96: Herpes Simplex Viruses

Herpes simplex viruses (HSV-1 and HSV-2) are enveloped, double-stranded DNA viruses. They are part of the herpes group, which also includes cytomegalovirus, Epstein-Barr virus, varicella zoster virus, and human herpes virus (HHV-6 and HHV-7). HSV infection is among the most prevalent of all viral infections encountered by humans.

A study from the United States found an overall incidence of 9.6 per 100,000 births in 2006. Separately, a range of 1 per 3000 to 1 per 20,000 is given for an overall incidence in newborn infants for 2012. Seroprevalence of HSV-1 and HSV-2 in pregnant women in the United States is ∼63% and 22%, respectively.

Two serologic subtypes can be distinguished by antigenic and serologic tests: HSV-1 (usually affects face and skin above the waist) and HSV-2 (genitalia and skin below the waist). Three quarters of neonatal herpes infections are secondary to HSV-2. HSV-1, however, can be the cause of maternal genital herpes infections in 9% of the cases, and its rate appears to be increasing. HSV infection of the neonate can be acquired at 1 of 3 times: intrauterine, intrapartum, or postnatal. Most infections (85%) are acquired in the intrapartum period as ascending infections with ruptured membranes (4–6 hours is considered a critical period for this to occur) or by delivery through an infected cervix or vagina. An additional 10% of infected neonates acquire the virus postnatally (eg, from someone shedding HSV from the mouth who then kisses the infant). The final 5% of neonatal HSV infections occur in utero. The usual portals of entry for the virus are the skin, eyes, mouth, and respiratory tract. Once colonization occurs, the virus may spread by contiguity or via a hematogenous route. The incubation period is from 2–20 days. Three general patterns of neonatal HSV infection are recognized: disease localized to the skin, eyes, and mouth (SEM); central nervous system (CNS) disease (with or without SEM involvement); and disseminated disease (which also may include signs of the first 2 groups). Maternal infection can be classified as either first-episode or recurrent infections. First-episode infections are further classified as either primary or first-episode nonprimary based on type-specific serologic testing. Primary infections are those in which the mother is experiencing a new infection with either HSV-1 or HSV-2 and has not already been infected with the other virus type. First-episode nonprimary infections are those in which the mother has a new infection with one virus type, usually HSV-2, but has antibodies to the other virus type, usually HSV-1. Infants born vaginally to mothers with a true primary infection are at highest risk, with a transmission rate of 50%. Those born to a mother with a first-episode nonprimary infection are at a somewhat lower risk of 30%. The lowest risk (<2%) infants are those who are born to a mother with recurrent infections. Maternal antibody is not always protective in the fetus.

The risk of genital herpes infection may vary with maternal age, socioeconomic status, and number of sexual partners. Only ∼12% of pregnant women who test seropositive for HSV-2 give a clinical history suggestive of the disease. The first-episode infection may stay “active” with asymptomatic cervical shedding for as long as 2 months. Besides a first-episode infection (primary or nonprimary), additional risk factors for neonatal HSV infection include the use of a fetal-scalp electrode and maternal age <21 years.

Congenital in utero HSV infection is rare and is associated with high rate of fetal demise; it shares clinical features such as microcephaly, hydrocephalus, and chorioretinitis with other congenital infections. In addition, skin ulcerations or scarring and eye damage are commonly noted. The neonatal disease is commonly acquired intrapartum. It may be localized or disseminated. Humoral and cellular immune mechanisms appear important in preventing initial HSV infections or limiting their spread. Infants with disseminated and SEM disease generally present at 10–12 days of life, whereas patients with CNS disease usually present at 16–19 days of life. More than 20% of infants with disseminated disease and 30–40% of infants with encephalitis never have skin vesicles (Plate 12).

1. SEM disease. In the era of acyclovir therapy, HSV disease localized to the skin, eyes, or oral cavity accounts for ∼45% of the cases. Skin lesions vary from discrete vesicles to large bullous lesions and denuded skin. It typically involves the presenting part (eg, vertex) and sites of skin trauma (eg, scalp electrodes). There is skin involvement in 80–85% of SEM cases. Ulcerative mouth lesions (∼10% of SEM cases) with or without cutaneous involvement can be seen. Ocular findings include keratoconjunctivitis and chorioretinitis (see Chapter 53). Without treatment, there is a high risk of progression to encephalitis or disseminated disease.

2. Disseminated disease carries the worst prognosis with respect to mortality and long-term sequelae. Patients commonly present with fever, lethargy, apnea, and a septic shock–like picture, including respiratory collapse, liver failure, neutropenia, thrombocytopenia, and disseminated intravascular coagulation (DIC). Approximately half of these cases also have localized disease as described previously, and 60–75% have CNS involvement. More than 20% of infants with disseminated disease will not develop any cutaneous vesicles during the course of their illness. Recognition of the disseminated HSV disease is often delayed. It should be suspected in any infant presenting with a sepsis-like picture associated with thrombocytopenia, elevated hepatic enzymes, and cerebrospinal fluid (CSF) pleocytosis. Infants with disseminated HSV infection account for 25% of all cases of neonatal herpes infection.

3. CNS disease accounts for ∼30% of neonatal HSV infection. CNS involvement can present with or without SEM lesions. Clinical manifestations include seizures (focal and generalized), lethargy, irritability, tremors, poor feeding, temperature instability, and a bulging fontanelle. These infants usually present at 16–19 days of age, and 30–40% have no herpetic skin lesions. CSF findings are variable and typically show a mild pleocytosis, increased protein, and a slightly low glucose.

Diagnosis of neonatal HSV infection can be challenging, and the diagnosis is often delayed. Early manifestations are subtle and nonspecific (especially for the disseminated form). The maternal history is often not helpful.

1. Laboratory studies

   1. Viral cultures. Isolation of HSV by culture remains the definitive diagnostic method of documenting HSV infection. Skin or mucous membrane lesions or surfaces (mouth, nasopharynx, conjunctivae, and anus) are scraped and transferred in appropriate viral transport media on ice. Swab specimens from mouth, nasopharynx, conjunctivae, and anus can be obtained with a single swab ending with the anus and placed in one viral transport media tube. With the exception of CNS involvement, the important information gathered from such cultures is the presence or absence of the replicating virus, rather than its precise location. Preliminary results may become available in 24–72 hours. Positive cultures obtained from any of these sites more than 12–24 hours after birth indicate viral replication and, therefore, are suggestive of infant infection rather than merely contamination after intrapartum exposure.

   2. Polymerase chain reaction (PCR). PCR is an important tool in the diagnosis of HSV infection. PCR has been used to detect HSV DNA in CSF and blood specimens. PCR is especially useful for the diagnosis of HSV encephalitis. Overall sensitivities of CSF PCR in neonatal HSV disease have ranged from 75 to 100% with overall specificities ranging from 71 to 100%. Negative CSF PCR does not exclude the diagnosis of HSV CNS disease; it may be negative early in the course of the disease or if the test is done after antiviral therapy has been given for a few days. PCR is especially important in monitoring therapy of CNS disease, with discontinuation of therapy only when PCR is negative.

   3. Immunologic assays. Immunologic assays to detect HSV antigen in lesion scrapings, usually using monoclonal anti-HSV antibodies in either an enzyme-linked immunosorbent assay or fluorescent microscopy assay, are very specific and 80–90% sensitive.

   4. Liver function tests (LFTs). Whole-blood sample for measuring LFTs, especially alanine aminotransferase, is recommended. HSV characteristically invade the liver and cause hepatocellular damage.

   5. Serologic tests. These are not helpful in the diagnosis of neonatal infection but are helpful in diagnosing and classifying maternal disease (primary versus secondary).

   6. Lumbar puncture. Should be performed in all suspected cases. CSF may be normal early in the course of the disease but typically will show a mononuclear cell pleocytosis, normal or moderately low glucose, and mildly elevated protein. Red blood cells are not notably increased in HSV CNS disease. PCR should always be performed on CSF.

2. Imaging and other studies

   1. Brain imaging with computed tomography (CT) or preferably magnetic resonance imaging (MRI). Recommended in all infants with HSV CNS disease. Findings include parenchymal brain edema or attenuation, hemorrhage, and destructive lesions, especially in the temporal lobe.

   2. Electroencephalogram (EEG). Should be performed in all neonates suspected to have CNS involvement (seizures, abnormal CSF, abnormal neurologic examination). EEG is often abnormal very early in the course of the CNS disease; it may show focal or multifocal epileptiform discharges before abnormal changes are detected by CT or MRI.

1. Antepartum. The history of genital herpes in a pregnant woman or in her partner(s) should be solicited and recorded in the prenatal record. If a positive history is obtained, the following steps may be taken:

   1. Antiviral therapy. Acyclovir or valacyclovir may be given to pregnant women who have a primary episode of genital HSV as well as to women with an active infection (primary or secondary) near or at the time of delivery. Multiple trials showed that prophylactic acyclovir beginning at 36 weeks' gestation reduces the risk of clinical HSV recurrence at delivery, cesarean delivery, and HSV viral shedding at delivery. Valacyclovir in randomized studies also demonstrated similar results. These studies did not identify any neonatal side effects from maternal suppressive therapy. These infants will need to be monitored closely because the risk of neonatal HSV infection is not totally eliminated. See dosing in Chapter 148.

   2. If there are no visible lesions at the onset of labor or prodromal symptoms, vaginal delivery is acceptable.

   3. Delivery by cesarean is recommended in women who have clinically apparent HSV infection. Debate exists if membranes have already been ruptured for >4 hours. Most experts still recommend cesarean delivery. All neonates delivered by cesarean should be monitored closely because neonatal HSV infections have occasionally occurred despite delivery before the membranes rupture.

   4. The ultimate preventive strategy might be the development of a vaccine to prevent HSV infection in the pregnant woman and her newborn infant. An inactivated glycoprotein-D-adjuvant vaccine has been evaluated and shown to be 70% effective in seronegative women (for both HSV-1 and HSV-2), but it is not effective in men or seropositive women.

2. Neonatal treatment

   1. Infants born to mothers with a genital lesion. If it is a known recurrent lesion and the infant is asymptomatic, the infection rate is 1–3%. Educate the parents regarding the signs and symptoms of early herpes infection. Consider surface (screening) cultures of the infant at 12–24 hours of age. Treat if symptoms develop or if the culture is positive. If the maternal infection is primary, or the first episode nonprimary, the risk to the infant is high (57% for primary and 25% for the first-episode nonprimary), and most clinicians recommend empirical acyclovir therapy after cultures have been obtained. Serologic testing of the mother will help classify the mother's infection (recurrent, primary, or first episode nonprimary).

   2. Pharmacologic therapy. Neonates with HSV disease should be treated with intravenous acyclovir at 60 mg/kg/d, divided, every 8 hours (20 mg/kg/dose). The dosing interval of intravenous acyclovir may need to be increased in premature infants, based on their creatinine clearance. Duration of therapy is 21 days for patients with disseminated or CNS disease and 14 days for those with SEM disease. All patients with CNS involvement should have a repeat lumbar puncture at the end of intravenous acyclovir therapy to determine whether CSF is PCR negative. Those infants who remain PCR positive should receive intravenous acyclovir therapy until PCR negativity is achieved. Absolute neutrophil counts should be followed twice weekly during the course of therapy. Lower dose acyclovir is associated with a higher morbidity and mortality and should be avoided. Trifluridine is the treatment of choice for ocular HSV infection in the neonate.

      Oral acyclovir suppressive therapy is recommended for 6 months after treatment of acute neonatal HSV disease. In particular, improved neurodevelopmental outcome has been observed with suppressive therapy after HSV CNS disease. Moreover, suppressive therapy has been associated with reduced recurrences of skin lesions after other forms of HSV. The oral acyclovir dose is 300 mg/m²/dose 3 times per day for 6 months.

3. Breast-feeding. The infant may breast-feed as long as no breast lesions are present on the mother, and the mother should be instructed in good hand washing technique.

4. Parents with orolabial herpes. Parents should wear a mask when handling the newborn and should not kiss or nuzzle the infant.

Antiviral therapy, especially high-dose acyclovir (60 mg/kg/d) has greatly reduced mortality for neonatal HSV infection. In the preantiviral era, 85% of patients with disseminated neonatal HSV disease died by 1 year of age, as did 50% of patients with CNS disease. With current antiviral therapy, 12-month mortality has been reduced to 29% for disseminated disease and 4% for CNS disease. Predictors of mortality include disease severity (pneumonia, DIC, seizures, and hepatitis), virus type (HSV-1 in systemic disease, HSV-2 in CNS disease), and prematurity. Systemic infection in premature infants is associated with near 100% mortality. Improvements in morbidity rates have not been as dramatic as with mortality. The proportion of survivors of disseminated neonatal HSV disease who have normal neurologic development has increased from 50% in the preantiviral era to 83% today. In the case of CNS disease, morbidity in survivors has not changed, with only ∼30% developing normally by 12 months of age. Persistently positive CSF PCR after 4 weeks of acyclovir therapy is associated with poor neurodevelopmental outcome. In contrast to the disseminated or CNS disease, morbidity after SEM disease has dramatically improved during the antiviral era, with <2% of acyclovir recipients having developmental delays. Survivors of neonatal HSV infections should undergo developmental assessments regularly. Cutaneous recurrences are relatively common (∼50%), especially for SEM disease. Suppressive oral acyclovir therapy may have a role in decreasing cutaneous recurrences and improves neurodevelopmental outcome.