Clinical and Economic Burden of Antibiotic Use Among Pediatric Patients With Varicella Infection in the Outpatient Setting: A Retrospective Cohort Analysis of Real-world Data in France.

BACKGROUND: Varicella infects 90% of children before age 9. Though varicella is self-limiting, its complications may require antibiotics, though how antibiotics are utilized for varicella in France is not well known. This study assessed antibiotic use and costs associated with varicella and its complications in pediatric patients managed in the outpatient setting in France. METHODS: A retrospective cohort study using the Cegedim Strategic Data-Longitudinal Patient Database, an electronic medical record database from general practitioners and office-based specialists in France, was conducted. Children <18 years old diagnosed with varicella between January 2014 and December 2018 with 3-month follow-up available were included. We used descriptive analysis to assess varicella-related complications, medication use, healthcare resource utilization and costs. RESULTS: Overall, 48,027 patients were diagnosed with varicella; 15.3% (n = 7369) had ≥1 varicella-related complication. Antibiotics were prescribed in up to 25.1% (n = 12,045/48,027) of cases with greater use in patients with complications (68.1%, n = 5018/7369) compared with those without (17.3%, n = 7027/40,658). Mean medication and outpatient varicella-related costs were €32.82 per patient with medications costing a mean of €5.84 per patient; antibiotics contributed ~23% to total costs annually. CONCLUSION: This study showed high antibiotic use for the management of varicella and its complications. A universal varicella vaccination program could be considered to alleviate complications and associated costs in France.

The Clinical and Economic Burden of Antibiotic Use in Pediatric Patients with Varicella Infection: a Retrospective Cohort Analysis of Real-World Data in England.

BACKGROUND: Varicella is a highly infectious disease, particularly affecting children, that can lead to complications requiring antibiotics or hospitalization. Antibiotic use for varicella management is poorly documented. This study assessed antibiotic use for varicella and its complications in a pediatric population in England. METHODS: Data were drawn from medical records in the Clinical Practice Research Datalink and Hospital Episode Statistics datasets. Patients <18 years old diagnosed with varicella during 2014-2018 with 3-month follow-up available were included. We described varicella-related complications, medication use, healthcare resource utilization, and costs from diagnosis until 3-month post-diagnosis. RESULTS: We identified 114,578 children with a primary varicella diagnosis. 7.7% (n = 8,814) had a varicella-related complication, the most common being ear, nose, and throat related (37.1%, n = 3,271). In all, 25.9% (n = 29,706/114,578) were prescribed antibiotics. A higher proportion of patients with complications than those without complications were prescribed antibiotics (64.3%, n = 5,668/8,814 vs. 22.7%, n = 24,038/105,764). Mean annualized varicella-related costs were £2,231,481 for the study cohort. Overall, antibiotic prescriptions cost ∼£262,007. CONCLUSIONS: This study highlights high antibiotic use and healthcare resource utilization associated with varicella management, particularly in patients with complications. A national varicella vaccination program in England may reduce varicella burden and related complications, medication use, and costs.

Correction: Universal varicella vaccination in Denmark: Modeling public health impact, age-shift, and cost-effectiveness.

[This corrects the article DOI: 10.1371/journal.pgph.0001743.].

Estimating the health economic impact of the universal varicella vaccination in Argentina from 2015 to 2019.

Since the introduction of Universal Varicella Vaccination (UVV) in the Argentinean National Immunization Program in 2015, a significant decline in the incidence of varicella has been reported. This study aimed to estimate the economic impact of single-dose UVV in Argentina from 2015 to 2019. The economic impact was assessed based on the observed incidence of varicella in the post-UVV period and the number of cases avoided, obtained from a previously published study that used an Autoregressive Integrated Moving Average (ARIMA) model. The weighted average cost per case was calculated using local studies. The post-UVV cost reductions were calculated by multiplying the number of cases avoided from 2015 -2019 by the weighted average cost per case. Data were summarized yearly and by peak (September-November) periods for the target (1-4 years) and overall populations. We estimated avoided costs of United States dollars (USD) $65 million in the target population and $112 million in the overall population over 4 years following UVV introduction. We observed a trend toward greater reductions in costs over time, with substantial differences observed in peak periods. We estimated that the single-dose UVV program considerably reduced the economic burden of varicella in Argentina by avoiding direct and indirect costs associated with varicella management.

Predicting Measles Outbreaks in the United States: Evaluation of Machine Learning Approaches.

BACKGROUND: Measles, a highly contagious viral infection, is resurging in the United States, driven by international importation and declining domestic vaccination coverage. Despite this resurgence, measles outbreaks are still rare events that are difficult to predict. Improved methods to predict outbreaks at the county level would facilitate the optimal allocation of public health resources. OBJECTIVE: We aimed to validate and compare extreme gradient boosting (XGBoost) and logistic regression, 2 supervised learning approaches, to predict the US counties most likely to experience measles cases. We also aimed to assess the performance of hybrid versions of these models that incorporated additional predictors generated by 2 clustering algorithms, hierarchical density-based spatial clustering of applications with noise (HDBSCAN) and unsupervised random forest (uRF). METHODS: We constructed a supervised machine learning model based on XGBoost and unsupervised models based on HDBSCAN and uRF. The unsupervised models were used to investigate clustering patterns among counties with measles outbreaks; these clustering data were also incorporated into hybrid XGBoost models as additional input variables. The machine learning models were then compared to logistic regression models with and without input from the unsupervised models. RESULTS: Both HDBSCAN and uRF identified clusters that included a high percentage of counties with measles outbreaks. XGBoost and XGBoost hybrid models outperformed logistic regression and logistic regression hybrid models, with the area under the receiver operating curve values of 0.920-0.926 versus 0.900-0.908, the area under the precision-recall curve values of 0.522-0.532 versus 0.485-0.513, and F2 scores of 0.595-0.601 versus 0.385-0.426. Logistic regression or logistic regression hybrid models had higher sensitivity than XGBoost or XGBoost hybrid models (0.837-0.857 vs 0.704-0.735) but a lower positive predictive value (0.122-0.141 vs 0.340-0.367) and specificity (0.793-0.821 vs 0.952-0.958). The hybrid versions of the logistic regression and XGBoost models had slightly higher areas under the precision-recall curve, specificity, and positive predictive values than the respective models that did not include any unsupervised features. CONCLUSIONS: XGBoost provided more accurate predictions of measles cases at the county level compared with logistic regression. The threshold of prediction in this model can be adjusted to align with each county's resources, priorities, and risk for measles. While clustering pattern data from unsupervised machine learning approaches improved some aspects of model performance in this imbalanced data set, the optimal approach for the integration of such approaches with supervised machine learning models requires further investigation.

Universal varicella vaccination in Denmark: Modeling public health impact, age-shift, and cost-effectiveness.

We modeled the long-term clinical and economic impact of two-dose universal varicella vaccination (UVV) strategies in Denmark using a dynamic transmission model. The cost-effectiveness of UVV was evaluated along with the impact on varicella (including age-shift) and herpes zoster burden. Six two-dose UVV strategies were compared to no vaccination, at either short (12/15 months) or medium (15/48 months) intervals. Monovalent vaccines (V-MSD or V-GSK) for the 1st dose, and either monovalent or quadrivalent vaccines (MMRV-MSD or MMRV-GSK) for the 2nd dose were considered. Compared to no vaccination, all two-dose UVV strategies reduced varicella cases by 94%-96%, hospitalizations by 93%-94%, and deaths by 91%-92% over 50 years; herpes zoster cases were also reduced by 9%. There was a decline in the total number of annual varicella cases in all age groups including adolescents and adults. All UVV strategies were cost-effective compared to no vaccination, with ICER values ranging from €18,228-€20,263/QALY (payer perspective) and €3,746-€5,937/QALY (societal perspective). The frontier analysis showed that a two-dose strategy with V-MSD (15 months) and MMRV-MSD (48 months) dominated all other strategies and was the most cost-effective. In conclusion, all modeled two-dose UVV strategies were projected to substantially reduce the clinical and economic burden of varicella disease in Denmark compared to the current no vaccination strategy, with declines in both varicella and zoster incidence for all age groups over a 50-year time horizon.

Impact assessment of immunization and the COVID-19 pandemic on varicella across Europe using digital epidemiology methods: A descriptive study.

BACKGROUND: Varicella is usually a mild disease in children but may be life-threatening, especially in adolescents and adults. Infection control measures implemented during the Coronavirus Disease 2019 (COVID-19) pandemic may have suppressed varicella transmission, potentially creating an 'immunity debt', particularly in countries without universal varicella vaccination. OBJECTIVES: To assess trends in Google search engine queries for varicella keywords as a proxy for varicella infection rates and to evaluate the effect of universal varicella vaccination on these trends. A further objective was to assess the impact of the COVID-19 pandemic on varicella keyword search query trends in countries with and without universal varicella vaccination. METHODS: This study used the keyword research tool, Google Trends, to evaluate trends in time series of the relative search query popularity of language-specific varicella keywords in 28 European countries from January 2015 through December 2021. The Google Ads Keyword Planner tool was used to evaluate absolute search volumes from March 2018 through December 2021. RESULTS: The relative search query popularity of varicella keywords displayed marked seasonal variation. In all 28 countries, the relative search query popularity of varicella keywords declined after the start of the COVID-19 pandemic (March 2020), compared with pre-pandemic levels (range, -18% to -70%). From April 2020 to July 2021, a period of intense COVID-19 transmission and infection control, absolute search volumes for varicella keywords were lower than pre-pandemic levels but rebounded after July 2021, when infection control measures were relaxed. CONCLUSION: This evaluation of search query trends demonstrated that search query data could be used as a proxy for trends in varicella infection rates and revealed that transmission of varicella may have been suppressed during the COVID-19 pandemic. Consideration should be given to using search query data to better understand the burden of varicella, particularly in countries where surveillance systems are inadequate.

Antimicrobial use for the management of varicella in Thailand: a retrospective observational study.

OBJECTIVE: To describe the clinical characteristics of varicella patients seeking medical consultation and the use of antimicrobials for their management in Thailand in the absence of universal varicella vaccination (UVV). METHODS: A multicenter, retrospective chart review of 260 children and adults with a primary diagnosis of varicella was conducted at one private and three public hospitals in Bangkok, Thailand. Charts of varicella patients (inpatient or outpatient) were randomly selected over a 5-year period. Key outcomes included clinical complications and the use of antibiotics, antivirals, and other medications. RESULTS: Charts of 200 children (mean age 5.7 years, range 0.3-16 years) and 60 adults (mean age 27.9 years, range 18-50 years) were reviewed. Fourteen patients (including 8 children) were hospitalized. Five percent of the children and none of the adults were immunocompromised. At least 1 varicella-related complication was reported by 7.3% (7% of children, 8.3% of adults, p = .778) of all patients, including 57.1% (62.5% of children, 50% of adults) of inpatients (p < .001, compared with outpatients). Skin/soft tissue infection (47.7%) and dehydration (47.4%) were the most common complications. Antivirals (mainly oral acyclovir) were prescribed to 46.5% of patients (31.5% of children, 96.7% of adults, p < .001). Antibiotics were prescribed to 20.8% of patients (19% of children, 26.7% of adults, p = .199). Topical, oral, and intravenous antibiotics were prescribed to 12.3%, 8.5%, and 1.2% of patients, respectively. Antimicrobial prescriptions were higher among adults (p < .001) and immunocompromised patients (p = .025). Apart from antimicrobials, acetaminophen (62.3%) and oral antihistamines (51.5%) were the most prescribed. CONCLUSION: A considerable number of varicella patients, both children and adults, seeking medical consultation in Thai hospitals are prescribed antibiotics and antivirals, with one-fifth of patients being prescribed an antibiotic and almost half prescribed an antiviral. The study may be of interest to policymakers in Thailand and other Asia-Pacific countries considering UVV implementation.

The Long-Term Clinical and Economic Impact of Universal Varicella Vaccination in Slovenia.

Background: Despite the substantial burden of varicella infection, Slovenia does not currently have a universal varicella vaccination (UVV) program. We modeled the long-term clinical and economic impact of implementing 2-dose UVV strategies compared with no vaccination in Slovenia. Methods: A previously published dynamic transmission model was adapted to the demographics, varicella seroprevalence, herpes zoster incidence, and contact patterns in Slovenia. Six 2-dose UVV strategies, vs no vaccination, were considered over a 50-year period, including monovalent vaccination (Varivax® [V-MSD] or Varilrix® [V-GSK]) at ages 12 and 24 months, or monovalent vaccination at 15 months followed by monovalent or quadrivalent vaccination (ProQuad® [MMRV-MSD] or Priorix- Tetra® [MMRV-GSK]) at 5.5 years. Costs, quality-adjusted life-years, and incremental cost-effectiveness ratios vs no vaccination were calculated to assess the economic impact of each strategy from payer and societal perspectives. Results: The incidence of varicella infection was estimated as 1228 per 100 000 population in the absence of UVV. Over 50 years, depending on vaccination strategy, UVV reduced varicella cases by 77% to 85% and was associated with substantial reductions in varicella deaths (39%-44%), outpatient cases (74%-82%), and hospitalizations (74%-82%). The greatest reductions were predicted with V-MSD (15 months/5.5 years) and V MSD/MMRV-MSD (15 months/5.5 years). Discussion: All 2-dose UVV strategies were cost-effective compared with no vaccination from payer and societal perspectives, with V-MSD (15 months/5.5 years) being the most favorable from both perspectives. Conclusion: Policymakers should consider implementing UVV to reduce the burden of varicella disease in Slovenia.

The health and economic impact of switching vaccines in universal varicella vaccination programs using a dynamic transmission model: An Israel case study.

Currently available health economic models for varicella infection are designed to inform the cost-effectiveness of universal varicella vaccination (UVV) compared with no vaccination. However, in countries with an existing UVV program, these models cannot be used to evaluate whether to continue with the current varicella vaccine or to switch to an alternative vaccine. We developed a dynamic transmission model that incorporates the historical vaccination program to project the health and economic impact of changing vaccination strategies. We applied the model to Israel, which initiated UVV in 2008 with a quadrivalent vaccine, MMRV-GSK, and switched to MMRV-MSD in 2016. The model was calibrated to pre-vaccination incidence data before projecting the impact of the historical and future alternative vaccination strategies on the clinical burden of varicella. Total costs and QALYs lost due to varicella infections were projected to compare continuing with MMRV-MSD versus switching to MMRV-GSK in 2022. Over a 50-year time horizon, continuing with MMRV-MSD reduced varicella incidence further by 64%, reaching 35 cases per 100,000 population by 2072, versus a 136% increase in incidence with MMRV-GSK. Continuing with MMRV-MSD reduced cumulative hospitalization and outpatient cases by 48% and 58% (vs. increase of 137% and 91% with MMRV-GSK), respectively. Continuing with MMRV-MSD resulted in 139 fewer QALYs lost with total cost savings of 3% compared with switching to MMRV-GSK, from the societal perspective. In Israel, maintaining the UVV strategy with MMRV-MSD versus switching to MMRV-GSK is projected to further reduce the burden of varicella and cost less from the societal perspective.

Modeling the Impact of Exogenous Boosting and Universal Varicella Vaccination on the Clinical and Economic Burden of Varicella and Herpes Zoster in a Dynamic Population for England and Wales.

Universal varicella vaccination (UVV) in England and Wales has been hindered by its potential impact on exogenous boosting and increase in herpes zoster (HZ) incidence. We projected the impact of ten UVV strategies in England and Wales on the incidence of varicella and HZ and evaluated their cost-effectiveness over 50 years. The Maternal-Susceptible-Exposed-Infected-Recovered-Vaccinated transmission model was extended in a dynamically changing, age-structured population. Our model estimated that one- or two-dose UVV strategies significantly reduced varicella incidence (70-92%), hospitalizations (70-90%), and mortality (16-41%) over 50 years. A small rise in HZ cases was projected with UVV, peaking 22 years after introduction at 5.3-7.1% above pre-UVV rates. Subsequently, HZ incidence steadily decreased, falling 12.2-14.1% below pre-UVV rates after 50 years. At a willingness-to-pay threshold of 20,000 GBP/QALY, each UVV strategy was cost-effective versus no UVV. Frontier analysis showed that one-dose UVV with MMRV-MSD administered at 18 months is the only cost-effective strategy compared to other strategies. HZ incidence varied under alternative exogenous boosting assumptions, but most UVV strategies remained cost-effective. HZ vaccination decreased HZ incidence with minimal impact on the cost-effectiveness. Introducing a UVV program would significantly reduce the clinical burden of varicella and be cost-effective versus no UVV after accounting for the impact on HZ incidence.

The impact of universal varicella vaccination on the clinical burden of varicella in Colombia: A National database Analysis, 2008-2019.

In 2015, one-dose universal varicella vaccination (UVV) was introduced in the Colombian National Immunization Program targeting children aged 12 months, expanding to a two-dose program in 2019. This study aimed to examine the effect of one-dose UVV on the burden of varicella in Colombia. A retrospective study was conducted using national databases to estimate incidence and mortality for the target (1-4 years old), non-target (less than 1 and 5 years and older) and overall (all age groups) populations from the pre-UVV period (January 2008-June 2015) to the post-UVV period (July 2015-December 2019). A time-series analyses with ARIMA modeling was used to project expected varicella incidence and mortality in the absence of UVV in the post-UVV period. UVV impact was estimated by comparing predicted and observed values, providing point estimates and prediction intervals (PI). Overall vaccination coverage rate was over 90 % from 2016-2019. Following UVV introduction, mean annual incidence rates reduced from 743.6 to 676.8 per 100,000 in the target population and from 203.2 to 198.1 per 100,000 in the overall population. Our study estimated a reduction in varicella incidence from 2017, with the highest reduction of 70.5 % (95 % PI: 78.2-54.2) and 54.8 % (95 % PI: 65.0-36.4) observed in 2019 for the target and the overall populations, respectively. The ARIMA model estimated UVV in Colombia to have prevented 198,236 varicella cases from 2015 to 2019. Mortality reduced in the overall population from 0.8 per 1,000,000 to 0.5 per 1,000,000 and from 1.3 per 1,000,000 to 0.5 per 1,000,000 in the target population, in the pre-UVV and post-UVV periods, respectively. However, these differences were not statistically significant. Our study showed a significant reduction in varicella incidence after implementation of a one-dose UVV program in Colombia, increasing over time. Further assessment is needed to evaluate the impact of a two-dose UVV program in Colombia.

Trends in Varicella Burden of Disease Following Introduction of Routine Childhood Varicella Vaccination in Argentina: A 12-Year Time Series Analysis.

One-dose universal varicella vaccination (UVV) was introduced in the Argentinian National Immunization Program in July 2015. This study examined the impact of one-dose UVV on varicella incidence and mortality in Argentina. Incidence and mortality data were obtained from official databases for pre-UVV (January 2008-June 2015) and post-UVV (July 2015-December 2019) periods. Time series analyses with autoregressive integrated moving average (ARIMA) modeling predicted varicella incidence and mortality in absence of UVV in the target (aged 1-4 years) and overall population. Predicted and observed values post-UVV were compared to estimate UVV impact. Mean annual incidence rates per 100,000 reduced from 1999 (pre-UVV) to 1122 (post-UVV) in the target population and from 178 to 154 in the overall population. Significant declines in incidence were observed, reaching reductions of 83.9% (95% prediction interval [PI]: 58.9, 90.0) and 69.1% (95% PI: 23.6, 80.7) in the target and overall populations, respectively, during peak months (September-November) post-UVV. Decreasing trends in mortality rate from 0.4 to 0.2 per 1,000,000 population were observed. Over the last four years, one-dose UVV has significantly reduced varicella burden of disease in Argentina. Continuous efforts to improve vaccination coverage rates and long-term follow-up are needed to better understand the benefits of the UVV program.

Comparison of performance of varicella vaccines via infectious disease modeling.

BACKGROUND: Population-level infectious disease models for varicella require vaccine parameters, namely 'take' and 'duration of protection' (defined here as vaccine performance), to quantify the impact of vaccination. Current published models for varicella use vaccine parameters derived from various methodologies which does not allow for the direct comparison of different vaccines. METHODS: We estimated take and duration of protection using deterministic compartmental models to simulate clinical trials of one- or two-dose varicella vaccination using Varivax® (V-MSD) and Varilrix® (V-GSK). We fit different models to clinical trial data on breakthrough infections and evaluated their respective goodness-of-fit using the Akaike Information Criterion (AIC). RESULTS: Based upon the clinical trial data, we estimated that 90.3% (95% CI: 87.8-92.9%) of the cohort gained permanent protection from breakthrough varicella after the first dose of V-MSD compared to 61.7% (95% CI: 58.2-65.3%) with the first dose of V-GSK. We further estimated that a total of 97.0% (95% CI: 95.2-98.8%) and 93.8% (95% CI: 92.2-95.4%) of the cohort were permanently protected after two-doses of V-MSD and V-GSK, respectively. According to the AIC, our new model (V-MSD AIC = 92.7; V-GSK AIC = 170.3) provided a better fit than an existing model (V-MSD AIC = 108.9; V-GSK AIC = 216.1). CONCLUSIONS: The model developed fits the long-term clinical trial data on breakthrough infections for both V-MSD and V-GSK, thus, allowing for the direct comparison of vaccine performance. We estimated that a single dose of V-MSD was more likely to provide permanent protection than a single dose of V-GSK, while the protection offered by two doses was similar for both vaccines.

Recognition & management of varicella infections and accuracy of antimicrobial recommendations: Case vignettes study in the US.

BACKGROUND: In 1995, the CDC recommended one-dose routine varicella immunization for children <12 years of age, expanding its recommendation to two doses in 2006. Today, with widespread varicella vaccination coverage, an estimated 3.5 million cases of varicella, 9,000 hospitalizations, and 100 deaths are prevented annually in the United States. Since varicella infections are now uncommon, health care providers (HCPs) may not recognize varicella infections and may prescribe inappropriate treatment. METHODS: An online survey of HCPs was conducted to assess recognition and management of varicella infections. Responses to eight varicella vignettes describing patients with varying varicella symptoms were analyzed and descriptive analyses performed. Stratified analysis comparing responses of those licensed before and in/after 1996 was also performed. RESULTS: 153 HCPs (50 nurse practitioners, 103 doctors) completed the survey. Mean age of respondents was 44 years. 62% were female, and 82% were licensed before 1996. Varicella infection was correctly diagnosed 79% of the time. HCPs correctly recognized uncomplicated varicella vignettes 85% of the time versus 61% of the time for complicated varicella vignettes. Antibiotics were recommended 17% of the time and antivirals 18% of the time, of which 25% and 69% (respectively) were not appropriate per guidelines. HCPs licensed before 1996 were better able to recognize varicella compared to those licensed later, but prescribed more antimicrobials medications to treat varicella. CONCLUSIONS: Although most HCPs recognized varicella infection, a sizable proportion could not recognize cases with complications, and some of the varicella cases were inappropriately treated with antibiotics and/or antivirals. Additional HCP training and high vaccination coverage are important strategies to avoid inaccurate diagnoses and minimize unnecessary exposure to antimicrobial/antiviral therapies.

Impact of universal varicella vaccination on the use and cost of antibiotics and antivirals for varicella management in the United States.

BACKGROUND: Our objective was to estimate the impact of universal varicella vaccination (UVV) on the use and costs of antibiotics and antivirals for the management of varicella among children in the United States (US). METHODS: A decision tree model of varicella vaccination, infections and treatment decisions was developed. Results were extrapolated to the 2017 population of 73.5 million US children. Model parameters were populated from published sources. Treatment decisions were derived from a survey of health care professionals' recommendations. The base case modelled current vaccination coverage rates in the US with additional scenarios analyses conducted for 0%, 20%, and 80% coverage and did not account for herd immunity benefits. RESULTS: Our model estimated that 551,434 varicella cases occurred annually among children ≤ 18 years in 2017. Antivirals or antibiotics were prescribed in 23.9% of cases, with unvaccinated children receiving the majority for base case. The annual cost for varicella antiviral and antibiotic treatment was approximately $14 million ($26 per case), with cases with no complications accounting for $12 million. Compared with the no vaccination scenario, the current vaccination rates resulted in savings of $181 million (94.7%) for antivirals and $78 million (95.0%) for antibiotics annually. Scenario analyses showed that higher vaccination coverage (from 0% to 80%) resulted in reduced annual expenditures for antivirals (from $191 million to $41 million), and antibiotics ($82 million to $17 million). CONCLUSIONS: UVV was associated with significant reductions in the use of antibiotics and antivirals and their associated costs in the US. Higher vaccination coverage was associated with lower use and costs of antibiotics and antivirals for varicella management.

Relative efficacy of varicella vaccines: network meta-analysis of randomized controlled trials.

OBJECTIVE: Although varicella vaccination is highly effective, no head-to-head randomized controlled trials (RCTs) have compared the efficacy of different vaccine formulations. This study assessed the relative efficacy of different varicella vaccines using network meta-analysis (NMA). METHODS: We estimated the relative efficacies of varicella vaccines and dosing regimens from RCTs using Bayesian NMA. Modeling-based time-series NMA (MBNMA) was performed, accounting for differences in time since vaccination, to extrapolate long-term vaccine efficacy (VE). RESULTS: Eight RCTs were included based on systematic review of biomedical databases. Efficacy data were reported for four varicella-containing vaccines: Varivax (V-MSD, one and two dose), Varilrix (V-GSK, one dose), Priorix-Tetra (MMRV-GSK, one dose), and Sinovac (V-Sinovac, one dose). All varicella vaccines were effective versus no vaccination. Two-dose V-MSD (98.29%, 95% credible interval [CrI] 96.08-99.23) showed significantly higher VE versus all one-dose varicella-containing vaccines, but no significant difference versus two-dose MMRV-GSK (95.19%, 95% CrI 90.3-97.63). Two-dose MMRV-GSK showed higher VE than one-dose V-GSK (66.47%; 95% CrI 43.02-79.43), but no significant differences in VE versus one-dose V-MSD or one-dose V-Sinovac. In one-dose comparisons, V-MSD showed significantly higher VE (93.09%, 95% CrI 89.13-95.96) than V-GSK, but no significant difference versus V-Sinovac (89.22%; 95% CrI 67.1-96.5). MBNMA indicated that protection against varicella was sustained without waning over the 10 year follow-up. CONCLUSIONS: Our study reported higher VE for two-dose V-MSD and MMRV-GSK. Among one-dose formulations, one-dose V-MSD was more efficacious than one-dose V-GSK. Policymakers should take into consideration differences in VE when implementing one- versus two-dose strategies in universal vaccination programs.

Use of M-M-R II outside of the routinely recommended age range - a systematic literature review.

M-M-R®II (M-M-R II) is routinely used in many countries at 12-15 months with a second dose at 4 to 6 years of age. However, the vaccine may need to be administered at other ages due to delays in the immunization schedule or in certain situations such as outbreaks or international travel. A systematic literature review was conducted to evaluate efficacy, immunogenicity and safety of M-M-R II among 6- to 11-month-olds and persons ≥7 years of age. A search for randomized controlled trials (RCTs) was conducted in 2019 including Medline, Embase and Cochrane CENTRAL. Only one study reported seroconversion rates after one dose in infants at 9 months of age: 87.4% (measles), 92.3% (mumps), and 91.2% (rubella); no safety data were reported. Seven studies reported immunogenicity and safety data for M-M-R II at ≥7 years of age. Seroconversion rates ranged from 96%-100% (measles), 65%-100% (mumps), and 91%-100% (rubella). Rates of selected adverse events ranged from 5.2%-8.7% for fever (≥38°C or ≥38.1°C), 2%-33.3% for injection site reactions, and 0.4% for measles/rubella-like rash (one study). No efficacy studies were found. This literature review identified RCTs with evidence to support that M-M-R II is immunogenic and well tolerated in individuals ≥7 years of age.

Economic burden of varicella in Europe in the absence of universal varicella vaccination.

BACKGROUND: Though the disease burden of varicella in Europe has been reported previously, the economic burden is still unknown. This study estimated the economic burden of varicella in Europe in the absence of Universal Varicella Vaccination (UVV) in 2018 Euros from both payer (direct costs) and societal (direct and indirect costs) perspectives. METHODS: We estimated the country specific and overall annual costs of varicella in absence of UVV in 31 European countries (27 EU countries, plus Iceland, Norway, Switzerland and the United Kingdom). To obtain country specific unit costs and associated healthcare utilization, we conducted a systematic literature review, searching in PubMed, EMBASE, NEED, DARE, REPEC, Open Grey, and public heath websites (1/1/1999-10/15/2019). The number of annual varicella cases, deaths, outpatient visits and hospitalizations were calculated (without UVV) based on age-specific incidence rates (Riera-Montes et al. 2017) and 2018 population data by country. Unit cost per varicella case and disease burden data were combined using stochastic modeling to estimate 2018 costs stratified by country, age and healthcare resource. RESULTS: Overall annual total costs associated with varicella were estimated to be €662,592,061 (Range: €309,552,363 to €1,015,631,760) in Europe in absence of UVV. Direct and indirect costs were estimated at €229,076,206 (Range €144,809,557 to €313,342,856) and €433,515,855 (Range €164,742,806 to €702,288,904), respectively. Total cost per case was €121.45 (direct: €41.99; indirect: €79.46). Almost half of the costs were attributed to cases in children under 5 years, owing mainly to caregiver work loss. The distribution of costs by healthcare resource was similar across countries. France and Germany accounted for 49.28% of total annual costs, most likely due to a combination of high numbers of cases and unit costs in these countries. CONCLUSIONS: The economic burden of varicella across Europe in the absence of UVV is substantial (over 600 M€), primarily driven by caregiver burden including work productivity losses.

Assessing the use of antibiotics and the burden of varicella in Belgium using a retrospective GP database analysis.

BACKGROUND: Varicella is a highly contagious infection that typically occurs in childhood. While most cases have a generally benign outcome, infection results in a considerable healthcare burden and serious complications may occur. OBJECTIVES: The objective of this study was to characterize the burden of varicella in a real-world primary care setting in Belgium, including the rate of varicella-related complications, medication management and general practitioner (GP) visits. METHODS: The study was a retrospective observational study using data from a longitudinal patient database in a primary care setting in Belgium. Patients with a GP visit and a varicella diagnosis between January 2016 and June 2019 were eligible and data one month prior and three months after the diagnosis were included. Outcomes included varicella-related complications, antibiotic use, antiviral use, and GP follow-up visits. Antibiotic use could be specified by class of antibiotic and linked to a diagnosis. Complications were identified based on concomitant diagnosis with varicella during the study period. RESULTS: 3,847 patients with diagnosis of varicella were included, with a mean age of 8.4 years and a comparable distribution of gender. 12.6% of patients with varicella had a concomitant diagnosis of a varicella-related complication. During the follow-up period, 27.3% of patients with varicella were prescribed antibiotics, either systemic (19.8%) and/or topical (10.3%). The highest rate of antibiotic prescriptions was observed in patients with complications (63.5%) and in patients younger than 1 year (41.8%). Nevertheless, 5.3% of the patients were prescribed antibiotics without a concomitant diagnosis of another infection. The most commonly prescribed systemic antibiotics were amoxicillin alone or combined with beta-lactamase inhibitor, and thiamphenicol. Fusidic acid and tobramycin were the most prescribed topical antibiotics. Antivirals were prescribed for 2.7% of the study population. 4.7% of the patients needed a follow-up visit with their GP. CONCLUSIONS: This study reports a substantial burden of varicella in a primary care setting in Belgium, with high rates of complications and antibiotic use.