Charles A. Alford

The outcome of congenital cytomegalovirus infection in relation to maternal antibody status.

Abstract Background. Intrauterine transmission of cytomegalovirus (CMV) can occur whether a mother has prior immunity or acquires CMV for the first time during pregnancy. The degree of protection afforded an infected infant by the presence of antibody in the mother before conception is uncertain. Methods. We compared the outcomes of CMV-infected infants born to mothers who acquired primary CMV infection during pregnancy (primary-infection group) with those of CMV-infected infants born to mothers with immunity (recurrent-infection group). Screening for viruria identified 197 newborns with congenital CMV infection. Stored serum samples were used to categorize maternal infection as either primary or recurrent. We followed 125 infants from the primary-infection group and 64 from the recurrent-infection group. Serial medical, audiologic, psychometric, and eye examinations were used to identify sequelae of CMV infection. Results. Only infants in the primary-infection group had symptomatic CMV infection at birth...

Vidarabine versus Acyclovir Therapy in Herpes Simplex Encephalitis

We randomly assigned 208 patients who underwent brain biopsy for presumptive herpes simplex encephalitis to receive either vidarabine (15 mg per kilogram of body weight per day) or acyclovir (30 mg per kilogram per day) for 10 days. Sixty-nine patients (33 percent) had biopsy-proved disease; 37 received vidarabine, and 32 acyclovir. The mortality in the vidarabine recipients was 54 percent, as compared with 28 percent in the acyclovir recipients (P = 0.008). Six-month mortality varied according to the Glasgow coma score at the onset of therapy. For scores of greater than 10, 7 to 10, and less than or equal to 6, mortality was 42, 46, and 67 percent in the patients treated with vidarabine, as compared with 0, 25, and 25 percent in those treated with acyclovir. A six-month morbidity assessment using an adapted scoring system revealed that 5 of 37 patients receiving vidarabine (14 percent) as compared with 12 of 32 receiving acyclovir (38 percent) were functioning normally (P = 0.021). Eight vidarabine-treated patients (22 percent) and three acyclovir-treated patients (9 percent) had moderate debility. Patients under 30 years of age and with a Glasgow coma score above 10 had the best outcome with acyclovir treatment. We conclude that acyclovir is currently the treatment of choice for biopsy-proved herpes simplex encephalitis.

Congenital Cytomegalovirus Infection: The Relative Importance of Primary and Recurrent Maternal Infection

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.

Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study.

We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex.Abstract We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex. (N Engl J Med 297:289–294, 1977)

Herpes Simplex Encephalitis: Vidarabine Therapy and Diagnostic Problems

To learn more about the treatment of herpes simplex encephalitis with vidarabine, we conducted an uncontrolled study of 132 patients referred to 22 hospitals because of suspected disease. All had a brain biopsy and were started on vidarabine, but only 75 were diagnosed by isolation of virus from a brain-biopsy specimen. Cumulative mortality in the latter group was 39 per cent at one year. Other than therapy, levels of consciousness and age were the major variables that influenced outcome. Of 23 patients under 30 years of age who were lethargic at the initiation of therapy, two died and 16 returned to normal. Of 26 patients over 30 years of age who were lethargic at the outset, nine died and 10 returned to normal. Semicoma and coma were associated with worse outcomes, especially in older patients. Our data suggest that outcome is improved with treatment; they provide more support for the use of brain biopsy to diagnose the infection and indicate a need for better therapy.

Symptomatic congenital cytomegalovirus infection : neonatal morbidity and mortality

Knowledge of the natural history of symptomatic congenital cytomegalovirus (CMV) infection in the newborn is essential in order to anticipate complications and assess the potential benefit from antiviral therapy. To define the disease course we reviewed data on 106 neonates with symptomatic congenital CMV infection diagnosed and managed by the investigators. Petechiae, jaundice and hepatosplenomegaly were each noted in 70% or more patients. Microcephaly was noted in 54 of 102 (53%) at birth. Elevated alanine aminotransferase, conjugated hyperbilirubinemia and thrombocytopenia were seen in 83, 81 and 77%, respectively. Eighty-six percent had at least two of the manifestations highly suggestive of congenital infection. Platelet count fell to its nadir during the second week of life whereas elevated alanine aminotransferase and direct bilirubin persisted past the first month. In spite of the difficulty in assessing central nervous system function in the newborn, evidence of damage was present in the majority. Seventy-two had microcephaly, poor suck, lethargy/hypotonia or seizures. Abnormal computerized tomographic scan was present in 16 of 20 (80%) and decreased hearing in 20 of 39 (56%). Cerebrospinal fluid protein was greater than 120 mg/dl in 24 of 52 (46%) and this elevation was associated with neurologic abnormalities as well as hearing loss. The mean length of hospital stay was 13 and 22.4 days for term and preterm infants, relatively. Thirteen infants (12%) died during the first 6 weeks of life. Disseminated CMV infection with multiorgan involvement was evident in 7 of 9 at postmortem examination. We conclude that neonates with symptomatic congenital CMV infection have a multi-system disease with significant morbidity and mortality.

Congenital cytomegalovirus infection. Occurrence in an immune population.

The overall prevalence of congenital cytomegalovirus infection among the offspring of a highly immune young female population was 2.4 per cent (23 of 939). To ascertain whether the presence of anticytomegalovirus antibodies protects the developing fetus, we examined the offspring of 239 prospectively studied women. Despite substantial levels of preconceptional antibodies, intrauterine cytomegalovirus infection occured in seven of 208 (3.4 per cent) seroimmune women. Three neonates with congenital infection were born to 31 initially seronegative women. All the congenitally infected infants had subclinical involvement. Maternal humoral immunity may not protect the fetus against congenital cytomegalovirus infection. Neutralization kinetics and restriction enzyme analysis with endonucleases (EcoR-1 and HinD 111) demonstrated antigenic and genetic homology between viral strains isolated from two siblings consecutively infected in utero, indicating that repeat maternal infection with the same virus is transmissible to sequential products of conception.

Adenine Arabinoside Therapy of Biopsy-Proved Herpes Simplex Encephalitis

We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex.Abstract We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex. (N Engl J Med 297:289–294, 1977)

Predictors of Morbidity and Mortality in Neonates with Herpes Simplex Virus Infections

BACKGROUND In a controlled trial comparing acyclovir with vidarabine in the treatment of neonatal herpes simplex virus (HSV) infection, we found no significant difference between the treatments in adjusted mortality and morbidity. Hence, we sought to define for the entire cohort (n = 202) the clinical characteristics that best predicted the eventual outcome in these neonates. METHODS Data were gathered prospectively at 27 centers between 1981 and 1988 in infants less than one month of age who had virologically confirmed HSV infection. We examined the outcomes by multivariate analyses of 24 variables. Disease was classified in one of three categories based on the extent of the involvement at entry into the trial: infection confined to skin, eyes, or mouth; encephalitis; or disseminated infection. RESULTS AND CONCLUSIONS There were no deaths among the 85 infants with localized HSV infection. The mortality rate was significantly higher in the 46 neonates with disseminated infection (57 percent) than in the 71 with encephalitis (15 percent). In addition, the risk of death was increased in neonates who were in or near coma at entry (relative risk, 5.2), had disseminated intravascular coagulopathy (relative risk, 3.8), or were premature (relative risk, 3.7). In babies with disseminated disease, HSV pneumonitis was also associated with greater mortality (relative risk, 3.6). In the survivors, morbidity was most frequent in infants with encephalitis (relative risk, 4.4), disseminated infection (relative risk, 2.1), seizures (relative risk, 3.0), or infection with HSV type 2 (relative risk, 4.9). With HSV infection limited to the skin, eyes, or mouth, the presence of three or more recurrences of vesicles was associated with an increased risk of neurologic impairment as compared with two or fewer recurrences.

Maternal Cytomegalovirus Excretion and Perinatal Infection

Abstract A prospective study of pregnant women revealed cytomegalovirus excretion from urine or cervix in 12 per cent. Increasing rate of infection with advancing gestation, stable antibody titers ...