Neonatal Herpes Simplex Virus Infection Research Articles

Neonatal Herpes Simplex Virus Infection in King County, Washington. Increasing Incidence and Epidemiologic Correlates

SULLIVAN-BOLYAI, JOHN; HULL, HARRY F.; WILSON, CHRISTOPHER; COREY, LAWRENCE Author Information

Advances in Antiviral Therapy

Recent developments have increased the options for treatment of viral infections. Vidarabine, an agent originally released for herpes simplex encephalitis, has more recently been shown to be of benefit in neonatal herpes simplex infection and in varicella-zoster infections in immunocompromised hosts. The introduction of acyclovir represents a major advance in antiviral therapy because of its low host toxicity and marked selectivity for herpes simplex and varicella-zoster viruses. Extensive controlled clinical trials demonstrate efficacy in the treatment of infections caused by these viruses in the immunocompromised host and in genital herpes simplex infections in normal hosts. The use of recombinant DNA technology has increased the purity, variety, and availability of interferons for clinical trial. Earlier experience with natural buffy coat-derived alpha interferon showed efficacy in the treatment of varicella-zoster infections in the immunocompromised host, as well as prophylaxis of herpes virus infections in high-risk populations. These results have to be confirmed using the newer interferon preparations. Under development are a variety of new drugs with broadened viral spectrum and improved pharmacokinetic properties. These include nucleoside analogues and novel interferons with modified amino acid sequences. One or more of these agents, used singly or in combination, may prove useful in the more difficult therapeutic problems, such as cytomegalovirus and hepatitis B infections.

Advances in antiviral therapy.

Recent developments have increased the options for treatment of viral infections. Vidarabine, an agent originally released for herpes simplex encephalitis, has more recently been shown to be of benefit in neonatal herpes simplex infection and in varicella-zoster infections in immunocompromised hosts. The introduction of acyclovir represents a major advance in antiviral therapy because of its low host toxicity and marked selectivity for herpes simplex and varicella-zoster viruses. Extensive controlled clinical trials demonstrate efficacy in the treatment of infections caused by these viruses in the immunocompromised host and in genital herpes simplex infections in normal hosts. The use of recombinant DNA technology has increased the purity, variety, and availability of interferons for clinical trial. Earlier experience with natural buffy coat-derived alpha interferon showed efficacy in the treatment of varicella-zoster infections in the immunocompromised host, as well as prophylaxis of herpes virus infections in high-risk populations. These results have to be confirmed using the newer interferon preparations. Under development are a variety of new drugs with broadened viral spectrum and improved pharmacokinetic properties. These include nucleoside analogues and novel interferons with modified amino acid sequences. One or more of these agents, used singly or in combination, may prove useful in the more difficult therapeutic problems, such as cytomegalovirus and hepatitis B infections.

Neonatal Herpes Simplex Virus Infection in King County, Washington. Increasing Incidence and Epidemiologic Correlates

The incidence of neonatal herpes simplex virus (HSV) infection in King County, Washington, has increased progressively from a rate of 2.6 per 100,000 live births to King County residents during the years 1966 through 1969 to 4.8, 7.4, and 11.9 cases per 100,000 live births for the years 1970 through 1973, 1974 through 1977, and 1978 through 1981, respectively. Detailed interviews of the parents of newborns with neonatal HSV-2 infection revealed clinically symptomatic genital herpes in the mother or father in 65% of the parents and serological and/or cultural evidence of HSV-2 infection in the mother in the other 35% of cases. Clinically symptomatic first episodes of genital herpes during pregnancy occurred in four of the mothers who were delivered of newborns with neonatal HSV-2 infection; two of the mothers were symptomatic at the time of birth. The other 16 interviewed mothers who delivered newborns with neonatal HSV-2 infection all had serological and/or cultural evidence of past HSV-2 infection but were asymptomatic at term. All six newborns with neonatal HSV-1 infection acquired the disease from nongenital sources, and two newborns seemed to have acquired the disease from nonmaternal sources. These data indicate that detailed interviews of the parents are often useful in increasing the clinician's index of suspicion for neonatal HSV infection. The increased prevalence of genital HSV infection in the United States seems to be associated with a concomitant increase in neonatal HSV infection. ( JAMA 1983;250:3059-3062)

DEFECTIVE HSV-SPECIFIC IMMUNITY FOLLOWING NEONATAL HSV ENCEPHALITIS

With effective anti-viral therapy increasing numbers of infants are surviving neonatal herpes simplex virus infections. Some survivors have recurrent HSV skin lesions, suggesting a relative deficiency of their HSV-specific immunity. To test this we used limiting dilution assays to determine the frequency of HSV specific T lymphocytes in the blood of healthy children and adults and survivors of neonatal HSV encephalitis. The subjects' serum IgG and IgM anti-HSV antibodies were determined independently by ELISA. 30% of randomly selected children aged 18 months - 12 years had HSV antibody and all of these had HSV-responsive lymphocytes in the blood with a frequency of 1:7,000 to 1:15,000. 80% of healthy adults were antibody positive and their responder lymphocyte frequencies were 1:10,000 to 1:20,000. Responder cell frequencies in antibody negative children or adults were 1:200,000 or less. The neonatal HSV survivors were aged 6 months - 7 years. All had IgG and IgM HSV antibodies but their T cell responder frequencies were 1:30,000 or less. Monocyte defects and antigen-specific immunosuppression were excluded as explanations for the low responder cell frequencies by in vitro cultures. These results suggest that the survivors of neonatal HSV may, like the survivors of congenital or neonatal CMV, have a deficiency of HSV specific T4+ cells due presumably to central failure of production or to lack of clonal expansion.

A Cluster of Neonatal Herpes Simplex Infections Without Mucocutaneous Manifestations

Three cases of neonatal disseminated herpes simplex virus (HSV) infection are reported. They were all due to different strains of HSV-1, according to restriction endonuclease studies, and they represent the first cluster of neonatal-HSV infection at Magee-Womens Hospital. The neonatal symptoms occurred early, suggesting intrauterine infection. None of the babies had mucocutaneous lesions, and the mothers were asymptomatic and had no history of previous genital HSV infection.

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)

The relative role of transplacental and milk immune transfer in protection against lethal neonatal herpes simplex virus infection in mice.

The role of passive maternal immunity in neonatal herpes simplex virus (HSV) infection is controversial. C57BL/6 mice born to HSV-immune mothers had significantly greater survival than those born to nonimmune mothers after an intraperitoneal or oral HSV challenge. In subsequent experiments with intraperitoneal and oral HSV challenge, non-immune mice that were foster fed for one week by actively or passively immunized mothers were significantly protected. Injections of passive antibody postpartum in nonimmune mother mice resulted in detectable transfer of antibody to HSV to their infant mice via breast milk. In mice, maternal breast milk, not transplacentally derived antibody, protects neonates from low-dose HSV infection.

Herpes simplex Virus Adsorption to and Survival within Placental Lymphoid Populations

Neonatal herpes simplex virus (HSV) infections are frequently characterized by widespread dissemination and high morbidity and mortality. To assess the potential role of the lymphocyte in permitting or promoting dissemination of HSV, we studied lymphoid populations of placental and adult blood with respect to HSV survival. Adsorption of HSV to the lymphocyte surface did not differ between placental and adult cells. Placental blood permitted greater survival of HSV than adult lymphocytes. T-cell-enriched lymphocytes appeared to be slightly more permissive than T-cell-depleted lymphocytes, but these differences were not statistically significant and apparently less than adult-placental blood differences. These findings lend support to the hypothesis that intracellular changes common to various neonatal lymphoid populations may permit or promote dissemination of HSV in the neonate.

Neonatal herpes simplex virus infection in King County, Washington. Increasing incidence and epidemiologic correlates

The incidence of neonatal herpes simplex virus (HSV) infection in King County, Washington, has increased progressively from a rate of 2.6 per 100,000 live births to King County residents during the years 1966 through 1969 to 4.8, 7.4, and 11.9 cases per 100,000 live births for the years 1970 through 1973, 1974 through 1977, and 1978 through 1981, respectively. Detailed interviews of the parents of newborns with neonatal HSV-2 infection revealed clinically symptomatic genital herpes in the mother or father in 65% of the parents and serological and/or cultural evidence of HSV-2 infection in the mother in the other 35% of cases. Clinically symptomatic first episodes of genital herpes during pregnancy occurred in four of the mothers who were delivered of newborns with neonatal HSV-2 infection; two of the mothers were symptomatic at the time of birth. The other 16 interviewed mothers who delivered newborns with neonatal HSV-2 infection all had serological and/or cultural evidence of past HSV-2 infection but were asymptomatic at term. All six newborns with neonatal HSV-1 infection acquired the disease from nongenital sources, and two newborns seemed to have acquired the disease from nonmaternal sources. These data indicate that detailed interviews of the parents are often useful in increasing the clinician's index of suspicion for neonatal HSV infection. The increased prevalence of genital HSV infection in the United States seems to be associated with a concomitant increase in neonatal HSV infection. (<i>JAMA</i>1983;250:3059-3062)

Neonatal Herpes Simplex Virus Infection in King County, Washington

The incidence of neonatal herpes simplex virus (HSV) infection in King County, Washington, has increased progressively from a rate of 2.6 per 100,000 live births to King County residents during the years 1966 through 1969 to 4.8, 7.4, and 11.9 cases per 100,000 live births for the years 1970 through 1973, 1974 through 1977, and 1978 through 1981, respectively. Detailed interviews of the parents of newborns with neonatal HSV-2 infection revealed clinically symptomatic genital herpes in the mother or father in 65% of the parents and serological and/or cultural evidence of HSV-2 infection in the mother in the other 35% of cases. Clinically symptomatic first episodes of genital herpes during pregnancy occurred in four of the mothers who were delivered of newborns with neonatal HSV-2 infection; two of the mothers were symptomatic at the time of birth. The other 16 interviewed mothers who delivered newborns with neonatal HSV-2 infection all had serological and/or cultural evidence of past HSV-2 infection but were asymptomatic at term. All six newborns with neonatal HSV-1 infection acquired the disease from nongenital sources, and two newborns seemed to have acquired the disease from nonmaternal sources. These data indicate that detailed interviews of the parents are often useful in increasing the clinician's index of suspicion for neonatal HSV infection. The increased prevalence of genital HSV infection in the United States seems to be associated with a concomitant increase in neonatal HSV infection.

Neonatal Herpes Simplex Virus Infection: Follow-up Evaluation of Vidarabine Therapy

An open study of vidarabine (adenine arabinoside) therapy was performed to verify the mortality from neonatal herpes simplex virus infection and to define further long-term morbidity. A total of 39 babies not previously reported were treated with either 15 mg/kg/d (16 newborns) or 30 mg/kg/d (23 newborns) of vidarabine administered intravenously for ten to 14 days. Outcome was compared with that from 56 newborns evaluated in a prior trial. Irrespective of the dose of medication, therapy decreased the mortality in babies with disseminated and CNS disease to 40%. The extent of organ involvement and, in particular, pulmonary herpes simplex infection were predictive of mortality (P = .001, for both). For these babies, 32% achieved normal developmental milestones 2 years after therapy. Disease localized to the skin, eye, and/or mouth was not associated with death. However, neurologic impairment occurred in 12% of this treated group of newborns. These findings underscore the value of vidarabine therapy of neonatal herpes simplex virus infection. However, an increase in dosage did not appear to result in significant improvement in either mortality or morbidity. Further improvement in the mode of therapy and the utilization of more potent antiviral drugs are currently being tested.

Disseminated Neonatal Herpes Simplex Virus Type 1 from a Maternal Breast Lesion

Most cases of neonatal herpes simplex virus (HSV) result from contact with infected secretions from the maternal genital tract.1 Postnatal acquisition of neonatal HSV infections, a subject recently reviewed by Light,2 is uncommon. We report a case of fatal neonatal HSV-1 infection acquired by contact with a maternal breast lesion. Restriction endonuclease "fingerprinting" revealed a similar pattern in the viruses isolated from the maternal breast lesion and the infant's skin lesion. The purpose of this report is to alert physicians of this potential route of transmission, especially in women experiencing primary mucocutaneous HSV infection at or near term. CASE REPORT A 3,693-g male infant was born to a 21-year-old white primigravida after an uneventful term pregnancy.

Additive effects of acyclovir and immune transfer in neonatal herpes simplex virus infection in mice.

Acyclovir had a dose-dependent, mild, but significant, inhibitory effect on interferon-stimulated human antiviral natural killer cytotoxicity in vitro. In a murine model of neonatal herpes simplex virus infection, acyclovir significantly (P < 0.05) increased survival afforded by the injection of human interferon and human mononuclear leukocytes from 67.8 to 88.6%.

Oral Herpesvirus Infection in Nursery Personnel: Infection Control Policy

A survey of 161 neonatal referral centers in the United States revealed that 83% exclude personnel with overt oral herpes simplex virus (HSV) lesions from direct patient care. Twenty-seven percent of hospitals exclude infected personnel from all hospital work. The high incidence of overt HSV lesions and the excretion of HSV among asymptomatic hospital personnel associated with an extremely low incidence of recognized neonatal HSV infection (especially type 1 HSV), suggest that the current policy of excluding such personnel from patient care should be reexamined.

Neonatal herpes simplex infection in the absence of mucocutaneous lesions

Six infants with disseminated HSV had no mucocutaneous lesions at any time during the course of the illness. These infants presented with lethargy, poor feeding, apnea, acidosis, and hepatomegaly. The diagnosis of HSV was made by culturing the infant's oropharynx and blood, and the maternal cervix. Eight infants with HSV encephalitis had no skin, eye, or mucous membrane lesions. These infants presented with lethargy and low-grade fever, followed within 24 hours by the onset of focal partial motor seizures. The seizures were refractory to anticonvulsant therapy. The mean CSF white cell count was 131 cells/mm3;the glucose and protein concentrations were in the normal range. Brain biopsy was required for the early diagnosis of HSV encephalitis. These 14 cases presented 70% (14/20) of all infants with neonatal HSV diagnosed during the study period. HSV infection should be considered in infants with no mucocutaneous lesions who have signs usually associated with bacterial sepsis or who develop focal seizures during the first three weeks of life.

Management of genital herpes simplex virus infection occurring during pregnancy

Genital herpes simplex virus (HSV) infection during pregnancy has caused considerable concern among lay and professional personnel in the past 10 years. Knowledge concerning the potential hazards of HSV to the newborn infant has increased the use of cesarean section for women who have or are suspected of having genital HSV infection near or at the time of labor. Because of this, a 57-month prospective study was begun at Vanderbilt University Hospital and its affiliate, Nashville General Hospital, January 1, 1976, and involved HSV culturing of all suspected genital herpes lesions during pregnancy. Those patients with positive HSV cultures prior to labor and without a subsequent negative culture underwent cesarean section. Those patients whose cultures reverted to negative were considered candidates for vaginal delivery. During the study period, there were 16,381 deliveries at the two institutions. One hundred twenty pregnant women were cultured, with 80 being HSV culture negative and 40 culture positive. The outcome of these pregnancies as well as a review of the experience with neonatal HSV infection in Middle Tennessee is presented. It is concluded that by utilizing HSV cultures of genital lesions as a guide to determining the route of delivery, the incidence of cesarean sections and neonatal HSV infection can be kept to a minimum.

Genital herpes simplex—concepts and treatment

Genital herpes simplex is an increasingly common venereal disease caused by either herpes simplex virus type 1 or 2. The disease can be manifested in a primary and/or recurrent form, the clinical features and complications of which are reviewed. Potential problems include psychosocial difficulties, neonatal herpes simplex infections, and the possibility of an oncogenic role in cervical cancer. Diagnostic modalities, prophylactic measures, and management technics are discussed.

Relationship of Antibody to Outcome in Neonatal Herpes Simplex Virus Infections

YEAGER, ANNE S.; ARVIN, ANN M.; URBANI, LENORE J.; KEMP, JOHN A. III Author Information

The Natural History of Herpes Simplex Virus Infection of Mother and Newborn

The controlled evaluation of vidarabine as therapy of neonatal herpes implex virus (HSV) infection provided an opportunity to collect data to further assess the natural history of maternal and newborn infections. Women delivering infected babies were young, nulliprous, and infrequent aborters. Nearly 50% of the gestations ended in premature labor. Maternal infection was asymptomatic in 39 of 56 (70%) of the mothers, at the time of delivery. However, risk factors included a past history of genital herpes at any time and exposure to a sexual partner with presumed HSV lesions. Associated diseases in children born to these women were common. Premature infants had an incidence of respiratory distress of 52% (14 of 27). Eight of 29 (28%) term newborns had a bacterial infection, antedating the onset of neonatal HSV infection. Virologic studies on infected newborns confirmed that skin lesions were the most frequent site for virus retrieval. Progression of disease from isolated skin lesions was common, occurring in 70% of babies whose presenting sign was skin vesicles. CSF was virus-positive from 14 babies and more frequently in those with localized CNS disease. Importantly, brain biopsy was necessary for diagnosis in four cases. Finally, neither the presence or absence of antibodies to HSV was useful in predicting either presentation or outcome of infection. These studies further emphasize the complex nature of HSV infections of the newborn and need for tertiary care.