Norovirus acute gastroenteritis among US and European travellers to areas of moderate to high risk of travellers' diarrhoea: a prospective cohort study.

BACKGROUND: Acute gastroenteritis (AGE) is a major medical condition for travellers worldwide, particularly travellers to low- and middle-income countries. Norovirus (NoV) is the most common cause of viral AGE in older children and adults, but data on prevalence and impact among travellers is limited. METHODS: Prospective, multi-site, observational cohort study conducted 2015-2017, among adult international travellers from the US and Europe to areas of moderate to high risk of travel-acquired AGE. Participants provided self-collected pre-travel stool samples and self-reported AGE symptoms while travelling. Post-travel stool samples were requested from symptomatic subjects and a sample of asymptomatic travellers within 14days of return. Samples were tested for NoV by RT-qPCR, genotyped if positive, and tested for other common enteric pathogens by Luminex xTAG GPP. RESULTS: Of the 1109 participants included, 437 (39.4%) developed AGE symptoms resulting in an overall AGE incidence of 24.7 per 100 person-weeks (95% CI: 22.4; 27.1). Twenty NoV-positive AGE cases (5.2% of those tested) were identified at an incidence of 1.1 per 100 person-weeks (95% CI: 0.7; 1.7). NoV-positive samples belonged mostly to genogroup GII (18, 85.7%); None of the 13 samples sequenced belonged to genotype GII.4. Clinical severity of AGE was higher for NoV-positive than for NoV-negative cases (mean modified Vesikari Score 6.8 vs 4.9) with more cases classified as severe or moderate (25% vs 6.8%). Eighty percent of NoV-positive participants (vs. 38.9% in NoV-negative) reported at least moderate impact on travel plans. CONCLUSIONS: AGE is a prevalent disease among travellers with a small proportion associated with NoV. Post-travel stool sample collection timing might have influenced the low number of NoV cases detected; however, NoV infections resulted in high clinical severity and impact on travel plans. These results may contribute to targeted vaccine development and the design of future studies on NoV epidemiology.

Incidence of Lyme Borreliosis in Germany: Exploring Observed Trends Over Time Using Public Surveillance Data, 2016-2020.

Background: Public surveillance of Lyme borreliosis (LB) occurs in 9 out of 16 federal states of Germany and remains a critical facet of disease epidemiology and trends. We describe the incidence, time trends, seasonality, and geographic distribution of LB in Germany using publicly reported surveillance data. Methods: We obtained LB cases and incidence (2016-2020) from the online platform SurvStat@RKI 2.0, maintained by the Robert Koch Institute (RKI). Data included clinically diagnosed and laboratory-confirmed LB reported by nine out of 16 federal states of Germany where LB notification is mandatory. Results: During 2016-2020, the nine federal states reported 63,940 LB cases, of which 60,570 (94.7%) were clinically diagnosed, and 3370 (5.3%) also had laboratory confirmation, with an average of 12,789 cases annually. Incidence rates were mostly stable over time. The average annual LB incidence was 37.2/100,000 person-years and varied by spatial level, ranging from 22.9 to 64.6/100,000 person-years among nine states; from 16.8 to 85.6/100,000 person-years among 19 regions; and from 2.9 to 172.8/100,000 person-years among 158 counties. Incidence was lowest among persons 20-24 years old (16.1/100,000 person-years) and highest among those 65-69 years old (60.9/100,000 person-years). Most cases were reported between June and September, with a peak in July of every year. Conclusion: The risk of LB varied substantially at the smallest geographic unit and by age group. Our results underscore the importance of presenting LB data at the most spatially granular unit and by age to allow implementation of efficient preventive interventions and reduction strategies.

The Landscape of Lyme Borreliosis Surveillance in Europe.

Purpose: Lyme borreliosis (LB) is the most prevalent tick-borne disease in Europe and the incidence of LB is increasing owing to an expansion in tick habitats. However, LB surveillance is quite heterogeneous across the continent, and for those countries with publicly available data, it is difficult to understand the differences in incidence between countries. The objective of our study was to summarize the publicly available data from surveillance for LB in the form of surveillance reports and/or dashboards and to compare the information available for various countries. Methods: We identified publicly available LB data (online dashboards and surveillance reports) in the European Union, European Economic Area, the United Kingdom, Russia, and Switzerland. Results: Of the 36 countries studied, 28 had LB surveillance in place; 23 had surveillance reports, and 10 had dashboards. The dashboards, in general, had more granular data compared with the surveillance reports, but the reports covered longer time periods. LB annual cases, incidence, age, and sex-stratified LB data; manifestations; and regional data were available for most of the countries. LB case definitions varied significantly among the countries. Conclusion: The study highlights large differences in LB surveillance systems, including representativeness, case definitions, type of data available that might inhibit comparison of data between countries and accurate determination of burden of disease, and risk groups within countries. Standardization of case definitions across countries would be a useful first step enabling comparisons between countries and contribute to recognizing the true burden of LB in Europe.

Incidence of Lyme Borreliosis in the Dutch General Practice Population: A Large-Scale Population-Based Cohort Study Across the Netherlands Between 2015 and 2019.

Background: There is a need for updated incidence rates (IRs) of Lyme borreliosis (LB) in Europe, including the Netherlands. We estimated LB IRs stratified by geographic area, year, age, sex, immunocompromised status, and socioeconomic status (SES). Methods: All subjects registered in the PHARMO General Practitioner (GP) Database without prior diagnosis of LB or disseminated LB and having ≥1 year of continuous database enrolment were included. IRs and corresponding confidence intervals (CIs) of GP-recorded LB, erythema migrans (EM), and disseminated LB were estimated during the period 2015‒2019. Results: We identified 14,794 events (suspected, probable, or confirmed) with a diagnostic code for LB that included 8219 with a recorded clinical manifestation: 7985 (97%) with EM and 234 (3%) with disseminated LB. National annual LB IRs were relatively consistent, ranging from 111 (95% CI 106‒115) in 2019 to 131 (95% CI 126‒136) in 2018 per 100,000 person-years. Incidence of LB showed a bimodal age distribution, with peak IRs observed among subjects aged 5‒14 and 60‒69 years in men and women. Higher LB incidence was found in subjects who were residents of the provinces of Drenthe and Overijssel, immunocompromised, or of lower SES. Similar patterns were observed for EM and disseminated LB. Conclusions: Our findings confirm that LB incidence remains substantial throughout the Netherlands with no indication of decline in the past 5 years. Foci in two provinces and among vulnerable populations suggest potential initial target groups for preventive strategies such as vaccination.

A Retrospective Database Study of Lyme Borreliosis Incidence in Poland from 2015 to 2019: A Public Health Concern.

Background: In Poland, Lyme borreliosis (LB) has been subject to mandatory public health surveillance since 1996 and, in accordance with EU regulations, Lyme neuroborreliosis has been reported to the European Centre for Disease Prevention and Control since 2019. In this study, the incidence, temporal trends, and geographic distribution of LB and its manifestations in Poland are described for the period 2015-2019. Methods: This retrospective incidence study of LB and its manifestations in Poland was based on data sent to the National Institute of Public Health-National Institute of Hygiene-National Research Institute (NIPH-NIH-NRI) by district sanitary epidemiological stations using the electronic Epidemiological Records Registration System and data from the National Database on Hospitalization. Incidence rates were calculated using population data from the Central Statistical Office. Results: During 2015-2019, Poland reported 94,715 cases of LB with an overall average incidence of 49.3 cases per 100,000 population. Cases increased from 2015 (11,945) to 2016 (20,857) and then remained stable through 2019. Hospitalization due to LB also rose during these years. LB was more common among women (55.7%). Erythema migrans and Lyme arthritis were the most common manifestations of LB. The highest incidence rates occurred among >50-year-olds, with a peak in 65-69-year-olds. The highest number of cases was recorded in the third and fourth quarters of the year (July-December). Incidence rates in the eastern and northeastern regions of the country were higher than the national average. Conclusions: LB is endemic in all regions of Poland, and many regions reported high incidence rates. Large variations in spatially granular incidence rates highlight the need for targeted prevention strategies.

Incidence of Lyme neuroborreliosis in Denmark: Exploring observed trends using public surveillance data, 2015-2019.

Lyme neuroborreliosis (LNB) can be a serious manifestation of Lyme borreliosis. We describe the incidence, time trends and geographic distribution of LNB in Denmark. We obtained LNB cases reported by laboratories and physicians (2015-2019) from the online platform maintained by the Statens Serum Institut (SSI) (2021b). The LNB incidence (per 100,000 persons) was calculated by dividing LNB cases by the population data (denominator) obtained from Statistics Denmark (2021). Between 2015 and 2019, laboratories reported annually 162 to 200 LNB cases, while physicians reported 48 to 68 cases. The annual LNB incidence notified by laboratories ranged from 2.8 (95% CI: 2.4‒3.3) to 3.4 (95% CI: 3.0‒4.0) per 100,000 persons for the 5 study years. The average annual LNB incidence per 100,000 persons for 5 Danish regions ranged from 2.3 to 3.3; for 11 provinces, from 1.9 to 7.6; and for 98 municipalities, from 0 to 22.1. Incidence peaks occurred in persons 5‒14 and 65‒74 years of age. Higher incidences were observed among males versus females in all age groups. LNB cases were reported throughout the year, with peaks in July to September. Notified LNB incidence in Denmark was moderate with no evidence of decline. Cases occurred across all regions but were focally concentrated among residents of some municipalities. Expanding the current surveillance system to include other manifestations of LB would be valuable to better understand geographic endemicity to inform targeted preventive measures.

Estimating baseline rates of adverse perinatal and neonatal outcomes using a facility-based surveillance approach: A prospective observational study from the WHO Global Vaccine Safety Multi-Country Collaboration on safety in pregnancy.

Background: Most perinatal and neonatal deaths occur in low- and middle-income countries (LMICs), yet, quality data on burden of adverse outcomes of pregnancy is limited in such countries. Methods: A network of 21 maternity units, across seven countries, undertook surveillance for low birthweight, preterm birth, small for gestational age (SGA), stillbirths, congenital microcephaly, in-hospital neonatal deaths, and neonatal infections in a cohort of over 85,000 births from May 2019 - August 2020. For each outcome, site-specific rates per 1,000 livebirths (or per 1,000 total births for stillbirth) and 95% confidence intervals (CI) were calculated. Descriptive sensitivity analysis was conducted to gain insight regarding underreporting of four outcomes at 16 sites. Findings: Estimated rates varied across countries and sites, ranging between 43·3-329·5 and 21·4-276·6/1000 livebirths for low birthweight and preterm birth respectively and 11·8-81/1,000 livebirths for SGA. No cases of congenital microcephaly were reported by three sites while the highest estimated rate was 13/1,000 livebirths. Neonatal infection and neonatal death rates varied between 1·8-73 and 0-59·9/1000 livebirths respectively while stillbirth rates ranged between 0-57·1/1000 total births across study sites. Results from the sensitivity analysis confirmed the underreporting of congenital microcephaly and SGA in our study. Interpretation: Our study establishes site-specific baseline rates for important adverse perinatal and neonatal outcomes and addresses a critical evidence gap towards improved monitoring of benefits and risks of emerging pregnancy and neonatal interventions. Funding: The study was sponsored by the World Health Organization with funding from the Bill and Melinda Gates Foundation.

Operational lessons learned in conducting an international study on pharmacovigilance in pregnancy in resource-constrained settings: The WHO Global Vaccine safety Multi-Country collaboration project.

The WHO Global Vaccine Safety Multi-Country Collaboration study on safety in pregnancy aims to estimate the minimum detectable risk for selected perinatal and neonatal outcomes and assess the applicability of standardized case definitions for study outcomes and maternal immunization in low- and middle-income countries (LMICs). This paper documents the operational lessons learned from the study. A prospective observational study was conducted across 21 hospitals in seven countries. All births occurring at sites were screened to identify select perinatal and neonatal outcomes from May 2019 to August 2020. Up to 100 cases per outcome were recruited to assess the applicability of standardized case definitions. A multi-pronged study quality assurance plan was implemented. The impact of the COVID-19 pandemic on site functioning and project implementation was also assessed. Multi-layered ethics and administrative approvals, limited clinical documentation, difficulty in identifying outcomes requiring in-hospital follow-up, and poor quality internet connectivity emerged as important barriers to study implementation. Use of electronic platforms, application of a rigorous quality assurance plan with frequent interaction between the central and site teams helped improve data quality. The COVID-19 pandemic disrupted data collection for up to 6 weeks in some sites. Our study succeeded in establishing an international hospital-based surveillance network for evaluating perinatal and neonatal outcomes using common study protocol and procedures in geographically diverse sites with differing levels of infrastructure, clinical and health-utilization practices. The enhanced surveillance capacity of participating sites shall help support future pharmacovigilance efforts for pregnancy interventions.

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.

WHO global vaccine safety multi-country collaboration project on safety in pregnancy: Assessing the level of diagnostic certainty using standardized case definitions for perinatal and neonatal outcomes and maternal immunization.

Standardized case definitions strengthen post-marketing safety surveillance of new vaccines by improving generated data, interpretation and comparability across surveillance systems. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project developed standardized case definitions for 21 key obstetric and neonatal terms following the Brighton Collaboration (BC) methodology. In this prospective cohort study, we assessed the applicability of GAIA definitions for maternal immunization exposure and for low birth weight (LBW), preterm birth, small for gestational age (SGA), stillbirth, neonatal death, neonatal infection, and congenital microcephaly. We identified the missing data elements that prevented identified cases and exposures from meeting the case definition (level 1-3 of BC diagnostic certainty). Over a one-year period (2019-2020), all births occurring in 21 sites (mostly secondary and tertiary hospitals) in 6 Low Middle Income Countries and 1 High Income Country were recorded and the 7 perinatal and neonatal outcome cases were identified from routine medical records. Up to 100 cases per outcome were recruited sequentially from each site. Most cases recruited for LBW, preterm birth and neonatal death met the GAIA case definitions. Birth weight, a key parameter for all three outcomes, was routinely recorded at all sites. The definitions for SGA, stillbirth, neonatal infection (particularly meningitis and respiratory infection) and congenital microcephaly were found to be less applicable. The main barrier to obtaining higher levels of diagnostic certainty was the lack of sonographic documentation of gestational age in first or second trimester. The definition for maternal immunization exposure was applicable, however, the highest level of diagnostic certainty was only reached at two sites. Improved documentation of maternal immunization will be important for vaccine safety studies. Following the field-testing of these 8 GAIA definitions, several improvements are suggested that may lead to their easier implementation, increased standardization and hence comparison across studies.

The burden of norovirus disease in children: a multi-country study in Chile, Brazil, Thailand and the Philippines.

BACKGROUND: Noroviruses (NoVs) cause acute gastroenteritis (AGE) worldwide, affecting children in particular. We aimed to estimate the burden of disease due to NoV among children aged <6 years in Brazil, Chile, Philippines and Thailand. METHODS: This was a prospective, hospital-based, observational study. Children were recruited over one year between 2014 and 2017. Four cohorts were analysed: community-acquired AGE outpatients and inpatients, nosocomial AGE inpatients, and asymptomatic outpatients. We collected demographic and clinical data, and a stool sample that was tested for NoV. Positive samples were tested for Rotavirus (RV) and NoV-genotyped. Disease severity was assessed by the Vesikari and modified Vesikari scores. Prevalence and incidence of NoV-AGE were estimated by cohort and country. RESULTS: 1637 participants yielded valid laboratory results. The proportion of NoV-positive cases was 23.8% (95% CI 20.8-27.2) in the outpatient cohort, 17.9% (15.0-21.3) in the hospital cohort, 21.4% (12.7-33.8) in the nosocomial cohort and 9.6% (6.9-13.2) in the asymptomatic cohort. Genotype GII.4 was predominant (58%). Less than 4% samples had RV coinfection. In general, NoV-positive subjects had more severe presentations than NoV-negative subjects. CONCLUSIONS: NoV caused AGE with substantial burden throughout the studied settings, with higher relative frequency in Brazil where RV vaccination coverage is high.

Brand-specific influenza vaccine effectiveness estimates during 2019/20 season in Europe - Results from the DRIVE EU study platform.

DRIVE (Development of Robust and Innovative Vaccine Effectiveness) is an IMI funded public-private platform that aims to annually estimate brand-specific influenza vaccine effectiveness (IVE), for public health and regulatory purposes. IVE analyses and reporting are conducted by public partners in the consortium. In 2019/20, four primary care-based test-negative design (TND) studies (Austria, England, Italy (n = 2)), eight hospital-based TND studies (Finland, France, Italy, Romania, Spain (n = 4)), and one population-based cohort study (Finland) were conducted. The COVID-19 pandemic affected influenza surveillance in all participating study sites, therefore the study period was truncated on February 29, 2020. Age-stratified (6 m-17y, 18-64y, ≥65y), confounder-adjusted, site-specific adjusted IVE estimates were calculated and pooled through meta-analysis. Parsimonious confounder-adjustment was performed, adjusting the estimates for age, sex and calendar time. TND studies included 3531 cases (351 vaccinated) and 5546 controls (1415 vaccinated) of all ages. IVE estimates were available for 8/11 brands marketed in Europe in 2019. Most children and adults < 64y were captured in primary care setting and the most frequently observed vaccine brand was Vaxigrip Tetra. The estimate against any influenza for Vaxigrip Tetra in primary care setting was 61% (95%CI 38-77) in children and 32% (95%CI -13-59) in adults up to 64y. Most adults ≥ 65y were captured in hospital setting and the most frequently observed brand was Fluad, with an estimate of 52% (95%CI 27-68). The population-based cohort covered 511,854 person-years and two vaccine brands. In children aged 2-6y, the IVE against any influenza was 68% (95%CI 58-75) for Fluenz Tetra and 71% (56-80) for Vaxigrip Tetra. In adults ≥ 65y, IVE against any influenza was 29% (20-36) for Vaxigrip Tetra. DRIVE is a growing platform. Public health institutes with surveillance data and hospitals in countries with high influenza vaccine coverage are encouraged to join DRIVE.

Systematic literature review of the impact and effectiveness of monovalent meningococcal C conjugated vaccines when used in routine immunization programs.

BACKGROUND: Monovalent meningococcal C conjugate vaccine (MCCV) was introduced into the routine immunization program in many countries in Europe and worldwide following the emergence of meningococcal serogroup C (MenC) in the late 1990s. This systematic literature review summarizes the immediate and long-term impact and effectiveness of the different MCCV vaccination schedules and strategies employed. METHODS: We conducted a systematic literature search for peer-reviewed, scientific publications in the databases of MEDLINE (via PubMed), LILACS, and SCIELO. We included studies from countries where MCCV have been introduced in routine vaccination programs and studies providing the impact and effectiveness of MCCV published between 1st January 2001 and 31st October 2017. RESULTS: Forty studies were included in the review; 30 studies reporting impact and 17 reporting effectiveness covering 9 countries (UK, Spain, Italy, Canada, Brazil, Australia, Belgium, Germany and the Netherlands). Following MCCV introduction, significant and immediate reduction of MenC incidence was consistently observed in vaccine eligible ages in all countries with high vaccine uptake. The reduction in non-vaccine eligible ages (especially population > 65 years) through herd protection was generally observed 3-4 years following introduction. Vaccine effectiveness (VE) was mostly assessed through screening methods and ranged from 38 to 100%. The VE was generally highest during the first year after vaccination and waned over time. The VE was better maintained in countries employing catch-up campaigns in older children and adolescents, compared to routine infant only schedules. CONCLUSIONS: MCCV were highly effective, showing a substantial and sustained decrease in MenC invasive meningococcal disease. The epidemiology of meningococcal disease is in constant transition, and some vaccination programs now include adolescents and higher valent vaccines due to the recent increase in cases caused by serogroups not covered by MCCV. Continuous monitoring of meningococcal disease is essential to understand disease evolution in the setting of different vaccination programs.

Vaccine effectiveness against laboratory-confirmed influenza in Europe - Results from the DRIVE network during season 2018/19.

The DRIVE project aims to establish a sustainable network to estimate brand-specific influenza vaccine effectiveness (IVE) annually. DRIVE is a public-private partnership launched in response to EMA guidance that requires effectiveness evaluation from manufacturers for all individual influenza vaccine brands every season. IVE studies are conducted by public partners in DRIVE. Private partners (vaccine manufacturers from the European Federation of Pharmaceutical Industries and Association (EFPIA)) provide written feedback moderated by an independent scientific committee. Test-negative design (TND) case-control studies (4 in primary care and five in hospital) were conducted in six countries in Europe during the 2018/19 season. Site-specific confounder-adjusted vaccine effectiveness (VE) estimates for any vaccine exposure were calculated by age group (<18 years (y), 18-64y and 65 + y) and pooled by setting (primary care, hospital) through random effects meta-analysis. In addition, one population-based cohort study was conducted in Finland. TND studies included 3339 cases and 6012 controls; seven vaccine brands were reported. For ages 65 + y, pooled VE against any influenza strain was estimated at 27% (95%CI 6-44) in hospital setting. Sample size was insufficient for meaningful IVE estimates in other age groups, in the primary care setting, or by vaccine brand. The population-based cohort study included 274,077 vaccinated and 494,337 unvaccinated person-years, two vaccine brands were reported. Brand-specific IVE was estimated for Fluenz Tetra (36% [95%CI 24-45]) for ages 2-6y, Vaxigrip Tetra (54% [43-62]) for ages 6 months to 6y, and Vaxigrip Tetra (30% [25-35]) for ages 65 + y. The results presented are from the second influenza season covered by the DRIVE network. While sample size from the pooled TND studies was still too low for precise (brand-specific) IVE estimates, the network has approximately doubled in size compared to the pilot season. Taking measures to increase sample size is an important focus of DRIVE for the coming years.

Norovirus Gastroenteritis among Hospitalized Patients, Germany, 2007-2012.

We estimated numbers of hospitalizations for norovirus gastroenteritis (NGE) and associated medical costs in Germany, where norovirus testing is high because reimbursement is affected. We extracted aggregate data for patients hospitalized with a primary or secondary code from the International Classification of Diseases, 10th Revision (ICD-10), NGE diagnosis during 2007-2012 from the German Federal Statistics Office. We assessed reliability of the coding system in patient records from a large academic hospital. Approximately 53,000-90,000 NGE hospitalizations occurred annually in Germany (21,000-33,000 with primary and 32,000-57,000 with secondary ICD-10-coded NGE diagnoses). Rates of hospitalization with NGE as primary diagnosis were highest in children <2 years of age; rates of hospitalization with NGE as secondary diagnosis were highest in adults >85 years of age. The average annual reimbursed direct medical cost of NGE hospitalizations was €31-43 million. Among patients with a NGE ICD-10 code, 87.6% had positive norovirus laboratory results.

Norovirus and Rotavirus Disease Severity in Children: Systematic Review and Meta-analysis.

BACKGROUND: Rotaviruses (RVs) and noroviruses (NoVs) are the most common causes of severe acute gastroenteritis in children. It is generally accepted that RVs cause severe acute gastroenteritis in a higher proportion of cases compared with NoVs. To our knowledge, there are no systematic reviews and meta-analyses comparing the severity of NoV and RV disease. METHODS: We searched MEDLINE for studies reporting data for NoV and RV medically attended disease severity in children. We included studies where all children had been tested for both NoV (reverse transcription polymerase chain reaction) and RV (enzyme-linked immunosorbent assay or reverse transcription polymerase chain reaction) and that reported disease severity using the Vesikari or modified Vesikari score, or provided clinical information on severity. We generated pooled estimates of the mean with 95% confidence intervals using random effects meta-analysis. RESULTS: We identified 266 publications, of which 31 were retained for qualitative analysis and 26 for quantitative analysis. Fourteen studies provided data on severity score for the meta-analysis. The pooled mean severity scores (95% confidence interval) among outpatients were 10 (8-12) and 11 (8-14) for NoV and RV, respectively. Among inpatients, they were 11 (9-13) for NoV and 12 (10-14) for RV. The difference was statistically significant among inpatients, but relatively small (1 point in a 20-point scale). About 20% more children with RV required rehydration when compared with children with NoV. CONCLUSIONS: NoV causes moderate to severe disease similar to RV in young children. This information should be useful for future evaluations of an eventual introduction of NoV vaccines in national immunization programs.

Estimation of the burden of varicella in Europe before the introduction of universal childhood immunization.

BACKGROUND: Varicella is generally considered a mild disease. Disease burden is not well known and country-level estimation is challenging. As varicella disease is not notifiable, notification criteria and rates vary between countries. In general, existing surveillance systems do not capture cases that do not seek medical care, and most are affected by underreporting and underascertainment. We aimed to estimate the overall varicella disease burden in Europe to provide critical information to support decision-making regarding varicella vaccination. METHODS: We conducted a systematic literature review to identify all available epidemiological data on varicella IgG antibody seroprevalence, primary care and hospitalisation incidence, and mortality. We then developed methods to estimate age-specific varicella incidence and annual number of cases by different levels of severity (cases in the community, health care seekers in primary care and hospitals, and deaths) for all countries belonging to the European Medicines Agency (EMA) region and Switzerland. RESULTS: In the absence of universal varicella immunization, the burden of varicella would be substantial with a total of 5.5 million (95% CI: 4.7-6.4) varicella cases occurring annually across Europe. Variation exists between countries but overall the majority of cases (3 million; 95% CI: 2.7-3.3) would occur in children <5 years. Annually, 3-3.9 million patients would consult a primary care physician, 18,200-23,500 patients would be hospitalised, and 80 varicella-related deaths would occur (95% CI: 19-822). CONCLUSIONS: Varicella disease burden is substantial. Most cases occur in children <5 years old but adults require hospitalisation more often and are at higher risk of death. This information should be considered when planning and evaluating varicella control strategies. A better understanding of the driving factors of country-specific differences in varicella transmission and health care utilization is needed. Improving and standardizing varicella surveillance in Europe, as initiated by the European Centre for Disease Prevention and Control (ECDC), is important to improve data quality to facilitate inter-country comparison.

Norovirus in Latin America: Systematic Review and Meta-analysis.

BACKGROUND: Noroviruses are increasingly recognized as a major cause of sporadic and epidemic acute gastroenteritis (AGE). Although there have been multiple studies published on norovirus epidemiology in Latin America, no comprehensive assessment of the role of norovirus has been conducted in the region. We aim to estimate the role of norovirus in the Latin American region through a systematic review and meta-analysis of the existing literature. METHODS: We carried out a literature search in MEDLINE, SciELO and LILACS. We included papers that provided information on the prevalence or incidence of norovirus (including seroprevalence studies and outbreaks), with a recruitment and/or follow-up period of at least 12 months and where the diagnosis of norovirus was confirmed by reverse transcription polymerase chain reaction. The data were pooled for meta-analysis to estimate the prevalence of norovirus AGE and norovirus asymptomatic infection with 95% confidence intervals (CIs). RESULTS: Thirty-eight studies were included in the review. Overall, the prevalence of norovirus among AGE cases was 15% (95% CI: 13-18). By location, it was 15% in the community (95% CI: 11%-21%), 14% in outpatient settings (95% CI: 10%-19%) and 16% in hospital locations (95% CI: 12%-21%). The prevalence of norovirus among asymptomatic subjects was 8% (95% CI: 4-13). Norovirus GII.4 strains were associated with 37%-100% of norovirus AGE cases, but only 7% of norovirus asymptomatic detections. CONCLUSIONS: Noroviruses are associated with almost 1 out of every 6 hospitalizations because of acute diarrhea in children younger than 5 years of age in Latin America.

The burden of norovirus disease in children in the European Union.

BACKGROUND: Noroviruses (NoVs) are the leading cause of acute gastroenteritis across all age groups. Because a vaccine is in clinical development, burden of disease data are required to guide the eventual introduction of this vaccine. In this study, we estimate the burden of NoV disease in children less than 5 years of age in the European Union (EU). METHODS: We carried out a literature search using PubMed to identify studies providing incidence or prevalence data for NoV disease in the EU. We applied the pooled average NoV incidence and prevalence rates to the EU population less than 5 years of age to obtain the annual number of NoV illnesses, medical visits, hospitalizations and deaths occurring in the EU among children younger than 5 years. RESULTS: Data from 12 studies were included. We estimate that NoV infection may cause up to 5.7 million illnesses in the community, 800,000 medical visits, 53,000 hospitalizations and 102 deaths every year in children younger than 5 years in the EU. CONCLUSION: The burden of NoV disease in children in the EU is substantial, and will grow in relative importance as rotavirus (RV) vaccines are rolled out in the EU. This burden of disease is comparable with the burden of RV disease in the EU before RV vaccine introduction. More country-specific studies are needed to better assess this burden and guide the potential introduction of a vaccine against NoV at the national level.

Use of colorimetric culture methods for detection of Mycobacterium tuberculosis complex isolates from sputum samples in resource-limited settings.

Despite recent advances, tuberculosis (TB) diagnosis remains imperfect in resource-limited settings due to its complexity and costs, poor sensitivity of available tests, or long times to reporting. We present a report on the use of colorimetric methods, based on the detection of mycobacterial growth using colorimetric indicators, for the detection of Mycobacterium tuberculosis in sputum specimens. We evaluated the nitrate reductase assay (NRA), a modified NRA using para-nitrobenzoic acid (PNB) (NRAp), and the resazurin tube assay using PNB (RETAp) to differentiate tuberculous and nontuberculous mycobacteria. The performances were assessed at days 18 and 28 using mycobacterium growth indicator tube (MGIT) and Löwenstein-Jensen (LJ) medium culture methods as the reference standards. We enrolled 690 adults with suspected pulmonary tuberculosis from a regional referral hospital in Uganda between March 2010 and June 2011. At day 18, the sensitivities and specificities were 84.6% and 90.0% for the NRA, 84.1% and 92.6% for the NRAp, and 71.2% and 99.3% for the RETAp, respectively. At day 28, the sensitivity of the RETAp increased to 82.6%. Among smear-negative patients with suspected TB, sensitivities at day 28 were 64.7% for the NRA, 61.3% for the NRAp, and 50% for the RETAp. Contamination rates were found to be 5.4% for the NRA and 6.7% for the RETAp, compared with 22.1% for LJ medium culture and 20.4% for MGIT culture. The median times to positivity were 10, 7, and 25 days for colorimetric methods, MGIT culture, and LJ medium culture,respectively. Whereas the low specificity of the NRA/NRAp precludes it from being used for TB diagnosis, the RETAp might provide an alternative to LJ medium culture to decrease the time to culture results in resource-poor settings.