Background: Neonatal herpes simplex virus (HSV) infections are one of the most clinically challenging infections of the newborn period because of the often subtle presentation and devastating consequences of a missed diagnosis. The availability of HSV polymerase chain reaction (PCR) testing has led to widespread use of both HSV testing and empiric therapy but guidelines for use are lacking. Studies to date, mainly based on emergency room data, show inconsistent and often inappropriate testing and empiric therapy. Our study examined patterns of cerebrospinal fluid (CSF) HSV PCR testing and empiric acyclovir therapy in hospitalized febrile neonates at a tertiary care Children’s Hospital.

Methods: We used chart review to identify infants age ≤ 60 days with diagnostic codes of fever hospitalized from 1/1/13-1/13/16. Laboratory data were used to identify infants hospitalized with CSF HSV PCR testing who did not have a diagnostic code of fever. Inclusion criteria were documented or reported fever of ≥38 degrees Celsius and a lumbar puncture completed at our institution with at least a cell count. Variables were abstracted by clinical record review. Primary outcomes were CSF HSV PCR testing and empiric acyclovir therapy. Associations between demographic and clinical variables and these outcomes were evaluated by logistic regression. Data are reported as proportions, median (Q1, Q3), and odds ratios (95% confidence interval).

Results: 564 infants met inclusion criteria. The median age at hospital admission was 28 days (18,42). A proven viral or bacterial infection was identified in 225 (39.9%); 5 with bacterial meningitis and 1 with HSV meningitis. CSF HSV PCR testing was sent in 26.2% of the infants and empiric acyclovir was started in 17.8%. CSF enteroviral PCR testing was sent in 28.9%. Significant positive associations found between HSV testing/empiric therapy were younger age, seizure, history of maternal vaginal lesions, postnatal HSV contact, vesicular lesions on exam, poor tone, bulging fontanelle, and CSF abnormalities. Significant positive associations were also found with season at time of admission (summer/fall) and enteroviral PCR being sent. Significant negative associations found between HSV testing/empiric therapy were the presence of a focal source of infection on exam, leukocytosis, and thrombocytosis. Both HSV testing and empiric therapy led to a longer length of stay.

Conclusions: In this retrospective study of a large cohort of hospitalized febrile neonates, HSV testing and empiric therapy were appropriately associated with risk factors such as seizure, the presence of vesicular skin lesions, and CSF abnormalities. Factors unrelated to HSV risk, such as season of admission and enteroviral CSF testing, were also strongly associated with HSV testing/empiric therapy. Both testing and empiric therapy led to an increased length of stay, which is important given the cost and risk of hospitalization. Criteria to guide appropriate HSV testing and empiric treatment are needed.