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Chickenpox is extremely contagious. Over 90% of unvaccinated people become infected, but infection occurs at different ages in different parts of the world — over 80% of people have been infected by the age of 10 years in the US, the UK, and Japan, and by the age of 20 to 30 years in India, South East Asia, and the West Indies.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent chickenpox in healthy adults and children? What are the effects of interventions to prevent chickenpox in children exposed prenatally? What are the effects of interventions to prevent chickenpox in immunocompromised adults and children? What are the effects of treatments for chickenpox in healthy adults and children? What are the effects of treatments for chickenpox in immunocompromised adults and children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 11 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: aciclovir, famciclovir, live attenuated vaccine, valaciclovir, and varicella zoster immunoglobulin.
Key Points
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.
Chickenpox is very contagious — in the UK, US, and Japan, >80% of people have been infected by the age of 10 years.
The most common complications are bacterial skin sepsis in children aged <5 years, acute cerebellar ataxia in older children, and varicella pneumonia in adults (which causes 20–30 hospital admissions per 10,000 adults).
Live attenuated varicella vaccine is effective at preventing chickenpox in healthy children not knowingly exposed to varicella zoster virus.
The vaccine may also reduce the incidence of chickenpox in healthy children exposed to varicella zoster virus, if administered within 3 days of exposure. In vaccinated children who develop varicella, disease is likely to be mild.
We found no RCT evidence examining the effect of the vaccine in healthy adults in either those not exposed or exposed to varicella zoster virus.
Newborns whose mothers' rashes appear in the last 5 days of pregnancy or within 2 days of birth have been reported, in small case series, to have a very high risk of severe chickenpox.
We found no evidence assessing aciclovir, famciclovir, or valaciclovir for preventing chickenpox in prenatally exposed children.
The evidence for the use of live attenuated varicella vaccine for prevention of chickenpox in immunocompromised children is from small uncontrolled studies. Overall, its use is a trade-off between benefits and harms. We found no RCT or observational evidence examining the effect of the vaccine in immunocompromised adults.
We don't know how effective famciclovir or valaciclovir are in preventing chickenpox in immunocompromised adults or children.
Aciclovir (high dose) has been shown to be beneficial in reducing clinical chickenpox in people with HIV infection. We don't know how effective it is in other immunocompromised people to prevent chickenpox.
Oral aciclovir also seems to effectively treat chickenpox if administered within 24 hours of onset of rash.
When given later than 24 hours after onset of rash, aciclovir does not seem so effective, although the evidence is sparse.
We found no RCT evidence assessing famciclovir or valaciclovir for treating chickenpox in healthy people.
In children with malignancy, intravenous aciclovir seems to reduce clinical deterioration from chickenpox.
We found no RCT evidence assessing how effective aciclovir, famciclovir, or valaciclovir are in treating immunocompromised adults with chickenpox.
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.
Incidence/
Prevalence
Chickenpox is extremely contagious. Over 90% of unvaccinated people become infected, but infection occurs at different ages in different parts of the world — over 80% of people have been infected by the age of 10 years in the US, the UK, and Japan, and by the age of 20 to 30 years in India, South East Asia, and the West Indies.
Aetiology/
Risk factors
Chickenpox is caused by exposure to varicella zoster virus.
Prognosis
Infants and children: In healthy children the illness is usually mild and self-limiting. In the US, mortality in infants and children (aged 1–14 years) with chickenpox is about 7/100,000 in infants, and 1.4/100,000 in children. 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 to 3/10,000 children.
Adults: Mortality in adults is higher, at about 31/100,000. Varicella pneumonia is the most common complication, 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 (77 children with both cancer and chickenpox; one child received zoster immunoglobulin within 72 hours of exposure) 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 1 in 4 (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, 9 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: 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.
Aims of
intervention
To prevent clinical chickenpox (characterised by a rash); to reduce the duration of illness and complications of chickenpox, with minimal adverse effects of treatment.
Outcomes
Rate of clinical chickenpox; duration of illness (time to no new lesions, and disappearance of fever); disease severity; complications of chickenpox; mortality; adverse effects of treatment.
Methods
Clinical Evidence search and appraisal June 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2010, Embase 1980 to June 2010, and The Cochrane Database of Systematic Reviews, May 2010 (online; 1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing >20 individuals of whom >80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. 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). 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.
Important outcomes
Complications of chickenpox, Disease severity, Duration of illness, Mortality, Rate of chickenpox
Studies (Participants)
Outcome
Comparison
Type of evidence
Quality
Consistency
Directness
Effect size
GRADE
Comment
What are the effects of interventions to prevent chickenpox in healthy adults and children who have not knowingly been exposed to varicella zoster virus?
3 (1241)
Rate of chickenpox
Live attenuated varicella vaccine versus placebo
4
0
0
0
0
High
What are the effects of interventions to prevent chickenpox in healthy adults and children exposed to varicella zoster virus?
3 (110)
Rate of chickenpox
Live attenuated varicella vaccine versus placebo
4
–2
0
0
0
Low
Quality points deducted for sparse data and incomplete reporting
3 (110)
Disease severity
Live attenuated varicella vaccine versus placebo
4
–1
0
0
+2
High
Quality point deducted for sparse data. Effect-size points added for RR >8
What are the effects of interventions to prevent chickenpox in immunocompromised adults and children?
8 (1792)
Rate of chickenpox
Aciclovir versus placebo
4
–1
0
0
+1
High
Quality point deducted for inclusion of unpublished data. Effect-size point added for OR <0.5
8 (1792)
Mortality
Aciclovir versus placebo
4
0
0
0
0
High
What are the effects of treatments for chickenpox in healthy adults and children?
3 (979)
Duration of illness
Aciclovir (within 24 hours after onset of rash) versus placebo in healthy children
4
0
0
0
0
High
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
3 (240)
Duration of illness
Aciclovir (later than 24 hours after onset of rash) versus placebo
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
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 treatments for chickenpox in immunocompromised adults and children?
1 (50)
Duration of illness
Intravenous aciclovir versus placebo
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
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
High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
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
Judith Breuer, Research Department of Infection, University College London, London, UK.
Helen Fifer, UCLH, London, UK.
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BMJ Clin Evid. 2011 Apr 11;2011:0912.
Live attenuated varicella vaccine for prevention in healthy children who have not knowingly been exposed to varicella zoster virus
Live attenuated varicella vaccine is effective at preventing chickenpox in healthy children not knowingly exposed to varicella zoster virus.
Benefits and harms
Live attenuated varicella vaccine versus placebo:
We found one systematic review (search date 2000, 2 RCTs). We also found three analyses of post-licence safety surveillance data.
Rate of chickenpox
Compared with placebo Live attenuated varicella vaccine is more effective at reducing the proportion of healthy children who develop chickenpox at 9 to 29 months (high-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Clinical chickenpox
RCT
914 healthy children aged 1 to 14 years In review
Proportion of children with clinical chickenpox
9 months
0/468 (0%) with live attenuated varicella vaccine 38/446 (9%) with placebo
ARR 8.5%
95% CI 6.1% to 11.5%
Protection level 100%
Effect size not calculated
live attenuated varicella vaccine
RCT
914 healthy children aged 1 to 14 years In review
Proportion of children with clinical chickenpox
2 years
1/163 (<1%) with live attenuated varicella vaccine 21/161 (13%) with placebo
OR 0.05
95% CI 0.01 to 0.35
Large effect size
live attenuated varicella vaccine
RCT
327 healthy children aged 10 to 30 months In review
Proportion of children with clinical chickenpox
mean follow-up of 29 months
5/166 (3%) with live attenuated varicella vaccine 41/161 (25%) with placebo
No data from the following reference on this outcome.
Further information on studies
None.
Comment
Clinical guide:
Chickenpox vaccine is a safe and effective vaccine against a usually mild disease in healthy children. The decision to use the vaccine depends on a trade-off between the potential benefits, harms, and cost. This trade-off will vary with the context. One systematic review (search date 2006) of outbreak studies (14 studies, 3157 children from populations where one dose of live attenuated varicella vaccine was offered as part of immunisation programme) assessed the proportion of vaccinated children developing clinical chickenpox during a varicella outbreak and found a combined vaccine effectiveness of 72.5%, 95% CI 68.5% to 76.0%. The review suggested that vaccine effectiveness was unrelated to vaccine coverage of the population. The limited effectiveness of single vaccination was confirmed by a change to vaccination policy in the US, where a universal one-dose childhood varicella vaccination programme was introduced in 1995. One systematic review (search date not reported) of US population studies assessing morbidity and mortality caused by varicella before and after the introduction of one-dose vaccination in 1995 found that, over the 10 years since its introduction, one-dose vaccination was 80% to 85% effective in preventing disease of any severity and >95% effective in preventing severe varicella. Hospital admissions for chickenpox were reduced by 75% to 88% and mortality from varicella was reduced by >74%. However, varicella outbreaks continued to occur. Therefore, in 2006 the US policy was changed to a two-dose varicella vaccine schedule. One systematic review (search date 2008) identified 7 longitudinal studies conducted in the US looking at the epidemiology of herpes zoster following the introduction of routine immunisation. It was unclear how many immunised people were included in the studies. Results of the studies were contradictory and the review concluded that there are currently insufficient data to assess the impact of immunisation on the incidence of shingles.
Substantive changes
No new evidence
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Live attenuated vaccine for prevention in healthy adults not knowingly exposed to varicella zoster virus
We found no direct information from RCTs about the effects of live attenuated varicella vaccine in healthy adults not knowingly exposed to varicella zoster virus.
Benefits and harms
Live attenuated varicella vaccine in healthy adults:
We found one systematic review. It found no RCTs assessing clinical outcomes in healthy adults.
Further information on studies
None.
Comment
Clinical guide:
Chickenpox vaccine is a safe and effective vaccine against a disease that is usually mild, at least in healthy children. Observational studies in adults show evidence of loss of vaccine-induced antibody in up to 30% of vaccinated adults. Low antibody concentration has been associated with increased risk of reinfection.
Substantive changes
No new evidence
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Live attenuated varicella vaccine for prevention in healthy children exposed to varicella zoster virus
Live attenuated varicella vaccine may reduce the incidence of chickenpox in healthy children exposed to varicella zoster virus, if administered within 3 days of exposure.
In vaccinated children who develop varicella, disease is likely to be mild.
Benefits and harms
Live attenuated varicella vaccine versus placebo:
We found one systematic review (search date 2008, 3 RCTs). The review did not perform a meta-analysis because of heterogeneity across RCTs in vaccine used (particularly in viral titre), study design, and outcome measures. We therefore report data from each RCT identified separately.
Rate of chickenpox
Compared with placebo Live attenuated varicella vaccine seems more effective at reducing the proportion of children who develop clinical chickenpox (low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Clinical chickenpox
Systematic review
42 children aged 12 months to 13 years, immunised within 72 hours of the first skin lesion appearing in a sibling Data from 1 RCT
Proportion of children with clinical chickenpox
28 days
9/22 (41%) with live attenuated varicella vaccine 9/20 (45%) with placebo
Significance not assessed
Systematic review
26 children aged 18 months to 16 years, immunised within 5 days of exposure to sibling with varicella Data from 1 RCT
Proportion of children with clinical chickenpox
timeframe not reported
4/13 (31%) with live attenuated varicella vaccine 12/13 (92%) with placebo
Significance not assessed
Systematic review
42 children aged 1 month to 11 years, immunised within 5 days of exposure to sibling with varicella Data from 1 RCT
Proportion of children with clinical chickenpox
4 to 8 weeks
0/21 (0%) with live attenuated varicella vaccine 21/21 (100%) with no vaccine
Compared with placebo Live attenuated varicella vaccine is more effective at reducing the proportion of children with chickenpox who develop moderate or severe disease (high-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Disease severity
Systematic review
42 children aged 12 months to 13 years, immunised within 72 hours of the first skin lesion appearing in a sibling Data from 1 RCT
Proportion of children with clinical chickenpox
28 days
1/9 (11%) with live attenuated varicella vaccine 8/9 (89%) with placebo
RR (placebo v vaccine) 8.0
95% CI 1.2 to 51.5
Large effect size
live attenuated varicella vaccine
Systematic review
26 children aged 18 months to 16 years, immunised following exposure to sibling with varicella Data from 1 RCT
Proportion of children with chickenpox who developed moderate or severe disease
timeframe not reported
4/13 (31%) with live attenuated varicella vaccine 12/13 (92%) with placebo
P <0.000003
Effect size not calculated
live attenuated varicella vaccine
Systematic review
42 children aged 1 month to 11 years, immunised following exposure to sibling with varicella Data from 1 RCT
Proportion of children with chickenpox who developed moderate or severe disease
4 to 8 weeks
0/21 (0%) with live attenuated varicella vaccine 21/21 (100%) with no vaccine
No data from the following reference on this outcome.
Complications of chickenpox
No data from the following reference on this outcome.
Duration of illness
No data from the following reference on this outcome.
Adverse effects
No data from the following reference on this outcome.
Further information on studies
None.
Comment
Clinical guide:
In the three RCTs identified by the review, most children received immunisation within 3 days following exposure to a varicella case. The evidence from these trials would support giving varicella vaccine as prophylaxis to exposed children, particularly in the household setting, as it reduces infection rates and disease severity. However, the number of participants in each trial was small, and none of the trials reported on adverse effects, so more data are needed.
Substantive changes
Live attenuated varicella vaccine for prevention in healthy children exposed to varicella zoster virus New option. Categorised as Likely to be beneficial.
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Live attenuated varicella vaccine for prevention in healthy adults exposed to varicella zoster virus
We don't know whether live attenuated varicella vaccine is effective for prevention of chickenpox in healthy adults exposed to varicella zoster virus, as we found no RCT evidence.
Benefits and harms
Live attenuated varicella vaccine versus placebo:
We found one systematic review (search date 2008), which identified no RCTs in healthy adults exposed to varicella zoster virus.
Further information on studies
None.
Comment
None.
Substantive changes
Live attenuated varicella vaccine for prevention in healthy adults exposed to varicella zoster virus New option. Categorised as Unknown effectiveness.
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Aciclovir for prevention in children exposed prenatally
We found no direct information from RCTs about the effects of aciclovir for preventing chickenpox in prenatally exposed children.
Benefits and harms
Aciclovir:
We found no systematic review or RCTs on the effects of aciclovir in prenatally exposed children.
Further information on studies
None.
Comment
Clinical guide:
Newborns whose mothers' rashes appear in the last 5 days of pregnancy, or within 2 days of birth, have been reported in small case series to have a high risk of severe chickenpox. On the basis of observational evidence and experience, most clinicians use varicella immunoglobulin in preference to aciclovir.
Substantive changes
No new evidence
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Famciclovir for prevention in children exposed prenatally
We found no direct information from RCTs about the effects of varicella zoster immunoglobulin in prenatally exposed children.
Newborns whose mothers' rashes appear in the last 5 days of pregnancy, or within 2 days of birth, have been reported in small case series to have a very high risk of severe chickenpox. Most clinicians use varicella zoster immunoglobulin in these children as, based on observational evidence and experience, most clinicians regard it as effective.
Newborns whose mothers' rashes appear in the last 5 days of pregnancy, or within 2 days of birth, have been reported in small case series to have a very high risk of severe chickenpox. RCTs into the effects of varicella zoster immunoglobulin have not been, and are unlikely to be, undertaken. Based on observational evidence and experience, most clinicians regard it as effective.
Substantive changes
Varicella zoster immunoglobulin for prevention in children exposed prenatally Evidence reassessed. Categorisation changed from Unknown effectiveness to Likely to be beneficial by consensus.
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Live attenuated varicella vaccine for prevention in immunocompromised children
In children with leukemia, routine use of live attenuated varicella vaccine is generally not recommended because of the risk of developing a rash post-immunisation.
In children with HIV, observational data suggest that live attenuated varicella vaccine is effective and is well tolerated.
Benefits and harms
Live attenuated vaccine:
We found no systematic review of RCTs or RCTs of live attenuated vaccine in children with immunocompromise (see comment below).
Further information on studies
None.
Comment
We found two systematic reviews (search dates not reported, 2007) of uncontrolled studies, case series, and case reports. The first review identified two uncontrolled clinical trials. The first trial (437 children with acute lymphocytic leukemia in remission who had received two doses of live attenuated varicella vaccine) found that clinical chickenpox developed in 36/437 (8%) vaccine recipients over a variable observation period of up to 9 years. Twenty-seven of the 36 live attenuated varicella vaccine recipients with clinical varicella did not receive varicella zoster immunoglobulin as post-exposure prophylaxis. In this group, 78% had mild disease, 18% moderate disease, and 4% severe disease. Eleven cases of varicella occurred after 83 household exposures; compared with historical attack rates, vaccination offered 86% protection against disease. The vaccine was associated with mild rash in 5% of children no longer receiving therapy for leukemia and in 40% of vaccine recipients still having maintenance therapy for leukemia. Rashes occurred at 7 to 40 days after the first dose of vaccine. Herpes zoster was 2.5-fold less likely in vaccine recipients than in matched controls who had been exposed to prior natural varicella. The second trial (97 HIV-infected children on antiretroviral therapy who received 2 doses of live attenuated varicella vaccine) found that out of 16 children exposed to varicella, none developed clinical chickenpox. The vaccine was associated with mild fever in 40% of children; adverse effects were similar to those seen in HIV-negative children. The second review assessed varicella vaccine in people receiving organ transplants; it did not assess rates of clinical chickenpox. Analysis of 89 children (included in 6 case series and 2 case series) who received live attenuated varicella vaccine found that 10/89 (11%) developed possible vaccine-associated localised or generalised rash.
Clinical guide:
The single-antigen vaccine is licensed for use in the US for HIV-infected children with CD4 counts >15%, and in Europe for HIV-infected children with CD4 >25% and for immunocompromised people with >1200 lymphocytes per microlitre of blood. The general approach to prevent development of varicella is to immunise children with leukemia before immunosuppression, where possible, or when chemotherapy is stopped temporarily. The consensus opinion is that varicella vaccination in these patients is a trade-off between benefits and harms.
Substantive changes
Live attenuated varicella vaccine for prevention in immunocompromised children New option. Categorised as Trade-off between benefits and harms by consensus.
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Live attenuated varicella vaccine for prevention in immunocompromised adults
High-dose aciclovir has been shown to be beneficial in reducing clinical chickenpox in people with HIV infection.
We found no direct information from RCTs about the effects of aciclovir in people with immunocompromise other than HIV or about the effects of lower doses in people with any form of immunocompromise.
Benefits and harms
Aciclovir versus placebo:
We found one systematic review (search date not reported, 8 RCTs) comparing high-dose aciclovir versus placebo in people with HIV. Three of the RCTs were unpublished, including two pharmaceutical company trials. We found no RCTs of low doses of aciclovir in people with HIV, and no RCTs of aciclovir in people with immunocompromise other than HIV.
Rate of chickenpox
Compared with placebo Aciclovir at doses of at least 3200 mg daily is more effective at reducing the proportion of people with HIV infection who develop chickenpox (high-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Clinical chickenpox
Systematic review
1792 people with different stages of HIV, median CD4 count 34/mm3 to 607/mm3 8 RCTs in this analysis
Proportion of people with chickenpox
up to 22 months
14/895 (2%) with aciclovir 54/897 (6%) with placebo
OR 0.29
95% CI 0.13 to 0.63
NNT 23
95% CI 17 to 39
The review reported that treatment effect did not vary significantly with CD4 count
Compared with placebo Aciclovir at doses of at least 3200 mg daily is more effective at reducing all-cause mortality at 48 months in people with HIV infection (high-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
All-cause mortality
Systematic review
1792 people with different stages of HIV, median CD4 count 34/mm3 to 607/mm3 8 RCTs in this analysis
All-cause mortality
48 months
247/895 (28%) with aciclovir 276/897 (31%) with placebo
OR 0.75
95% CI 0.57 to 1.00
HR 0.78
95% CI 0.65 to 0.93
The review reported that treatment effect did not vary significantly with CD4 count
We found no direct information from RCTs about whether varicella zoster immunoglobulin is better than no active treatment or immune serum globulin at preventing chickenpox in immunocompromised adults and children.
Based on observational evidence and experience, most clinicians regard varicella zoster immunoglobulin as effective in this population.
Benefits and harms
Varicella zoster immunoglobulin versus placebo:
We found no systematic review or RCTs.
Varicella zoster immunoglobulin versus immune serum globulin:
We found no systematic review or RCTs.
Further information on studies
None.
Comment
Clinical guide:
Varicella zoster immunoglobulin is frequently used to prevent chickenpox in exposed susceptible immunocompromised children. Most clinicians use varicella zoster immunoglobulin in these patients. Based on observational evidence and experience, most clinicians regard it as effective.
Substantive changes
Varicella zoster immunoglobulin for prevention in immunocompromised people Evidence reassessed, taking into consideration consensus and clinical experience. Categorisation changed from Unknown effectiveness to Likely to be beneficial by consensus.
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Immune serum globulin for prevention in immunocompromised people
We found no direct information from RCTs about whether immune serum globulin is better than varicella zoster immunoglobulin at preventing chickenpox in immunocompromised adults and children.
Benefits and harms
Immune serum globulin versus varicella zoster immunoglobulin:
See varicella zoster immunoglobulin for prevention in immunocompromised people.
Further information on studies
None.
Comment
None.
Substantive changes
No new evidence
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Aciclovir (within 24 hours after onset of rash) for treatment in healthy people
Oral aciclovir seems to effectively treat chickenpox if administered within 24 hours of onset of rash.
Benefits and harms
Aciclovir (within 24 hours after onset of rash) versus placebo in healthy children:
We found one systematic review (search date 2008, 3 RCTs, 979 children and adolescents) comparing aciclovir versus placebo given within 24 hours of onset of rash in otherwise healthy children and adolescents aged 0 to 18 years.
Duration of illness
Compared with placebo in healthy children Aciclovir given within 24 hours of onset of rash is more effective at reducing the duration of fever in healthy children, but is no more effective at reducing the time to no new lesions (high-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Time to no new lesions
Systematic review
979 children and adolescents 3 RCTs in this analysis
Time to no new lesions
with aciclovir with placebo Absolute results not reported
WMD –0.8 days
95% CI –1.6 days to +0.02 days
Not significant
Duration of fever
Systematic review
979 children and adolescents 3 RCTs in this analysis
Duration of fever
with aciclovir with placebo Absolute results not reported
No data from the following reference on this outcome.
Rate of chickenpox
No data from the following reference on this outcome.
Complications of chickenpox
No data from the following reference on this outcome.
Disease severity
No data from the following reference on this outcome.
Adverse effects
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Adverse effects
Systematic review
979 children 3 RCTs in this analysis
Adverse effects
with aciclovir with placebo
The review found no significant differences between treatment and control groups, or unfavourable trends in children taking aciclovir (no further data reported)
Aciclovir (within 24 hours after onset of rash) versus placebo in healthy adults:
We found one systematic review (search date 1997, 3 RCTs). The review did not perform a meta-analysis and so we report data from relevant studies separately. Two RCTs compared aciclovir given >24 hours after the onset of rash versus placebo and are not discussed here.
Duration of illness
Compared with placebo in healthy adults Aciclovir given within the first 24 hours of onset of rash seems more effective at reducing the time to full crusting in healthy adults (moderate-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Time to full crusting
Systematic review
148 adults Data from 1 RCT
Time to full crusting
5.6 days with aciclovir (800 mg 5 times daily) 7.4 days with placebo
Compared with placebo in healthy adults Aciclovir given within the first 24 hours of onset of rash seems more effective at reducing the number of lesions in healthy adults (moderate-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Number of lesions
Systematic review
148 adults Data from 1 RCT
Number of lesions
268 lesions with aciclovir (800 mg 5 times daily) 500 lesions with placebo
No data from the following reference on this outcome.
Rate of chickenpox
No data from the following reference on this outcome.
Complications of chickenpox
No data from the following reference on this outcome.
Adverse effects
No data from the following reference on this outcome.
Further information on studies
None.
Comment
In healthy people who make an uneventful recovery without treatment, the effect on the measured outcomes was small and of questionable clinical importance.
Clinical guide:
Evidence is sparse, but symptomatic treatments are commonly used in practice, and may be beneficial. Paracetamol is used to reduce fever, topical calamine or crotamiton to soothe the skin and possibly relieve itching, and a sedating antihistamine at night to help sleep, and possibly break the itch-scratch-itch cycle. Should viral complications of chickenpox (e.g., pneumonia or encephalitis) develop in healthy people, aciclovir is indicated.
Substantive changes
No new evidence
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Aciclovir (later than 24 hours after onset of rash) for treatment in healthy people
When given later than 24 hours after onset of rash, aciclovir does not seem so effective for treatment of chickenpox in adults, although the evidence is sparse.
We found no direct information from RCTs comparing aciclovir given >24 hours after rash versus no active treatment in children and adolescents.
Benefits and harms
Aciclovir (later than 24 hours after onset of rash) versus placebo:
We found one systematic review (search date 1997, 3 RCTs). It did not perform a meta-analysis.
Duration of illness
Compared with placebo Aciclovir started >24 hours after the onset of rash seems no more effective at reducing the time to full crusting or time to new lesions in healthy adults (moderate-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Time to full crusting
Systematic review
148 adults Data from 1 RCT
Time to full crusting
7 days with aciclovir (800 mg 5 times daily) given 24 to 72 hours after onset of rash 6.8 days with placebo
P >0.2
Not significant
Time to no new lesions
Systematic review
68 adults Data from 1 RCT
Time to no new lesions
1 day with aciclovir given >24 hours after onset of rash 1 day with placebo
P = 0.55
Not significant
Systematic review
100 adults Data from 1 RCT
Time to no new lesions
with aciclovir given >24 hours after onset of rash with placebo Absolute results not reported
P values reported separately for different severities of eruption; all P >0.05
No data from the following reference on this outcome.
Rate of chickenpox
No data from the following reference on this outcome.
Complications of chickenpox
No data from the following reference on this outcome.
Disease severity
No data from the following reference on this outcome.
Adverse effects
No data from the following reference on this outcome.
Different timings of administration of aciclovir (later than 24 hours after onset of rash) versus each other:
We found one RCT.
Duration of illness
Starting aciclovir on second day from onset of rash compared with starting aciclovir on third day from onset of rash Aciclovir started on the second day from onset of rash may be more effective at reducing the duration of rash in healthy children and adults and at reducing duration of fever in adolescents. However, we don't know how starting aciclovir on the second day of rash compares with starting aciclovir on the third day at reducing rash in adolescents and adults, or at reducing fever in children and adults (very low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Duration of rash
RCT
77 children, adolescents, and adults
Median number of days to no new lesions in children
4 days with aciclovir started on second day from onset of rash 5 days with aciclovir started on third day from onset of rash
P <0.04
Effect size not calculated
aciclovir started on second day from onset of rash
RCT
77 children, adolescents, and adults
Median number of days to no new lesions in adolescents and adults
with aciclovir started on second day from onset of rash with aciclovir started on third day from onset of rash Absolute results not reported
P >0.05
Not significant
Duration of fever
RCT
77 children, adolescents, and adults
Median number of days to lowering of fever in adolescents
2 to 3 days with aciclovir started on second day from onset of rash 3 to 4 days with aciclovir started on third day from onset of rash
P <0.02
Effect size not calculated
aciclovir started on second day from onset of rash
RCT
77 children, adolescents, and adults
Median number of days to lowering of fever in children and adults
with aciclovir started on the second day from onset of rash with aciclovir started on the third day from onset of rash Absolute results not reported
No data from the following reference on this outcome.
Rate of chickenpox
No data from the following reference on this outcome.
Complications of chickenpox
No data from the following reference on this outcome.
Disease severity
No data from the following reference on this outcome.
Adverse effects
No data from the following reference on this outcome.
Further information on studies
None.
Comment
Clinical guide:
Evidence is sparse, but symptomatic treatments are commonly used in practice, and may be beneficial. Paracetamol is used to reduce fever, topical calamine or crotamiton to soothe the skin and possibly relieve itching, and a sedating antihistamine at night to help sleep and possibly break the itch-scratch-itch cycle. If viral complications of chickenpox (e.g., pneumonia or encephalitis) develop in healthy people, aciclovir is indicated.
We found no direct information from RCTs about the effects of aciclovir for treating chickenpox in immunocompromised adults.
Benefits and harms
Aciclovir:
We found no systematic review or RCTs assessing aciclovir for treating chickenpox in immunocompromised adults.
Further information on studies
None.
Comment
Despite scarce evidence, aciclovir is indicated in immunocompromised people because of the poor prognosis without treatment and the relatively minor harmful effects of the drug.
Substantive changes
No new evidence
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Aciclovir for treatment in immunocompromised children
In children with malignancy, intravenous aciclovir seems to reduce clinical deterioration from chickenpox.
Benefits and harms
Intravenous aciclovir versus placebo:
We found two placebo-controlled RCTs of intravenous aciclovir in children with cancer who were receiving chemotherapy.
Duration of illness
Compared with placebo Intravenous aciclovir may be more effective at reducing time to full crusting of lesions in children with cancer who are receiving chemotherapy. However, we don't know whether intravenous aciclovir is more effective at reducing duration of fever (very low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Time to full crusting
RCT
50 children aged 1 to 14 years with chickenpox, 60% of whom had a rash for >24 hours
Time to full crusting of lesions (children not transferred to open-label aciclovir)
5.7 days with aciclovir 7.1 days with placebo
P <0.013
Exclusion from the analysis of children taking placebo who deteriorated clinically means that the effect of placebo may have been over-estimated
Effect size not calculated
aciclovir
Duration of fever
RCT
50 children aged 1 to 14 years with chickenpox, 60% of whom had a rash for >24 hours
Duration of fever (children not transferred to open-label aciclovir)
with aciclovir with placebo Absolute results not reported
Reported as not significant
P value not reported
Exclusion from the analysis of children taking placebo who deteriorated clinically means that the effect of placebo may have been over-estimated
No data from the following reference on this outcome.
Disease severity
Compared with placebo In children with cancer who are receiving chemotherapy, intravenous aciclovir may be more effective at reducing the proportion of children who deteriorate clinically (very low-quality evidence).
Ref (type)
Population
Outcome, Interventions
Results and statistical analysis
Effect size
Favours
Clinical deterioration
RCT
50 children aged 1 to 14 years with chickenpox, 60% of whom had a rash for >24 hours
Proportion of children who deteriorated clinically (transferred to open-label aciclovir)
1/25 (4%) with aciclovir 12/25 (48%) with placebo
RR 0.08
95% CI 0.01 to 0.59
NNT 3
95% CI 2 to 4
Large effect size
aciclovir
RCT
20 children, mean age 6.4 years
Proportion of children who deteriorated clinically (transferred to open-label aciclovir)
1/8 (12%) with aciclovir 5/12 (42%) with placebo
RR 0.30
95% CI 0.04 to 2.10
RCT was too small to exclude a clinically important difference
Despite scarce evidence, aciclovir is indicated in immunocompromised people because of the poor prognosis without treatment and the relatively minor harmful effects of the drug.
Substantive changes
No new evidence
BMJ Clin Evid. 2011 Apr 11;2011:0912.
Famciclovir for treatment in immunocompromised people
