The economic burden of varicella among children in France: a caregiver survey.

To estimate the economic burden of varicella among children in France from family and societal perspectives. We conducted an online cross-sectional survey of caregivers of 185 French children (≤ 17 years) diagnosed with varicella in the previous six weeks. Data collected included varicella-related healthcare resource use, out-of-pocket costs, missed school days, and workdays missed by either parents or other caregivers. Mean and median direct and indirect costs (2022 Euros) were calculated using survey data and published literature. The annual societal burden of pediatric varicella in France was estimated. Of the 185 children, 95.1% had ≥ 1 outpatient visit, 10.3% had ≥ 1 emergency room visit, and 2.2% were hospitalized. The median [interquartile range, IQR] number of outpatient visits/child was 1.0 [1.0 - 2.0]. The median length of hospital stay among those hospitalized (n = 4) was 5.0 [3.5 - 6.5] days. Caregivers of 185 children missed a median of 2.0 [0 - 5.0] workdays; 113 families (61.1%) had ≥ 1 parent miss work. A median of 5.0 [3.0 - 7.0] school days were missed by 170 children who attended preschool or school. The median direct out-of-pocket cost to the family was €30.0 [€17.0 - €60.0]. The median [IQR] societal costs per varicella case were €455.2 [€70.5 - €1013.5]; the median [IQR] direct and indirect costs per child were €60.8 [€39.0 - €102.7] and €364.7 [€0.0 - €911.7] respectively. The annual societal burden of varicella among children in France was estimated to be €450,427,578 (95% CI: €357,144,618 - €543,710,538), with indirect costs accounting for 85%. CONCLUSIONS: A substantial economic burden is associated with pediatric varicella in France, primarily due to the productivity loss among caregivers. WHAT IS KNOWN: • Although varicella is considered a mild disease, it poses a significant burden on caregivers and society. Our study aimed to estimate the economic burden of varicella among children in France from family and societal perspectives to support policymakers in understanding the value of UVV in France. WHAT IS NEW: • We conducted an online survey of caregivers of 185 French children (≤17 years) diagnosed with varicella and collected data on varicella-related healthcare resource use, missed school days and workdays. Our study estimated annual societal burden of pediatric varicella in France. Out of 185 children with varicella, most (95.1%) had at least one outpatient visit, 10.3% had at least one emergency room visit, and 2.2% were hospitalized. 61.1% of parents with sick child, missed work and median productivity loss was 2.0 workdays. Additionally, 170 children who attended school or preschool missed a median of 5.0 school days. • The societal burden of pediatric varicella in France was estimated to be €450,427,578 (95% CI, €357,144,618 - €543,710,538), with indirect costs accounting for 85%. Pediatric varicella is associated with a substantial economic burden in France, primarily due to high productivity losses among parents and caregivers.

A very low prevalence of SARS-CoV-2 infection but a high prevalence of other respiratory virus infections in children admitted to paediatric emergency departments.

AIM: To investigate the prevalence of infections by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses among children admitted to paediatric emergency departments (PEDs). METHODS: From April to July 2020, a prospective, multicentre cohort study was conducted in the PEDs of eight French university hospitals. Regardless of the reason for admission, a nasopharyngeal swab sample from each child was screened using reverse transcription polymerase chain reaction tests for SARS-CoV-2 and other respiratory viruses. We determined the prevalence of SARS-CoV-2 and other respiratory viruses and identified risk factors associated with a positive test. RESULTS: Of the 924 included children (median [interquartile range] age: 4 years [1-9]; boys: 55%), 908 (98.3%) were tested for SARS-CoV-2. Only three samples were positive (0.3%; 95% confidence interval: 0.1-1) and none of these children had symptoms of coronavirus disease 2019. Of the 836 samples (90%) tested for other viruses, 129 (15.4%) were positive (primarily rhinovirus). Respiratory viruses were significantly more common in young children and in children with respiratory tract symptoms and fever. CONCLUSION: The prevalence of SARS-CoV-2 among children admitted to emergency departments was low. In contrast, and despite social distancing and other protective measures, the prevalence of other respiratory viruses detection was high.

Clavulanate combinations with mecillinam, cefixime or cefpodoxime against ESBL-producing Enterobacterales frequently associated with blaOXA-1 in a paediatric population with febrile urinary tract infections.

OBJECTIVES: Oral treatment of febrile urinary tract infections (FUTIs) can be impaired by MDR Enterobacterales often combining ESBL and inhibitor-resistant genes. We studied the impact of ß-lactamases and Enterobacterales' genotypes on the cefixime, cefpodoxime and mecillinam ± amoxicillin/clavulanate MICs. MATERIALS AND METHODS: In this multicentric study, we included 251 previously whole-genome-sequenced ESBL-producing Enterobacterales, isolated in French children with FUTIs. The MICs of cefixime, cefpodoxime, mecillinam alone and combined with amoxicillin/clavulanate were determined and analysed with respect to genomic data. We focused especially on the isolates' ST and their type of ß-lactamases. Clinical outcomes of patients who received cefixime + amoxicillin/clavulanate were also analysed. RESULTS: All isolates were cefixime and cefpodoxime resistant. Disparities depending on blaCTX-M variants were observed for cefixime. The addition of amoxicillin/clavulanate restored susceptibility for cefixime and cefpodoxime in 97.2% (MIC50/90 of 0.38/0.75 mg/L) and 55.4% (MIC50/90 of 1/2 mg/L) of isolates, respectively, whatever the ST, the blaCTX-M variants or the association with inhibitor-resistant ß-lactamases (34.2%). All isolates were susceptible to mecillinam + amoxicillin/clavulanate with MIC50/90 of 0.19/0.25 mg/L, respectively. Neither therapeutic failure nor any subsequent positive control urine culture were reported for patients who received cefixime + amoxicillin/clavulanate as an oral relay therapy (n = 54). CONCLUSIONS: Despite the frequent association of ESBL genes with inhibitor-resistant ß-lactamases, the cefixime + amoxicillin/clavulanate MICs remain low. The in vivo efficacy of this combination was satisfying even when first-line treatment was ineffective. Considering the MIC distributions and pharmacokinetic parameters, mecillinam + amoxicillin/clavulanate should also be an alternative to consider when treating FUTIs in children.

Diversity and trends in population structure of ESBL-producing Enterobacteriaceae in febrile urinary tract infections in children in France from 2014 to 2017.

BACKGROUND: The population structure of extraintestinal pathogenic Escherichia coli evolves over time, notably due to the emergence of antibiotic-resistant clones such as ESBL-producing Enterobacteriaceae (ESBL-E). OBJECTIVES: To analyse by WGS the genetic diversity of a large number of ESBL-E isolated from urinary tract infections in children from paediatric centres across France between 2014 and 2017 and collected by the National Observatory of febrile urinary tract infection (FUTI) caused by ESBL-E. METHODS: A total of 40 905 Enterobacteriaceae-positive urine cultures were identified. ESBL-E were found in 1983 samples (4.85%). WGS was performed on 251 ESBL-E causing FUTI. STs, core genome MLST (cgMLST), serotype, fimH allele, ESBL genes and presence of papGII key virulence factor were determined. RESULTS: E. coli and Klebsiella pneumoniae were found in 86.9% (218/251) and 11.2% (28/251) of cases, respectively. Several STs predominate among E. coli such as ST131, ST38, ST69, ST73, ST95, ST405, ST12 and ST1193, while no ST emerged in K. pneumoniae. E. coli ST131, ST38 and ST1193 increased during the study period, with a heterogeneity in papGII prevalence (64.5%, 35% and 20% respectively). Most isolates harboured the CTX-M type (97%) with a predominance of blaCTX-M-15. blaCTX-M-27, an emerging variant in E. coli, is found in various STs. cgMLST enabled discrimination of clusters within the main STs. CONCLUSIONS: The predominance of ST131, and the emergence of other STs such as ST38 and ST1193 combined with ESBL genes deserves close epidemiological surveillance considering their high threat in infectious disease. cgMLST could be a discriminant complementary tool for the analyses.

Development of Reliable and Validated Tools to Evaluate Technical Resuscitation Skills in a Pediatric Simulation Setting: Resuscitation and Emergency Simulation Checklist for Assessment in Pediatrics.

OBJECTIVES: To develop a reliable and validated tool to evaluate technical resuscitation skills in a pediatric simulation setting. STUDY DESIGN: Four Resuscitation and Emergency Simulation Checklist for Assessment in Pediatrics (RESCAPE) evaluation tools were created, following international guidelines: intraosseous needle insertion, bag mask ventilation, endotracheal intubation, and cardiac massage. We applied a modified Delphi methodology evaluation to binary rating items. Reliability was assessed comparing the ratings of 2 observers (1 in real time and 1 after a video-recorded review). The tools were assessed for content, construct, and criterion validity, and for sensitivity to change. RESULTS: Inter-rater reliability, evaluated with Cohen kappa coefficients, was perfect or near-perfect (>0.8) for 92.5% of items and each Cronbach alpha coefficient was ≥0.91. Principal component analyses showed that all 4 tools were unidimensional. Significant increases in median scores with increasing levels of medical expertise were demonstrated for RESCAPE-intraosseous needle insertion (P = .0002), RESCAPE-bag mask ventilation (P = .0002), RESCAPE-endotracheal intubation (P = .0001), and RESCAPE-cardiac massage (P = .0037). Significantly increased median scores over time were also demonstrated during a simulation-based educational program. CONCLUSIONS: RESCAPE tools are reliable and validated tools for the evaluation of technical resuscitation skills in pediatric settings during simulation-based educational programs. They might also be used for medical practice performance evaluations.

[Diagnosis of invasive Neisseria meningitidis infections]. / Diagnostic des infections invasives à Neisseria meningitidis.

DIAGNOSIS OF INVASIVE NEISSERIA MENINGITIDIS INFECTIONS. Invasive meningococcal infections are unpredictable, difficult to diagnose and extremely serious, with a high risk of death and sequelae in survivors. They primarily affect subjects with no underlying pathology, but risk factors have been identified. The most frequent clinical forms are meningitis, septicemia and meningococcal septic shock, including purpura fulminans. Atypical presentations, such as pneumonia, epiglottitis and digestive tract infections, are increasingly common, especially since the incidence of serogroups W and Y has risen. They can lead to misdiagnosis and are associated with higher case-fatality rates.

DIAGNOSTIC DES INFECTIONS INVASIVES À NEISSERIA MENINGITIDIS. Les infections invasives à méningocoques sont imprévisibles, de diagnostic difficile et dans certains cas peuvent être d'une extrême gravité, avec un risque élevé de décès et de séquelles chez les survivants. Elles touchent majoritairement des sujets sans pathologie sous-jacente même s'il existe des facteurs de risque. Les formes cliniques les plus fréquentes sont les méningites, les septicémies et le choc septique méningococcique dont le purpura fulminans, et peuvent se combiner. Les présentations atypiques, notamment les pneumonies, les épiglottites et les formes digestives sont de plus en plus souvent rencontrées, en particulier depuis l'augmentation de l'incidence des sérogroupes W et Y. Elles peuvent conduire à des erreurs de diagnostic et sont associées à des taux de létalité plus élevés.

[Antibiotic treatment of invasive meningococcal infections]. / Traitement antibiotique des infections invasives méningococciques.

ANTIBIOTIC TREATMENT OF INVASIVE MENINGOCOCCAL INFECTION. Invasive meningococcal infections (IMI) are extremely severe pathologies that justify very early antibiotic therapy to limit complications and death. Three different situations may arise: 1) clinical suspicion of purpura fulminans in the pre-hospital setting, 2 confirmed or strongly suspected IMI, 3) post-exposure chemoprophylaxis of a patient's contacts. In the first two situations, 3rd generation cephalosporins (C3G), cefotaxime or ceftriaxone are the reference antibiotics, and have the advantage of having an impact on nasopharyngeal carriage of meningococcus. Chemoprophylaxis of contact subjects is based on rifampicin, but ciprofloxacin (subject to retained sensitivity) and C3Gs are possible alternatives.

TRAITEMENT ANTIBIOTIQUE DES INFECTIONS INVASIVES MÉNINGOCOCCIQUES. Les infections invasives méningococciques (IIM) sont des pathologies qui peuvent dans certains cas devenir sévères justifiant une antibio thérapie très précoce afin de limiter les complications et les décès. Trois situations différentes peuvent se présenter : 1) suspicion clinique de purpura fulminans en préhospitalier ; 2) IIM confirmée ou fortement suspectée ; 3) chimioprophylaxie postexposition des cas contacts d'un malade. Dans les deux premières situations, les céphalosporines de troisième génération (C3G), céfotaxime ou ceftriaxone, sont les antibiotiques de référence, et ont l'avantage d'avoir un impact sur le portage nasopharyngé du méningocoque. La chimioprophylaxie des sujets contacts repose sur la rifam picine, mais la ciprofloxacine (sous réserve d'une sensibilité conservée) et les C3G sont des alternatives possibles.

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.

Use of Rapid Antigen Triple Test Nasal Swabs (COVID-VIRO ALL-IN TRIPLEX: Severe Acute Respiratory Syndrome Coronavirus 2, Respiratory Syncytial Virus, and Influenza) in Children With Respiratory Symptoms: A Real-life Prospective Study.

Background: In autumn 2022, the epidemics due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV), and influenza overlapped, and these diseases can present with the same symptomatology. The use of a triple antigen test (SARS-CoV-2 + influenza A/B + RSV) seems crucial for accurate viral diagnosis in the context of implementing long-acting monoclonal antibody vaccination against RSV in the upcoming RSV season. Methods: We assessed the usefulness of the triple test in real life in this prospective study performed from October 2022 to May 2023 and involving 116 pediatricians (2 emergency department pediatricians and 114 ambulatory pediatricians). Children <15 years old with flu-like illness (with fever), bronchiolitis (dyspnea ± wheezing), otitis, and croup were enrolled and sampled with a nasal triple test. Results: For 8329 children with flu-like illness (65.3%), bronchiolitis (17.9%), otitis (8.8%), and croup (6.3%), the use of the triple test led to a viral diagnosis in 47.9% of cases. The highest RSV positivity occurred in children with bronchiolitis (32.9%). The highest influenza A and B positivity (24.6% and 19.6%) occurred in children with flu-like illness. A succession of 3 epidemics (RSV and influenza A and B) occurred over time with several overlap periods. Conclusions: The triple test allowed for a viral diagnosis in half of our cases. The upcoming introduction of RSV prevention will emphasize the need for active surveillance with viral results both in ambulatory settings and hospitals. Clinical Trials Registration. NCT0441231.

Antimicrobial treatment of skin and soft tissue infections.

Bacterial skin infections are common in children, and frequently do not require systemic antibiotic therapy, particularly for superficial forms. In these cases, washing (with soap and water) and careful rinsing of the lesion are the key points of treatment. A semiotic analysis must precede any therapeutic decision to assess the appropriateness of antibiotic therapy, need for drainage (which may be spontaneous or surgical) and possible existence of symptoms related to toxin production, which are frequent signs of severity. The bacterial species most frequently implicated in children are Staphylococcus aureus and Streptococcus pyogenes. Given the low incidence of methicillin-resistant S. aureus in France (<10%), the first-line antibiotic treatment is amoxicillin-clavulanate, to which an anti-toxin treatment such as clindamycin may be added for patients with overt toxin signs.

Antibiotic treatment of neuro-meningeal infections.

In France, conjugated pneumococcal vaccination has considerably modified the profile of pneumococcal meningitis by eliminating the most virulent strains resistant to beta-lactams. Over recent years, the nationwide pediatric meningitis network of the Pediatric Infectious Disease Group (GPIP) and the National Reference Centre of Pneumococci have not recorded any cases of meningitis due to pneumococcus resistant to third-generation cephalosporins (C3G), even though in 2021, strains with a less favorable profile appeared to emerge. These recent data justify renewal of the 2016 recommendations and limitation of vancomycin to the secondary phase of treatment of pneumococcal meningitis when the MIC of the isolated strain against injectable C3Gs is >0.5 mg/L. The only major change proposed by the GPIP in this 2023 update of its recommendations is discontinuation of the recommendation of a combination of ciprofloxacin and cefotaxime in Escherichia coli meningitis in newborns and young infants. The nationwide observatory of meningitis in children is a valuable tool because of its completeness and its continuity over the past 15 years. The maintenance of epidemiological surveillance will allow us to adapt new therapeutic regimens to the evolution of pneumococcal susceptibility profiles and to future serotype-specific changes. Community-acquired cerebral abscesses are rare diseases, of which the management requires a rigorous approach: high-quality imaging, bacteriological sampling prior to antibiotic therapy whenever possible, and antibiotic treatment including metronidazole in addition to cefotaxime. Multidisciplinary collaboration, including infectious disease and neurosurgical advice, is always called for.

Anti-infective treatment of gastro-intestinal tract infections in children.

Gastroenteritis is most often viral in origin and Rotavirus and Norovirus most frequently implicated in young children. Stool-based multiplex Polymerase Chain Reaction (PCR) can detect bacteria, viruses or parasites that may or may not be responsible for gastroenteritis (colonization). While the etiological profile of these digestive infections has greatly benefited from PCR, in the absence of underlying pathologies the presence of potential pathogens does not justify anti-infectious treatment. Indeed, very few bacterial causes require antibiotic treatment, apart from shigellosis, severe forms of salmonellosis and a few Campylobacter sp. infections. The development of antibiotic resistance in Salmonella sp., Shigella sp. and Campylobacter sp. is a cause for concern worldwide, limiting therapeutic options. The antibiotics proposed in this guide are in line with the joint recommendations of the European Society of Pediatric Infectious Diseases and the European Society of Pediatric Gastroenterology and Nutrition. Azithromycin is preferentially used to treat infections with Shigella sp. or Campylobacter sp. Ceftriaxone and ciprofloxacin are recommended for salmonellosis requiring antibiotic therapy. Empirical treatments without bacterial identification are not indicated except in cases of severe sepsis or in subjects at risk (e.g., sickle-cell disease). Metronidazole should be prescribed only for acute intestinal amebiasis after microbiological confirmation.

Evaluation of compliance with early postbirth follow-up and unnecessary visits to the paediatric emergency department: a prospective observational study at the Lenval Children's Hospital in Nice.

OBJECTIVE: To evaluate compliance with the French National Authority for Health's (Haute Autorité de Santé, HAS) postbirth follow-up recommendations for newborns attending our paediatric emergency department (PED) and identify risk factors associated with non-compliance and unnecessary emergency department utilisation. DESIGN: Prospective, single centre. SETTING: Fourth biggest PED in France in terms of attendance (CHU-Lenval). PATIENTS: 280 patients of whom 249 were included in the statistical analysis. MAIN OUTCOME MEASURES: The primary outcome of this study was the evaluation of compliance of the care pathway for newborns consulting at the PED with respect to the French postbirth follow-up recommendations. Secondary outcome was the assessment of whether the visit to the PED was justified by means of PED reception software and two postconsultation interviews RESULTS: 77.5% (193) of the newborns had non-compliant care pathways and 43% (107) of PED visits were unnecessary. Risk factors associated with a non-compliance regarding the HAS's postbirth follow-up recommendations were: unnecessary visit to the PED (OR 2.0, 95% CI 1.1 to 3.9), precariousness (OR 2.8, 95% CI 1.4 to 6.2), birth in a public maternity hospital (OR 2.5, 95% CI 1.3 to 4.8) and no information about HAS's postbirth follow-up recommendations on discharge from maternity ward (OR 11.4, 95% CI 5.8 to 23.3). Risk factors for unnecessary PED visits were: non-compliant care pathway (OR 2.0, 95% CI 1.1 to 3.9) and a first medical visit at a PED (OR 1.8, 95% CI 1.1 to 3.1). CONCLUSION: Postbirth follow-up may lead to decrease unnecessary emergency department visits unnecessary emergency department visits. TRIAL REGISTRATION NUMBER: The study bears the clinical trial number NCT02863627.

Validation of the Computerized Pediatric Triage Tool, pediaTRI, in the Pediatric Emergency Department of Lenval Children's Hospital in Nice: A Cross-Sectional Observational Study.

Introduction: A reliable pediatric triage tool is essential for nurses working in pediatric emergency departments to quickly identify children requiring priority care (high-level emergencies) and those who can wait (low-level emergencies). In the absence of a gold standard in France, the objective of our study was to validate our 5-level pediatric triage tool -pediaTRI- against the reference tool: the Pediatric Early Warning Score (PEWS) System. Materials and Methods: We prospectively included 100,506 children who visited the Pediatric Emergency Department at Lenval Children's Hospital (Nice, France) in 2016 and 2017. The performance of pediaTRI to identify high-level emergencies (severity levels 1 and 2) was evaluated in comparison with a PEWS ≥ 4/9. Data from 2018-19 was used as an independent validation cohort. Results: pediaTRI agreed with the PEWS score for 84,896 of the patients (84.5%): 15.0% (14.8-15.2) of the patients were over-triaged and 0.5% (0.5-0.6) under-triaged compared with the PEWS score. pediaTRI had a sensitivity of 76.4% (74.6-78.2), a specificity of 84.7% (84.4-84.9), and positive and negative likelihood ratios of 5.0 (4.8-5.1) and 0.3 (0.3-0.3), respectively, for the identification of high-level emergencies. However, the positive likelihood ratios were lower for patients presenting with a medical complaint [4.1 (4.0-4.2) v 10.4 (7.9-13.7 for trauma), and for younger children [1.2 (1.1-1.2) from 0 to 28 days, and 1.9 (1.8-2.0) from 28 days to 3 months]. Conclusion: pediaTRI has a moderate to good validity to triage children in a Pediatric Emergency Department with a tendency to over-triage compared with the PEWS system. Its validity is lower for younger children and for children consulting for a medical complaint.

Overview of meningococcal epidemiology and national immunization programs in children and adolescents in 8 Western European countries.

Background: In Europe, meningococcal (Men) vaccines are available against 5 of the 6 serogroups responsible of nearly all cases of invasive meningococcal disease (IMD). Meningococcal vaccination has been introduced in the national immunization programs (NIPs) for children and adolescents of numerous European countries, but with no consistent strategy across countries. Objectives: To describe IMD epidemiology, NIPs, and vaccination coverage rates (VCRs) in children and adolescents in 8 Western European countries. Methods: Epidemiological data (from 1999 to 2019), NIPs regarding meningococcal vaccination status, and VCRs were collected from the European Centre for Disease Prevention and Control (ECDC) and/or national websites. Results: MenB was the most common serogroup. In Belgium, Spain, France, the Netherlands, the United Kingdom (UK), and Portugal, incidence was greater for MenW than MenC. In 2019, MenB risk was covered in 2 countries (Italy, UK). MenC risk was covered in all countries, via MenC only (countries: N = 3), MenACWY only (N = 2), or MenC (infants/children) and MenACWY (adolescents) (N = 3) vaccination. VCRs were higher in children than adolescents. Conclusion: Our study confirmed the diversity of NIPs, including in neighboring European countries with similar factors like economic resources and epidemiological risk, thus indicating that other factors underlie NIPs. Convergence toward a more common immunization program including MenACWY and MenB vaccination would promote equity and safe travel regarding infectious diseases for young people, and possibly improve the understanding of vaccination by patients and healthcare professionals.

Hexavalent vaccines: What can we learn from head-to-head studies?

BACKGROUND: Three hexavalent vaccines against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B virus (HBV), and Haemophilus influenzae type b (Hib) are licensed in Europe: Infanrix hexa (DT3aP-HBV-IPV/Hib), Hexyon (DT2aP-HBV-IPV-Hib) and Vaxelis (DT5aP-HBV-IPV-Hib). METHODS: A systematic literature search was performed in various electronic databases to identify published peer-reviewed head-to-head studies comparing any licensed hexavalent vaccine to another. RESULTS: Predefined inclusion criteria were met by 12 articles. Individual studies concluded that the 3 hexavalent vaccines have acceptable safety profiles although some significant differences were observed in their reactogenicity profiles. The immunogenicity of DT2aP-HBV-IPV-Hib and DT5aP-HBV-IPV-Hib was non-inferior versus DT3aP-HBV-IPV/Hib. Some differences in immune responses to common antigens were observed, but their clinical relevance was not established. Anti-filamentous hemagglutinin (FHA) from pertussis and anti-polyribosylribitol phosphate (PRP) from Hib antibody concentrations tended to be higher, and anti-HBV and anti-pertussis toxin (PT) from pertussis antibody concentrations lower in DT2aP-HBV-IPV-Hib versus DT3aP-HBV-IPV/Hib vaccinees. Anti-PT and post-primary anti-PRP antibody concentrations tended to be higher, and anti-HBV, anti-FHA, anti-pertactin from pertussis and post-booster anti-PRP antibody concentrations lower in DT5aP-HBV-IPV-Hib versus DT3aP-HBV-IPV/Hib recipients. Slightly lower immune responses towards most vaccine antigens were observed with 2 + 1 versus 3 + 1 schedules post-primary vaccination, suggesting that 2 + 1 schedules should only be considered in countries with very high vaccination coverage. CONCLUSION: Although the licensed hexavalent vaccines are generally considered similar, analyses of immunogenicity data from head-to-head trials highlighted differences that could be related to differences in composition and formulation. In addition, the demonstrated non-inferiority of the immunogenicity of the more recent vaccines versus DT3aP-HBV-IPV/Hib does not allow a full bridging to similar efficacy, effectiveness and safety. The availability of DT3aP-HBV-IPV/Hib over > 20 years allowed to collect a wealth of data on its long-term immunogenicity, safety and effectiveness in clinical and post-marketing studies, and makes it a key pillar of pediatric immunization.

Quick-Wee versus bladder stimulation to collect midstream urine from precontinent infants under 1 year of age: a study protocol for a randomised controlled trial (ES.Stimquick.U).

INTRODUCTION: Urinary tract infections occur in around 1%-4% of boys and 3%-8% of girls under 2 years old. Diagnosis is difficult because of non-specific symptoms and the risk of urine analysis contamination depending on the sampling method used for precontinent infants. The American Academy of Pediatrics recommend transurethral catheterisation and suprapubic aspiration because of a low contamination rate but these techniques are invasive. On the other hand, while the National Institute for Health and Care Excellence advocate clean catch urine for its minimal invasiveness and acceptable contamination rate, it is difficult to accomplish in precontinent infants. Two recent methods have been described: the Quick-Wee method by Kaufman et al (suprapubic stimulation with cold saline-soaked gauze); and bladder stimulation by Herreros et al then by Tran et al (pubic tapping alternating with lumbar massage). This study aims to compare the effectiveness in collecting midstream urine by bladder stimulation vs the Quick-Wee method in infants under 1 year, before walking. METHODS AND ANALYSIS: This study is a multicentre randomised controlled trial of 230 infants under 1 year and before walking who need urine analysis, conducted in four paediatric emergency departments in France. Patients will be randomised into two groups: bladder stimulation and Quick-Wee method.The primary endpoint will be the success rate of voiding at least 2 mL of urine in less than 5 min.Secondary outcomes are the time to collect at least 2 mL of urine, comfort, quality of urine and the risk factors associated with failure of the two techniques. ETHICS AND DISSEMINATION: The study protocol was approved by the French national ethic committee (consultative committee of the protection of persons). The results of the study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Clinical Trials Registry - NCT04587999. DATE AND PROTOCOL VERSION IDENTIFIER: October 2020, V.1.

Factors Associated With Severe SARS-CoV-2 Infection.

BACKGROUND: Initial reports on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in children suggested that very young age and comorbidities may increase risk of severe evolution, but these findings remained to be confirmed. We aimed to analyze the clinical spectrum of hospitalized pediatric SARS-CoV-2 infection and predictors of severe disease evolution. METHODS: We conducted a French national prospective surveillance of children hospitalized with SARS-CoV-2 infection. We included all children with confirmed SARS-CoV-2 infection in 60 hospitals during February 15 to June 1, 2020. The main outcome was the proportion of children with severe disease, defined by hemodynamic or ventilatory (invasive or not) support requirement. RESULTS: We included 397 hospitalized children with SARS-CoV-2 infection. We identified several clinical patterns, ranging from paucisymptomatic children, admitted for surveillance, to lower respiratory tract infection or multisystem inflammatory syndrome in children. Children <90 days old accounted for 37% of cases (145 of 397), but only 4 (3%) had severe disease. Excluding children with multisystem inflammatory syndrome in children (n = 29) and hospitalized for a diagnosis not related to SARS-CoV-2 (n = 62), 23 of 306 (11%) children had severe disease, including 6 deaths. Factors independently associated with severity were age ≥10 years (odds ratio [OR] = 3.4, 95% confidence interval: 1.1-10.3), hypoxemia (OR = 8.9 [2.6-29.7]), C-reactive protein level ≥80 mg/L (OR = 6.6 [1.4-27.5]). CONCLUSIONS: In contrast with preliminary reports, young age was not an independent factor associated with severe SARS-CoV-2 infection, and children <90 days old were at the lowest risk of severe disease evolution. This may help physicians to better identify risk of severe disease progression in children.

Humoral immunity to SARS-CoV-2 and seasonal coronaviruses in children and adults in north-eastern France.

BACKGROUND: Children are underrepresented in the COVID-19 pandemic and often experience milder disease than adolescents and adults. Reduced severity is possibly due to recent and more frequent seasonal human coronaviruses (HCoV) infections. We assessed the seroprevalence of SARS-CoV-2 and seasonal HCoV specific antibodies in a large cohort in north-eastern France. METHODS: In this cross-sectional seroprevalence study, serum samples were collected from children and adults requiring hospital admission for non-COVID-19 between February and August 2020. Antibody responses to SARS-CoV-2 and seasonal HCoV (229E, HKU1, NL63, OC43) were assessed using a bead-based multiplex assay, Luciferase-Linked ImmunoSorbent Assay, and a pseudotype neutralisation assay. FINDINGS: In 2,408 individuals, seroprevalence of SARS-CoV-2-specific antibodies was 7-8% with three different immunoassays. Antibody levels to seasonal HCoV increased substantially up to the age of 10. Antibody responses in SARS-CoV-2 seropositive individuals were lowest in adults 18-30 years. In SARS-CoV-2 seronegative individuals, we observed cross-reactivity between antibodies to the four HCoV and SARS-CoV-2 Spike. In contrast to other antibodies to SARS-CoV-2, specific antibodies to sub-unit 2 of Spike (S2) in seronegative samples were highest in children. Upon infection with SARS-CoV-2, antibody levels to Spike of betacoronavirus OC43 increased across the whole age spectrum. No SARS-CoV-2 seropositive individuals with low levels of antibodies to seasonal HCoV were observed. INTERPRETATION: Our findings underline significant cross-reactivity between antibodies to SARS-CoV-2 and seasonal HCoV, but provide no significant evidence for cross-protective immunity to SARS-CoV-2 infection due to a recent seasonal HCoV infection. In particular, across all age groups we did not observe SARS-CoV-2 infected individuals with low levels of antibodies to seasonal HCoV. FUNDING: This work was supported by the « URGENCE COVID-19 ¼ fundraising campaign of Institut Pasteur, by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (Grant No. ANR-10-LABX-62-IBEID), and by the REACTing (Research & Action Emerging Infectious Diseases), and by the RECOVER project funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No. 101003589, and by a grant from LabEx IBEID (ANR-10-LABX-62-IBEID).