Herpes Simplex Virus Infection in Neonates

Abstract & Commentary

By Hal B. Jenson, MD, FAAP, Professor of Pediatrics, Tufts University School of Medicine, and Chief Academic Officer, Baystate Medical Center, Springfield, MA, is Associate Editor for Infectious Disease Alert

Dr. Jenson is on the speaker's bureau for Merck.

Synopsis: Neonatal herpes simplex virus (HSV) infection remains a rare and serious disease. It is also treatable with early initiation of acyclovir. The incidence of neonatal HSV infection overlaps that of bacterial meningitis. Both entities must always be considered in the evaluation of symptomatic neonates.

Source: Caviness AC, et al. The prevalence of neonatal herpes simplex virus infection compared with serious bacterial illness in hospitalized neonates. J Pediatr. 2008;153:164-169.

A retrospective study of all 5,817 neonates (≤ 28 days of age) admitted from the Emergency Department to Texas Children's Hospital from 2001 through 2005 found that 8.6% (95% CI, 7.9-9.3%) had documented viral infections (8.4% non-HSV and 0.2% HSV), and 4.6% (95% CI, 4.1-5.2%) had documented serious bacterial infections. The most common viruses identified were respiratory syncytial virus (47%), rhinoviruses (16%), and enteroviruses (13%), with only 10 cases (2%) caused by HSV. All three forms of neonatal HSV disease were observed: three had disseminated disease, three had central nervous system disease, and four had skin, eye, and mouth disease. There were 21 cases of bacterial meningitis, most commonly caused by group B streptococcus (57%) and Escherichia coli (14%).

Neonates in the second week of life had the highest incidence of HSV infections (0.6%), with a higher prevalence among hypothermic neonates (1.1%) than among febrile neonates (0.3%), although this was not statistically significant. The prevalence of all HSV infections (0.2%) was two times lower than bacterial meningitis (0.4%), although confidence intervals of point estimates overlapped.

Of the 204 neonates with fever and pleocytosis, 1% (95% CI, 0.1-3.5%) had HSV meningitis and 5.4% 95% CI, 2.7-9.4%) had bacterial meningitis. Febrile neonates with polymorphonuclear cell pleocytosis had a statistically higher prevalence of bacterial meningitis (14.9%) than HSV infection (0.0%), and febrile neonates with mononuclear cell pleocytosis had a significantly higher prevalence of HSV infection (1.6%) than bacterial meningitis (0.8%).

Of the 10 neonates with HSV infection, five were euthermic, three were febrile, and two were hypothermic. Of the three neonates with confirmed HSV infection that presented with fever, one was well appearing, one was lethargic, and one had a vesicular rash on the eyelid. Also, six of the 10 neonates with HSV infection had a vesicular rash: five (one with central nervous system disease and four with skin, eye, and mouth disease) had vesicular lesions on the scalp (3), eyelid (1), or generalized lesions (1); and one (with fever and CNS disease) had vesicular lesions in the genital area after admission to the hospital.

Commentary

Bacteremia and bacterial meningitis are the major concerns when evaluating febrile neonates. Neonatal HSV infection is a rare but important cause of neonatal disease. It is important because of its severity and because it is a treatable viral infection. There are three forms of neonatal HSV infection that are often discussed: 1) disseminated disease, involving the central nervous system, liver, and lungs; 2) central nervous system disease only; and 3) skin, eye, and mouth disease. There should be caution in using these discrete categories, as there is evidence of other involvement that is inapparent at the time of treatment: cases of HSV neurological involvement and sequelae have been documented following appropriate management for skin, eye, and mouth disease.

This study of 5,827 hospitalized neonates found that the incidence of HSV infection (0.2%; 95% CI, 0.1-0.3%) was not statistically different from bacterial meningitis (0.4%; 95% CI, 0.2-0.6%) but lower than all serious bacterial infections (4.6%). These results underscore that vertically transmitted HSV must be considered in all neonates who present with fever or hypothermia, or with suggestive symptoms, even in the absence of fever. This is especially true for neonates presenting with symptoms during 7-21 days of life, when most cases of neonatal HSV infection present.

These results also underscore the insensitivity of fever to identify serious infections in neonates; five of the 10 neonates with HSV infection were euthermic. Other suggestive symptoms of HSV infection include constitutional symptoms (eg, lethargy), rash (especially any vesicular rash), seizures, or respiratory distress or elevated hepatic enzymes, which may be evidence of disseminated HSV infection. Focality of seizures is not specific for HSV meningitis in neonates because, in this age group, focal seizures usually progress rapidly to generalized seizures.

To confirm HSV as the etiology, PCR of the CSF for HSV DNA is the most sensitive test for central nervous system involvement, and cultures of vesicular lesions are the most useful test if such lesions are present. Disseminated disease is suggested by respiratory distress or elevated hepatic enzymes. The addition of acyclovir to antibiotics for treatment of neonates with fever or lethargy should always be considered, and acyclovir should be administered if the presentation and initial laboratory findings suggest possible HSV infection, pending PCR results of the CSF, and cultures of the conjunctiva and any vesicular rash, if present. If the neonate is clinically unstable and unable to tolerate a lumbar puncture, appropriate antibiotics for bacterial meningitis and acyclovir for HSV meningitis is usually begun pending subsequent re-evaluation.