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Editor,—Varicella, caused by primary infection with varicella zoster virus (VZV), is a common and highly contagious disease of childhood, and accounts for about one million cases per year in Japan. In 1994, the Welfare Ministry of Japan approved the use of oral aciclovir to treat varicella infections in otherwise healthy children. In spite of the recommendation that the treatment should not be usedroutinely for varicella in otherwise healthy children, the number of children treated with oral aciclovir has been increasing gradually in Japan.
It has rarely been reported that immunocompromised children with chronic VZV infection became resistant to aciclovir. However, no evidence that oral aciclovir treatment in otherwise healthy children with varicella leads to the appearance of resistant virus has been shown. To know the potential of antiviral resistance, we measured the susceptibilities to aciclovir in the paired isolates from otherwise healthy children with varicella, before and during the oral aciclovir treatment.
This study was conducted at the paediatric outpatient clinic of Showa Hospital for one month in 1996. Six otherwise healthy children with varicella diagnosed by characteristic skin lesions of primary VZV infection were included in this study with an age range from 11 months to 5 years. All received oral aciclovir for five days, starting at the first visit to the clinic, at a dose of 20 mg/kg four times a day, and recovered completely. Informed consent was obtained from the parents.
For VZV isolation, an attempt was made to take vesicular fluid serially twice from the patients, before and during the oral aciclovir treatment. The procedure for virus isolation from vesicles was described in a previous paper.1
The susceptibilities of the isolated viruses to aciclovir were determined by examining the effective concentration for 50% and 80% plaque reduction (EC50 and EC80).2-4 Briefly, confluent cell monolayers in 6 cm plastic dishes in duplicate were infected with 100 plaque forming units of the cell-free isolated viruses for hour hour, and incubated in maintenance medium (Eagle’s minimal essential medium supplemented with 2% bovine calf serum) containing aciclovir (0, 0.5, 1, 2, and 5 μg/ml). After five days of incubation, the number of plaques were counted with a microscope. This assay was performed three times. With the mean values, the EC50 and EC80were determined graphically. The statistical difference in susceptibilities (EC50 and EC80 values) of VZV isolates to aciclovir was evaluated using the Student’s ttest.
The age, sex, and time of VZV isolation are shown in table 1. Oral aciclovir treatment was started within 48 hours of illness in the six patients. The paired isolates were taken at intervals of one to three days. Table 2 shows the EC50 and EC80 values of the isolates to aciclovir. In both values, there was no significant difference between before and during the oral aciclovir treatment.
In our previous study,1 the rate of VZV isolation from vesicles in otherwise healthy children with varicella who received no antiviral treatment was 100% during the first two days after the onset of the disease, and declined gradually with time to 17% on the sixth day of disease. In another study (unpublished), we showed VZV was isolated easily from vesicles of patients with varicella in the first two days after oral aciclovir treatment, as in this study, but the rate declined with time more rapidly than from those without the aciclovir treatment. This is why there was variation in the timing of the paired isolates between one and three days.
No statistical difference of susceptibility to aciclovir was demonstrated between the two groups (EC50 and EC80) in each pair and mean value. We showed no evidence of the appearance of resistant virus to aciclovir, when otherwise healthy children with varicella received the oral aciclovir treatment within three days. However, the number of patients in this trial was too small to enable us to draw any firm conclusions. It remains unknown whether the oral aciclovir treatment of varicella in otherwise healthy children increases the chance of aciclovir resistant mutant strains emerging.
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