maternal infection in half the cases. Altogether, there were 32 cases of congenital cytomegalovirus infection - 16 in each group. Whereas primary maternal infection resulted in fetal infection in only half the cases, it was more likely to ge associated with clinically apparent disease than was recurrent infection. When these cases were combined with 28 cases of congenital infection retrospectively identified at other prenatal clinics, five of 33 infected infants born after primary maternal infection had clinically apparent disease, as compared with none of 27 born after recurrent maternal infection. We conclude that congenital cytomegalovirus infection resulting from primary maternal infection is more likely to be serious than that resulting from recurrent infection, and is more likely to occur in upper socioeconomic groups.
A Chilean population was compared to low-income and middle/upper-class populations in Birmingham, Ala., with regard to prevalence of congenital cytomegalovirus infection as well as the importance of this infection in neonatal deaths. In the highly seroimmune Chilean (98%) and low-income Birmingham (82%) groups, congenital infections occurred more often (1.7% and 1.9%, respectively) than in the less immune (56%) middle/upper-income group in Birmingham (0.6%). In 407 autopsies reviewed in Chile no neonatal deaths were attributed to cytomegalic inclusion disease, whereas in Birmingham cytomegalovirus was the cause of death in nine of 938 (1%) newborn infants. These findings further support the concept that, despite an apparent lack of protection against intrauterine transmission, maternal immunity reduces the risk of severe fetal infection.
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Specific IgM antibodies that persisted for up to four months were detected by radioimmunoassay (RIA) in the sera of 16 (55%) of 29 women with primary infections due to cytomegalovirus (CMV). The RIA for IgM detected primary infections in six (86%) of seven sera obtained within four months of seroconversion. In contrast, IgM antibodies were never detected by RIA in 104 serum samples from 18 women with recurrent infections due to CMV, irrespective of whether intrauterine transmission of virus had occurred. Specific IgM antibodies were also detected in the earliest samples during pregnancy of serum from three (14%) of 21 women whose type of infection with CMV was unknown but who had been delivered of congenitally infected infants. All of these results show that primary infection with CMV in the first trimester of pregnancy can be diagnosed by testing a single serum sample by RIA for IgM antibodies. Attempts to measure IgM antibodies by immunofluorescence gave a high frequency (19 [18%] of 104) of false-positive reactions.
Shedding of cytomegalovirus (CMV) was studied in 142 women who gave birth to congenitally infected infants and in 81 seropositive control mothers (mothers of uninfected infants). Viral cultures from the throat, vagina, and urine were obtained at intervals between one month and nearly 12 years after delivery. In both groups the prevalence of excretion of CMV was greater in younger women and fell to low levels by age 30. Considering all of the sites of infection, 60% of the mothers of infected infants were shedding CMV within the first three months post partum compared with 18% of the control mothers; CMV shedding rates declined during the first 12 months post partum to 35% in the former group and to 3% in the latter. More than three years after delivery, seven (15%) of 45 mothers who transmitted CMV still had viruria. The excretion of CMV is common and persistent in mothers of children with congenital infections due to CMV.
Antibody to varicella-zoster virus was measured in Vero cell cultures by a conventional and an enhanced plaque neutralization test. In the latter, heterologous antibody to human immunoglobulin was added to the virus-serum mixture to potentiate the neutralization reaction. The antibody to human immunoglobulin enhanced the sensitivity of the neutralization test seven- to 107-fold as compared with the conventional procedure. The test was highly reproducible in that individual serum titers fluctuated in a twofold range on repeated testing. A prozone phenomenon was observed in the enhanced neutralization test in low-titered sera, but not with high-titered sera or with specimens of cerebrospinal fluid. The specificity of the test was confirmed by the detection of seroconversion in recipients of live varicella virus vaccine.
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Specific immunoglobulin M antibodies were detected by radioimmunoassay (RIA-IgM) in cord sera from 83/93 (89%) babies congenitally infected with cytomegalovirus (CMV) but in 0/104 cord sera from uninfected control subjects. The type of maternal infection did not affect the ability of the assay to identify congenital infections, but increased RIA-IgM titers were found more frequently in cord sera from babies infected following primary CMV infections (9/18; 50%) than following recurrent CMV infections (1/12; 8%) (P less than .05). The magnitude of the fetal immune response was related to disease inasmuch as 14/40 (35%) babies with increased RIA-IgM titers were symptomatic at birth compared with 1/43 (2%) with lower titers (P less than .001). When combined with the results of testing for rheumatoid factor and total IgM, the RIA-IgM assay defined subgroups of babies with generally poor (7/15; 47% symptomatic at any stage) or generally good (0/21 symptomatic) prognoses. Prospective studies currently identifying cases of congenital CMV infection may wish to use these three serologic techniques as the results obtained appear to have prognostic significance for those babies who are initially asymptomatic.
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The risk of transmission of cytomegalovirus (CMV) infection from congenitally infected infants to nonimmune medical attendants is unknown. The case of a CMV-seronegative, pregnant nurse who seroconverted after caring for an infant with symptomatic CMV infection is reported. She elected to be aborted and the fetal tissue contained CMV. Isolates from the nurse, the fetal tissue, and the infant to whom the nurse was exposed were examined for genetic relatedness by restriction enzyme analysis. As expected, the isolates from the nurse and the fetal tissue were identical. However, the virus isolated from the symptomatic infant was different from the strain infecting the nurse. These data indicate that the nurse acquired her infection from a source other than the index infant, either within the hospital or within the community.
The possibility of transmission of cytomegalovirus (CMV) from congenitally infected infants to susceptible medical personnel produces anxiety because the risks have not been defined. A physician conceived her first child while caring for an infant in the intensive care nursery who died with congenital CMV infection. The physician had serologic evidence of active CMV infection confirmed by isolation of virus from multiple sites. She elected to have her pregnancy interrupted. CMV was isolated from the placenta and fetal brain. Restriction enzyme analysis was employed to test all the CMV isolated for genetic relatedness. Virus isolated from the physician and her fetus was identical. The virus from the index nursery infant was different from the strain infecting the physician and her fetus. These data indicate that the physician acquired her virus from a source other than the index infant.
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In an examination of paired sera from pregnant women, 9 of 57 women who had JC virus antibodies in their first specimens exhibited virus reactivation, as judged by a fourfold or greater rise in JC virus hemagglutination-inhibiting antibodies; 43 women remained seronegative through pregnancy. JC virus-specific immunoglobulin M was not demonstrated in umbilical cord sera of six infants born to mothers showing reactivation or in 300 additional umbilical cord sera from normal pregnancies.
Cell-mediated immune responses in 27 infants and children with cytomegalovirus (CMV) infection acquired between birth and 1 year of age were compared with responses in 13 children who had neonatal herpes simplex virus (HSV) infection. Infection was asymptomatic in 25 of 27 CMV-infected children; the 13 patients with HSV infection were all ill as newborns. The median age when studied was 46 months for children infected with CMV and 24 months for those infected with HSV. We measured lymphocyte transformation responses (LTRs) to CMV antigens in the former group and to HSV type 1 (HSV-1) (and in six cases to HSV-2) in the latter group, with the results expressed as a stimulation index. Based on the results in seropositive and seronegative adult control subjects, stimulation indexes of greater than or equal to 3 were considered indicative of a positive LTR. Among the CMV-infected children, a positive LTR was observed in 0 to 13 assays performed before 1 year of age, 3 of 8 assays performed between 1 and 4 years of age, and 9 of 15 assays performed over 4 years of age. In contrast, a positive LTR to HSV-1 was seen in 15 to 18 assays performed in children under 1 year of age and in 14 of 16 assays performed in survivors of neonatal HSV infection older than 1 year. Six HSV-2-infected patients were tested simultaneously 13 times with HSV-1 and HSV-2 antigens. Those patients under 6 months of age responded similarly to each antigen, whereas those who were older had significantly higher LTRs to HSV-2. Children with CMV infection that was acquired early had persistently diminished specific LTRs. In contrast, after neonatal HSV infection, LTRs to HSV were present even in infancy and became more specific for the infecting type with increasing age.