A Prominent Group in The Burden of Childhood Chickenpox: Adolescents

It was long assumed, before recent developments proved otherwise, that the presence of an infection with varicella zoster virus (VZV) was inevitably associated with a rash. We now know, due to the use of polymerase chain reaction (PCR) and other methods that have improved diagnosis, that patients can harbor infections with VZV even in the absence of cutaneous manifestations Such “occult” VZV infections often affect the nervous and gastrointestinal systems. Central nervous system (CNS) VZV infections without rash were initially identified at autopsy [1] and subsequently in patients with meningitis through the PCR detection of VZV DNA in cerebrospinal fluid (CSF) [2]. Although there appears to be a relationship between VZV infection and arterial ischemic stroke (AIS) [3], these patients also do not display a rash when they develop symptoms involving the CNS. In the current issue of Clinical Infectious Diseases, Thomas et al describe the connection between varicella and subsequent AIS in children. They used 4 large databases and a self-controlled case series, analyzing data from strokes in the varicella cases. Data were analyzed 0–6 months after an episode of varicella and again at a later time. This method avoids confounding factors and is efficient at relating a rare condition, such as stroke in childhood, to a common infection, varicella, although it does not provide information on the absolute risk of postvaricella stroke. Thomas et al’s study revealed that in the 6 months following varicella, the incidence of childhood stroke is increased by a factor of approximately 4. There was no significant increase in strokes in adults after varicella, nor was there any increase in strokes 7– 12 months after varicella in children. The pathogenesis of postvaricella stroke is not known, but VZV can infect cerebral arteries, which provokes inflammatory responses that damage the infected arteries and may lead to aneurysms [4–6]. Because the interval between an episode of varicella and a stroke can be as long as 6 months, reactivation of latent VZV acquired during varicella, rather than a smoldering persistent infection in arteries, seems more likely to cause AIS, although either possibility remains plausible. The VZV that infects arteries could be delivered from sensory neurons in which VZV reactivates or as a result of a viremia. It may well be that most strokes following varicella are, in reality, strokes following zoster without rash. When one such stroke develops, there may be recurrences [7]. Strokes may also follow classic zoster, particularly when the ophthalmic branch of the trigeminal nerve is involved. It is conceivable that AIS after varicella in children is a manifestation of a rare defect in innate immunity described in certain severe alpha herpesvirus infections [8–12]. One mystery is why VZV would be at increased risk for reactivation soon after varicella. This timing may reflect the putative immunologic predisposition. Clearly, additional knowledge of the state of VZV prior to infection of cerebral arteries, as well as the immunologic status of the host who has experienced a VZV-induced stroke, is needed. A relationship between zoster and stroke was appreciated before postvaricella stroke was recognized. At first termed giant cell arteritis, it now appears that this vasculitis syndrome is similar to what is termed VZV vasculopathy [13]. VZV vasculopathy may be a subset of giant cell arteritis. It was recognized historically that in the months following zoster, patients (usually adults) might manifest symptoms of stroke ipsilateral to the side of the body where zoster occurred. Because strokes in children are unusual or rare, this increase in CNS disease from varicella, albeit serious to individuals, is not a major public health problem. The morbidity (which may be long-lasting) Received 16 September 2013; accepted 18 September 2013; electronically published 2 October 2013. Correspondence: Anne A. Gershon, MD, Department of Pediatrics, Columbia University College of Physicians and Surgeons, 622 W 168th St, PH 19-110, New York, NY 10032 (aag1@columbia.edu). Clinical Infectious Diseases 2014;58(1):69–71 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cit663

To estimate the medical and economic or societal costs of chickenpox in young children using a descriptive study Children under 5 years of age attending 124 Sydney childcare centres who were reported as having chickenpox were studied to assess the costs of medication use and medical consultations, days of care missed, and parental costs resulting from lost time from work and alternate childcare costs. There were 174 children (92 girls and 79 boys; in three the sex was not stated) who missed a mean of 5.5 days of care because of chickenpox, currently valued at $154. Medical costs were valued at $33 per child, based on 0.97 medical visits, and topical and oral medication. Labour costs resulting from parental work absenteeism were valued at $160 or $345 depending on the method of calculation, whilst direct economic costs of $24 were incurred through use of alternate childcare arrangements. Total costs including those incurred by secondary cases and by rare hospitalisations were in the range of $393-$578 per affected child. Medical costs of chickenpox in children are small relative to costs incurred as a result of parental work absenteeism and to costs of foregone childcare. Ascribing precise work-related costs should take into account some capacity to make up lost work time. Such data will be required when determining the cost-benefit of childhood varicella immunisation.

Oka/Merck varicella vaccine has been studied in this institution since 1981. Persistence of antibody for 6 to 8 years has been demonstrated; however, cases of chickenpox have been seen in immunized children. The severity of chickenpox in healthy children who have received Oka/Merck varicella vaccine since 1981 is described. All vaccinees who developed chickenpox-like rashes more than 6 weeks postimmunization were examined. Of 2163 vaccinees, 164 were examined, of whom 114 had rashes consistent with chickenpox. When sera were available (46%), antibody studies uniformly confirmed varicella-zoster virus infection. Chickenpox occurred 2 to 96 months (median of 44 months) postimmunization. The range for the number of skin lesions was 1 to 285 (median 18) in seroconverters. Symptoms included itching in 39%, fever in 9%, headaches in 7%, lymphadenopathy in 3%, and malaise in 2%; 54% were asymptomatic, except for the rash. The median time to total healing was 5 days. The median time lost from school was 2 days. Thirteen of the children in whom infections developed had failed to seroconvert after immunization. Their infections were similar in severity to those of children who had seroconverted originally. When varicella was introduced into families as a result of chickenpox in an immunized family member (index case), the rate of secondary chickenpox among immunized siblings was 12.2%. Eleven such secondary cases were similar in severity to the 9 index cases. It is concluded that chickenpox is generally mild in previously immunized children.

One hundred ninety-one varicella-susceptible children with leukemia in remission were immunized with live attenuated varicella vaccine. There was serological evidence of an immune response in approximately 80% after one dose and in more than 90% after two doses. The major side effect was mild to moderate rash, seen especially in children with maintenance chemotherapy suspended for one week before and one week after vaccination. Children with rash had higher antibody titers than those without rash, but those with rash were also at risk (10%) to transmit vaccine virus to others. Twenty-two vaccinees subsequently had household exposures to varicella or zoster. The attack rate of clinical varicella in these vaccinees was 18%, significantly lower than the attack rate of approximately 90% in varicella-susceptible persons with household exposures. All cases of clinical illness were extremely mild, with an average of about 50 vesicles. The mild character of the illness was clearly different than varicella in unimmunized children receiving chemotherapy for leukemia. Varicella vaccine was approximately 80% effective in preventing clinical varicella in children with leukemia and completely effective in preventing severe varicella in this high-risk group.

Live attenuated varicella vaccines for the prevention of varicella (chickenpox) has been demonstrated both in randomised controlled trials (RCTs) and in population-based immunisation programmes in countries such as the United States. However, many countries do not routinely immunise children against varicella, and exposures continue to occur. Although the disease is often mild, complications such as secondary bacterial infection, pneumonitis and encephalitis occur in about 1% of cases, usually leading to hospitalisation. The use of varicella vaccine in persons who have recently been exposed to the varicella zoster virus has been studied as a form of post-exposure prophylaxis (PEP). To assess the efficacy and safety of vaccines for use as PEP for the prevention of varicella in children and adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2008, Issue 1); MEDLINE (1966 to February 2008); and EMBASE (January 1990 to February 2008). RCTs and quasi-RCTs of varicella vaccine for PEP compared with placebo or no intervention. The outcome measures were efficacy in prevention of clinical cases and/or laboratory-confirmed clinical cases and adverse effects following vaccination. Two review authors independently extracted and analysed data using Review Manager software. Three studies involving 110 healthy children who were siblings of household contacts were identified as suitable for inclusion. The studies varied in quality, study design, vaccine used, and outcomes measured and, as such, were not suitable for meta-analysis. Overall, 13 out of 56 vaccine recipients (18%) developed varicella compared with 42 out of 54 placebo (or no vaccine) recipients (78%). Of the vaccine recipients who developed varicella, the majority only had mild disease (with less than 50 skin lesions). In the three studies, most subjects received PEP within three days following exposure; too few subjects were vaccinated four to five days post exposure to ascertain the efficacy of vaccine given more than three days after exposure. No included studies reported on adverse events following immunisation. These small trials suggest varicella vaccine administered within three days to children following household contact with a varicella case reduces infection rates and severity of cases. No RCTs for adolescents or adults were identified. However safety was not adequately addressed.

We compared the complications of varicella requiringhospitalisation in healthy children before and after theintroduction of varicella vaccine in Taiwan. Overall, themean age of children in post-vaccine period was signi-ficantly older than in the pre-vaccine period, suggestinga change in the epidemiology of varicella in our countryafter the introduction of varicella vaccine.The live attenuated varicella vaccine prevents most ofthe morbidity caused by varicella in children [1] and wasfirst commercially available in Taiwan in September1997. However, routine immunisation is not uniformlyrecommended in all practices caring for children andcoverage is not included in health insurance system. Wecompared the complications of primary varicellarequiring hospitalisation in healthy children before andafter the introduction of varicella vaccine to determinethe potential benefits of routine immunisation.A retrospective analysis of hospital records ofchildren less than 15 years of age admitted with ICDcode 052 (varicella) from two study periods wasperformed. The pre-vaccine period was from 1 Septem-ber 1996 to 31 August 1997 and the post-vaccine periodwas from 1 September 1998 to 31 August 1999. Healthychildren with varicella as the primary indication forhospitalisation were included in the study. Varicella-associated complication was defined as a condition orevent occurring within 14 days of onset of varicella towhich varicella zoster virus infection may in some wayhave contributed [4]. Data were statistically analysed.A total of 180 children, 121 in the pre-vaccine and 59in the post-vaccine period were included in the study.Demographics and complications of varicella in hospi-talised children during the pre-vaccine and post-vaccineperiods are shown in Table 1. The mean age of childrenwas 3.23 years in the post-vaccine and 2.51 years in thepre-vaccine period, respectively. Children in the post-vaccine period were significantly older than those in thepre-vaccine period (P=0.005). Bacterial skin and softtissue infections were the most frequent complications(56.7%), followed by respiratory and central nervoussystem complications. Our study showed that there wasa marked reduction by 51% in the number of casesadmitted because of varicella associated complicationsin the post-vaccine period.Although varicella is a mild disease of childhood,serious complications requiring hospitalisation and evendeath may occur in healthy children [1, 3,4]. The age ofchildren hospitalised for complications of varicella in thepost-vaccine period was significantly higher than that inthe pre-vaccine period. The upward shift in age distri-bution of varicella was observed, which means greatermorbidity because more serious complications are likelyto occur in the adults [1]. Of particular concern is wheninfection occurs in pregnant women.Our hospital served mostly the Taoyuan county,representing 7.5% of the total population of the coun-try. The sales of varicella vaccine in our country wereabout 150,000/year over the past 3 years. Transferringthis number to children aged 1–14 years in this area, lessthan 10% of children had received the vaccine.Currently, there are still about 10% female and 20%male susceptible to varicella in Taipei [5] and the selec-tive use of vaccine will likely increase this proportion inthe future. With the use of varicella vaccine, the circu-lation of wild-type virus decreases leaving many non-immunised children unexposed to natural infection, thusbecoming susceptible adults. If the immunisation rate israised above 90%, the disease burden will decrease in allages [2]. If universal immunisation is not implemented,epidemiological changes are anticipated.The complications of varicella infection in the post-vaccine period did not differ much from those in thepre-vaccine period. Children in the post-vaccine period

One hundred ninety-one varicella-susceptible children with leukemia in remission were immunized with live attenuated varicella vaccine. There was serological evidence of an immune response in approximately 80% after one dose and in more than 90% after two doses. The major side effect was mild to moderate rash, seen especially in children with maintenance chemotherapy suspended for one week before and one week after vaccination. Children with rash had higher antibody titers than those without rash, but those with rash were also at risk (10%) to transmit vaccine virus to others. Twenty-two vaccinees subsequently had household exposures to varicella or zoster. The attack rate of clinical varicella in these vaccinees was 18%, significantly lower than the attack rate of approximately 90% in varicella-susceptible persons with household exposures. All cases of clinical illness were extremely mild, with an average of about 50 vesicles. The mild character of the illness was clearly different than varicella in unimmunized children receiving chemotherapy for leukemia. Varicella vaccine was approximately 80% effective in preventing clinical varicella in children with leukemia and completely effective in preventing severe varicella in this high-risk group. (<i>JAMA</i>1984;252:355-362)

The prevention of varicella (chickenpox) using live attenuated varicella vaccines has been demonstrated both in randomised controlled trials (RCTs) and in population-based immunisation programmes in countries such as the United States and Australia. Many countries do not routinely immunise children against varicella and exposures continue to occur. Although the disease is often mild, complications such as secondary bacterial infection, pneumonitis and encephalitis occur in about 1% of cases, usually leading to hospitalisation. The use of varicella vaccine in persons who have recently been exposed to the varicella zoster virus has been studied as a form of post-exposure prophylaxis (PEP). To assess the efficacy and safety of vaccines for use as PEP for the prevention of varicella in children and adults. We searched CENTRAL (2014, Issue 1), MEDLINE (1966 to March week 1, 2014), EMBASE (January 1990 to March 2014) and LILACS (1982 to March 2014). We searched for unpublished trials registered on the clinicaltrials.gov and WHO ICTRP websites. RCTs and quasi-RCTs of varicella vaccine for PEP compared with placebo or no intervention. The outcome measures were efficacy in prevention of clinical cases and/or laboratory-confirmed clinical cases and adverse events following vaccination. Two review authors independently extracted and analysed data using Review Manager software. We identified three trials involving 110 healthy children who were siblings of household contacts. The included trials varied in study quality, vaccine used, length of follow-up and outcomes measured and, as such, were not suitable for meta-analysis. We identified high or unclear risk of bias in two of the three included studies. Overall, 13 out of 56 vaccine recipients (23%) developed varicella compared with 42 out of 54 placebo (or no vaccine) recipients (78%). Of the vaccine recipients who developed varicella, the majority only had mild disease (with fewer than 50 skin lesions). In the three trials, most participants received PEP within three days following exposure; too few participants were vaccinated four to five days post-exposure to ascertain the efficacy of vaccine given more than three days after exposure. No included trial reported on adverse events following immunisation. These small trials suggest varicella vaccine administered within three days to children following household contact with a varicella case reduces infection rates and severity of cases. We identified no RCTs for adolescents or adults. Safety was not adequately addressed.

For the current issue of the Journal, we asked Dr Jane McDonald to comment on and put into context the Cochrane Review on vaccines for postexposure prophylaxis against varicella in children and adults.

ABSTRACTBACKGROUND: Live attenuated varicella vaccines for the prevention of varicella (chickenpox) has been demonstrated both in randomised controlled trials (RCTs) and in population-based immunisation programmes in countries such as the United States. However, many countries do not routinely immunise children against varicella, and exposures continue to occur. Although the disease is often mild, complications such as secondary bacterial infection, pneumonitis and encephalitis occur in about 1% of cases, usually leading to hospitalisation. The use of varicella vaccine in persons who have recently been exposed to the varicella zoster virus has been studied as a form of post-exposure prophylaxis (PEP).OBJECTIVE: To assess the efficacy and safety of vaccines for use as PEP for the prevention of varicella in children and adults.CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2008, Issue 1); MEDLINE (1966 to February 2008); and EMBASE (January 1990 to February 2008).SELECTION CRITERIA: RCTs and quasi-RCTs of varicella vaccine for PEP compared with placebo or no intervention. The outcome measures were efficacy in prevention of clinical cases and/or laboratory-confirmed clinical cases and adverse effects following vaccination.DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and analysed data using Review Manager software.MAIN RESULTS: Three studies involving 110 healthy children who were siblings of household contacts were identified as suitable for inclusion. The studies varied in quality, study design, vaccine used, and outcomes measured and, as such, were not suitable for meta-analysis. Overall, 13 out of 56 vaccine recipients (18%) developed varicella compared with 42 out of 54 placebo (or no vaccine) recipients (78%). Of the vaccine recipients who developed varicella, the majority only had mild disease (with less than 50 skin lesions). In the three studies, most subjects received PEP within three days following exposure; too few subjects were vaccinated four to five days post exposure to ascertain the efficacy of vaccine given more than three days after exposure. No included studies reported on adverse events following immunisation.AUTHORS CONCLUSIONS: These small trials suggest varicella vaccine administered within three days to children following household contact with a varicella case reduces infection rates and severity of cases. No RCTs for adolescents or adults were identified. However safety was not adequately addressed.

Herpes Simplex Virus (HSV)-1 and -2, and Varicella Zoster Virus (VZV)

The search for new effective and safe medications for external therapy of varicella in children remains highly relevant. Objective. To evaluate the efficacy and safety of a topical gel containing ammonium glycyrrhizinate for the treatment of varicella in children. Patients and methods. This study included 32 patients with varicella aged between 4 and 9 years. Study participants were randomized into two groups: patients in the experimental group received topical therapy with ammonium glycyrrhizinate, whereas patients in the control group received topical therapy with a medicine containing calamine and zinc oxide. Results. Patients in the experimental group demonstrated faster recovery than in control group: they had shorter period of new rash, shorter duration of rash on the mucous membranes; on day 4, there was a significant decrease in the proportion of patients with local edema and hyperemia in the area of rash; there was also a reduction in itching during the entire observation period, while patients in the control group had worsening of itching on days 5 and 6; we observed a 2-day reduction in the duration of secondary bacterial infection of rash. In the experimental group, there was a decrease in the proportion of patients with fatigue and its duration (to 4 days), as well as faster restoration of appetite compared to control group. Conclusion. Our findings allow us to recommend the gel containing ammonium glycyrrhizinate for effective topical therapy of varicella in children. Key words: ammonium glycyrrhizinate, varicella, glycyrrhizic acid, children, topical therapy

not available&#x0D; DS (Child) H J 2022; 38(2): 107-110

Chickenpox in childhood: A review prepared for the UK Advisory Group on Chickenpox on behalf of the British Society for the Study of Infection

Wild-type varicella zoster infection (WTVZV) up to 8 yr of age has been shown to protect against atopic dermatitis (AD) and asthma. We sought to determine whether WTVZV in childhood protects against atopic disorders, allergic sensitization or decreases serum Immunoglobulin E (IgE) levels. We conducted a retrospective, practice-based study of outpatient pediatric practices in NY. One hundred children with WTVZV up to 8 yr of age and 323 children who received varicella vaccine (VV) were randomly selected. WTVZV up to 8 yr of age is associated with decreased odds of subsequent asthma (exact logistic regression; OR = 0.12, 95% CI = 0.03-0.57, p = 0.003), allergic rhinoconjunctivitis (OR = 0.16, 95% CI = 0.05-0.49, p = 0.0003), and AD (OR = 0.57, 95% CI = 0.33-0.96, p = 0.02), but not food allergies (p = 0.78); decreased total serum IgE levels [mixed linear model, LSM (95% CI): 129.09 (33.22-501.63) vs. 334.21 (102.38-1091.04) IU/ml; p = 0.02] remained significant at all time intervals after WTVZV (<5, 5-10, and >10) compared with VV (p = 0.003-0.03). WTVZV was associated with decreased allergic sensitization (logistic regression, OR = 0.11, 95% CI = 0.03-0.38, p = 0.0004). WTVZV is also associated with persistently decreased numbers of peripheral blood lymphocytes (p < 0.0001) for up to 12 yr (p = 0.0003-0.047), monocytes (p = 0.002) for up to 16 yr (p < 0.001) and basophils at ages 4-6, 10-12, and 14-16 (p < 0.03). WTVZV up to 8 yr of age protects against atopic disorders, which is likely mediated by suppression of IgE production and allergic sensitization, as well as altered leukocyte distributions.