Mary L. Kumar

Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: Results of a phase I/II trial

BACKGROUND Neonatal herpes simplex virus (HSV) infections limited to the skin, eyes and mouth (SEM) can result in neurologic impairment. A direct correlation exists between the development of neurologic deficits and the frequency of cutaneous HSV recurrences. Thus, the National Institutes of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted a Phase I/II trial of oral acyclovir therapy for the suppression of cutaneous recurrences after SEM disease in 26 neonates. METHODS Infants < or = 1 month of age with virologically confirmed HSV-2 SEM disease were eligible for enrollment. Suppressive oral acyclovir therapy (300 mg/m2/dose given either twice daily or three times per day) was administered for 6 months. RESULTS Twelve (46%) of the 26 infants developed neutropenia (< 1000 cells/mm3) while receiving acyclovir. Thirteen (81%) of the 16 infants who received drug 3 times per day experienced no recurrences of skin lesions while receiving therapy. In comparison, a previous Collaborative Antiviral Study Group study found that only 54% of infants have no cutaneous recurrences in the 6 months after resolution of neonatal HSV disease if oral acyclovir suppressive therapy is not initiated. In one infant, HSV DNA was detected in the cerebrospinal fluid during a cutaneous recurrence, and an acyclovir-resistant HSV mutant was isolated from another patient during the course of the study. CONCLUSIONS Administration of oral acyclovir can prevent cutaneous recurrences of HSV after neonatal SEM disease. The effect of such therapy on neurologic outcome must be assessed in a larger, Phase III study. As such, additional investigation is necessary before routine use of suppressive therapy in this population can be recommended.

A prospective randomized double-blind study to evaluate the effect of dexamethasone in acute laryngotracheitis

To determine whether a single dose of dexamethasone (0.6 mg/kg) is useful in the treatment of acute laryngotracheitis (croup), 29 hospitalized patients with acute laryngotracheitis were randomly assigned in a double-blind fashion to receive either parenterally administered dexamethasone (n = 16) or a saline placebo (n = 13). Severity of the illness was assessed by a clinical croup score based on retractions, stridor, air entry, cyanosis, and level of consciousness. Twelve hours from the time of injection, the patients receiving the dexamethasone had a statistically significant decline in median croup score from 4.5 to 1.0 (p less than 0.001), whereas the patients receiving the placebo did not. By 24 hours, a decline of two or more points in the total croup score was noted in 85% of the patients in the dexamethasone group compared with 33% of the patients in the placebo group (p = 0.027). During this same period, only 19% of patients receiving dexamethasone required two or more racemic epinephrine treatments in comparison with 62% of patients who received the placebo (p less than 0.05). There was no statistical difference between the two groups in improvement in oxygen saturation, respiratory rates, or duration of hospitalization. We conclude that dexamethasone is beneficial in reducing the overall severity of moderate to severe acute laryngotracheitis during the first 24 hours after injection.

Congenital and postnatally acquired cytomegalovirus infections: Long-term follow-up

To determine long-term outcome of children with inapparent congenital cytomegalovirus infection, an assessment of congenitally infected children observed since birth was undertaken. Children with early postnatal acquisition of CMV infection were also evaluated. Cognitive, behavioral, neurologic, audiometric, and speech and language evaluations were performed in 48 patients, including 17 congenitally infected children, 10 children with postnatal infection, and 21 uninfected control subjects. Mean IQ of the three groups of children did not differ significantly. Behavioral, neurologic, speech and language examinations similarly failed to distinguish differences among the three groups. Audiologic abnormalities were present in four congenitally infected children, including one child with a severe unilateral sensorineural loss; in none of the children was hearing loss functionally significant. No hearing abnormalities were detected in postnatally infected children. Although inapparent CMV infection can result in audiologic sequelae, the continued lack of cognitive, behavioral, and neurologic sequelae in these school-age children reemphasizes the need to focus attention on prevention of primary maternal CMV infection to avoid the potentially devastating effects of intrauterine CMV infection.

Inapparent congenital cytomegalovirus infection. A follow-up study.

Abstract A follow-up study on 15 children with congenital cytomegalovirus infection was undertaken to assess physical and mental development in their first four years of life. Infection was inapparent at birth in all children except one. Assessment included a complete physical examination, psychologic testing and virologic studies. None of the children who appeared normal at birth and at one year manifested any late sequelae at four years of age. The mean IQ of the infected children was 85.2, whereas that of the eight controls was 86.5. Eleven of the 15 children (73 per cent) were excreting virus; nine of these had detectable cytomegalovirus complement-fixing antibody. All seven males tested had viruria, as compared to four out of eight females (p<0.05). Complement-fixation titers in virus-negative children were not significantly different from titers in virus-positive children. (N Engl J Med 288:1370–1372, 1973)

Antibody persistence after primary measles-mumps-rubella vaccine and response to a second dose given at four to six vs. eleven to thirteen years.

BACKGROUND Since 1989 the American Academy of Pediatrics and the ACIP have recommended a second dose of measles-mumps-rubella vaccine (M-M-R-II) at either school entry or age 11 to 13 years. Unfortunately few studies are available to compare responses to vaccine at the two ages. We performed a prospective trial to determine the persistence of antibody to measles, mumps and rubella vaccination in two age groups and the response to a second dose given at either 4 to 6 or 11 to 13 years. METHODS Thirty-eight children 4 to 6 years old and 57 children 11 to 13 years old were given a second dose of M-M-R-II as they presented for yearly examinations. All had received the first dose at > or = 15 months of age. Measles and rubella antibody were measured by enzyme-linked immunosorbent assay (ELISA) and neutralizing antibody (NT) assay, and mumps antibody was measured by an ELISA method only. An IgM-ELISA antibody assay for measles was used in selected children. Prevaccination and 3- to 4-week post-vaccination sera were obtained. Measles ELISA, measles-neutralizing antibody (NT) and rubella-neutralizing antibody (NT) assays were performed in all children. Seventy-nine of the 95 children had sufficient sera for repeat measles tests, as well as mumps and rubella ELISA determinations. RESULTS Before the second dose ELISA seropositivity rates for measles and mumps were not significantly different between the two groups. Rubella ELISA seropositivity was 67% in 11- to 13-year-olds, compared with 90% in 4- to 6-year-olds (P < 0.01), suggestive of waning immunity. Rubella NT seropositivity was also lower in 11- to 13-year-olds than in 4- to 6-year-olds (63% vs. 100%, P < 0.01). After revaccination, 100% of the children become seropositive for all 3 antibodies. We performed measles IgM-ELISA testing on all 17 measles-seronegative children, as well as 15 seropositive children and 19 children who were 1 month postvaccination with the first M-M-R-II at 15 months. The purpose was to determine whether the seronegative children were primary or secondary failures. Five of the 17 children with undetectable pre-second dose antibody made IgM measles antibody after revaccination, suggesting that they were primary vaccine failures. CONCLUSIONS Because all children became seropositive after revaccination, the age of administration can be based on the convenience of vaccine scheduling. However, in view of the apparent decline in rubella antibodies at 11 to 13 years, future studies of rubella vaccination should address the issue of whether earlier boosting leads to greater susceptibility at the time of reproductive age.

Postnatally acquired cytomegalovirus infections in infants of CMV-excreting mothers

A prospective study of cytomegalovirus-excreting pregnant women allowed us to identify a group of infants at high risk of acquiring CMV infection. Eighty-one infants free of CMV infection at birth were observed during the first year of life. Twenty-one became infected with CMV; 16 (76%) of these were detected within the first 14 weeks of life. Placental cultures from two of the 21 infants were CMV positive. The geometric mean cord blood antibody titers of postnatally infected and uninfected infants did not differ significantly. Clinical symptoms, including hepatosplenomegaly, lymphadenopathy, or pneumonia, occurred in association with CMV infection in seven infants. Postnatally acquired CMV infections can be symptomatic, and by virtue of their prevalence, constitute an important health problem.

A prospective study of maternal cytomegalovirus infection and its effect on the fetus

In order to define the effects of maternal cytomegalovirus infection in pregnancy and to identify risk factors associated with delivery of a cytomegalovirus-infected infant, a cohort of 1089 adolescents were prospectively evaluated during pregnancy. One hundred twenty-four subjects (11.4%) manifested cytomegaloviruria during pregnancy. Primary cytomegalovirus infection, defined virologically and serologically, occurred in three subjects. Infants of 119 cytomegalovirus-excreting mothers were cultured at birth, with detection of 12 congenital infections (10%), including one infant delivered of a mother with a third-trimester primary infection. A high titer of urinary virus or a fourfold or greater increase in antibody during the third trimester was significantly associated with delivery of a congenitally infected infant. All maternal and infant infections were asymptomatic. None of the congenitally infected infants manifested adverse effects during the first year of life. Our data demonstrate that pregnant women with cytomegaloviruria are at increased risk of being delivered of congenitally infected infants, particularly if active infection occurs late in pregnancy. If the maternal infection represents reactivation, overall probability of a poor fetal outcome is low.

Should all pregnant women be screened for hepatitis B

To assess the sensitivity of historical risk factors for identification for hepatitis B surface antigen (HBsAg)-positive parturients, 4399 pregnant women were consecutively screened for HBsAg. Information regarding risk for hepatitis B infection was obtained from each HBsAg-positive parturient. Twenty-three HBsAg-positive subjects were identified (5.2/1000 deliveries). The HBsAg carrier rate (18/2231, or 8.1/1000 deliveries) was significantly higher in women of black, Asian, or Hispanic origin than in the remaining ethnic groups (non-Hispanic whites plus all others, 5/2168, or 2.3/1000 deliveries) (chi square, 5.95; p = 0.016). Risk factors for identification of HBsAg-positive women were present in 10 of 22 asymptomatic subjects (sensitivity, 45%; 95% confidence interval, 24% to 68%). Much of the information required to assess one of these risk factors, previous infection, involved detailed questioning and is unlikely to be obtained in the context of conventional obstetrical care. Routine maternal HBsAg screening programs may be needed if transmission of hepatitis B from mother to infant is to be prevented.

Respiratory syncytial virus-specific immunoglobulins in preterm infants

Incomplete transfer of maternal antibodies specific to respiratory syncytial virus (RSV) has been suggested as an explanation for the increased risk of RSV infections in preterm infants. Antibodies directed against the two major RSV envelope glycoproteins, F and G, are protective in vitro and in vivo. Our study was conducted to measure IgG, IgG1, IgG2, and IgG3 antibody titers against the RSV F and G glycoproteins in cord sera from infants born at different gestational ages. Titers of neutralizing antibody were measured in a subset of the subjects. The mean (+/- SEM) log2 titers of IgG antibodies directed against the RSV F and G glycoproteins were significantly lower in infants born at < or = 28 weeks of gestation (11.2 and 10.8 for F and G glycoproteins, respectively) than in term infants (12.6 and 12.8 for F and G, respectively) (p < 0.05). Preterm infants born at > or = 29 weeks had titers of antibodies against the F glycoprotein comparable to those of term infants. The highest titers of RSV-specific antibodies were in the IgG1 and IgG2 subclasses. Mean (+/- SEM) neutralizing antibody titers were lower in infants born at < or = 28 weeks (7.7 +/- 0.4) than in term infants (10.2 +/- 0.3) (p < 0.001). We conclude that (1) RSV-specific antibody titers were lower than in term infants only in the most premature infants (< or = 28 weeks) and (2) preterm infants born at > or = 29 or > or = 33 weeks of gestation had RSV-specific titers against F and G glycoproteins, respectively, that were comparable to those of term infants. Preterm infants born at < or = 28 weeks could represent a target population for passive immunoprophylaxis.

Immune response to measles vaccine in 6-month-old infants of measles seronegative mothers.

Determinants of measles vaccine-induced immune response in infancy include maternal immune status and the infants age at immunization. In a previously published study, 74% of 19 6-month-old infants developed neutralizing antibody. Two of the infants were born to measles seronegative mothers. In order to (1) assess the prevalence of measles seronegativity in a population of US mothers born after 1960 and (2) assess the immunogenicity of standard titer measles vaccine in 6-month-old infants of measles seronegative mothers, mothers with healthy term (> or = 37 weeks gestation) infants attending well child care clinics at MetroHealth Medical Center were prospectively screened for measles antibody by EIA. If negative, maternal samples were retested for neutralization (NT) antibody. Fifteen of 169 women were seronegative by both assays. Six-month-old infants of 9 of these 15 seronegative mothers were enrolled in the pediatric vaccine study. Serological response of these 9 infants to monovalent measles vaccine (Attenuvax) was compared to the responses of 17 6-month-old infants of seropositive mothers and 15 15-month-old toddlers from our previous study. All 9 infants of seronegative mothers became EIA seropositive after the vaccine compared to 9 of 17 6-month-old infants born to seropositive mothers (p = 0.02). Differences in NT seroconversion rates (100% vs 70.6%) were not statistically significant. The comparison group of 15-month-old vaccinees showed 100% seroconversion by both assays. The NT geometric mean titer (GMT) was higher in the 15-month-old toddlers than in the 6-month-old infants born to seronegative mothers (87.2 vs 33.9, p < 0.01), suggesting age-related differences in humoral immune response unrelated to passively transferred maternal antibody.