Herpes simplex virus (HSV) infections of humans have been documented since the advent of writing. The spectrum of disease was expanded to include primary and recurrent infections of mucous membranes (gingivostomatitis, herpes labialis, and genital HSV infections), keratoconjunctivitis, neonatal HSV infection, visceral HSV infections of the immunocompromised host, HSV encephalitis, Kaposi's varicella-like eruption, and an association with erythema multiforme. Cumulative experience suggests that factors associated with pregnancy may place both the mother and fetus at increased risk for severe infection, possibly because of altered cell-mediated immunity. The major risk to the fetus is with primary or initial genital HSV infection of the mother. PCR evaluation of cerebrospinal fluid can be utilized to monitor therapeutic outcome in patients with herpes simplex encephalitis. The use of HSV for gene therapy heralds a new era of herpes biology, the conversion of a hazardous foe into a user-friendly surgical tool. Asymptomatic shedding of virus can continue despite clinically effective suppression with acyclovir, so the possibility of person-to-person transmission persists. Newborns with HSV infections can be classified as having disease that is localized to the skin, eyes, and mouth; affects the central nervous system (CNS); or is disseminated. Drug resistance was considered rare and resistant isolates were thought to be less pathogenic until a series of acyclovir-resistant HSV isolates from patients with AIDS were characterized. The risk of nephrotoxicity can be minimized by administering acyclovir by slow infusion and ensuring adequate hydration.

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Herpes Simplex Viruses

Cytomegalovirus establishes a lifelong latent infection following primary infection that can periodically reactivate with shedding of infectious virus. Primary infection, reactivation and reinfection during pregnancy can all lead to in utero transmission to the developing fetus. Congenital CMV infections are a major cause of permanent hearing loss and neurological impairment. In this literature review, we found that CMV infection was relatively common among women of reproductive age, with seroprevalence ranging from 45 to 100%. CMV seroprevalence tended to be highest in South America, Africa and Asia and lowest in Western Europe and United States. Within the United States, CMV seroprevalence showed substantial geographic variation as well, differing by as much as 30 percentage points between states, though differences might be explained by variation in the types of populations sampled. Worldwide, seroprevalence among non-whites tended to be 20-30 percentage points higher than that of whites (summary prevalence ratio (PR) = 1.59, 95% confidence interval (CI) = 1.57-1.61). Females generally had higher seroprevalences than males, although in most studies the differences were small (summary PR = 1.13, 95% CI = 1.11-1.14). Persons of lower socioeconomic status were more likely to be CMV seropositive (summary PR = 1.33, 95% CI = 1.32-1.35). Despite high seroprevalences in some populations, a substantial percentage of women of reproductive age are CMV seronegative and thus at risk of primary CMV infection during pregnancy. Future vaccine or educational campaigns to prevent primary infection in pregnant women may need to be tailored to suit the needs of different populations.

Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection.

Respiratory syncytial virus (RSV) was first isolated from a chimpanzee with common-cold-like illness.(53a) Shortly thereafter, the virus was recovered from young children with severe lower respiratory tract disease in Baltimore. (11,16) Since its initial isolation from infants with respiratory disease almost 20 yr ago, RSV has emerged as the major lower respiratory tract pathogen of infancy and early childhood throughout the world. (3,15,16,69) In all geographic areas it is now clear that RSV is the major cause of bronchiolitis and pneumonia in infants and young children. RSV presents a special challenge to the epidemiologist since this virus exhibits a pattern of infection and disease unlike that of any of the other known respiratory tract viral pathogens. Unanswered are many pressing questions concerning the pathogenesis of serious life-threatening disease of the lower respiratory tract produced by this virus during early infancy.

Respiratory Syncytial Virus

Herpes simplex virus infections

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The Interferon System

Prevention of transfusion-acquired cytomegalovirus infections in newborn infants

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.

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

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...

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

Neutralizing antibody titers to herpes simplex virus type 1 (HSV-1) and HSV-2 were measured at birth in normal infants and uninfected infants of mothers with genital HSV infections during pregnancy and at the onset of infection in 5 infants with mild infections and 11 infants with severe infections. Thirty-eight percent of premature and 29% of term infants had neutralization titers of <1:5. High titers ([unk]1:40) were found in 55% of infants of mothers with primary infections during pregnancy and in 76% of infants of mothers with recurrent infections. The mean titers to HSV-1 and -2 in 5 infected infants with mild infections were 1:56 and 1:65 at the time of onset of infection, whereas the mean titers in 11 infants with severe infections were 1:11 and 1:12. Six natally exposed infants who remained asymptomatic were also studied and had a mean titer to HSV-1 of 1:85 and to HSV-2 of 1:69. Therefore, infants with high titers of transplacentally derived antibody had a more favorable outcome than infants with lower titers. Ninety-five percent of the infants of mothers with recurrent infections had a Rawls index of more than 85, suggesting that the antibody response was to HSV-2. However, low levels of antibody with this type specificity failed to protect four infants from infection with HSV-2. Augmentation of the neutralization titer to HSV-2 by the amount of complement present in cord serum was less than twofold. The study suggests that the quantity of antibody derived transplacentally affects the outcome of infection after natal exposure to herpes simplex virus. Complete neutralization of virus by antibody may occur in some infants, and prolongation of the incubation period and modification of the infection may occur in others.

https://iai.asm.org/content/iai/29/2/532.full.pdf

Relationship of antibody to outcome in neonatal herpes simplex virus infections.

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 mother9s 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. Most cases of neonatal HSV infection will not be avoidable until the epidemiology of primary maternal infection and of nonmaternal sources of infection is understood and the identification of women with HSV who are never symptomatic is improved.

Anne S. Yeager

Papers

Prevention of transfusion-acquired cytomegalovirus infections in newborn infants

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

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

Relationship of antibody to outcome in neonatal herpes simplex virus infections.

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