Herpes Simplex Neonatorum

Etiology

There are 8 herpes viruses,  Herpes simplex virus type 1 (HSV-1), Herpes simplex virus type 2 (HSV-2), Cytomegalovirus (CMV), Epstein-Barr virus (EBV),  Varicella-zoster, Human herpesvirus 6 (HHV-6), Human herpesvirus 7 (HHV-7), and human herpesvirus 8 (HHV-8). Herpes simplex neonatorum is the transmission of either HSV-1 or HSV-2 from the mother to child during gestation via the placenta, during delivery via vaginal secretions, or perinatally via direct contact with active lesions.

Epidemiology

The incidence of HSV-1 and HSV-2 has changed over the past few decades. Currently, over one-third of the world’s population has recurrent HSV infection. By age 5, 35% of black children are infected by HSV-1, and 18% of white children are infected. Genital herpes is predominately caused by HSV-2 in the United States; however, in Japan, the predominant cause of genital herpes is caused by HSV-1.[1] 

Pathophysiology

The HSV is a double-stranded DNA virus that is large and has a surrounding lipid envelope. The DNA in HSV-1 and HSV-2 have many similarities, thus causing much cross-reactivity in antibody production. The virus enters the body through epithelial cells or mucous membranes. When it has replicated within the nucleus of the cells, it travels down the axon to the neurons, where it can establish a latent infection.

History and Physical

The cutaneous findings are scarring, active lesions, hypo, and hyperpigmentation of the skin, cutis aplasia, and macular rashes. In the eyes, one may see microphthalmia, retinal dysplasia, optic atrophy, and or chorioretinitis. Neurologically one can see microcephaly, encephalomalacia, hydranencephaly, and intracranial calcifications. Infants with disseminated disease often present in the first three weeks of life with symptoms of sepsis. Multiple organ systems can be affected by this illness, causing jaundice, abnormal liver function, hypoglycemia, hypotension, coagulopathy, pneumonia, and even respiratory failure. Encephalitis is present 75% of the time in disseminated disease, thus causing seizures.  Rarely do these infants present with vesicular lesions. Death usually results from shock, progressive liver failure, severe coagulopathy, respiratory failure, and progressive neurological deterioration. These infants usually present around the second or third week of life. They may initially have a fever, poor feeding, or present with a sudden episode of seizures or apnea. Between 60% and 70% of babies classified as having CNS disease have associated skin lesions at some point in the course of their illness. Skin, eye, and mouth disease also presents in the second to the third week of life. Typical vesicular lesions on an erythematous base are the presenting sign. Rarely are lesions present in the mouth. Conjunctivitis is often present and, left untreated, may develop into herpetic keratitis and possibly even corneal blindness. SEM has low mortality but reoccurs in 90% of patients.[2] 

Evaluation

Viral culture is the “gold standard” for verification of HSV infection. Cultures should be obtained from lesions that are scraped or from the mucous membranes and transported to a viral lab on ice. The virus can also be cultured from cerebrospinal fluid (CSF), blood, urine, stool, rectum, oropharynx, and conjunctivae. After the virus is inoculated into the cell culture system and grows, it may then be further identified as HSV-1 or HSV-2. The greatest viral yield continues to be isolated from intact skin lesions, which are scraped and from the conjunctivae. Polymerase chain reaction (PCR) allows for the rapid diagnosis of HSV in the clinical setting. PCR is very accurate, with a reported sensitivity of 80% and an overall specificity of 71%.  A Tzank smear looks for multinucleated giant cells in any lesion that may be suspicious of HSV. Other laboratory studies may be abnormal but not diagnostic, yet may be suggestive of HSV infection, including leukopenia, thrombocytopenia, elevated liver enzymes, hypoglycemia, and elevated protein in the CSF.[3] 

Treatment / Management

They may require intubation and placement on ventilators and or can have severe hypotension requiring volume boluses and pressors for blood pressure support. Once they are respiratory, neurologically, and hemodynamically stable, one may start appropriate intravenous antiviral therapy. Congenital HSV-infected infants still require therapy. Intravenous (IV) acyclovir for 21 days is thought to prevent further replication of the virus and to decrease the number of future outbreaks. CT or MRI of the brain should be performed to evaluate the brain for any signs of abnormal findings. A pediatric ophthalmologist should evaluate for signs of keratitis or optic atrophy. Infants with disseminated or CNS disease should be treated with intravenous (IV) acyclovir 20 mg/kg/dose every 8 hours for a total of 21 days. If CSF is unable to be obtained for culture or PCR, one should err on the side of caution and treat for a full 21 days.  Also, at the end of the 21-day treatment, a blood HSV PCR should be sent to ensure the virus has been eliminated. Morbidity from disseminated (SEM) disease has dramatically improved with the use of acyclovir.  Duration is limited to a 14-day treatment, and a blood HSV PCR should be obtained, and if the results are positive, the infant should be treated for another seven days or until a negative result is obtained. In premature infants with HSV disease requiring acyclovir, the dosing interval may need to be increased secondary to their decreased creatinine clearance. All patients receiving acyclovir should be followed twice weekly for signs of a low absolute neutrophil count, as this occurs in approximately one-fifth of all patients.[4][5][6] (A1)

After IV treatment, suppressive therapy with oral acyclovir 300 mg/m² per dose three times per day for six months.[5](A1)

Differential Diagnosis

• Neonatal sepsis

• Pediatric aphthous ulcers

• Pediatric chickenpox

• Pediatric cytomegalovirus infection

• Pediatric enteroviral infections

• Pediatric erythema toxicum

• Pediatric sepsis

• Zoster