This multicenter observational study examined the association between delayed administration of acyclovir and death among neonates with HSV. Delayed receipt of acyclovir >1 day after admission was associated with higher in-hospital mortality rates. The association was strongest for neonates aged 14 days or younger, for whom the risk of disseminated infection and consequently the risk of death are greatest. In addition, the response seemed to be time-dependent; each additional day of delay was associated with an even greater mortality rate compared with the previous day.
Neonatal HSV infection is a severe disease with high mortality rates despite intravenous acyclovir therapy.10
An open-label trial compared different acyclovir dosage regimens among 88 neonates with HSV. The 12-month mortality rates for neonates who received “high-dose” acyclovir (60 mg/kg per day), that is, 31% among neonates with disseminated disease and 6% among neonates with central nervous system disease, were threefold lower than those observed with the standard dosage regimen (30 mg/kg per day).10
After publication of that study in 2001, administration of high-dose acyclovir quickly became the standard of care.21
However, the mean duration of symptoms before study enrollment was >5 days.10
This delay from symptom onset to initiation of appropriate therapy presents an additional opportunity to improve clinical outcomes. Earlier initiation of acyclovir therapy for neonates with HSV might lead to even lower mortality rates by preventing progression to more-severe disease. Progression from isolated cutaneous disease to involvement of other sites occurs within 1 week for approximately three-fourths of untreated infants.3,22
Whitley et al5
compared the clinical presentation of neonates with HSV during 2 consecutive time periods, 1973–1981 and 1982–1987. The duration of symptoms before therapy decreased from 6.5 days in the first time period to 4.8 days in the second time period, concomitant with a significant decrease in the number of neonates with disseminated disease and an increase in skin, eye, and mouth disease. The authors postulated that earlier diagnosis in the second period (1982–1987) might have identified more skin, eye, and mouth disease before progression to the disseminated form.5
It is possible that earlier initiation of acyclovir treatment (even 1–2 days sooner) would halt this progression.
Clinicians must weigh the potential risks of empiric therapy for uninfected neonates against the risks of delaying administration of acyclovir to HSV-infected neonates when earlier therapy is associated with lower mortality rates. Because measures of illness severity (eg, vasoactive agent infusions) also were associated with death, the benefits of early acyclovir therapy might be greater earlier in the course of the illness, before neonates require such therapeutic interventions. Some clinicians argue that empiric acyclovir treatment always should accompany HSV testing, especially for infants aged 21 days or younger12
; our study supports this approach. It is not clear which neonates should be tested for HSV,23
and there are many factors that influence clinicians' decision to test.1,24
Future studies should attempt to identify the subset of neonates at low risk of HSV, a population that might not require routine HSV testing and empiric acyclovir treatment.
This multicenter observational study has several limitations. Discharge diagnosis coding might be unreliable for specific diseases. However, we included patients who had a discharge diagnosis of HSV and received treatment with acyclovir, which made it likely that the patients truly had HSV infection. Also, because freestanding children's hospitals often do not have birthing units, our results might not be generalizable to premature infants in birthing units, for whom the risk of HSV infection might be higher.25
In addition, there might be unmeasured confounding or residual confounding according to indication for early versus delayed acyclovir therapy, related to clinical presentation. This effect might influence our results in 2 different ways. First, we would expect that patients who received early acyclovir treatment would be sicker than those who received delayed acyclovir treatment. We included variables associated with greater severity of illness (such as receipt of vasoactive agent infusions) in the propensity score and separately as covariates in multivariate analyses. However, we could not account for clinical or laboratory factors, such as hypothermia or disseminated intravascular coagulation, which also might have influenced the timing of acyclovir administration. It is likely that such findings would lead to early administration of acyclovir and thus bias our results toward finding no difference. Because we found an association between delayed acyclovir therapy and mortality rates, it is possible that earlier initiation of acyclovir treatment would be associated with an even greater benefit than found in our study. Second, we cannot exclude the possibility that the early acyclovir treatment group included a disproportionate number of patients with disease limited to cutaneous or mucosal surfaces at presentation. Because outcomes are better with skin, eye, and mouth disease, this would have biased our results toward finding a mortality rate difference when none existed. We minimized the impact of such misclassification by including HSV without complications in our propensity score and as a covariate in our multivariate analyses. We also repeated the analysis with the exclusion of patients with HSV without complications. Furthermore, the odds of death increased with each additional day of delay in the initiation of acyclovir treatment. We would not expect such a progressive increase in the odds of death if the mortality rate differences were attributable solely to differences in the type of disease at presentation.
We also could not verify the dose of acyclovir used. After publication of the study by Kimberlin et al10
in 2001, high-dose acyclovir therapy immediately became the standard of care for neonates with HSV at our institution, as well as at other freestanding children's hospitals. In addition, high-dose acyclovir therapy was recommended by the American Academy of Pediatrics in 2003,21
the first year of our study. Therefore, it is unlikely that deaths in this study were the result of suboptimal acyclovir dosing.
Misclassification of the exposure (ie, delayed acyclovir receipt) might have occurred. Exposure is classified according to day (from midnight to midnight) in the PHIS, rather than 24-hour blocks after admission. Therefore, patients who received acyclovir within 24 hours after hospitalization might have been classified as receiving delayed acyclovir treatment. This misclassification would be most important within the first 24 hours, after which days are more important. This misclassification of patients would be expected to bias our results toward finding no difference; therefore, our results might underestimate the mortality rate difference between patients who received early versus delayed acyclovir treatment. Misclassification of exposure also might have occurred for patients who were transferred from another institution, who would have been classified erroneously as receiving early acyclovir treatment if acyclovir therapy was initiated within 24 hours after transfer to the PHIS-participating hospital but >24 hours after presentation for care. This potential misclassification would have biased our results toward finding no mortality rate difference. When we limited our analysis to patients with on-site CSF studies, the odds of death with delayed acyclovir treatment were increased. Therefore, the mortality rate for neonates who receive delayed acyclovir therapy might be higher than the rate reported in this study. Finally, other important outcomes, such as neurologic morbidity, could not be measured in this study.