Clinical progress note: Evaluation and management of neonatal herpes simplex virus disease.

Abstract

Neonatal herpes simplex virus (HSV) disease has a relatively low incidence compared to other infections in neonates but carries significant morbidity and mortality risks. Neonatal HSV disease occurs in infants up to 42 days of age, and the incidence is approximately 1500 infants annually in the United States or 5–33 per 100,000 live births.1, 2 The adoption of high-dose acyclovir as the current standard of care treatment has greatly improved morbidity and mortality in neonatal HSV infection. However, morbidity, including resultant neurodevelopmental delays, remains at 45% of patients with central nervous system (CNS) disease, and mortality in disseminated disease still approaches 41%.3 We summarize the current literature regarding best practices for the evaluation and management of neonatal HSV infections. We performed a PubMed database search in October 2022 with the terms “neonatal,” “herpes simplex virus,” and “HSV” and limited the selected articles to those published within the past 5 years. We performed an additional database search to cross-reference literature using Ovid Medline in January 2023 using the terms “neonatal HSV” and “neonatal herpes virus.” We additionally included the American Academy of Pediatrics Red Book: Report of the Committee on Infectious Diseases as it is a seminal reference for pediatric infectious diseases evaluation and management. Neonatal HSV is most commonly acquired by passage through the birth canal. Both HSV-1 and HSV-2 can cause any form of neonatal HSV disease, but the majority of cases are now due to HSV-1.2, 4 Transmission occurs peripartum in about 85% of cases and postpartum in 10%.1 Postpartum transmission is most commonly from a family member or caregiver with an active infection on their hands or mouth.5 Mothers with a first-time primary HSV infection during pregnancy are at the highest risk of transmitting HSV to their infants, as they do not yet have HSV antibodies that would pass transplacentally to provide some protection for their infants.2 The risk of transmission in the setting of a primary genital HSV infection is estimated to be 25%–60%.5 Mothers with a prior HSV-1 or HSV-2 infection who acquire the other HSV type during pregnancy (known as a first-episode nonprimary infection) as well as mothers with recurrent HSV infection are at lower risk for transmitting to their infant because of the presence of antibodies.1 The risk of transmission to infants born to a mother with recurrent infection is under 2%.5 However, the majority of infants who contract neonatal HSV disease are born to women without a history or clinical findings of genital HSV disease. Thus, a lack of maternal infection history should not rule out an HSV diagnosis in an infant. While annual incidence has been estimated at 1500 infants a year in the United States,2 more recent studies suggest this incidence may be increasing. A large, longitudinal cohort study of more than 2 million births estimated an increase in incidence from 3.4 per 10,000 births in 2009 to 5.3 per 10,000 births in 2015.6 Another cross-sectional study of 26,533 infants evaluated for CNS infection in emergency departments across the United States found a prevalence of 0.42% infants under 60 days old, or 1 in 237, with the highest frequency in the second week of life and substantially lower frequency in the 2nd month of life.7 Neonatal HSV disease is classified into three categories: skin, eye, and mouth (SEM), CNS, and disseminated disease. SEM disease is isolated to skin lesions or mucous membranes, most commonly the mouth or eye, and is the most common manifestation of neonatal HSV disease occurring in 45% of infants. Over 80% of infants with SEM disease have skin vesicles. CNS disease occurs in 30% of infants with neonatal HSV disease and is characterized by neurologic symptoms such as seizures (sometimes focal), irritability, poor feeding, and temperature instability. The remaining 25% of neonatal HSV disease is disseminated disease involving multiple organs, most commonly the liver, lungs, and CNS, with CNS involvement occurring in infants with disseminated diseases in up to 75% of cases. Disseminated HSV can also include the adrenal glands. Specific symptoms should prompt evaluation for HSV disease: seizures, lethargy, ill-appearance, fevers (particularly in the first 3 weeks of life), skin vesicles, or maternal fever 48 h before or 48 h after delivery.5, 8 However, the presentation of disseminated HSV infection can be nonspecific, and clinicians should maintain a high index of suspicion for any infant with sepsis, liver dysfunction, disseminated intravascular coagulation, or pneumonia (especially hemorrhagic).5 Infants with disseminated disease and CNS disease also develop skin vesicles in about two-thirds of cases.9 Disconcertingly, infants with HSV disease may not present with fever at all; instead, they may present with nonspecific symptoms such as hypothermia, ill appearance, respiratory distress, and poor feeding.10 Hypothermia in particular has been associated with neonatal HSV disease and should prompt evaluation for HSV. In a study of infants with hypothermia, the prevalence of HSV was 2% of the infants who had HSV testing performed.11 The age of presentation varies, as infants presenting with SEM or disseminated disease typically present around 10–12 days of life, and infants with CNS disease present later around 16–19 days of life.1, 2 Certain lab findings should raise suspicion for neonatal HSV disease: CSF pleocytosis, elevated alanine aminotransferase (ALT), leukopenia, and thrombocytopenia.8 Infants undergoing evaluation for neonatal HSV should have surface swabs obtained from the eye, nasopharynx, mouth, and rectum and sent for culture or polymerase chain reaction (PCR), as well as blood and CSF PCR. Any suspicious skin lesions should also be swabbed and sent for culture or PCR. Although viral culture remains the gold standard, PCR is commonly used due to quicker turnaround times and high sensitivity.1 One single-center study found PCR resulted 6.8 days sooner than culture, without sacrificing sensitivity or specificity.12 Nationally, rates of HSV testing vary significantly.7 HSV testing has been associated with a 23% longer length of stay; however, this increase in resource utilization should be balanced with the decreased risk of morbidity and mortality.10, 11, 13 Acyclovir is the only recommended treatment for neonatal HSV disease and should be started empirically in any patient with clinical suspicion. Before antiviral therapy, mortality from CNS disease and disseminated disease was 50% and 85%, respectively. However, high-dose acyclovir (20 mg/kg/dose every 8 h) has decreased the mortality to 4% for CNS disease and 30% for disseminated disease.2, 14 Treatment duration is 14 days of intravenous acyclovir for SEM disease and 21 days for CNS or disseminated disease (see Figure 1). Intravenous acyclovir is associated with reversible nephrotoxicity and neutropenia. It is recommended that infants have twice weekly complete blood counts with differentials and daily creatinine levels for monitoring purposes. Infants with CNS disease should have a repeat lumbar puncture with HSV PCR testing before the end of the 21 days. If the PCR is still positive, acyclovir is continued for an additional week. A repeat negative HSV PCR of the CSF is required before discontinuation of acyclovir therapy. All infants with neonatal HSV disease should be evaluated by ophthalmology for ocular involvement and have neuroimaging performed (preferably magnetic resonance imaging but head ultrasound or computed tomography are alternative options).5 Infants with ocular infection including superficial keratitis may be started on 1% trifluridine or 0.15% ganciclovir ophthalmic drops in addition to parenteral acyclovir.5 All infants with any form of neonatal HSV disease should be transitioned from parenteral acyclovir to oral acyclovir for suppressive therapy at a dosage of 300 mg/m2/dose three times a day for a duration of 6 months. This has been associated with reduced recurrence of skin lesions and improved neurologic outcomes in infants with CNS disease. The practice of empiric acyclovir therapy varies significantly nationally. One large multicenter study calculated the number needed to treat (NNT) with empiric acyclovir to ensure all cases of neonatal HSV were initially treated was 237.7 This number goes down for the youngest age group (0- to 28-day-old infants) to 152 needed to treat. The NNT increases for the second month of life (29- to 60-day-old infants) to 583.7 There is not currently a vaccine to prevent primary HSV infection, although there are several candidates in development.1 Current recommendations by the American College of Obstetricians and Gynecologists include daily suppressive antiviral therapy for all pregnant women with recurrent genital herpes starting at 36 weeks gestation. Cesarean delivery is recommended for mothers with active genital lesions or prodromal symptoms (vulvar pain or burning) at the time of delivery.15 Invasive monitoring including fetal scalp electrodes has been shown to increase the risk for HSV transmission due to disruption of the cutaneous barrier, and its use should be avoided in any women with active lesions.2, 15 Neonatal HSV disease has a wide range of presentations, with symptoms and lab findings that can be seen in other common neonatal infections. Clinicians must maintain a high index of suspicion for this disease even in the absence of characteristic lesions or history. Decisions regarding testing and treatment should balance the risk of adverse outcomes from an unidentified or untreated infection with the risks associated with over-testing and overtreatment (including cost, health system resource utilization, and medication side effects). Current literature emphasizes the variation in disease presentation, evaluation, and empiric treatment practices among different institutions, as well as the effectiveness and relative safety of acyclovir as a treatment. Future areas of study could include the development of an externally validated algorithm to better guide evaluation and management. The authors declare no conflict of interest.