Plasma and cerebrospinal fluid herpes simplex virus levels at diagnosis and outcome of neonatal infection

Abstract

Objective: To evaluate the utility of quantitative herpes simplex virus (HSV) polymerase chain reaction (PCR) levels for prognosis and management of neonatal HSV disease.

Study design: Clinical and virologic data were abstracted by medical record review from neonatal HSV cases treated at Seattle Children's Hospital between 1993 and 2012. HSV PCR results from plasma (n = 47), cerebrospinal fluid (n = 56), or both (n = 40) at the time of diagnosis were available from 63 infants; 26 with skin-eye-mouth (SEM), 18 with central nervous system (CNS), and 19 with disseminated (DIS) disease.

Results: Plasma HSV PCR was positive in 78% of the infants with SEM, 64% with CNS and 100% with DIS disease. Mean plasma viral level was 2.8 log10 copies/mL in SEM, 2.2 log10 copies/mL in CNS, and 7.2 log10 copies/mL in DIS infants. The HSV levels were higher among infants who died compared with surviving infants, 8.1 log10 copies/mL (range 7.7-8.6) vs 3.8 log10 copies/mL (range 0.0-8.6), P = .001, however, level of HSV DNA in the cerebrospinal fluid or in plasma did not correlate with neurologic outcome. Dynamics of HSV clearance from plasma during high-dose acyclovir treatment showed single-phase exponential decay with a median viral half-life of 1.26 days (range: 0.8-1.51).

Conclusions: Plasma HSV levels correlate with clinical presentation of neonatal HSV disease and mortality, but not neurologic outcome.

Figure 1

Plasma (1a) and CSF (1b) HSV viral levels at diagnosis according to clinical classification and viral type. Values below the limit of detection (dotted line) were separated for visual clarity. Horizontal bars indicate the median HSV DNA level in copies/mL.

Figure 2. HSV viral clearance in six infants with DIS disease during acyclovir treatment

Black horizontal lines represent duration of IV ACV treatment: in infant 3, acyclovir was stopped prior to clearance of HSV viremia. Viral levels continued to decrease and became undetectable after discontinuation of acyclovir. Infant 6 experienced an increase in HSV DNA copy number shortly after the first discontinuation of acyclovir. This was associated with an increase in serum hepatic transaminases, which prompted retreatment. No acyclovir resistance mutations were detected and the viremia eventually cleared after discontinuation of a second course of acyclovir. This infant was infected with HSV2 and also was positive for CSF PCR. He was neurologically normal at age 5 years. Dashed lines are fit on a simple exponential decay model: for infant 6, only data during the primary decay phase (through day 28) were modeled.