Characteristics to Identify Young Infants at Low Risk for HSV

Source: Dantuluri KL, O’Connell NS, Liu G, et al. Identifying infants at low risk for neonatal herpes simplex virus infection. J Pediatric Infect Dis Soc. 2025;14(7):piaf055; doi: 10.1093/jpids/piaf055.Investigators from Wake Forest University, Winston-Salem, NC, and The Ohio State University, Columbus, OH, conducted a retrospective case control study to determine the likelihood of neonatal herpes simplex (HSV) infection in infants evaluated for sepsis without any high-risk characteristics for HSV. Cases were patients <42 days old diagnosed with neonatal HSV at a single institution between 2008 and 2023. Only infants who presented after discharge from their birth hospitalization were included. The diagnosis of HSV was confirmed by polymerase chain reaction (PCR) or culture. Cases were further classified as having mucocutaneous/skin, eye, mouth (SEM), central nervous system (CNS), or disseminated HSV. A total of 4 controls were matched to each case and included infants admitted for a sepsis evaluation within 45 days of the corresponding case. Control group A comprised patients who were tested for HSV and who tested negative. Control group B were infants who were representative of all infants admitted for sepsis evaluation and may or may not have been tested for HSV. If infants in control group B were tested for HSV, the test was negative. High-risk characteristics included seizure activity, skin lesions, cerebrospinal fluid (CSF) pleocytosis (>20 WBC/μL), thrombocytopenia (150,000/μL), elevated alanine aminotransferase (ALT, defined as 1.5 x upper limits of normal), and the presence of critical illness. The proportion of cases and controls with each high-risk characteristic were compared. In addition, multivariate regression analyses were used to assess the difference in the presence of 0 vs ≥1 high-risk characteristic between cases and controls. Separate analyses were conducted in which cases and patients in control groups A or B were assessed, and confounding variables were included in the models.During the study period, 32 infants with neonatal HSV were identified and matched to 64 patients in control group A and 64 in control group B. Demographic characteristics were similar in the cases and controls. Among the cases, 50% had SEM disease. Overall, 31 of 32 cases had at least 1 high-risk characteristic for HSV. The presence of each high-risk characteristic was significantly higher among cases than in controls, including seizures (P <0.001), skin lesions (P <0.001), CSF pleocytosis (P = 0.009), elevated ALT (P = 0.043), thrombocytopenia (P <0.001), and presence of critical illness (P <0.001). The likelihood of having at least 1 high-risk characteristic for HSV was significantly lower in control group A (adjusted odds ratio [aOR], 0.07; 95% confidence interval [CI], 0.01, 0.30) and control group B (aOR, 0.02; 95% CI, 0, 0.08) than in case infants.The authors conclude that, among infants <42 days old presenting for sepsis evaluation, those without HSV are unlikely to have any high-risk characteristics for neonatal HSV.Dr Chang has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The AAP Febrile Infant Guideline1 states that HSV testing should be considered in neonates who present for sepsis evaluations with certain risk factors, including hypothermia. However, universal testing and empiric acyclovir treatment of all hypothermic neonates for a rare infection is unlikely to be cost-effective,2 while targeted testing is challenging due to a lack of robust evidence for risk stratification. As a result, there is wide variability in approach in both hypothermic3 and febrile young infants. (See AAP Grand Rounds. 2021;46[6]:69.)4Data from the current study add an important step toward a more evidence-based approach in deciding which young infants are at low risk for having HSV and could forgo evaluation and empiric treatment. Though the AAP guideline lists leukopenia as a risk factor for HSV infections, leukopenia was not one of the risk factors examined in this study based on previous findings.5 In addition, the AAP guideline considers hypothermia to be a risk factor, but hypothermia did not occur more frequently in HSV cases (16%) than controls (group A 34%, group B 30%; P = 0.162) in this study.Due to the rarity of the infection, the sample size in this study is small and a notable limitation. It also is unclear whether a high-risk characteristic is consistently present early in the clinical course at the time of decision-making around testing, particularly in disseminated disease that can present nonspecifically without skin lesions. (See AAP Grand Rounds. 2022;48[1]):7.)6Well-appearing febrile or hypothermic young infants without any high-risk characteristics for HSV may be able to forgo empiric testing and treatment.Empiric use of acyclovir poses the risk of adverse drug events, including neutropenia, thrombocytopenia, and nephrotoxicity.7 Targeted evaluation and management of neonatal HSV infection has the potential to minimize duration as well as cost of hospitalization in low-risk infants.