Neonatal Herpes Simplex Virus Infection

1. Neonatal herpes simplex virus is a virus capable of infecting the central nervous system of neonates, causing significant morbidity and mortality.

2. Neonatal herpes simplex virus should be considered as a possible etiologic factor when a neonate presents with signs of sepsis.

After completing this article, readers should be able to:

1. Discuss the timing and risk factors for neonatal infection.

2. Review the clinical manifestation of neonatal infection and disease.

3. Discuss the diagnostic evaluation of neonatal herpes simplex virus (HSV) disease.

4. Identify the treatment of neonatal HSV.

5. Identify the outcomes of neonatal HSV treatment.

Numerous viruses are capable of infecting the central nervous system (CNS) of neonates, but herpes simplex virus (HSV) is among the most severe, with significant mortality and morbidity. Unlike other viral pathogens, HSV is treatable using a commercially available antiviral drug, acyclovir. Neonatal HSV infection is primarily acquired during the peripartum period, which improves the likelihood that antiviral therapy can be beneficial. Viral damage is of a relatively short duration in neonatal HSV disease acquired at birth compared with injury to the developing fetal brain from viruses that are acquired in utero. Studies conducted by the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group over the course of 4 decades have advanced our knowledge of the favorable impact that antiviral therapy has on neonatal HSV disease outcomes. Many neonates now are effectively treated and experience no long-term sequelae of this potentially devastating infection. Without treatment, however, neonatal HSV disease can be fatal and extremely devastating. It is important for clinicians and healthcare professionals to recognize signs of neonatal HSV infection. This can lead to prompt diagnosis and treatment, leading to a better prognosis for infants affected by the virus.

The HSV consists of enveloped, double-stranded DNA. (1) The virus establishes latency after a primary infection, and then periodically reactivates and causes recurrent symptomatic disease. It can also cause asymptomatic viral shedding that is clinically unapparent. The incidence of neonatal HSV infection is between 1 in 3,000 and 1 in 20,000 live births. (1) Recent data suggest that this disease incidence may be increasing. (2) Neonatal HSV is acquired in 1 of 3 distinct periods: intrauterine, peripartum, and postpartum. Most infants (∼85%) acquire the infection perinatally or in the peripartum period. (3) Approximately 10% of neonates with HSV disease are infected postnatally, and 5% acquire the infection during the intrauterine period. (3)

Risk factors that increase the likelihood of HSV transmission from a pregnant woman who is shedding HSV genitally to her infant include:

1. Type of maternal infection (primary vs recurrent) (4)(5)(6)(7)(8)

2. Maternal antibody status (8)(9)(10)(11)

3. Longer duration of rupture of membranes (7)

4. Integrity of mucocutaneous barriers (using fetal scalp probe, incisions, etc) (8)(12)(13)

5. Mode of delivery (cesarean vs vaginal delivery) (8)

Infants born to women with primary (ie, first episode) genital HSV infection near the time of delivery are known to be at much greater risk of developing neonatal herpes than are infants who are born to women with recurrent genital HSV infection near the time of delivery (25%–60% vs <2%, respectively). (4)(5)(6)(7)(8) This increased risk is because of 2 main factors. First, there is a lower concentration of transplacentally passed HSV-specific antibodies in infants born to women with primary infections, because the pregnant woman has not had time to generate anti-HSV immunoglobulin G. (10) In addition, newly developed antibodies tend to be less effective in binding viral peptides. Second, a larger burden of the virus is shed vaginally and for a longer period in the genital tract of women with primary infection compared with those with recurrent HSV infection. (14) This was demonstrated in a landmark study of approximately 60,000 women in labor who did not have any symptoms of genital HSV infection at the time of delivery. In approximately 40,000 of these women, a vaginal swab was obtained for HSV detection within 48 hours of delivery (Fig 1). (8) Of these 40,000 women, 121 were identified to have asymptomatic shedding of HSV and had serum specimens available for HSV serologic testing, thereby allowing for the determination of first episode versus recurrent maternal infection. The trial found that 57% of infants born to women with primary infection who were shedding the virus in their genital tracts at delivery developed neonatal HSV; 25% of infants born to women with first episode nonprimary infection (had preexisting HSV-1 antibody and acquired HSV-2 or vice versa) developed neonatal HSV; and only 2% of infants born to women with recurrent HSV developed neonatal HSV (Fig 1). (8) This same large study also confirmed that cesarean delivery effectively decreased transmission of HSV to the neonate when women are shedding this virus in their genital tracts. (7) Despite this degree of protection, the risk of HSV transmission is not eliminated by cesarean delivery, and there are still cases of infants delivered via cesarean section who are found to have HSV. (15)(16)(17)

Based on the extent of involvement, neonatal HSV infection is classified into 1 of 3 categories: disseminated disease; CNS infection; or skin, eyes, and mouth (SEM) infection. Disseminated disease involves multiple organs including, but not limited to, lung, liver, adrenal glands, brain, and skin. CNS disease involves the brain, with or without skin involvement, but no visceral organ dysfunction. SEM disease is limited only to these areas of the body. This classification system is predictive of morbidity and mortality, with disseminated disease having the most significant mortality and CNS disease having the most significant morbidity. (18)(19)(20)(21)(22)(23)(24)

Disseminated infection can manifest as severe hepatitis, disseminated intravascular coagulation, pneumonitis, and possibly CNS involvement (found in 60%–75% of cases). (19)(20)(21)(22)(23) The mean age at presentation of disseminated infection is approximately 11 days after birth. Interestingly, more than 40% of cases of disseminated HSV disease do not develop skin findings, which can complicate the ability to make the diagnosis promptly. (16)(19)(24)(25)

Neonatal HSV CNS disease can present as seizures (focal or generalized), lethargy, poor feeding, irritability, tremors, temperature instability, and bulging fontanelle. The mean age at presentation for CNS disease is approximately 16 days after birth. (19) Approximately 60% to 70% of infants with CNS disease will also have skin manifestations at some point in the disease course. (19)(24) Mortality is usually due to devastating brain destruction and atrophy, causing neurologic and autonomic dysfunction.

SEM disease is associated with the best outcomes, with virtually no mortality and with morbidity associated solely with cutaneous recurrences but no neurologic sequelae. In addition, infants with SEM disease are most likely to have skin lesions (in >80% of patients), which facilitates diagnosis and allows prompt initiation of antiviral treatment before the disease progresses to involve other organs. Presenting signs and symptoms of SEM disease include skin vesicles, fever, lethargy, and conjunctivitis. (19) The mean age at presentation for SEM disease is approximately 12 days after birth. (16)

The diagnosis of neonatal HSV infections requires sampling of multiple sites (1):

1. Swabs of mouth, nasopharynx, conjunctivae, and rectum should be tested for HSV surface cultures (if available) or polymerase chain reaction (PCR).

2. Specimens of skin vesicles should be tested for culture (if available) or PCR.

3. Cerebrospinal fluid (CSF) specimens should be tested for HSV PCR.

4. Whole blood samples should be tested for HSV PCR.

5. Alanine aminotransferase should be measured as an indicator of hepatic involvement (1)

In the past, the presence of red blood cells in CSF was suggestive of HSV CNS infection, likely as a result of relatively advanced disease due to diagnostic limitations; however, with the development of more advanced imaging and diagnostic capabilities, hemorrhagic HSV encephalitis is less commonly seen now, and as such, most HSV CNS CSF indices do not have significant numbers of red blood cells. (1) Performance of whole blood PCR adds to the other diagnostic tools (surface and CSF cultures and CSF PCR), but should not be used as the sole test for ruling in or ruling out neonatal HSV infection. Furthermore, viremia and DNAemia can occur in any of the 3 types of neonatal HSV disease, so a positive whole blood PCR simply rules in neonatal HSV infection but does not assist in disease classification. HSV isolates from culture or HSV DNA detected on PCR can be typed to determine whether it is HSV type 1 or HSV type 2. Chest radiographs and liver function tests can aid in the diagnosis of disseminated infection. Histologic testing is of low yield because it has low sensitivity and should not be used for diagnosis. All infants with HSV disease, regardless of classification, need to have an ophthalmologic examination to look for ocular involvement such as uveitis, conjunctivitis, and keratitis. Infected neonates with any extent of disease manifestations should undergo neuroimaging studies (magnetic resonance imaging preferably, but head computed tomography or ultrasonography are acceptable) to establish baseline brain anatomy. (1) Later findings can include brain abscesses (particularly in the temporal lobe) or severe encephalomalacia. (1)

Before antiviral therapies were developed and used, disseminated HSV disease caused death by 1 year of age in 85% of patients. In infants with CNS disease, mortality was 50% (Table 1). (22)(26) In a series of research studies conducted by the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group between 1974 and 1997, parenteral vidarabine, lower-dose acyclovir (30 mg/kg per day), and higher-dose acyclovir (60 mg/kg per day) were evaluated sequentially. (20)(22)(27) In the first of these studies, 10 days of vidarabine decreased mortality rates compared with placebo at 1 year both for patients with disseminated disease (rates decreased from 85% to 50%) and for those with CNS disease (rates decreased from 50% to 14%). Following comparison of lower-dose acyclovir with vidarabine for 10 days, parenteral acyclovir became the primary treatment choice for neonatal HSV disease because of its more favorable safety profile and its relative ease of administration (vidarabine required prolonged infusion times in large volumes of fluid). A subsequent study of higher-dose acyclovir for 21 days produced further reductions in 1-year mortality rates to 29% for disseminated disease (Fig 2) (18) and 4% for CNS disease (Fig 3). (18)

These series of studies determined that infants with neonatal HSV disease should be treated with parenteral acyclovir at a dose of 20 mg/kg per dose administered every 8 hours; the dosing interval may need to be increased in premature infants based on their creatinine clearance. (28) The treatment duration is 21 days for infants with disseminated disease or CNS disease, while infants with SEM disease should be treated for 14 days. (1) All patients with CNS involvement should have a repeat lumbar puncture near the end of the 21-day course of acyclovir to document that the CSF PCR is negative; if the PCR remains positive, another week of parenteral acyclovir should be administered, and lumbar punctures should be repeated in that manner until a negative CSF PCR is achieved. (19)(29)

The primary toxic effect of higher-dose parenteral acyclovir is neutropenia. (18) Thus, absolute neutrophil counts (ANCs) should be monitored twice weekly throughout the course of parenteral therapy. If ANC is less than 500/μL, either acyclovir treatment can be withheld or granulocyte colony-stimulating factor can be administered. Parenteral acyclovir dosing can resume when the ANC is higher than 750/μL. (18)

Oral acyclovir suppressive therapy for 6 months after acute parenteral treatment improves neurodevelopmental outcomes in infants with CNS disease. (1) It is well-known that HSV establishes latency in the sensory ganglia, and occasionally reactivates and causes recurrence of disease. However, it is not well-known if the virus subclinically reactivates in the brain after neonatal HSV has been treated, particularly with CNS involvement. If it does reactivate, it could be the cause of poor neurodevelopmental outcomes in patients with CNS involvement. A recent study involving infants with neonatal HSV with CNS involvement compared Bayley mental-developmental scores at 1 year in infants receiving suppressive therapy with acyclovir for 6 months versus infants receiving placebo (Table 2). (30) The study found that the acyclovir group had a significantly higher mean Bayley score than the placebo group (88.24 vs 68.12, P=.046). Suppressive acyclovir therapy also has been proven to prevent skin recurrences in HSV disease of all types. (30) Thus, infants should receive oral acyclovir at 300 mg/m² per dose 3 times daily as suppressive therapy for 6 months after the initial parenteral treatment course. This dose should be adjusted for growth monthly, and ANCs should be monitored at 2 and 4 weeks after starting therapy and then monthly thereafter while oral acyclovir is administered. (1)

Until recently, improvement in morbidity outcomes after antiviral treatment was less dramatic than mortality for neonates with disseminated disease or CNS disease. Oral acyclovir suppressive therapy has significantly improved the neurologic outcomes of infants with CNS involvement. (22) Without treatment, 50% of neonates who survived disseminated HSV disease were developing normally at 1 year of age. (22) With the use of higher-dose acyclovir for 21 days, the number of infants developing normally at 1 year of age after disseminated HSV disease has increased to 83% (Fig 4). (18) Similarly, for CNS HSV disease, 33% of patients demonstrate normal neurologic development at 1 year of age after 10 days of lower-dose acyclovir therapy, compared with 31% of children treated with higher-dose acyclovir for 21 days. However, with concomitant use of oral acyclovir therapy for 6 months, this percentage of infants with normal neurodevelopment at 1 year increases to 69% (Fig 4). (30) Morbidity of SEM disease also has dramatically improved since the introduction of antiviral treatment. In the preantiviral era, 38% of patients with SEM disease were developing normally at 1 year of age, but with antiviral therapy, this risk is eliminated completely (due to SEM disease not progressing to CNS or disseminated disease). (19)

Neonatal HSV disease is known to have devastating neurologic effects. Fortunately, over the past decades, much has been learned about the natural history, pathogenesis, diagnosis, and treatment of this severe infection. In the 21st century, neonatal HSV disease is treatable, and management recommendations have been standardized and implemented. As more knowledge is obtained, more questions are formed. These questions in turn drive the next series of studies, with further promise of continued advances for the future.

ANC

absolute neutrophil count

CNS

central nervous system

CSF

cerebrospinal fluid

HSV

herpes simplex virus

PCR

polymerase chain reaction

SEM

skin, eyes, and mouth