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Three Part Question

In [uncomplicated chicken pox infection in immunocompetent children] is [oral acyclovir] beneficial in [reducing severity and duration of infection]?

Clinical Scenario

A 4-year-old child is brought to the emergency department by her mother because of a rash that has developed over the preceding 24 hours. The rash is that of uncomplicated chicken pox infection and the child has no medical history of note and is not immunocompromised. You wonder whether the prescribing of oral acyclovir would reduce the disease severity and duration compared to the advising of symptomatic control only.

Search Strategy

Medline 1966 – 07 / 04 using the Ovid interface. The Cochrane Library Issue 2, 2004
[(aciclovir OR acyclovir).mp. AND (chickenpox OR chicken pox).mp.] LIMIT to human AND English language AND all child <0 to 18 years> AND randomised controlled trial.
Cochrane "aciclovir and chicken pox"

Search Outcome

The Medline search found 14 papers of which 3 were relevant to the topic. Papers were excluded if they had no placebo group. These three papers have since been subject to a systematic-review by the Cochrane Review Group. The review was first published in 1999 with the most recent substantive amendment made in February 2004.
See table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Balfour HH et al 1990 USA	105 children, mean age 8.05 years with laboratory confirmed varicella. Randomised to age and weight related dose of acyclovir v placebo	Randomised, placebo controlled double blind trial (level 1b)	Time to reduction of fever and cessation of itching, number of skin lesions, time to cutaneous healing,	Acyclovir group: defervesced sooner (median 1 day v 2 days; p = 0.001), experienced onset of cutaneous healing sooner (median, 2 days v 3 days; p = 0.002), and had fewer skin lesions (median, 500 v 336; p = 0.02), no change in complication rate (10% v 13.5%)	Quality score (Jadad scale) = 4 Pharmaceutical sponsorship, inadequate discussion of withdrawn patients
Dunkle LM et al 1991 USA	815 children, mean age 5.18 years with clinically diagnosed varicella. Randomised to weight related dose of acyclovir v placebo	Multi-centre, double blind placebo controlled trial (level 1b)	Maximum of lesions, number with >500 lesions, residual lesions at 28 days	Acyclovir group: had fewer lesions (mean 294 v 347; p<0.001), smaller proportion had >500 lesions (21% v 38%; p<0.001), accelerated progression to crusting and healing plus fewer residual lesions at 28 days. No significant difference in disease complications	Quality score (Jadad scale) = 3 Pharmaceutical sponsorship, poorly described methods of randomisation and double blinding
Balfour HH et al 1992 USA	68 children, mean age 14.8 years with laboratory confirmed varicella. Randomised to acyclovir 800 mg QDS or placebo	Randomised, placebo controlled double blind trial (level 1b)	Days to max number of lesions and cessation of itching, maximum number of lesions, residual lesions at 28 days	Acyclovir group had reduction in: time to cessation of new lesions (p<0.001), maximum number of lesions (p = 0.019), time to defervescence (p = 0.045), number of lesions at 28 days (mean 22.7 v 92.7), constitutional illness score (mean 0.5 v 1.5, p = 0.05)	Quality score (Jadad scale) = 3 Pharmaceutical sponsorship, poorly described methods of randomisation and double blinding
Klassen et al 2004	988 children aged between 2 and 18 years as per three studies	Cochrane Systematic Review (level 1a)	Number of days to no new lesions, number of days to no fever, maximum number of lesions, days to relief of itching, complication rate	2 of 3 studies showed statistically significant reduction in days to no new lesions, days to relief of itching and reduction of maximum number of lesions. Days to no fever reduced in all studies. Numerous adverse reactions noted in both groups but no significant difference between groups regarding complications arising from varicella	Meta-analysis not done due to small number of studies and their different study populations

Comment(s)

Chickenpox (varicella) remains a common and highly contagious childhood illness among immunocompetent children. Although generally self-limiting, the infection usually presents with an itchy vesicular rash over the trunk and face, fever, and mild systemic upset. Disease complications include secondary bacterial infection of cutaneous lesions, encephalitis, cerebella ataxia, pneumonia, and otitis media. The economic burden is thought to come from the time taken off work by the child's caregiver. All three papers were randomised double blind placebo controlled trials carried out in the USA. Between them they looked at 988 patients aged between 2 and 18 years with either clinical of laboratory diagnoses of varicella. Although the number of days to no new lesions and number of days to reduction of fever were reduced by one day in the acyclovir groups, the findings that one could consider to be more clinically relevant were less definite. Reported adverse effects were similar in both groups and there was no significant difference between the treatment groups with respect to all skin, central nervous system, and respiratory complications arising from chickenpox infection. Balfour and colleagues showed that the efficacy of acyclovir improves if treatment is initiated within 24 of rash onset, which in practical terms is a diagnostic window often difficult to achieve. Although Balfour et al also show that initiating treatment within 48 hours has greater benefit than 72 hours, one may ask oneself if the modest benefits in outcome, when weighed against the strict compliance required for four times daily medication over five days are of clinical worth. Concerns have been raised regarding the development of resistance to acyclovir. The Cochrane Review concluded that there is evidence to suggest that strains of varicella resistant to acyclovir do not occur. There is no published evidence to show a positive outcome in cost-benefit analysis and the Cochrane Review showed no reduction in the number of days missed from school between the treatment groups. Possible issues with the studies were that all three had pharmaceutical sponsorship and other than the study of Dunkle and colleagues, they comprised relatively small patient numbers.

Clinical Bottom Line

Oral acyclovir shortens time to fever reduction and time to no new lesions by one day but has no effect on complication rates secondary to infection. These reductions were only seen if treatment was initiated with 24 hours of rash onset. Use of acyclovir should not currently be recommended in immunocompetent children with chickenpox infection.

References

1. Balfour HH Jr, Kelly JM, Suarez CS et al. Aciclovir treatment of varicella in otherwise healthy children. Journal of Pediatrics 1990;116(4):633-9.
2. Dunkle LM, Arvin AM, Whitley RJ et al. A controlled trial of aciclovir for chickenpox in normal children New England Journal of Medicine 1991;325(22):1539-44.
3. Balfour HH Jr, Rotbart HA, Feldman S et al. Aciclovir treatment of varicella in otherwise healthy adolescents.The Collaborative Acyclovir Varicella Study Group. Journal of Pediatrics 1992;120(4 Pt 1):627-33.
4. Klassen TP, Belseck EM, Wiebe N, Hartling L. Acyclovir for treating varicella in otherwise healthy children and adolescents (Cochrane Review). In: The Cochrane Library, Issue 3, 2004. Chichester, UK: John Wiley & Sons, Ltd.