KEY POINTS

• 1.
  

  Neonatal herpes simplex virus (HSV) infections can cause potentially devastating infections in newborn infants.

  
  
• 2.
  

  HSV has a double-stranded linear DNA genome and is seen in two variants, HSV-type 1 and HSV-type 2.

  
  
• 3.
  

  Neonatal HSV infections occur in three patterns: prenatal, perinatal, and postnatal. Perinatal infections are most common and are associated with serious morbidity and mortality.

  
  
• 4.
  

  HSV infections can be confirmed by isolating the virus in enhanced viral culture, detecting herpes DNA in polymerase chain reactions, detecting herpes antigens by rapid direct fluorescent antibody tests, and enzyme immunoassays.

  
  
• 5.
  

  Acyclovir is the recommended antiviral agent for treatment of all types of HSV disease. The duration of acyclovir therapy depends on the type of infection and the response of neonatal HSV.

  
  
• 6.
  

  The outcome of HSV infection of neonates depends on clinical types. HSV infection is life-lasting, even with appropriate treatment. Neonatal central nervous system infection is an important cause of neurodevelopmental delay. The disseminated disease is most serious and may cause mortality in up to 30% of infected infants.

Background

Neonatal herpes simplex virus (HSV) can cause potentially devastating infection in newborn infants. These infections have been noted in about 0.2% of all neonatal intensive care admissions and account for 0.6% of neonatal mortality in the United States. Infected infants need prolonged monitoring and treatment, and with a high incidence of long-term morbidity, they frequently need considerable healthcare resources.

Virus

HSV has a double-stranded linear DNA genome of 150,000 base pairs that encode more than 80 polypeptides. The nucleocapsid is composed of 162 capsomeres arranged in a 20-faced polyhedron, which is covered by a lipid tegument containing polyamines ( Fig. 32.1 ). There are two variants, HSV-type 1 and HSV-type 2, but the two share several homologous DNA sequences and encoded glycoproteins, suggesting evolution from a common ancestor virus. Acute infections have a cytolytic effect, but the virus may also persist lifelong in an intracellular latent state that is not susceptible to antiviral agents.

Schematic Figure Showing the Structure of a Herpes Simplex Virus.

There is a lipid envelope studded with proteins, a protective tegument, and a protein nucleocapsid shell, all of which enclose a central DNA core.

Epidemiology

Neonatal HSV infections are seen in 3 to 30 per 100,000 live births. In the United States about 1500 cases are reported per year ; the incidence of neonatal HSV disease has a direct relationship with the prevalence of HSV-type 2 genital infections in the general population. There are some concerns that the incidence of central nervous system (CNS) and disseminated HSV infections may have increased since the year 2000. ^{, ,} Early testing and empiric treatment for HSV infections should be considered in all ill febrile neonates, and this approach may improve the survival rate and reduce the long-term sequelae.

There are three patterns of neonatal (<3 months of age) HSV disease ^, :

• 1.
  

  Prenatal, seen in 1 in 250,000 infants;

  
  
• 2.
  

  Perinatal, seen in 1 in 3200 to 10,000 live births and associated with serious morbidity and mortality; and

  
  
• 3.
  

  Postnatal, seen in about 1 in 100,000 live births.

Neonatal HSV infections account for 1.2% of all emergency room admissions in the United States. Studies show three patterns of neonatal HSV disease: localized to the skin, eyes, and mouth (SEM) in approximately 40%; to the CNS in 30%; and disseminated infection in 30%. These infections are seen most often between 7 and 14 days after birth, and the frequency declines in the second month after birth.

Clinical Manifestation

The clinical manifestations of neonatal HSV infections may vary depending on the timing of infection. Both HSV-type 1 and HSV-type 2 may cause any of these three patterns, although HSV-type 2 infections may have poorer outcomes. ^{, , ,}

Prenatal infections account for 1% to 2% of all neonatal HSV disease. Some infants show only residua of past disease with cutaneous scarring, eye involvement, and CNS features such as microcephaly or hydranencephaly. Others may show active infection, ranging from just a few skin vesicles to severe pneumonitis or disseminated disease with fatal multisystem organ failure. ^,

Prenatal or congenital HSV infections result from maternal viremia and transplacental acquisition or ascending infections through the membranes that are either ruptured or may be intact but with altered permeability. The histopathological changes may be limited to placental infarcts, plasma cell deciduitis, and lymphoplasmacytic villitis or may clearly extend to the fetus with necrotizing, calcifying funisitis. Severe cases show hydrops fetalis and fetal death. HSV can often be cultured from the placenta or identified using molecular techniques, such as polymerase chain reaction (PCR), immunohistochemistry, or in-situ hybridization. A high index of suspicion is needed.

Perinatal infections account for nearly 85% of all neonatal HSV infections. The virus may be transmitted to the infant during delivery from visible or unnoticed lesions in the maternal genital tract. It can enter the baby’s body via the oral or genital mucosa, conjunctiva, or breaches in the skin; move into the sensory nerve endings; and then be transported retrograde via the axons to the dorsal root ganglia.

The risk of perinatal infections increases with :

• •
  

  Primary (versus recurrent) maternal infection

  
  
• •
  

  Low maternal immunity to HSV

  
  
• •
  

  Prolonged rupture of membranes

  
  
• •
  

  Use of fetal scalp monitors

  
  
• •
  

  Mode of delivery (higher risk in vaginal versus cesarean section delivery)

Ascending infections frequently follow prolonged rupture of membranes, but an intact amniotic membrane may not be protective in all cases. Neonatal HSV infections have even been documented after cesarean delivery in women with intact membranes. ^,

Perinatal infections may be difficult to diagnose because there may not be a recorded maternal history of HSV infection. Maternal fever is a risk factor, but it is not very useful because of its frequent occurrence during labor. ^, In infected neonates, the initial manifestations may be vague, such as variability in temperature, respiratory difficulties, jaundice, feeding problems, and lethargy. ^, However, these symptoms can quickly progress to hypotension, disseminated intravascular coagulation, and multisystem organ failure. Perinatal HSV infections are seen in three patterns: SEM, CNS, and disseminated disease.

CNS Disease

About 30% of infants with HSV disease have isolated CNS involvement. ^, This CNS infection may result either from retrograde extension from the nasopharynx and olfactory nerves or via hematogenous spread. HSV meningoencephalitis typically manifests between 7 and 21 days after birth but can be delayed up to the second month. CNS involvement may or may not be associated with SEM (skin lesions are seen in 60%–70% of patients) and/or disseminated disease.

Early CNS disease is often asymptomatic, but clinical features such as irritability, tremors, lethargy, poor feeding, fluctuation of temperature, focal or generalized seizures, and bulging anterior fontanel can be seen with disease progression. ^{, ,} Cerebrospinal fluid (CSF) analysis may be inconclusive in early phases of the disease, but as the disease progresses, there may be mononuclear cell pleocytosis, moderately low glucose levels, and elevation in protein concentrations. The presence of red blood cells is not common. Infants with CNS disease need to be evaluated and treated promptly with a high index of suspicion, because in the absence of noticeable skin lesions, it may be hard to distinguish CNS disease from other causes of neonatal sepsis or meningitis. ^, In many infants, there may be a need for empiric acyclovir therapy until the results of HSV DNA, PCR, and other CSF studies are available. ^,

Brain neuroimaging such as computed tomography (CT) and magnetic resonance imaging (MRI) may be normal at disease onset, but abnormalities such as parenchymal brain edema or attenuation, hemorrhage, or destructive lesions start appearing within a few hours ( Fig. 32.2 ). ^, Although not specific, electroencephalographic abnormalities are often seen early in the course of CNS infection, with focal or multifocal periodic epileptiform discharges and frank seizure activity. ^,

Central Nervous System Imaging From an Infant With Herpes Simplex Virus Encephalitis.

(A) On the day of disease onset, (1) noncontrast computed tomography (CT) appeared normal, but (2) magnetic resonance imaging (MRI) showed restricted diffusion in bilateral temporoparietal lobes, suggesting cytotoxic edema (blue arrows) . T2- and T1-weighted images showed signal changes and mild edema (blue arrows) . (B) Three days later, (1) noncontrast CT showed bilateral temporoparietal lobe hypodensities (arrow) , and (2) MRI showed worsening of cytotoxic edema (blue arrows) . Postcontrast images showed subtle meningovascular enhancement (white arrows) . These changes were prominent in diffusion-weighted (DW) and apparent diffusion coefficient (ADC) images. (C) One month after disease onset, MRI showed resolving cytotoxic edema, but there was global volume loss and gyriform enhancement (arrow) . (D) Three months later, there was extensive cystic encephalomalacia (blue arrows) . DW MRI and ADC maps show signal changes based on diffusion of water molecules in cells. Failure of normal diffusion across cell membranes and consequent cytotoxic edema (restricted diffusion), such as in encephalitis and stroke, is hyperintense on DW imaging and hypointense on ADC maps. T2-weighted images show edema and inflammation as hyperintense signals. T1-weighted images are useful for morphologic assessment but are relatively insensitive to detect pathology, particularly in early disease. Encephalomalacia looks hypointense on T1 images.

Diagnosis

Neonatal HSV disease is a clinically challenging problem because it starts with subtle, nonspecific manifestations that may mimic bacterial sepsis or other viral diseases such as those due to enteroviruses. A history of perinatal exposure in mothers with active genital lesions is helpful but frequently not present. A recent study matched 149 infants ≤60 days of age with 1340 control infants, all of whom were evaluated for infection, including CSF analysis. Age, preterm birth, a history of seizure activity at home, ill appearance, abnormal temperature, vesicular rash, thrombocytopenia, neutropenia, and CSF pleocytosis were all significantly associated with HSV infection. The study authors proposed a scoring mechanism based on these factors, to aid in HSV clinical decision-making.

HSV infections can be confirmed by isolating the virus in enhanced viral culture, detecting herpes DNA in PCR, or detecting herpes antigens by rapid direct fluorescent antibody tests ^, and enzyme immunoassays. ^, Direct fluorescent antibody is specific but not as sensitive. Generally, the serology is not of help in the diagnosis of neonatal herpes infection at the time of presentation. For culture, surface swabs from the conjunctivae, mouth, nasopharynx, and rectum are used. Viral cultures may be positive in >90% cases. ^, If obtained 12 to 24 hours after birth, positive cultures indicate ongoing viral replication and not contamination from intrapartum exposure. Specimens from fresh vesicular lesions usually are positive within 24 hours of incubation, whereas CSF or other site specimens may need few days. Negative viral cultures after 10 days of incubation are usually considered negative.

If skin or mucous membrane lesions are present, swabs/scrapings can be obtained for cultures, PCR, or direct immunofluorescence (may not be as sensitive). HSV PCR assays of the skin and mucosal specimens are accepted alternatives. ^, All infants suspected of having an HSV infection should undergo a lumbar puncture and CSF analysis by PCR. Cultures are useful but may not be as sensitive as PCR. ^, Blood and plasma may be used for culture and/or PCR but are not as sensitive (positive in about 85% of cases). However, the detection of herpes DNA in the blood or plasma of neonatal disseminated HSV disease confirms the diagnosis and provides the opportunity for starting acyclovir early in the course of the disease. ^{, ,} Detection of >7 log10 copies per mL suggests increased risk of mortality. Specimens such as tracheal aspirates in intubated infants, peritoneal fluid in neonates undergoing peritoneal drainage, or laparotomy for other reasons can also be used for viral culture and PCR. Suspicious skin lesions can also be evaluated by biopsy and histopathology (see Fig. 32.2 ).

All infants with HSV disease should undergo neuroimaging with MRI or CT. MRI is generally more sensitive than CT. ^, Neuroimaging may be normal early in the course of the disease, but as the disease progresses, parenchymal brain edema or abnormal attenuation, hemorrhage, or destructive lesions become evident. ^, The classic destructive lesions may be multifocal, with involvement limited to the temporal lobe or extended to the brainstem or cerebellum ( Fig. 32.3 ). ^, Prenatal ultrasound may be useful; it may show damage in the fetal brain. However, postnatal ultrasound is not so accurate for estimating the extent of CNS disease. Infants with CNS HSV disease should undergo electroencephalography, particularly if there are seizures, abnormal movements, or abnormal CSF. The most common findings are focal or multifocal periodic or quasiperiodic epileptiform discharges. ^{, , , ,}

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