Neonatal herpes simplex virus (HSV) disease is a condition that may mimic bacterial sepsis, oftentimes leading to a delay in diagnosis and prompt institution of appropriate testing and treatment. It is imperative that pediatric providers across subspecialties remain aware of this disease and its presentation as it carries significant rates of morbidity and mortality if untreated. This article reviews how proper recognition, diagnosis, and treatment of neonatal HSV disease can minimize neurologic sequelae and decrease mortality.
A 3-week-old neonate was transferred from a referring institution with parental report of 24 hours of fever, lethargy, and witnessed seizure activity. Historical inquiry revealed that she was born at 40 weeks' gestational age via an uncomplicated, spontaneous vaginal delivery to a healthy mother who received prenatal care with negative serologic testing. One week prior to presentation, the patient's mother noticed what she described as “white blisters” around the umbilical stump. After cleansing the area with rubbing alcohol, she noted that they quickly resolved. The patient remained well until 2 days prior to presentation when she was noted to be febrile with temperatures up 100.3ºF. The following day she was noted to be lethargic and experienced a 1-minute episode of right upper extremity shaking. History was negative for symptoms and signs consistent with respiratory infection, emesis, and changes in voiding and stooling patterns; however, a sibling was reportedly ill with a rhinovirus infection 1 week prior to admission.
On presentation to the referring facility, her examination was notable primarily for a fever of 101.5ºF and lethargy. A rash around the umbilicus that was in the process of healing was not blistering or purulent. During the initial examination, she had a brief episode of seizure-like activity consisting of right upper extremity shaking that was self-limited. Neonatal sepsis testing was initiated and a complete blood count revealed a total white blood cell count (WBC) of 18.7 k/muL (differential unavailable). A lumbar puncture was performed, and cerebrospinal fluid (CSF) cytology was remarkable for an elevated WBC count of 33 cells/muL, a red blood cell count of 48 cells/muL, with 18% neutrophils, 76% lymphocytes, and 6% monocytes. CSF chemistries demonstrated a decreased glucose level of 47 mg/dL and elevated protein of 141 mg/dL. Blood, urine, and CSF cultures were collected. CSF enteroviral polymerase chain reaction (PCR) and CSF herpes simplex virus (HSV) PCR were also obtained, and ampicillin at 50 mg/kg/dose every 6 hours and gentamicin at 2.5 mg/kg/dose every 12 hours were started. The infant was then transferred to our institution for further care.
On presentation, she was febrile with temperatures up to 102ºF and intermittently apneic with desaturations to 88%. She was lethargic, and her anterior fontanelle was full but not tense, with an exaggerated Moro reflex and a cluster of periumbilical hypopigmented macules (Figure 1). A serum HSV DNA PCR, surface HSV DNA PCRs (conjunctivae, oropharynx, and rectum), and a respiratory viral PCR panel were collected. Empiric intravenous ampicillin, gentamicin, and acyclovir were started to provide coverage for the most common bacterial and viral etiologies of neonatal fever. The pediatric infectious diseases and neurology departments were consulted. Due to concern for seizure activity, she was started on phenobarbital with a loading dose of 20 mg/kg once, followed by a maintenance dose of 2.5 mg/kg every 12 hours, and continuous video electroencephalogram was instituted that showed evidence of spikes in the left temporal and occipital lobes without epileptiform discharges. High flow nasal cannula was required due to mild hypoxia and brief periods of apnea, which was attributed to possible pneumonitis. Computed tomography (CT) scan of the head without contrast showed hypoattenuation within the left temporal and occipital lobes (Figure 2), and a subsequent magnetic resonance image (MRI) of the brain showed diffusion restriction as well as edema affecting the left temporal, parietal, and occipital lobes in addition to the thalamus and insula (Figure 3), suggestive of viral encephalitis.
Hypopigmented periumbilical macules noted at time of presentation.
Computed tomography of the head, demonstrating hypoattenuation in the left temporal and occipital lobes (arrows).
A magnetic resonance image of the brain showing (from left-to-right) T1-weighted, T2-weighted, and reverse-diffusion weighted images consistent with viral encephalitis. Restricted diffusion (solid arrows) as well as edema (dashed arrows) are seen in the left temporal lobe, parietal lobe, occipital lobe, thalamus, and insula.
By 48 hours of hospitalization, the high-flow oxygen was discontinued, although she remained febrile with temperatures up 101.5ºF. The patient's HSV DNA PCR assays from her mucous membranes were negative at 48 hours, as were the HSV CSF DNA PCR and enteroviral CSF RNA PCR from the referring facility at 72 hours. Despite the negative assays, acyclovir was continued given her history, clinical presentation, and radiologic findings. Nine days after presentation, her serum HSV DNA PCR assay showed as positive for HSV-2, confirming the diagnosis of neonatal HSV disease. Clinically, her fever and lethargy improved while on intravenous acyclovir monotherapy, and she was discharged to a rehabilitation facility to complete the remainder of the 21-day course. Six months of suppressive oral acyclovir was recommended with close observation by the infectious disease and neurology departments.
A Serious Infection
HSV types 1 and 2 are enveloped DNA viruses that belong to the family of human herpes viruses that cause a wide array of symptoms ranging from innocuous “fever blisters” to meningoencephalitis, which has significant potential for morbidity and mortality. HSV types 1 and 2 establish latency after primary infection and can cause recurrent disease and/or asymptomatic shedding.1 Early recognition and treatment of neonatal HSV disease is not only associated with better outcomes, but can also prevent progression to disseminated disease, which has a mortality rate of 54% despite treatment.2,3 Use of antiviral therapy has successfully reduced the prevalence of disseminated disease from 50% to approximately 23%.2 Thus, proper diagnosis and management of neonatal HSV disease depends on the recognition of specific clinical manifestations, the use of correct laboratory methods to enable diagnosis, and the prompt institution of appropriate therapy with parenteral acyclovir, pending results of the investigation.
Epidemiology and Transmission
The incidence of neonatal HSV disease is wide and ranges from 1 in 3,000 to 1 in 20,000 live births1 and an estimated 1,500 cases are diagnosed annually in the United States.4 Transmission occurs primarily via the perinatal route, accounting for approximately 85% of cases.1 Ten percent of infections are transmitted postnatally through direct contact by a caregiver and <5% of infections are acquired via intrauterine transmission, resulting in exceedingly rare congenital infection.1 Infants born to mothers with a primary HSV infection near the time of delivery have a 25% to 60% risk of transmission.1 This is significantly higher when compared to mothers who experience viral shedding because of a recurrent infection, which is <2%.5 Interestingly, inquiring about maternal history of HSV infection is not helpful in making the diagnosis because >75% of infected infants are born to mothers who are asymptomatic or unaware of their HSV status.1,6
Three Manifestations of Neonatal Herpes Simplex Virus
Pediatric providers should be aware that neonatal HSV disease can manifest in several ways: (1) skin, eye, mouth (SEM) disease; (2) central nervous system (CNS) disease, and (3) disseminated disease; the prevalence rates are 45%, 30%, and 25%, respectively.1 Although two-thirds of neonates with disseminated or CNS disease present with skin lesions, they are not always identified at the time of symptom onset, making the diagnosis extremely challenging.1 Most neonatal HSV infections present within the first 6 weeks of life; however, almost all infants develop manifestations of disease within the first month. Those with disseminated and SEM disease are more likely to present between the first and second weeks of life and those with CNS disease, in the second to third weeks of life.7 Although nonspecific, various presenting symptoms of neonatal HSV can provide valuable insight and should raise the suspicion of the provider as to its potential presence. If meningoencephalitis is present, seizures, focal neurologic deficits, and CSF abnormalities are likely to be reported or clinically apparent. This is important in late autumn and winter when enteroviruses are not known to be circulating. SEM disease should always be suspected whenever a vesicular rash is noted in a neonate, regardless of how clinically well they appear. Places where vesicles are commonly found include areas of trauma to the skin, most notably former fetal scalp electrode sites. Lastly, disseminated HSV disease should be suspected in the presence of fever, hepatitis, respiratory distress, and coagulopathy, especially in the absence of a bacteriologic diagnosis.1
Considerations in Diagnosis
Laboratory methods for detecting HSV infection have traditionally included the viral culture, PCR assay, or rapid direct immunofluorescent assay (DFA).1 Historically, the gold standard for diagnosis was isolation of HSV from viral culture. However, advances in technology have increased the use of the HSV DNA PCR assay. DFA was traditionally used as rapid diagnostic alternative to culture, but it is less sensitive than culture, offers little advantage over the PCR assay,8 and hence has fallen out of favor. There is little role for serologic testing due to the presence of transplacentally acquired maternal antibodies that may confound the evaluation.4
Current guidelines recommend all neonates with suspected HSV infection have the following specimens collected: (1) surface swabs of mouth, nasopharynx, conjunctivae, and anus for HSV culture plus an optional PCR assay; (2) skin specimens of vesicles for HSV culture plus an optional PCR assay; (3) CSF sample for PCR assay; and (4) whole blood sample for PCR assay.1 Collecting surface specimens more than 12 to 24 hours after birth decreases the risk for contamination from intrapartum exposure. Viral culture remains the preferred method for surface specimens. However, despite a paucity of data on the performance of the PCR assay on surface samples,1 the PCR assay remains a widely used test for these samples at many institutions. In contrast, the PCR assay on CSF is a sensitive (approximately 75%–100%) and specific (approximately 71%–100%) test for the detection of CNS involvement. It is more sensitive than culture and thus is the preferred test for CSF samples.9 The HSV DNA CSF PCR assay may reveal positive results as early as 1 day after the onset of symptoms. However, a negative result, particularly if the test is performed early during illness, does not rule out the presence of HSV infection, and consideration must be given to retesting when there is high clinical suspicion and a negative PCR for HSV in the CSF.4,9,10 Similarly, the PCR assay of whole blood or plasma is critical in making the diagnosis. One study11 demonstrated that plasma HSV PCR was positive in 78% of infants with SEM, 64% with CNS, and 100% with disseminated disease. Another large retrospective study12 of children age 0 to 19 years with HSV disease demonstrated that the blood HSV PCR might oftentimes be the only positive test. The blood HSV PCR assay was the first positive test in 19% (n = 4/21) and the only positive test in 10% (n = 2/21) of infants (n = 6/21). Of these cases, four patients had disseminated disease and two had CNS disease. This highlights a challenge in diagnosis and the importance of thorough specimen collection despite the high sensitivity and specificity of PCR assays.2,4
Treatment and Sequelae
Given the emergent nature of neonatal HSV disease and the fact that it is associated with high morbidity and mortality rates if untreated, when suspected, parenteral acyclovir should be initiated pending results of the investigation at a dose of 20 mg/kg per dose every 8 hours. Once the diagnosis is confirmed, acyclovir should be continued for a total of 14 days in the case of SEM disease and for a minimum of 21 days in CNS or disseminated disease. It is important to emphasize that there are no data to support the use of oral agents in the treatment of neonatal HSV disease. Regardless of disease type, it is recommended that all infected infants have an ophthalmologic examination and neuroimaging in the form of an MRI, CT, or ultrasound as a part of their overall evaluation. Those neonates with proven CNS involvement should have a repeat lumbar puncture performed near the end of the initial treatment period to document clearance of HSV DNA from the CSF. Although extremely rare, should the PCR remain positive, treatment should be extended for 1 additional week with reassessment of the CSF toward the end of the extended course. The prognosis of treated neonatal HSV infection depends on the type of disease. Infants with sole SEM involvement have a mortality rate of 0% and a 5% chance of adverse sequelae. This is in stark contrast to neonates with CNS disease who have mortality and morbidity rates of 15% and 54%, respectively, and those with disseminated disease whose rates approach 54% and 38%, respectively.3 Presence of seizures at the initiation of antiviral therapy was correlated with abnormal developmental at age 12 months.7
Completion of initial parenteral therapy is followed by suppressive therapy with oral acyclovir for 6 months regardless of disease type, which has been shown to improve neurodevelopmental outcomes as well as prevent recurrent skin lesions. Kimberlin et al.13 demonstrated that infants with CNS disease on suppressive therapy scored higher on neurodevelopmental scales and were less likely to suffer adverse neurologic outcomes. About 69% had normal neurologic outcomes compared to 33% in the placebo group; 19% had severe impairment on suppressive therapy compared to 33% in the placebo group. Dosing of acyclovir is 300 mg/m2 3 times daily, weight-adjusted monthly for growth. Neutropenia is a major side effect of acyclovir and typically occurs early during treatment, so absolute neutrophil count monitoring is recommended at 2 and 4 weeks after initiation of therapy, then continued monthly during the treatment course.1,7
Neonates presenting with vesicular skin lesions, focal neurologic deficits, and/or clinical sepsis with evidence of multisystem organ involvement in the absence of a bacteriologic diagnosis should prompt providers to strongly consider neonatal HSV disease as an etiology. Untreated SEM disease progresses to meningoencephalitis and/or disseminated infection in approximately 75% of neonates. Given the relatively high rates of morbidity and mortality associated with this condition, initiating parenteral acyclovir therapy pending further investigation is imperative. Clinical manifestations, in addition to multisite PCR assays to assess for the presence of HSV DNA, assist in disease classification and diagnosis that ultimately determine duration of therapy as well as overall prognosis. Given the demonstrated finding of improved neurodevelopmental outcomes and skin recurrences, all survivors of neonatal HSV should receive 6 months of suppressive oral acyclovir therapy after completion of parenteral therapy with close clinical monitoring.
- Kimberlin D, Brady M, Jackson M, Long S, eds. Red Book: 2015 Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2015:432–445.
- Whitley RJ, Corey L, Arvin A, et al. , Changing presentation of herpes simplex virus infection in neonates. J Infect Dis. 1988;158(1):109–116. doi:10.1093/infdis/158.1.109 [CrossRef]
- Long S, Pickering L, Prober C. Principles and Practice of Pediatric Infectious Diseases. 4th ed. Edinburgh, Scotland: Elsevier Saunders; 2012.
- Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol. 2007;31(1):19–25. doi:10.1053/j.semperi.2007.01.003 [CrossRef]
- Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant. JAMA. 2003;289(2):203–209. doi:10.1001/jama.289.2.203 [CrossRef]
- Kimberlin DW, Baley JCommittee on Infectious DiseasesCommittee on Fetus and Newborn. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions. Pediatrics. 2013;131(2):e635–646. doi:10.1542/peds.2012-3216 [CrossRef]
- Kimberlin DW, Lin C-Y, Jacobs RF, et al. , Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics. 2001;108(2):223–229. doi:10.1542/peds.108.2.223 [CrossRef]
- Reina J, Saurina J, Fernandez-Baca V, Munar M, Blanco I. Evaluation of a direct immunofluorescence cytospin assay for the detection of herpes simplex virus in clinical samples. Eur J Clin Microbiol Infect Dis. 1997;16(11):851–854. doi:10.1007/BF01700419 [CrossRef]
- Kimberlin DW, Lakeman FD, Arvin AM, et al. , Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. J Infect Dis. 1996;174:1162–1167. doi:10.1093/infdis/174.6.1162 [CrossRef]
- Frenkel LM. Challenges in the diagnosis and management of neonatal herpes simplex virus encephalitis. Pediatrics. 2005;115(3):795–797. doi:10.1542/peds.2004-1941 [CrossRef]
- Melvin AJ, Mohan KM, Schiffer JT, et al. , Plasma and cerebrospinal fluid herpes simplex virus levels at diagnosis and outcome of neonatal infection. J Pediatr. 2015;166(4):827–833. doi:10.1016/j.jpeds.2014.11.011 [CrossRef]
- Cantey JB, Mejías A, Wallihan R, et al. , Use of blood polymerase chain reaction testing for diagnosis of herpes simplex virus infection. J Pediatr. 2012;161(2):357–361. doi:10.1016/j.jpeds.2012.04.009 [CrossRef]
- Kimberlin DW, Whitley RJ, Wan W, et al. , Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med. 2011;365(14):1284–1292. doi:10.1056/NEJMoa1003509 [CrossRef]