Herpes simplex virus (HSV) infections in the neonatal period continue to be troublesome for practitioners, despite advances in neonatal medicine. Morbidity and mortality have decreased secondary to therapeutic advances and with current antiviral therapeutic strategies. HSV was first described in the 1930s, and at that time mortality was 100%. In the 1970s, the drug vidarabine was introduced, but it was extremely toxic to the neonate, and there was little improvement in outcome. With the development of acyclovir in the 1980s, there was a vast improvement in overall survival of these infected infants. At present, mortality of infants with the 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.
At present, there are eight recognized groups of herpes viruses. These include 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.
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, thus causing an increase in spreading of HSV. By age 5, 35% of black children are infected by HSV-1, and 18% of white children are infected. However, by adulthood, these differences have disappeared, and the percentage of adults testing positive for HSV-1 is 70% to 80%. 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.
Due to the high incidence of HSV infection in the general population and low incidence of herpes simplex neonatorum, it is thought that mothers with established HSV infections, and therefore a strong immune response to the virus, are less likely to transmit the infection to their newborns. Consistent with this, the majority of cases of herpes simplex neonatorum are babies born to younger mothers who have no prior history of herpes simplex symptoms, and are most likely experiencing their primary HSV infection near the time of delivery.
The HSV is a double-stranded DNA virus which 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 the 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.
The incidence of herpes simplex infections at any time in the neonatal period is approximately 9.6 per 100,000 births in the United States. Intrauterine or congenital infection of HSV occurs in approximately 1 in 300,000 deliveries. These infants usually have a triad of clinical findings consisting of cutaneous manifestations, ophthalmologic findings, and neurologic findings. 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 the disseminated disease often present in the first 3 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. Clinical manifestations of CNS disease alone or in association with the disseminated disease include seizures, lethargy, irritability, tremors, poor feeding, temperature instability, bulging fontanel and pyramidal tract signs. 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 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 a low mortality but reoccurs in 90% of patients. If SEM is left untreated, 75% of infants will develop disseminated or CNS disease.
Early recognition and treatment continue to be needed for a good outcome in these infants. Despite improvements in laboratory testing, since 1981 no significant change has been made from the onset of symptoms to the start of treatment with antiviral therapy. At present, viral culture continues to be the “gold standard” for official verification of HSV infection. Cultures should be obtained from lesions which are scraped or from the mucous membranes and transported to a viral lab on ice. Also, it should be noted that virus can also be cultured from cerebrospinal fluid (CSF), blood, urine, stool, rectum, oropharynx and the conjunctivae. After the virus is inoculated into the cell culture system and grows, it may be then 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 rapid diagnosis of HSV in the clinical setting. PCR is very accurate with a reported sensitivity of 80% and an overall specificity of 71%. This high sensitivity is mainly dependent on how the specimens are collected and if they are collected properly. PCR is a rapid assay detecting DNA sequence of HSV in the given sample. Although PCR is a rapid form of detection, there still has to be a high index of suspicion by the clinician to order the appropriate test and if positive to start treatment as soon as possible. A Tzank smear, not often performed anymore, and much less expensive looks for multi-nucleated giant cells in any lesion that may be suspicious of HSV. One must have an adequate sample of lesions to scrape, and if giant cells are present, it doesn’t differentiate between HSV-1, HSV-2 or varicella zoster. If a Tzank is done on a patient, it is recommended that one also send HSV cultures on the same sample. Other laboratory studies may be abnormal, but not diagnostic, yet may be suggestive of HSV infection include leukopenia, thrombocytopenia, elevated liver enzymes, hypoglycemia and elevated protein in the CSF.
Prompt treatment of these infants is critical to have a favorable outcome. First and foremost is ABC; airway, breathing, and circulation, as these infants can be extremely ill on presentation. They may require intubation and placement on ventilators and or can have severe hypotension requiring volume boluses and pressors for blood pressure support. However they present, once they are respiratory, neurologically and hemodynamically stable, one may start appropriate intravenous antiviral therapy. Congenital HSV is one of the most devastating of the four disease caused by HSV and has the highest morbidity. However, even though the damage to the infant was done in-utero, these 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 the eyes for signs of keratitis or optic atrophy. These infants will require long care follow-up and will need extensive developmental pediatric care for life. Infants with disseminated or CNS disease should be treated with intravenous (IV) acyclovir 20 mg/kg/dose every 8 hrs 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. Clinical trials have shown that this treatment with acyclovir, 60 mg/kg/day, improves outcome and has improved rates of survival when compared to the previously recommended dose of 30 mg/kg/day. 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 SEM disease has dramatically improved with the use of acyclovir. In the high dose study of 60mg/kg/day, no patients had any neurological sequelae at 12 months of age. 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.
Currently, the recommendations are that 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 no prior history of HSV, whether it be C-section or vaginal delivery, should be screened more vigorously. These infants require skin, and mucosal HSV cultures (conjunctivae, mouth, nasopharynx and rectum, and scalp electrode site if present), blood for HSV PCR, CSF for indices and HSV PCR, and IV acyclovir should be started pending lab results. If the mother has documented or assumed the first-episode infection, and the neonate's evaluation results are negative, the infant should be treated empirically with IV acyclovir for ten days to prevent progression from neonatal infection to disease. However, if these lab studies are positive, then treatment should be 14 to 21 days, followed by a negative HSV PCR at the completion of treatment. 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, blood for HSV PCR.
There remains some controversy on prophylactically treating these infants for the first year of life after an infection with HSV during the neonatal period. A large study was performed from 1997 through 2008 and showed some promise. Their data supported the use of suppressive therapy with 300 mg oral acyclovir per square meter per dose administered three times daily for 6 months after the initial treatment of neonatal HSV disease. Also, babies with skin, eye, and mouth disease can benefit because therapy helps to prevent kin recurrences, whereas babies with CNS disease may have additional benefit concerning neurodevelopmental outcomes. However, they lost 38% of infants to long-term follow-up, and the Bayley Scales of Development assessment was not able to be performed. Any woman in labor that has lesions that resemble that of HSV should be tested for HSV via PCR. Currently, there are ongoing early trials for an HSV-2 vaccine, and the preliminary results appear promising.