Continuing Education Activity
Herpes simplex virus (HSV) infections in the neonatal period continue to be troublesome for practitioners. In the 1970s, the drug vidarabine was introduced, but it was extremely toxic to the neonate, and there was little improvement in outcomes. The development of acyclovir in the 1980s led to significant improvements in the survival of infected infants. Mortality of infants with the disseminated disease has decreased from 85 percent to 29 percent, and patients with central nervous system (CNS) disease has decreased from 50 percent to roughly 4 percent in industrialized countries. This activity reviews the evaluation and management of neonatal herpes and stresses the role of the interprofessional team in the care of affected patients.
Objectives:
- Identify the etiology of neonatal herpes.
- Describe the evaluation of neonatal herpes.
- Outline the treatment options available for neonatal herpes.
- Explain interprofessional team strategies for improving care coordination to advance outcomes for patients with neonatal herpes.
Introduction
With the development of acyclovir in the 1980s, there was a vast improvement in the overall survival of these infected infants. At present, the mortality of infants with disseminated disease has decreased from 85% to 29%, and patients with central nervous system (CNS) disease has decreased from 50% to roughly 4% in industrialized countries. Unfortunately, it remains elevated in developing nations.
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]
After IV treatment, suppressive therapy with oral acyclovir 300 mg/m2 per dose three times per day for six months.[5]
Differential Diagnosis
- Pediatric aphthous ulcers
- Pediatric cytomegalovirus infection
- Pediatric enteroviral infections
- Pediatric erythema toxicum
Pearls and Other Issues
All infants born to mothers with a history of genital HSV have surface and mucosal cultures performed at 24 hours of life and also a blood HSV PCR. If these studies are negative, and the infant is asymptomatic, the infant may be discharged with the mother. Infants born to mothers with active genital lesions and having a prior history of HSV, whether it be C-section or vaginal delivery, are to be screened with mucosal HSV cultures and blood for HSV PCR.
Enhancing Healthcare Team Outcomes
An interprofessional team can improve outcomes for infants with disseminated HSV. The involvement of primary care providers, neonatologists, infectious disease, specialty-trained nurses, and pharmacists is recommended. Prompt recognition and treatment are imperative. Nurses administer treatment, monitor patients, and keep the team apprised of patient status. Infectious disease or pediatric pharmacists review medications and check doses. [Level 5]
Herpes Simplex Neonatorum