What have we learnt about rotavirus in Spain in the last 10 years?

En España, las vacunas frente a rotavirus (RV) están disponibles desde 2006 pero no están ni recomendadas ni financiadas por el Sistema Nacional de Salud. Sin embargo, a través de las recomendaciones de la Asociación Española de Pediatría se han alcanzado coberturas de vacunación intermedias. Se ha realizado una revisión sistemática de la literatura sobre los estudios realizados en España en los últimos 12 a˜nos (2006-2018) en relación con la infección y las vacunas frente a RV. Se identifican 43 estudios que cumplían los criterios de selección. La carga de enfermedad en población <5 a˜nos en atención primaria oscila entre 15 y 19 casos por 1.000 ni˜nos y en hospitalaria entre 120 y 480 casos por 100.000, lo que supone una importante repercusión económica y social. Las vacunas frente a RV han mostrado en España una efectividad de entre el 83 y el 96% y un impacto de hasta un 70% de reducción de hospitalizaciones, que es dependiente de la cobertura de vacunación alcanzada. Se identifican además nuevas líneas de investigación relacionadas con el papel de la vacuna del RV y la protección frente a convulsiones, o el papel del microbiota, entre otros. La información actualmente disponible refrenda la importante carga de enfermedad por RV en España y la elevada efectividad de las vacunas disponibles. Estas evidencias permiten una reevaluación de las recomendaciones nacionales sobre vacunación frente a RV.Vaccines against rotavirus (RV) have been available in Spain since 2006, but they are neither recommended nor financed by the National Health System. Nevertheless, through recommendations of the Spanish Association of Paediatrics vaccination has achieved interme- diate coverage. A systematic literature review was performed on studies carried out in Spain in the last 12 years (2006-2018) on RV infection and vaccination. Results: A total of 43 studies were identified that met the inclusion criteria. The disease burden in children less than 5 years in the Primary Care setting ranged from 15 to 19 cases per 1,000 children, and between 120 and 480 cases per 100,000 in the hospital setting, which has a significant economic and social impact. Vaccines against RV have shown an effectiveness of between 83% and 96%, and an impact of up to 70% in reducing hospital admissions, which is dependent on the achieved vaccine coverage. New research lines are identified, such as the role of the rotavirus vaccine and protection against seizures or the impact on the gut microbiota. The current available information supports the significant burden of rotavirus disease in Spain and the high effectiveness of the available vaccines. This evidence should allow for an updated re-evaluation of the national recommendations on rotavirus vaccination.La redacción de este artículo ha sido apoyada en parte a través de una beca de MSD España.Medicin

Variation in antibiotic prescription rates in febrile children presenting to emergency departments across Europe (MOFICHE) : A multicentre observational study

Funding Information: This project has received funding from the European Union?s Horizon 2020 research and innovation programme under grant agreement No. 668303. The Research was supported by the National Institute for Health Research Biomedical Research Centres at Imperial College London, Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. For the remaining authors no sources of funding were declared. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We acknowledge all research nurses for their help in collecting data, and Anda Nagle (Riga) and the Institute of Microbiology at University Medical Centre Ljubljana for their help in collecting data on antimicrobial resistance. Members of the PERFORM consortium are listed in S11 Text. Publisher Copyright: Copyright: © 2020 Hagedoorn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background The prescription rate of antibiotics is high for febrile children visiting the emergency department (ED), contributing to antimicrobial resistance. Large studies at European EDs covering diversity in antibiotic and broad-spectrum prescriptions in all febrile children are lacking. A better understanding of variability in antibiotic prescriptions in EDs and its relation with viral or bacterial disease is essential for the development and implementation of interventions to optimise antibiotic use. As part of the PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union) project, the MOFICHE (Management and Outcome of Fever in Children in Europe) study aims to investigate variation and appropriateness of antibiotic prescription in febrile children visiting EDs in Europe. Methods and findings Between January 2017 and April 2018, data were prospectively collected on febrile children aged 0–18 years presenting to 12 EDs in 8 European countries (Austria, Germany, Greece, Latvia, the Netherlands [n = 3], Spain, Slovenia, United Kingdom [n = 3]). These EDs were based in university hospitals (n = 9) or large teaching hospitals (n = 3). Main outcomes were (1) antibiotic prescription rate; (2) the proportion of antibiotics that were broad-spectrum antibiotics; (3) the proportion of antibiotics of appropriate indication (presumed bacterial), inappropriate indication (presumed viral), or inconclusive indication (unknown bacterial/viral or other); (4) the proportion of oral antibiotics of inappropriate duration; and (5) the proportion of antibiotics that were guideline-concordant in uncomplicated urinary and upper and lower respiratory tract infections (RTIs). We determined variation of antibiotic prescription and broad-spectrum prescription by calculating standardised prescription rates using multilevel logistic regression and adjusted for general characteristics (e.g., age, sex, comorbidity, referral), disease severity (e.g., triage level, fever duration, presence of alarming signs), use and result of diagnostics, and focus and cause of infection. In this analysis of 35,650 children (median age 2.8 years, 55% male), overall antibiotic prescription rate was 31.9% (range across EDs: 22.4%–41.6%), and among those prescriptions, the broad-spectrum antibiotic prescription rate was 52.1% (range across EDs: 33.0%–90.3%). After standardisation, differences in antibiotic prescriptions ranged from 0.8 to 1.4, and the ratio between broad-spectrum and narrow-spectrum prescriptions ranged from 0.7 to 1.8 across EDs. Standardised antibiotic prescription rates varied for presumed bacterial infections (0.9 to 1.1), presumed viral infections (0.1 to 3.3), and infections of unknown cause (0.1 to 1.8). In all febrile children, antibiotic prescriptions were appropriate in 65.0% of prescriptions, inappropriate in 12.5% (range across EDs: 0.6%–29.3%), and inconclusive in 22.5% (range across EDs: 0.4%–60.8%). Prescriptions were of inappropriate duration in 20% of oral prescriptions (range across EDs: 4.4%–59.0%). Oral prescriptions were not concordant with the local guideline in 22.3% (range across EDs: 11.8%–47.3%) of prescriptions in uncomplicated RTIs and in 45.1% (range across EDs: 11.1%–100%) of prescriptions in uncomplicated urinary tract infections. A limitation of our study is that the included EDs are not representative of all febrile children attending EDs in that country. Conclusions In this study, we observed wide variation between European EDs in prescriptions of antibiotics and broad-spectrum antibiotics in febrile children. Overall, one-third of prescriptions were inappropriate or inconclusive, with marked variation between EDs. Until better diagnostics are available to accurately differentiate between bacterial and viral aetiologies, implementation of antimicrobial stewardship guidelines across Europe is necessary to limit antimicrobial resistance.publishersversionPeer reviewe

Effectiveness of rotavirus vaccination in Spain

With the aim of determining rotavirus vaccine effectiveness (RVVE) in Spain, from Oct-2008/Jun-2009, 467 consecutive children below 2 years old with acute gastroenteritis (AGE) were recruited using a pediatric research network (ReGALIP-www.regalip.org) that includes primary, emergency and hospital care settings. Of 467 enrolled children, 32.3% were rotavirus positive and 35.0% had received at least one dose of any rotavirus vaccine. RRVE to prevent any episode of rotavirus AGE was 91.5% (95% CI: 83.7%-95.6%). RVVE to prevent hospitalization by rotavirus AGE was 95.6% (85.6-98.6%). No differences in RVVE were found regarding the vaccine used. Rotavirus vaccines have showed an outstanding effectiveness in Spain

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection

Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study

BackgroundThe PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice.MethodsFebrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed.FindingsOf 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92-5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07-7.59), Group A streptococcus (OR 2.73, 95% CI 1.13-6.09) and E. coli (OR 2.7, 95% CI 1.02-6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11-0.46), influenza B (OR 0.12, 95% CI 0.02-0.37) and RSV (OR 0.16, 95% CI: 0.06-0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23-0.72) and EBV (OR 0.71, 95% CI 0.56-0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively.InterpretationMost febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics.FundingEU Horizon 2020 grant 668303

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection ar

Why are pediatric empyemas on the increase in Spain?

Existe la percepción entre los pediatras españoles de que el número de casos de empiema pediátrico ha aumentado significativamente en los últimos años; sin embargo, la información objetiva disponible es limitada, y además es una patología de libre declaración para la que no existen sistemas específicos de vigilancia epidemiológica activa. En este trabajo se revisa la situación del empiema pediátrico en España, y se discute las principales hipótesis que se han planteado en la bibliografía internacional para explicar este incremento, así como las limitaciones de las fuentes disponibles. Se concluye que, aunque la información disponible es limitada: a) la incidencia de empiema pediátrico está aumentando en nuestro país, tanto globalmente como la específicamente ocasionada por neumococo; b) la causa de este incremento es desconocida, y hasta la fecha no existen datos que permitan vincularlo a la vacuna antineumocócica conjugada heptavalente, y c) esta situación justifica la puesta en marcha de sistemas prospectivos de vigilancia y control del empiema y, una vez más, pone de relieve la importancia de implantar y desarrollar sistemas de vigilancia activa de la enfermedad neumocócica.There is a widespread perception among Spanish pediatricians that the incidence of empyema has significantly increased in the last few years, even though the objective information available is limited, and there is no specific active epidemiological surveillance system for this condition. In the present article, we review the situation of empyema in Spain, and discuss the main hypotheses put forward in the international literature to explain this increase, as well as the limitations of the sources available. Despite the scarcity of information, we draw the following conclusions: 1) the incidence of pediatric empyema is increasing in Spain, both generally and when caused by pneumococcus in particular; 2) the reason for this increase remains unknown, and to date no firm link has been established between this phenomenon and the heptavalent conjugate pneumococcal vaccine; and 3) this situation justifies the establishment of prospective systems for the surveillance and control of empyema and, once again, highlights the importance of developing active surveillance systems for pneumococcal disease.Medicin

Respiratory syncytial virus prefusion F protein vaccine in older adults

Respiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection. In an ongoing, international, placebo-controlled, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive a single dose of an AS01-adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA) or placebo before the RSV season. The primary objective was to show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season. The criterion for meeting the primary objective was a lower limit of the confidence interval around the efficacy estimate of more than 20%. Efficacy against severe RSV-related lower respiratory tract disease and RSV-related acute respiratory infection was assessed, and analyses according to RSV subtype (A and B) were performed. Safety was evaluated. A total of 24,966 participants received one dose of the RSVPreF3 OA vaccine (12,467 participants) or placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR-confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% confidence interval [CI], 57.9 to 94.1), with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% (95% CI, 62.4 to 99.9) against severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator) and 71.7% (95% CI, 56.2 to 82.3) against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). High vaccine efficacy was observed in various age groups and in participants with coexisting conditions. The RSVPreF3 OA vaccine was more reactogenic than placebo, but most adverse events for which reports were solicited were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups. A single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions. (Funded by GlaxoSmithKline Biologicals; AReSVi-006 ClinicalTrials.gov number, NCT04886596.)