Humoral and cell-mediated immunity in neonates with herpes simplex virus infection.

Fifty-nine neonates with herpes simplex virus (HSV) infection were evaluated with use of assays for neutralizing antibody (NAb), lymphocyte transformation (LT), alpha interferon production, and virus-specific antibody (immunoblots). Infants with disseminated disease or onset in the first week of life were more likely to lack NAb. Patients treated with vidarabine were more likely than those treated with acyclovir to develop a fourfold rise in NAb titer. Infants with encephalitis showed a broader spectrum of IgG and IgM antibody reactivity against HSV proteins by immunoblotting than did those who had earlier onset of mucocutaneous illness. Only 10 of 33 infants had HSV-specific LT, compared with eight of eight adults with primary HSV. Neonates with positive LT were more likely to show a fourfold rise in NAb titer. In vitro alpha interferon production was diminished in infants, compared with values in adults.

Low risk of herpes simplex virus infections in neonates exposed to the virus at the time of vaginal delivery to mothers with recurrent genital herpes simplex virus infections.

We studied the risk of herpes simplex virus (HSV) infections in neonates exposed to HSV at the time of vaginal delivery to mothers with a history of recurrent genital HSV infections. None of 34 infants exposed to HSV type 2 acquired an HSV infection. On the basis of this sample, the 95 percent confidence limit for the theoretical maximum infection rate is 8 percent. Cord blood or blood obtained during the first two weeks of life was available from 33 of the 34 exposed, uninfected neonates. All 33 of the samples possessed demonstrable neutralizing antibody to HSV type 2, and 79 percent had titers above 1:20. These results were compared with those in a previously studied group of neonates with HSV infections; the latter infants were significantly less likely at the onset of symptoms to have demonstrable neutralizing antibody to HSV type 2 (P = 0.000148) or to have titers above 1:20 (P less than 0.00001). We conclude that given the low attack rate, empirical antiviral therapy is not warranted in all infants of mothers with recurrent genital HSV infection who are exposed to the virus in the birth canal. Our findings suggest that the presence and titer of neutralizing antibody to HSV contribute to the low attack rate.

Failure of antepartum maternal cultures to predict the infant's risk of exposure to herpes simplex virus at delivery.

In 414 pregnant women with a history of recurrent genital herpes simplex infection, we studied the correlation between asymptomatic viral shedding in late pregnancy and at the time of delivery. Antepartum cultures for asymptomatic reactivation of herpes simplex virus were positive in 17 of the 414 women (4.1 percent). None of these women had positive cultures at the time of delivery. Cultures of specimens obtained at delivery from 5 of 354 asymptomatic mother-infant pairs (1.4 percent) were positive for asymptomatic excretion of herpes simplex virus. None of these women had had antepartum cultures that documented asymptomatic excretion of herpes simplex virus, despite the fact that culturing was repeatedly performed during the four weeks before delivery. Asymptomatic shedding of herpes simplex virus occurred with the same frequency at delivery, whether or not any episodes of symptomatic recurrence were noted during the pregnancy (1.4 vs. 1.3 percent). We conclude that antepartum maternal cultures do not predict the infant's risk of exposure to herpes simplex virus at delivery.

Sequelae of acquired cytomegalovirus infection in premature and sick term infants.

To assess the risk of long-term sequelae after acquired cytomegalovirus (CMV) infection in premature and sick term infants, 55 CMV infected patients were matched prospectively with 55 control patients and these matched pairs were evaluated at 3 years of age. Sensorineural hearing losses were present in four of 43 CMV infected patients (all mild-moderate) and in two of 43 controls (one severe). The incidence of neurologic sequelae was not increased in CMV infected patients with birth weight greater than 2000 gm. Among patients with birth weight less than 2001 gm, moderately abnormal EEGs were found in four (17%) of 23 CMV infected patients and in one (4%) of 23 controls, and severe handicaps occurred in four (14%) of 29 CMV infected patients and in two (7%) of 29 controls. Severe handicaps in premature infants were significantly (P less than 0.05) associated with early onset of CMV excretion (less than 8 weeks of age) and severe cardiopulmonary disease. Among the premature infants who were documented early excretors, three of 13 had severe neuromuscular impairment, four of 13 had severe handicaps (DQ less than 70, severe neuromuscular impairment, or profound loss of vision or hearing), and an additional four had DQs of 70 to 79. Among their matched control subjects, none of 13 had severe neuromuscular impairment, two of 13 had severe handicaps, and an additional two had DQs between 70 and 79. None of the premature infants who were documented late excretors (greater than or equal to 8 weeks of age) had any neurologic sequelae. The risk of neurologic sequelae and handicap may be increased in premature infants with onset of CMV excretion in the first 2 months of life.

Intestinal flora in the second week of life in hospitalized preterm infants fed stored frozen breast milk or a proprietary formula.

Twenty infants fed stored frozen breast milk or a proprietary formula only had both aerobic and anaerobic cultures performed at a chronologic age of 8 to 14 days. Nine out of 10 stools from the infants fed stored frozen breast milk contained Enterobacteriaceae and one stool was sterile. One contained a Pseudomonas species; one contained anaerobic gram-positive rods; one contained anaerobic gram-negative rods; and four contained anaerobic gram-positive cocci. No anaerobes were found in six stools. Six stools had aerobic gram-positive cocci, none of which was hemolytic. Nine out of 10 stools from infants fed a proprietary formula had Enterobacteriaceae. Six stools had anaerobic gram-positive rods, three had anaerobic gram-negative rods, and four had gram-positive cocci. Four stools had no anaerobic bacteria. All 10 stools had nonhemolytic aerobic gram-positive cocci. Enterobacteriaceae were predominant in the stools of the infants fed either stored frozen breast milk or a proprietary formula, and the colony counts of aerobic bacteria were similar in both groups. This pattern of intestinal flora in hospitalized preterm infants in the second week of life is very different from that of normal term infants and may contribute to their increased incidence of systemic and localized infections. The use of stored frozen breast milk for the purpose of suppressing coliform and other potentially pathogenic organisms may not be effective in hospitalized preterm infants who have been treated previously with broad-spectrum, parenteral antibiotics.

Genital herpes simplex infections: effect of asymptomatic shedding and latency on management of infections in pregnant women and neonates.

Asymptomatic shedding of herpes simplex virus (HSV) at delivery occurred in 2.4% of women with a past history of recurrent genital infections; using current methods, this could not be predicted in advance. In addition, only 22% of the mothers of infected infants had an elicitable history of recurrent genital infections. Passively derived neutralizing antibody titers of 1:106 to HSV-1 and 1:67 to HSV-2 were found in 22 exposed infants who remained asymptomatic as compared with 1:8 and 1:8, respectively, in ill infants, suggesting that transfer of antibody from the mother may be an important host defense. Among treated infants, a more rapid rise in antibody titer was seen in infants receiving adenine arabinoside than in those receiving acyclovir; two of the latter infants developed a severe infection in a second organ following cessation of the drug. Exposure of infants to HSV appears inevitable at this time. The extreme variability in outcome is probably related to host factors that are poorly understood at present.

Experimental anaerobic brain abscess. Computerized tomographic and neuropathological correlations.

The neuropathological progression of brain abscess formation induced by a mixed anaerobic culture of Bacteroides fragilis and Staphylococcus epidermidis was studied experimentally in dogs. Histological findings were correlated with computerized tomographic (CT) brain scans. The evolution of brain abscess formation could be divided into three stages based on histological criteria: early cerebritis (Days 1 to 3); late cerebritis (Days 4 to 9); and capsule formation (Day 10 and later). Capsule formation could not be divided into early and late stages because encapsulation was delayed compared with a previously reported model of alpha-Streptococcus brain abscess. Histologically, there was evidence for a very virulent infection. Leptomeningitis was significant even in the late stages. Early ventricular rupture occurred in 25% of the animals. A pattern of extensive purulent encephalitis was seen in 25% of the animals. In the early cerebritis stage, blood vessels near the necrotic center were engorged and were surrounded by hemorrhage and/or protein-rich fluid. Cerebral edema was extensive. Although fibroblasts appeared in late cerebritis, there was marked delay of capsule formation. Three-week-old lesions still had areas of incomplete capsule formation and foci of uncontrolled infection. In the cerebritis stages, CT scans showed an area of ring enhancement which was incomplete on early scans (at 5 minutes after injection of contrast material) but partially filled in and thickened on delayed scans (at 20 to 45 minutes). On even later delayed scans there was no decrease in intensity of ring enhancement. Lesions in which capsule formation occurred also showed ring enhancement, but delayed scans showed a decrease in the intensity of enhancement. The lesions that ruptured into the ventricular system showed atypical CT findings, with either lack of contrast enhancement (histologically there was minimal cerebritis adjacent to the abscess cavity) or a marked delay in contrast enhancement (cerebritis was more extensive and corresponded to the width of ring of enhancement). This study suggests that Bacteroides fragilis is a virulent organism in the brain. The developing abscesses enlarged quickly, were prone to early ventricular rupture, and showed incomplete and delayed encapsulation.

Asymptomatic shedding of herpes simplex virus from the cervix and lesion site during pregnancy. Correlation of antepartum shedding with shedding at delivery.

Asymptomatic shedding of herpes simplex virus (HSV) was detected in 0.83% of 955 cultures obtained from pregnant women with culture-proved recurrent genital HSV infections during pregnancy; seven (2.3%) of 299 women had asymptomatic shedding. In addition, one (2.3%) of 42 pregnant women with recurrent genital infection in the past but no attacks during pregnancy shed HSV when asymptomatic. Shedding occurred more frequently from the usual lesion site than from the cervix. The virus was not isolated at delivery from women with asymptomatic antepartum shedding. When an active lesion was present, concomitant shedding of HSV from the cervix occurred in seven (3.6%) of 193 pregnant women with vulvar lesions and in one (2.1%) of 47 women with lesions remote from the vulva. Ninety-two percent of the latter lesions were caused by type 2 HSV. In women who have had recurrent genital HSV infections in the past, asymptomatic shedding occurs in those with active attacks during pregnancy as well as in those asymptomatic throughout pregnancy; however, asymptomatic shedding during the antepartum period does not predict asymptomatic shedding at delivery.

Reasons for the absence of a history of recurrent genital infections in mothers of neonates infected with herpes simplex virus.

Thirty-one cases of neonatal herpes simplex (HSV) infection were evaluated to determine how often mothers of infected infants lacked a history of recurrent genital infections and the reasons for its absence. A history of recurrent genital infections was elicited from eight (26%) of the mothers. Nine (29%) of the mothers had primary infections; three of these were oral and six were genital. The mother was not the source of infection in three (9.6%) cases. In eleven (35%) cases, the mother had antibody to HSV but did not have a history or findings of primary or recurrent infection. Two of these mothers had positive cervical or vaginal cultures, but neither had genital lesions typical of HSV in the perinatal period. Two mothers had recurrent HSV infections documented later. The source of the HSV infection remained uncertain in 23% of cases including two in which only the father had a history of recurrent genital infection. When mothers with primary infections in the perinatal period were excluded, the HSV neutralization titers of the mothers of infected infants were similar to the titers of the mothers with recurrent genital infections whose infants were not infected. In contrast, the infected infants had titers fourfold lower than their mother's titer as well as fourfold lower than the 16 infants exposed to HSV who remained uninfected. This discrepancy suggests that the mothers may have had a rise in titer late in pregnancy or that placental transport of antibody was limited. Although 26% of the mothers of infected infants had recurrent genital infections, only three (9.6%) had an easily elicitable history.(ABSTRACT TRUNCATED AT 250 WORDS)

Transmission of cytomegalovirus to mothers by infected infants: another reason to prevent transfusion-acquired infections.

Forty-seven percent of mothers who were seronegative to cytomegalovirus at the time an infected infant entered their home seroconverted within 12 months of exposure. In contrast the seroconversion rate was 2.4% among mothers of uninfected infants discharged from the same nursery and ranges from 1.4 to 2.6% in studies reported by others. All infants shed virus throughout the follow-up period. It was not possible to determine whether length of exposure or the age of the child were important factors in determining risk of seroconversion; however, most seroconversions occurred after the child had been home for 4 months or longer. Two mothers became pregnant while still seronegative. Transfusion-acquired infections are one avoidable source of transmission from infant to mother. Seronegative mothers in continuing contact with excreting infants are at risk of acquiring a cytomegalovirus infection and of transmitting it to their fetus should they become pregnant.

Sequelae of maternally derived cytomegalovirus infections in premature infants.

Eighteen of 106 (17%) infants of seropositive mothers, with birth weights less than 1500 gm, acquired cytomegalovirus from a maternal source. Neutropenia, lymphocytosis, thrombocytopenia, and hepatosplenomegaly developed in some infants concomitant with the onset of CMV excretion. Infected infants who excreted CMV at less than 7 weeks of age had longer oxygen requirements than infants who did not excrete CMV until they were older. Passively derived maternal antibody to CMV fell more rapidly over the first few months of life in sick premature infants than would be expected in term infants. Among six infected premature infants, five had undetectable antibody titers when CMV excretion began. Loss of passively acquired antibody and early excretion of virus appear to be associated with symptomatic CMV infections in premature infants of seropositive mothers.

Detection of type-specific antibody to herpes simplex virus type 1 by radioimmunoassay with herpes simplex virus type 1 glycoprotein C purified with monoclonal antibody.

Herpes simplex virus type 1 (HSV-1) and HSV-2 specify at least four glycoproteins designated gA/gB, gC, gD, and gE. Previous studies have shown that gC produced by HSV-1 is antigenically distinct from the corresponding HSV-2 glycoprotein. With the exception of gC, the glycoproteins of both serotypes share antigenic sites. Standard serological assays fail to differentiate the antibody to the shared antigenic determinants from the type-specific antibody. In this paper, we describe a procedure for purifying gC from HSV-1-infected cell extracts with an immunoadsorbent prepared with an HCL monoclonal antibody. When used in a solid-phase radioimmunoassay, gC proved to be a type-specific antigen for quantitation of antibody to HSV-1. Among individuals who had no antibody to HSV at the onset of infection, all of those with primary HSV-1 infection developed antibody to gC. Subjects with primary HSV-2 infection failed to develop antibody reactive with gC of HSV-1 (P less than 0.01). Both immunoglobulin G and M antibodies against gC were detected in sera from subjects with either primary or recurrent HSV-1 infection. Higher antibody titers to gC were found in sera from individuals with recurrent infection than in sera from those with primary HSV-1 infection.

Need for measles revaccination in adolescents: correlation with birth date prior to 1972.

Measles hemagglutination inhibition (HI) antibody titers of less than 1:4 were significantly (P less than 0.05) more prevalent among subjects born from 1962 through 1971 and vaccinated with a single dose of live measles virus vaccine at 12 months of age (14.5%) than among subjects born during the same years but vaccinated at 13 months or older (2.3%). For subjects born in 1972 through 1976, however, this difference was not statistically significant; titers of less than 1:4 occurred in 6.2% of those vaccinated at 12 months, compared to 0% in those vaccinated at 13 months or older. A decline in maternally derived measles HI antibody may be related to the increased rate of HI antibody titers of 1:4 or greater following vaccination of more recently born subjects. Following revaccination of subjects whose measles HI antibody titers were less than 1:4, measles HI titers were lower than would be expected after successful primary vaccination. Nevertheless, measles HI antibody persisted at a level of 1:4 or more until the latest titer measurement of this study (one to two years after revaccination) in 87.5% of those whose initial vaccination had been at 11 or 12 months of age. No adverse reactions to revaccination occurred. Revaccination programs should be considered for adolescents and young adults born before 1972 who received live measles virus vaccine at or before 12 months. Children born from 1972 through 1976 who were vaccinated at 12 months or later are not in need of revaccination.

The effect of short-term corticosteroid treatment on the CT appearance of experimental brain abscesses.

The effect of short-term corticosteroid treatment on contrast enhancement was investigated in an experimental brain abscess model. The degree of enhancement was reduced in the cerebritis stage, unaffected in the capsule stage, and intermediate in the transitional stage. The area and pattern of enhancement were also altered in the cerebritis stage. Although the magnitude of the entire cerebritis time-density curve (extended for 60 minutes) was decreased by the steroids, its configuration was unchanged. Prior to steroid administration, the 10- and 60-minute components of the curve discriminated between cerebritis and capsule stages, with the latter exhibiting a far lower 60-minute value. Implications for treatment of brain abscesses are discussed.

Neutralization of herpes simplex virus by antibody in amniotic fluid.

The ability of amniotic fluid to neutralize herpes simplex virus type 2 (HSV-2) was quantitated and compared with the serum neutralization titer in 158 pregnant women. Neutralizing activity was expressed as the ability of 0.1 ml of amniotic fluid to reduce the expected number of plaque-forming units (pfu) in the inoculum by 99%. All amniotic fluid samples from 32 women with serum titers of 1:40 or greater neutralized 5 pfu or more; at term, 96% of these fluid samples neutralized 50 pfu or more, 83% neutralized 500 pfu or more, and 61% neutralized 5000 pfu or more. Only 76% of the amniotic fluid samples obtained at term from women with serum titers of 1:5 to 1:39 contained detectable neutralizing activity and only 8% neutralized 5000 pfu or more. None of the amniotic fluid samples from 30 women with serum titers less than 1:5 neutralized 5 pfu or more. All neutralizing activity was removed when immunoglobulin G was removed from the amniotic fluid samples. Sera were obtained from 51 pregnant women 4 to 8 weeks prior to delivery. All women with serum titers of 1:40 or higher gave birth to infants who also had serum titers of 1:40 or higher. Therefore, it is possible to predict the neutralization titer in amniotic fluid and in the infant's serum by measuring the mother's titer in the third trimester.