Neonatal herpes simplex virus infection

PURPOSE OF REVIEW: In spite of the availability of antiviral therapy for the treatment of neonatal herpes simplex virus infections, the outcome remains poor, particularly for babies with disseminated multi-organ infection or central nervous system disease. This review considers recent advances that impact on disease management. RECENT FINDINGS: Two areas of investigation have impacted on our understanding of neonatal herpes simplex virus infection. First, the transmission of infection from mother to baby has been clarified by extensive epidemiological investigations of genital herpes in pregnant women at term. Risk factors for neonatal herpes simplex virus disease include first-episode maternal infection in the third trimester, invasive monitoring, delivery before 38 weeks, and maternal age of less than 21 years. Regarding the management of neonatal herpes simplex virus disease, the utilization of high-dose acyclovir (20 mg/kg every 8 h) for 21 days significantly reduces mortality for babies with either encephalitis or disseminated disease. SUMMARY: Recent findings from epidemiological studies have identified women at risk of delivering a child who develops neonatal herpes simplex virus infection, and suggest methods to decrease maternal-fetal transmission. If infection is identified in the pregnant woman, cesarean delivery decreases the frequency of neonatal disease. With neonatal disease, acyclovir should be administered promptly at higher dosages and for longer periods than previously reported.     

Limited antibody-dependent cellular cytotoxicity antibody response induced by a herpes simplex virus type 2 subunit vaccine

The humoral response to a herpes simplex virus (HSV) type 2 subunit vaccine containing recombinant glycoproteins B (gB2) and D (gD2) was tested in 3 groups of patients. These included HSV-seronegative, HSV-1-seropositive, and HSV-2-seropositive individuals. There were excellent antibody responses, as measured by gB2- and gD2-specific ELISAs and HSV-2 neutralization assays. However, in 2 HSV-2 antibody-dependent cellular cytotoxicity (ADCC) assays, there were relatively low antibody responses, especially among HSV-seronegative individuals. The low ADCC responses may be associated with the poor efficacy of this vaccine observed in clinical trials.     

Role of antibody-dependent cellular cytotoxicity in defense against herpes simplex virus infections

Antibody-dependent cellular cytotoxicity (ADCC) to cells infected with herpes simplex virus (HSV) is a mechanism of destruction of these cells by a combination of antiviral antibody and immunoglobulin Fc receptor-positive leukocytes. It has been well defined in vitro as a rapid lytic response utilizing minute amounts of IgG antibody. In vitro studies have shown ADCC restriction of the spread of virus. In vivo studies using adoptive transfer of human or murine ADCC effector cells plus antibody and ADCC-active, nonneutralizing F(ab1)2 antibody fragments or monoclonal antibodies have demonstrated the important role of this response in animal models of HSV infection. In humans, ADCC effector function and/or antibody levels have been associated with the outcome of infection, especially in immunocompromised patients and neonates. Reconstitution of this mechanism with appropriate antibodies or cytokines in high-risk hosts, with the resultant amelioration of severe HSV infection, will validate ADCC as a critical component of antiviral defense.     

Changing presentation of herpes simplex virus infection in neonates

We compared the clinical presentation of 95 newborns with herpes simplex virus (HSV) infection from 1973 through 1981 (first period) with data from 196 newborns evaluated from 1982 through 1987 (second period). There was a significant change in the presentation of infection in these infants. From the first to the second period, the frequency of disseminated disease decreased from 50.5% to 22.9%, whereas the frequency of skin, eye, and mouth (SEM) diseases increased from 17.9% to 43.4% (P less than .001). The frequency of infants with central nervous system (CNS) disease remained relatively unchanged--31.6% versus 33.7%. We also compared the demographic and clinical characteristics of the infants and their mothers. For neonates with CNS or disseminated infection, disease duration and frequency of prematurity were significantly decreased in the second period, as was the frequency of skin vesicles for newborns with SEM or disseminated infection. These changes are most likely the consequence of recognizing and treating SEM infection before its progression to more-severe disease.     

Early childhood stress is associated with elevated antibody levels to herpes simplex virus type 1

It is well known that children need solicitous parenting and a nurturing rearing environment to ensure their normal behavioral development. Early adversity often negatively impacts emotional and mental well-being, but it is less clearly established how much the maturation and regulation of physiological systems is also compromised. The following research investigated the effect of 2 different types of adverse childhood experiences, early deprivation through institutionalization and physical abuse, on a previously unexplored outcome: the containment of herpes simplex virus (HSV). The presence of HSV-specific antibody in salivary specimens was determined in 155 adolescents, including 41 postinstitutionalized, 34 physically-abused, and 80 demographically-similar control youth. Across 4 school and home days, HSV antibody was higher in both postinstitutionalized and physically-abused adolescents when compared with control participants. Because the prevalence of HSV infection was similar across the groups, the elevated antibody was likely indicative of viral recrudescence from latency. Total secretory Ig-A secretion was associated with HSV, but did not account for the group differences in HSV-specific antibody. These findings are likely caused by a failure of cellular immune processes to limit viral reactivation, indicating a persistent effect of early rearing on immune functioning. The fact that antibody profiles were still altered years after adoption into a more benevolent setting with supportive families suggests these results were not caused by contemporaneous factors, but rather reflect a lingering influence of earlier life experiences.     

Nosocomial herpes simplex virus infection associated with oral endotracheal intubation

Background: To determine by culture the frequency of herpes simplex virus reactivation complicating oral endotracheal intubation. Additionally, clinical appearance and recognition of patient infection by attendant health care workers were studied. Last, evidence of any occupational acquisition of herpes simplex virus infection was sought.Methods: In a prospective, non-randomized study, three serial viral cultures were taken of oro-facial or mucosal sites on the day of oral endotracheal intubation and in the subsequent 3rd and 5th or 7th days from 51 consecutive adults undergoing oral endotracheal intubation in a suburban community hospital. Clinical variables including appearances of lesions and therapeutic interventions were noted during serial assessments by study authors. Employee health records were reviewed for evidence of health care worker occupational herpes simplex virus infection associated with these cases.Results: Of 51 patients, 4 were culture positive on the day of oral endotracheal intubation. Of the remaining 47 patients, serial cultures during the first week post intubation revealed herpes simplex virus in 25 (53.2%) patients. Of cohort variables studied, a history of prior oral herpes simplex virus was significantly associated with a subsequent positive viral culture for herpes simplex virus (relative risk, 2.29; 95% confidence interval, 1.48 to 3.56). Typical or atypical lesions were visible in only 52% of the herpes simplex virus culture-positive cases. No occupational transmission of herpes simplex virus was detected. Tape-securing practices appeared to contribute to the morbidity of herpes simplex virus eruptions.Conclusions: Nosocomial reactivation of herpes simplex virus infection complicated oral endotracheal intubation in our patient population in approximately one half of the patients who were intubated for more than 48 hours during the first week after the procedure. Clinically, the infection was recognizable in only one half of the virus culture-positive cases. Increased awareness of this infection is needed by health care workers, patients, and families. More information is needed on optimal therapy and prevention.     

Degradation of cellular mRNA during infection by herpes simplex virus.

The fate of preexisting mRNA sequences was examined after infection by herpes simplex virus. Murine erythroid cells transformed by Friend leukemia virus were used as the host. Such cells, when exposed to 2% dimethyl sulfoxide, produce large amounts of globin and globin mRNA. The protein and its mRNA are easily recognized at 4 days by electrophoresis in high percentage acrylamide gels and by hybridization to cDNA, respectively. Herpes simplex virus replicates in these cells. By 2 hr after infection the rate of protein synthesis decreases to 30% of the level in mock-infected cells and only 49+/-8% (SEM) of the globin mRNA sequences present prior to infection could be detected by hybridization to cDNA. At 4 hr after infection, when the rate of protein synthesis in infected cells is at a maximum, only about 15% of the globin mRNA sequences remained. Control experiments support the hypothesis that globin mRNA sequences are degraded after infection by herpes simplex virus.     

Strategies for the prevention of neonatal infection with herpes simplex virus: a decision analysis.

Decision analysis was used in the evaluation of nine strategies for the prevention of neonatal infection with herpes simplex virus (HSV). These strategies involve physical examination at labor, weekly screening of pregnant women for shedding of HSV, use of serologic methods specific for HSV type 2, and performance of a rapid diagnostic test at labor. Rates of cesarean delivery and of neonatal infection with HSV were estimated for each strategy, and the estimates were compared with those for a strategy of no intervention. The effects of variations in the sensitivities and specificities of the diagnostic and serologic tests used were analyzed. Given the currently available data and technology, physical examination at labor is the optimal strategy if the primary goal is to minimize the ratio of excess cesarean sections to cases of neonatal HSV infection averted.     

Chronic-dose acyclovir to suppress frequently recurring genital herpes simplex virus infection: effect on antibody response to herpes simplex virus type 2 proteins

To determine the effect of prolonged suppressive acyclovir therapy on the antibody response to herpes simplex virus type 2 (HSV-2) proteins, we studied sequential sera from 33 patients with frequently recurring (six or more recurrences per year) genital herpes. Twenty-two patients received 400 mg of oral acyclovir and 11 received placebo, twice daily for one year. Sera collected at enrollment, after six months and 12 months of therapy, and during the first recurrence after cessation of therapy were evaluated by western blot for levels of antibodies to HSV-2, gB, gG, gC/gE, VP16, and gD. Mean levels declined by 27%-39% after one year of acyclovir. The magnitude of the decrease in antibody levels was not correlated with disease severity either during or after therapy. Patients with high relative antibody levels to gB after therapy had more-severe first recurrences after therapy than did patients with antibody levels to gB less than or equal to the median. Antibody levels were not restored after the first untreated recurrence.     

Transmission of infection with herpes simplex virus by renal transplantation

Disseminated infection with herpes simplex virus type 2 was identified in two patients 20 days after they had received kidney transplants from the same organ donor. Neither patient had neutralizing antibody to herpes simplex virus before transplantation, and both had herpes simplex virus isolated from surveillance cultures of urine before the onset of clinical symptoms. A clear focus of primary infection was not found in either patient. Analysis of the patients' isolates by DNA restriction endonuclease analysis strongly suggested that the strains were identical. These data implicate the allografts as the source of the viral infection.     

Secretory IgA antibody in cervicovaginal secretions from women with genital infection due to herpes simplex virus

Sequential samples of cervicovaginal secretions from women with untreated first and recurrent episodes of genital infection due to herpes simplex virus type 2 (HSV-2) were assayed for IgA antibodies to HSV-2 by using fluorescent antibodies to human secretory piece (sIgA) and human IgA. Among women with first-episode genital herpes, sIgA antibody to HSV-2 was detected in 20 of 31 women from whom HSV was isolated from the cervix, compared with four of 13 women from whom it was not (P less than .05). Among women with first-episode genital herpes, the mean titer of sIgA antibody to HSV-2 peaked between days 9 and 16 of disease, whereas among women with recurrent genital HSV, the peak occurred at days 3-8 of disease. HSV-2 was not isolated from the cervix from any of 130 samples taken when titers of sIgA antibody to HSV-2 were greater than or equal to 1:2, compared with 98 of 259 samples taken when titers were less than or equal to 1:2 (P less than or equal to .01).     

Correlation of herpes simplex virus types 1 and 2 with clinical features of infection.

Strains (338) of herpes simplex virus (HSV) were isolated in Stockholm during 1965-1974. By immunoelectroosmophoresis it was possible to identify all strains as either HSV type 1 (HSV-1) or 2 (HSV-2). No strains of intermediate antigenic type or with untypable characteristics were found. The antigenic type of HSV was correlated with body site and clinical features of infection. A case of severe, recurrent, abdominal pain in association with HSV-2 infection is described. In one patient with acute aseptic meningitis, both coxsackievirus A9 and HSV-2 were isolated from the same specimen of cerebrospinal fluid. Serology suggested a primary infection with coxsackievirus A9 and a recurrent HSV-2 infection. HSV-1 was isolated from specimens of cerebrospinal fluid. Serology suggested a primary infection with coxsackievirus A9 and a recurrent HSV-2 infection. HSV-1 was isolated from specimens of cerebrospinal fluid from two of four adults with HSV encephalitis.     

Epitopes of herpes simplex virus type 1 glycoprotein B that bind type-common neutralizing antibodies elicit type-specific antibody-dependent cellular cytotoxicity.

A panel of 45 well-characterized monoclonal antibodies (MAbs) reactive to glycoprotein B (gB) of herpes simplex virus (HSV) type 1 was tested by ELISA and in antiviral functional assays (that included virus neutralization, antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent complement-mediated lysis), using type 1 or 2 virus strains. All MAbs were ELISA-reactive. Eleven of the MAbs mediated neutralization and 9 mediated ADCC. All of the ADCC epitopes were contained within the amino-terminal half of the extracellular portion of gB. The ADCC reactions were strictly type 1-specific, whereas 9 of 11 neutralizing MAbs exhibited type-common activity. There was some association between the ADCC and neutralization activities, since of 12 MAbs with functional activity, 8 were positive in both assays. These results suggest that differences in the presentation of gB, and perhaps HSV-1 gB versus HSV-2 gB, on free virus and virus-infected cells determine epitope availability.     

Use of interleukin-2 and macrophages to treat herpes simplex virus infection in neonatal mice

We have developed a model of therapy for herpes simplex virus (HSV) infection in neonatal mice. Using a lower dose of virus (10(2) plaque-forming units administered intraperitoneally), we have been able to treat infected mice with syngeneic or allogeneic adult mouse macrophages in combination with three doses of human recombinant interleukin-2. Therapy resulted in a 42%-85% survival rate. Although production of antibody to HSV was associated with successful treatment, early administration of antibody did not improve survival.