Neonatal herpes simplex virus infections are uncommon, but because of the morbidity and mortality associated with the infection they are often considered in the differential diagnosis of ill neonates. The use of polymerase chain reaction for diagnosis of central nervous system infections and the development of safe and effective antiviral therapy has revolutionized the diagnosis and management of these infants. Initiation of long-term antiviral suppressive therapy in these infants has led to significant improvement in morbidity. This article summarizes the epidemiology of neonatal herpes simplex virus infections and discusses clinical presentation, diagnosis, management, and follow up of infants with neonatal herpes disease.
Key points
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Neonatal herpes simplex virus (HSV) infection can be difficult to differentiate from other causes of neonatal sepsis.
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The three major forms of neonatal HSV infection are disseminated disease (25% of cases); central nervous system (CNS) disease (30%); and skin, eye, and mouth disease (45%).
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The use of high-dose acyclovir for neonatal HSV disease has dramatically reduced mortality and morbidity from this disease.
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Disseminated HSV disease has a higher mortality rate (29%) than CNS disease (4%), but a lower frequency of disabilities 1 year after disease (disseminated, 17%; CNS, 69%).
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Neonates with HSV disease should receive oral acyclovir suppressive therapy for 6 months after completion of intravenous acyclovir treatment.
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New guidelines provide an evidence-based approach to evaluation and treatment of neonates born to women with active genital herpetic lesions.
Viral structure
Herpes simplex viruses (HSV)-1 and -2 belong to alphaherpesviridae and are large, enveloped virions with an icosahedral nucleocapsid arranged around a linear, double-stranded DNA core. There is considerable cross-reactivity between HSV-1 and -2 glycoproteins, which mediate attachment to and penetration into cells and evoke host immune responses. Antigenic specificity is provided by glycoprotein gG, with the antibody response allowing for distinction between HSV-1 and -2.
Viral structure
Herpes simplex viruses (HSV)-1 and -2 belong to alphaherpesviridae and are large, enveloped virions with an icosahedral nucleocapsid arranged around a linear, double-stranded DNA core. There is considerable cross-reactivity between HSV-1 and -2 glycoproteins, which mediate attachment to and penetration into cells and evoke host immune responses. Antigenic specificity is provided by glycoprotein gG, with the antibody response allowing for distinction between HSV-1 and -2.
Maternal genital herpes
Terminology
Primary infection refers to acquisition of HSV-1 or -2 without prior exposure to either virus and hence no preformed antibodies. Nonprimary infection refers to acquisition of HSV-2 in an individual with prior HSV-1 antibodies and vice versa.
Reactivation is isolation of same type of virus from genital lesions as pre-existing type-specific antibodies. Symptomatic shedding refers to presence of lesions characteristic of genital herpes and detection of HSV-1 or -2 from the lesions by culture or polymerase chain reaction (PCR). Subclinical shedding refers to isolation of HSV-1 or -2 from genital mucosa by culture or PCR in the absence of lesions.
Epidemiology of Genital Infections During Pregnancy
Genital herpes infections are caused by HSV-1 or -2 and most infections are asymptomatic. HSV-2 seroprevalence among pregnant women is estimated to be 20% to 30% with approximately 10% of HSV-2 seronegative women living with a seropositive partner and hence at risk for acquisition of genital herpes during pregnancy. Among discordant couples, women seronegative for HSV-1 and -2 have an estimated 3.7% chance for seroconversion, whereas the risk for women already seropositive for HSV-1 to seroconvert to HSV-2 is estimated to be 1.7%. Similar to nonpregnant women, two-thirds of women who acquire genital HSV infection during pregnancy are either asymptomatic or have nonspecific symptoms. Among women with history of genital herpes acquired before pregnancy, 75% have at least one recurrence during pregnancy and 14% have prodromal symptoms or lesions at the time of delivery. For neonatal transmission, women must be shedding the virus symptomatically or asymptomatically around the time of delivery. It has been shown that 0.2% to 0.39% of all pregnant women shed HSV in the genital tract around the time of delivery irrespective of prior history of HSV, and this incidence of shedding increases to 0.77% to 1.4% among women with prior history of recurrent genital herpes.
Distinguishing primary and nonprimary first-episode genital herpes episodes during pregnancy is based on information obtained from combination of genital culture or PCR data and serology. The risk of transmission of HSV to the neonate remains significantly higher with primary maternal infections acquired closer to the time of delivery compared with recurrent infections (50%–60% with primary infections vs <3% for recurrent infections), most likely caused by decreased transplacentally acquired antibody levels in the neonate and exposure in the birth canal to increased quantities of virus for longer duration. Fortunately, most genital herpes infections during pregnancy are recurrent and are associated with a lower risk of transmission to the neonate.
Neonatal herpes
Epidemiology
HSV infection of the neonate is an uncommon occurrence with an estimated rate of approximately 1 in 3200 deliveries. Neonatal HSV infections occur far less frequently compared with other serious neonatal infections overall. With approximately 4 million deliveries per year in the United States, an estimated 1500 cases of neonatal HSV disease occur annually in the United States. When compared with other reportable congenital infections, such as syphilis, toxoplasmosis, and rubella, the overall incidence of neonatal HSV disease is higher yet the disease still does not require mandatory reporting.
Factors Influencing Transmission of HSV to Neonate
Factors that influence transmission of HSV to neonate include the following:
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Type of maternal infection (primary vs secondary)
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Maternal antibody status
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Mode of delivery (vaginal vs cesarean section)
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Duration of rupture of membranes
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Integrity of cutaneous barrier (use of fetal scalp electrodes and other instrumentation)
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Type of HSV (HSV-1 vs -2)
The risk of neonatal acquisition of HSV is significantly higher with first-episode primary and first-episode nonprimary maternal infections when compared with recurrent genital infections. Brown and colleagues evaluated approximately 40,000 pregnant women to assess the effect of maternal serologic status and cesarean section on transmission of HSV to the neonate. Of the approximately 40,000 women in the study who had cultures obtained from the external genitalia, approximately 31,000 women had serologic results available. Of these, 121 women were identified who were asymptomatically shedding virus at the time of delivery and who had serologic analysis. The risk of neonatal transmission was identified as 57% with first-episode primary infection compared with 25% with first-episode nonprimary infection and 2% with recurrent genital HSV infections. This study, for the first time, also documented the protective effect of cesarean section in preventing neonatal HSV. Other statistically significant risk factors in this large study for transmission of HSV to neonate were isolation of HSV-1 from genital lesions when compared with HSV-2 and use of invasive monitoring techniques, such as fetal scalp electrodes.
In a smaller study of approximately 7000 women at risk of acquiring HSV during pregnancy, Brown and colleagues documented a maternal seroconversion rate of 3.2% and noted that HSV seroconversion completed before labor was not associated with increased neonatal morbidity but infections acquired close to labor were associated with increased incidence of neonatal HSV and worse morbidity.
Cesarean delivery has been proved to be effective in preventing the transmission of HSV to the neonate. It is important, however, to note that neonatal HSV cases have occurred despite cesarean delivery before rupture of membranes. Evidence also exists for prolonged rupture of membranes and disruption of mucocutaenous barrier by the use of fetal scalp electrodes and other instrumentation to affect the acquisition of neonatal HSV disease.
Prematurity as a risk factor for acquisition of neonatal HSV is not well studied. Although there is a larger proportion of premature infants with neonatal HSV compared with the general population and neonatal HSV infections in this population is associated with significant mortality and morbidity, it is not well known if genital herpes leads to prematurity or prematurity increases the risk of acquiring neonatal HSV.
Although it has been shown that the chances of acquisition of HSV-1 are decreased in women seropositive for HSV-2, transmission of HSV-1 to the neonate has been documented to be high irrespective of primary or recurrent infection when compared with HSV-2 transmission patterns.
Neonatal HSV Disease Classification and Clinical Presentation
Neonatal HSV is acquired during one of three time periods: (1) in utero (5%); (2) peripartum (85%); or (3) postnatal (10%). HSV infection acquired in the intrauterine, peripartum, or postnatal period is classified into the following types and is predictive of mortality and morbidity ( Table 1 ) : disseminated disease; central nervous system (CNS) disease; and skin, eye, or mouth (SEM) disease.
| Clinical Characteristic | Disseminated Disease | CNS Disease | SEM Disease |
|---|---|---|---|
| Mode of acquisition | Peripartum/postpartum | Peripartum/postpartum | Peripartum/postpartum |
| Frequency | 25% | 30% | 45% |
| Sites of involvement | CNS, liver, lung, adrenal, skin, eye, mucus membranes | Central nervous system with or without skin involvement | Skin, eye, mucus membranes |
| Presentation | Encephalitis, respiratory failure, hepatic failure, disseminated intravascular coagulation ± rash | Seizures, lethargy, irritability, poor feeding, temperature instability ± rash | ± vesicular rash |
| Mortality | 29% | 4% | — |
| Normal development 1 y after treatment without subsequent antiviral suppressive therapy | 83% | 31% | 100% |
Intrauterine infection
In utero infection with HSV is a rare entity but is unlikely to be missed because of presentation at birth and extent of involvement. It occurs in approximately 1 in 300,000 deliveries. Affected infants present with a triad of clinical findings : cutaneous (scarring, rash, aplasia cutis, hyperpigmentation or hypopigmentation); ophthalmologic (microphthalmia, chorioretinitis, optic atrophy); and neurologic (intracranial calcifications, microcephaly, encephalomalacia).
Disseminated disease
In the preantiviral era, disseminated HSV infections accounted for one-half to two-thirds of all children with neonatal HSV disease. Since the development and use of antiviral therapy, disseminated disease has decreased to approximately 25% of all neonatal herpes and usually presents around day 10 to 12 of life. Two-thirds of infants with disseminated disease also have concurrent encephalitis. Disseminated disease involves multiple organs, including CNS, lungs, liver, adrenal, and SEM. Although presence of a vesicular rash greatly facilitates identification of neonates with HSV disease, 20% of infants with disseminated disease never develop a vesicular rash. These patients usually present with viral sepsis, including respiratory failure, hepatic failure, and disseminated intravascular coagulation. Death from disseminated disease is usually caused by severe coagulopathy and extensive hepatic and pulmonary involvement.
CNS disease
Almost one-third of cases of neonatal herpes disease present as encephalitis and are categorized as CNS disease with or without skin involvement and tend to present later than the other two entities at 16 to 19 days of life. Clinical manifestations include focal or generalized seizures, lethargy, irritability, poor feeding, temperature instability, and bulging fontanelle. A total of 60% to 70% of infants with CNS disease have skin lesions at some point during the course of the illness. In the absence of skin lesions, the clinical presentation is indistinguishable from other causes of viral or bacterial sepsis. Mortality in these neonates is usually caused by devastating brain destruction with acute neurologic and autonomic dysfunction. Unlike herpes simplex encephalitis beyond the neonatal period, where there is a higher predilection for the temporal lobe to be involved, neonatal HSV often involves multiples areas of the brain.
SEM disease
Infection limited to SEM has historically accounted for 20% of cases of neonatal herpes disease but has increased to approximately 45% with the introduction of antiviral therapy. Eighty percent of neonates with SEM disease have a vesicular rash on physical examination and usually present to medical attention around day 10 to 12 of life.
Differential Diagnosis
Several other infectious and non-infectious conditions mimic neonatal HSV disease. Bacterial pathogens include group B Streptococcus , Listeria monocytogenes , Staphylococcus aureus , Escherichia coli , and other gram-negative bacteria. Viral exanthematous infections that are confused for neonatal HSV include varicella-zoster virus infection, enteroviral sepsis, and symptomatic cytomegalovirus infection. Noninfectious cutaneous disorders should be considered and include erythema toxicum, incontinentia pigmenti, and Bednar’s aphthae.
Evaluation of the neonate with suspected HSV infection
Viral Culture
Isolation of HSV by culture remains the definitive method of diagnosing neonatal HSV infection ( Box 1 ). Conjunctivae, nasopharynx, mouth, and anus (surface cultures) are swabbed and transported in appropriate transport media on ice to a diagnostic virology laboratory for inoculation into cell culture systems that are monitored for cytopathic effects. Typing of an isolate may be performed by one of several techniques for prognostic purposes. Others sites from which HSV can be cultured include cerebrospinal fluid (CSF) and blood. Of sites routinely cultured for HSV, skin and eye or conjunctival cultures provide the greatest yield.
- 1.
Specimens to obtain before initiating anti-viral therapy
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CSF – Indices, bacterial culture, HSV DNA PCR
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Surface cultures ± PCR
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Base of vesicle or suspicious lesions culture ± PCR
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Whole Blood – PCR
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Whole Blood – Alanine aminotransferase (ALT)
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Treatment of Neonatal HSV
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Intravenous Acyclovir
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Dose – 60 mg/kg/day divided in 3 doses
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Duration of Treatment:
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SEM Disease – 14 days
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CNS Disease – Minimum 21 days a
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Disseminated Disease – 21 days
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Antiviral Suppressive Therapy after Treatment (SEM, CNS and Disseminated Disease):
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Oral acyclovir 300 mg/m2/dose, three times a day for 6 months
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Monitor absolute neutrophil count while on therapy
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a In neonates with positive CSF HSV PCR at the end of therapy, antiviral therapy should be continued until PCR negativity is achieved.
Polymerase Chain Reaction
The application of PCR to CSF samples has revolutionized the diagnosis of CNS neonatal herpes disease. However, performance of PCR is highly dependent on the manner the CSF sample is collected, stored, and transported to the laboratory. The overall sensitivities of CSF PCR in neonatal HSV disease have ranged from 75% to 100%, with overall specificities ranging from 71% to 100%. The results of the PCR should always be interpreted, taking into consideration the clinical presentation of the neonate. A negative PCR result from the CSF does not rule out neonatal HSV disease, because the test may be negative in very early stages of the infection as a result of low viral load or the sensitivity of the test being used. In comparison, blood PCR in neonatal HSV has been evaluated to a lesser extent and in smaller cohorts.
Serologic Testing
Serologic diagnosis of neonatal HSV is not very helpful and is not usually recommended because of transplacentally acquired maternal IgG, which confounds the assessment of neonatal antibody levels during acute infection. Serial antibody assessment may be useful in specific circumstances where a mother with primary genital HSV late in gestation transfers very little antibody to the neonate. Overall, serologic studies play no role in the diagnosis of neonatal HSV infection and are not currently recommended for diagnostic purposes.
Specimens to Obtain Before Starting Antiviral Therapy
Before initiation of empiric parenteral antiviral therapy, the following specimens should be collected to aid in the diagnosis of neonatal HSV disease or to determine if antiviral therapy may be discontinued if HSV has been excluded :
- 1.
CSF for indices, bacterial culture, and HSV DNA PCR
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Swab for viral culture from the base of vesicles, suspicious areas, and mucous membrane lesions for viral culture; PCR may be performed in addition to cultures, if desired
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Swab from mouth, conjunctiva, nasopharynx, and rectum (surface cultures) for viral culture; PCR may be performed in addition to cultures, if desired
- 4.
Whole blood for HSV DNA PCR
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Blood to determine alanine aminotransferase (ALT)
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