Abstract
Introduction
Chickenpox is extremely contagious. More than 90% of unvaccinated people will become infected during their lifetime, but infection occurs at different ages in different parts of the world. In the US, the UK, and Japan, more than 80% of people have been infected by the age of 10 years, and by the age of 20 to 30 years in India, South East Asia, and the West Indies. It is usually a mild and self-limiting disease, but it can be severely complicated by pneumonitis or disseminated disease in some individuals, particularly neonates and those who are immunocompromised.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatment for chickenpox in healthy adults and children (including neonates) within 24 hours after onset of rash? What are the effects of treatment for chickenpox in healthy adults and children (including neonates) later than 24 hours after onset of rash? What are the effects of treatment for chickenpox in immunocompromised adults and children (including neonates)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2014 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).
Results
We found six studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic overview we present information relating to the effectiveness and safety of aciclovir, within 24 hours of onset of rash or later than 24 hours of onset of rash, in otherwise-healthy adults and children (including neonates); and aciclovir in immunocompromised adults and children (including neonates).
Key Points
Chickenpox is caused by primary infection with the varicella zoster virus. In healthy people, it is usually a mild, self-limiting illness, characterised by low-grade fever, malaise, and a generalised, itchy, vesicular rash.
Disease can be severely complicated by pneumonitis or disseminated disease in some individuals, such as neonates, pregnant women, and those who are immunocompromised.
Treatment of chickenpox with oral aciclovir given within 24 hours of onset of rash may be more effective than placebo in otherwise healthy children. It also seems to be more effective than placebo at treating chickenpox in otherwise healthy adults.
When given later than 24 hours after onset of rash, aciclovir does not seem so effective at treating chickenpox compared with placebo, although the evidence for this is sparse.
In clinical practice, intravenous aciclovir is used to treat severe disease irrespective of time of onset of rash. However, this is not based on evidence from placebo-controlled RCTs, as such studies would be considered unethical.
Intravenous aciclovir may be more effective than placebo at reducing time to full crusting and clinical deterioration from chickenpox in children with malignancy and receiving chemotherapy.
We found no evidence comparing intravenous aciclovir and placebo in other immunocompromised children.
We found no evidence assessing aciclovir for the treatment of chickenpox in immunocompromised adults.
Placebo-controlled RCTs assessing antivirals, such as aciclovir, in treating immunocompromised adults are unlikely to be carried out, as this is now considered unethical. However, the treatment effects of aciclovir are likely to be the same for immunocompromised adults as they are for immunocompromised children.
In clinical practice, treatment of chickenpox in immunocompromised adults is usually initiated with intravenous aciclovir due to the poor absorption of oral aciclovir and the potential risk of rapid disease progression.
Clinical context
About this condition
Definition
Chickenpox is caused by primary infection with varicella zoster virus. In healthy people, it is usually a mild, self-limiting illness, characterised by low-grade fever, malaise, and a generalised, itchy, vesicular rash. However, severe disease can develop leading to pneumonitis, hepatitis, thrombocytopenia, or encephalitis. Risk of severe disease is higher in pregnancy, in neonates (<28 days of life), and in people who are immunocompromised due to medication or disease. In most people, infection is uncomplicated. The most common complication in immunocompetent people is secondary bacterial skin infection, often seen in children younger than 5 years of age. Less commonly, acute cerebellar ataxia can occur in older children. At all ages, infection can be complicated by soft tissue or deeper invasive group A streptococcal infection. Following primary infection, the varicella zoster virus remains latent in the body. Subsequently, it can re-activate to cause herpes zoster (shingles).The prevention and treatment of herpes zoster is outside the scope of this review (see review on Postherpetic neuralgia).
Incidence/ Prevalence
Chickenpox is extremely contagious. More than 90% of unvaccinated people will become infected during their lifetime, but infection occurs at different ages in different parts of the world. In the US, the UK, and Japan, more than 80% of people have been infected by the age of 10 years, and by the age of 20 to 30 years in India, South East Asia, and the Caribbean.
Aetiology/ Risk factors
Chickenpox is caused by primary infection with the varicella zoster virus.
Prognosis
Infants and children In healthy children, the illness is usually mild, self-limiting, and uncomplicated. In the US, mortality in infants and children (aged 1–14 years) with chickenpox was about 7/100,000 in infants, and 1.4/100,000 in children. However, mortality has fallen with the introduction of universal varicella vaccination in the US. In Australia, mortality from chickenpox is about 0.5 to 0.6/100,000 in children aged 1 to 11 years, and about 1.2/100,000 in infants. Bacterial skin sepsis is the most common complication in children under 5 years of age, and acute cerebellar ataxia is the most common complication in older children; both cause hospital admission in 2–3/10,000 children. Adults Mortality in adults is higher, at about 31/100,000, reflecting the more severe clinical course seen overall in this age group. Varicella pneumonia is the most common manifestation of severe disease, causing 20 to 30 hospital admissions/10,000 adults. Activation of latent varicella zoster virus infection can cause herpes zoster, also known as shingles (see review on Postherpetic neuralgia). Cancer chemotherapy One case series found that more children receiving chemotherapy developed progressive chickenpox with multiple organ involvement compared with those in remission (19/60 [32%] of children receiving chemotherapy v 0/17 [0%] of children in remission), and more children died (4/60 [7%] of children receiving chemotherapy v 0/17 [0%] of children in remission). HIV infection One retrospective case series (45 children with AIDS; no treatment reported) found that one in four (25%) children with AIDS who acquired chickenpox in hospital developed pneumonia, and 5% died. In a retrospective cohort study (73 children with HIV and chickenpox; 83% with symptomatic HIV; 14 children received varicella zoster immunoglobulin, of which nine received varicella zoster immunoglobulin within 48 hours of exposure), infection beyond 2 months occurred in 10 children (14%), and recurrent varicella zoster virus infections occurred in 38 children (55%). There was a strong association between an increasing number of recurrences and low CD4 cell counts. Half of recurrent infections involved generalised rashes, and the other half had zoster. Newborns Newborns are at high risk if they develop chickenpox within the first 28 days of life. Exposure in these cases is often from a mother who has been infected with the varicella zoster virus in late pregnancy. If the mother develops a rash between 7 days before to 7 days after delivery, there will be no passive transfer of protective antibody from the mother to the baby, putting the neonate at high risk. We found no cohort studies of untreated children with perinatal exposure to chickenpox. One cohort study (281 neonates receiving varicella zoster immunoglobulin because their mothers had developed a chickenpox rash during the month before or after delivery) found that 134 (48%) developed a chickenpox rash and 19 (14%) developed severe chickenpox. Sixteen (84%) of the 19 cases of severe chickenpox occurred in neonates of mothers whose rash had started between 4 days before and 2 days after delivery. Pregnancy There is a higher risk of severe chickenpox at all stages of pregnancy. During the first trimester there is a risk of developing fetal varicella syndrome which may lead to fetal death, even with non-severe maternal disease.
Aims of intervention
To reduce the duration of illness and complications of chickenpox, with minimal adverse effects of treatment.
Outcomes
Duration of illness (time to no new lesions, and disappearance of fever); disease severity; complications of chickenpox; mortality; adverse effects.
Methods
Search strategy BMJ Clinical Evidence search and appraisal January 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to January 2014, Embase 1980 to February 2014, The Cochrane Database of Systematic Reviews 2013, issue 12 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in the English language, at least single-blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Data and quality To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Chickenpox: treatment.
| Important outcomes | Complications of chickenpox, Disease severity, Duration of illness, Mortality | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatment for chickenpox in healthy adults and children (including neonates) within 24 hours after onset of rash? | |||||||||
| 3 (979) | Duration of illness | Aciclovir (within 24 hours after onset of rash) versus placebo in healthy children (including neonates) | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for unclear allocation concealment and pharmaceutical-sponsored studies |
| 1 (76) | Duration of illness | Aciclovir (within 24 hours after onset of rash) versus placebo in healthy adults | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (76) | Disease severity | Aciclovir (within 24 hours after onset of rash) versus placebo in healthy adults | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| What are the effects of treatment for chickenpox in healthy adults and children (including neonates) later than 24 hours after onset of rash? | |||||||||
| 3 (240) | Duration of illness | Aciclovir (later than 24 hours after onset of rash) versus placebo in healthy adults | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (77) | Duration of illness | Different timings of administration of aciclovir (later than 24 hours after onset of rash) versus each other in healthy adults and children | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results; consistency point deducted for conflicting results in children and adolescents |
| What are the effects of treatment for chickenpox in immunocompromised adults and children (including neonates)? | |||||||||
| 1 (50) | Duration of illness | Intravenous aciclovir versus placebo in immunocompromised children | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and possibility of over-estimation of effect of placebo; directness point deducted for narrow population |
| 2 (70) | Disease severity | Intravenous aciclovir versus placebo in immunocompromised children | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and possibility of over-estimation of effect of placebo; directness point deducted for narrow population |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Varicella zoster immunoglobulin (VZIG)
Prepared from units of donor plasma selected for high titres of antibodies to varicella zoster virus.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Jonathan Cohen, University College London Hospital, London, UK.
Judith Breuer, Research Department of Infection, University College London, London, UK.
References
- 1.Guess HA, Broughton DD, Melton LJ, et al. Population-based studies of varicella complications. Pediatrics 1986;78:723–727. [PubMed] [Google Scholar]
- 2.Lee BW. Review of varicella zoster seroepidemiology in India and Southeast Asia. Trop Med Int Health 1998;3:886–890. [DOI] [PubMed] [Google Scholar]
- 3.Garnett GP, Cox MJ, Bundy DA, et al. The age of infection with varicella-zoster virus in St Lucia, West Indies. Epidemiol Infect 1993;110:361–372. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kowitdamrong E, Pancharoen C, Thammaborvorn R, et al. The prevalence of varicella-zoster virus infection in normal healthy individuals aged above 6 months. J Med Assoc Thailand 2005;88(Suppl 4):S7–11. [PubMed] [Google Scholar]
- 5.Preblud SR. Varicella: complications and costs. Pediatrics 1986;78:728–735. [PubMed] [Google Scholar]
- 6.Marin M, Zhang JX, Seward JF. Near elimination of varicella deaths in the US after implementation of the vaccination program. Pediatrics 2011;128:214–220. [DOI] [PubMed] [Google Scholar]
- 7.Scuffman PA, Lowin AV, Burgess MA. The cost effectiveness of varicella vaccine programs for Australia. Vaccine 1999;18:407–415. [DOI] [PubMed] [Google Scholar]
- 8.Feldman S, Hughes WT, Daniel CB. Varicella in children with cancer: seventy-seven cases. Pediatrics 1975;56:388–397. [PubMed] [Google Scholar]
- 9.Leibovitz E, Cooper D, Giurgiutiu D, et al. Varicella-zoster virus infection in Romanian children infected with the human immunodeficiency virus. Pediatrics 1993;92:838–842. [PubMed] [Google Scholar]
- 10.von Seidlein L, Gillette SG, Bryson Y, et al. Frequent recurrence and persistence of varicella-zoster virus infections in children infected with human immunodeficiency virus type 1. J Pediatr 1996;128:52–57. [DOI] [PubMed] [Google Scholar]
- 11.Miller E, Cradock-Watson JE, Ridehalgh MK. Outcome in newborn babies given anti-varicella-zoster immunoglobulin after perinatal maternal infection with varicella-zoster virus. Lancet 1989;2:371–373. [DOI] [PubMed] [Google Scholar]
- 12.Klassen TP, Hartling L, Wiebe N, et al. Acyclovir for treating varicella in otherwise healthy children and adolescents. In: The Cochrane Library, Issue 12, 2013. Search date 2008. 16235308 [Google Scholar]
- 13.Alfandari S. Second question: antiviral treatment of varicella in adult or immunocompromised patients. Med Malad Infect 1998;28:722–729. Search date 1997. [Google Scholar]
- 14.Balfour HH Jr, Edelman CK, Anderson RS, et al. Controlled trial of acyclovir for chickenpox evaluating time of initiation and duration of therapy and viral resistance. Pediatr Infect Dis J 2001;20:919–926. [DOI] [PubMed] [Google Scholar]
- 15.Nyerges G, Meszner Z, Gyarmati E, et al. Aciclovir prevents dissemination of varicella in immunocompromised children. J Infect Dis 1988;157:309–313. [DOI] [PubMed] [Google Scholar]
- 16.Prober CG, Kirk LE, Keeney RE. Aciclovir therapy of chickenpox in immunosuppressed children: a collaborative study. J Pediatr 1982;101:622–625. [DOI] [PubMed] [Google Scholar]