Neonatal Herpes Encephalitis Caused by a Virologically Confirmed Acyclovir-Resistant Herpes Simplex Virus 1 Strain

Abstract

A neonate with herpes simplex virus 1 encephalitis was treated with intravenous acyclovir. During the course of therapy, the infection became intractable to the treatment and a mutation in the viral thymidine kinase gene (nucleotide G375T, amino acid Q125H) developed. This mutation was demonstrated in vitro to confer acyclovir resistance. CASE REPORTA 13-day-old boy was admitted to National Defense Medical College Hospital due to lethargy and failure to thrive. He was born at 39 weeks 5 days of gestation and 2,558 g birth weight to a healthy 35-year-old mother (gravida 2, para 2). Group B streptococcus (GBS) was detected from the mother's vagina in the third trimester, but the baby's bacterial culture tests performed at birth, including throat, skin, and blood analyses, were negative for GBS. The mother did not have a history of genital herpes. Her herpes simplex virus 1 (HSV-1) and HSV-2 serostatus was not examined, and her history of acyclovir (ACV) use was not clear. Furthermore, the genital swab culture examination for HSV was not performed. On admission, physical examination of the boy revealed skin blisters on the forehead and upper lip. A swab from the blister showed positive and negative reactions for the specific antigens of HSV-1 and HSV-2, respectively, in a direct immunofluorescent antibody assay (Denka Seiken Co. Ltd., Tokyo, Japan) performed by a qualified clinical laboratory (SRL Inc., Tokyo, Japan). A serum sample collected on admission showed positive and negative reactions in the enzyme-linked immunosorbent assay for detection of anti-HSV IgM and IgG antibody (SRL Inc.), respectively. A lumbar puncture revealed pleocytosis (547 cells/l) and an elevated protein level (168 mg/dl) in the cerebrospinal fluid (CSF). The CSF was also positive for HSV-1 DNA, which was determined by a previously reported method (1) in PCR testing (SRL Inc.). The boy was diagnosed as having neonatal herpes encephalitis (NHE), and intravenous highdose ACV (60 mg/kg/day) treatment was initiated. His general status improved with resolution of the skin lesions within a few days of the beginning of treatment. However, the viral load in the CSF determined by TaqMan-based quantitative real-time PCR (SRL Inc.), which dropped temporarily, increased again after 4 weeks from the initiation of ACV treatment (Fig. 1A) without obvious deterioration in clinical symptoms. Because the standard dose of ACV was given and drugs which have antagonistic effects for ACV were not used, we assumed that an ACV-resistant HSV-1 strain had developed. The ACV concentration in the CSF was not measured. Foscarnet, an antiviral drug recommended for treatment of ACV-resistant HSV infections (2), was not immediately available. Therefore, vidarabine (15 mg/kg/day) was added to the therapeutic regimen from the fifth week of the treatment course. Subsequently, HSV-DNA in the CSF decreased to a level that was finally undetectable; hence, the antiviral drug treatment was terminated. Because virus isolation from the CSF of the patient was unsuccessful, as is c...

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