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BACKGROUND: Bone and joint infections (BJIs) are treated with intravenous antibiotics, which are burdensome and costly. No randomised controlled studies have compared if initial oral antibiotics are as effective as intravenous therapy. We aimed to investigate the efficacy and safety of initial oral antibiotics compared with initial intravenous antibiotics followed by oral antibiotics in children and adolescents with uncomplicated BJIs. METHODS: From Sept 15, 2020, to June 30, 2023, this nationwide, randomised, non-inferiority trial included patients aged 3 months to 17 years with BJIs who presented to one of the 18 paediatric hospital departments in Denmark. Exclusion criteria were severe infection (ie, septic shock, the need for acute surgery, or substantial soft tissue involvement), prosthetic material, comorbidity, previous BJIs, or antibiotic therapy for longer than 24 h before inclusion. Patients were randomly assigned (1:1), stratified by C-reactive protein concentration (<35 mg/L vs ≥35 mg/L), to initially receive either high-dose oral antibiotics or intravenous ceftriaxone (100 mg/kg per day in one dose). High-dose oral antibiotics were coformulated amoxicillin (100 mg/kg per day) and clavulanic acid (12·5 mg/kg per day) in three doses for patients younger than 5 years or dicloxacillin (200 mg/kg per day) in four doses for patients aged 5 years or older. After a minimum of 3 days, and upon clinical improvement and decrease in C-reactive protein, patients in both groups received oral antibiotics in standard doses. The primary outcome was sequelae after 6 months in patients with BJIs, defined as any atypical mobility or function of the affected bone or joint, assessed blindly, in all randomised patients who were not terminated early due to an alternative diagnosis (ie, not BJI) and who attended the primary outcome assessment. A risk difference in sequelae after 6 months of less than 5% implied non-inferiority of the oral treatment. Safety outcomes were serious complications, the need for surgery after initiation of antibiotics, and treatment-related adverse events in the as-randomised population. This trial was registered with ClinicalTrials.gov, NCT04563325. FINDINGS: 248 children and adolescents with suspected BJIs were randomly assigned to initial oral antibiotics (n=123) or initial intravenous antibiotics (n=125). After exclusion of patients without BJIs (n=54) or consent withdrawal (n=2), 101 patients randomised to oral treatment and 91 patients randomised to intravenous treatment were included. Ten patients did not attend the primary outcome evaluation. Sequelae after 6 months occurred in none of 98 patients with BJIs in the oral group and none of 84 patients with BJIs in the intravenous group (risk difference 0, one-sided 97·5% CI 0·0 to 3·8, pnon-inferiority=0·012). Surgery after randomisation was done in 12 (9·8%) of 123 patients in the oral group compared with seven (5·6%) of 125 patients in the intravenous group (risk difference 4·2%, 95% CI -2·7 to 11·5). We observed no serious complications. Rates of adverse events were similar across both treatment groups. INTERPRETATION: In children and adolescents with uncomplicated BJIs, initial oral antibiotic treatment was non-inferior to initial intravenous antibiotics followed by oral therapy. The results are promising for oral treatment of uncomplicated BJIs, precluding the need for intravenous catheters and aligning with the principles of antimicrobial stewardship. FUNDING: Innovation Fund Denmark and Rigshospitalets Forskningsfond.
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Administración Intravenosa , Antibacterianos , Humanos , Niño , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Dinamarca , Adolescente , Administración Oral , Femenino , Masculino , Preescolar , Lactante , Artritis Infecciosa/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis ß-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-ß (transforming growth factor-ß) (highest in the Veillonella cluster) and Wnt/ß-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microbiota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches.
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Asma , Hipersensibilidad , Microbiota , Femenino , Masculino , Humanos , Transcriptoma , Ruidos Respiratorios/genética , Asma/genética , Microbiota/genéticaRESUMEN
Rationale: There is a major unmet need for improving the care of children and adolescents with severe asthma and wheeze. Identifying factors contributing to disease severity may lead to improved diagnostics, biomarkers, or therapies. The airway microbiota may be such a key factor. Objectives: To compare the oropharyngeal airway microbiota of children and adolescents with severe and mild/moderate asthma/wheeze. Methods: Oropharyngeal swab samples from school-age and preschool children in the European U-BIOPRED (Unbiased BIOmarkers in the PREDiction of respiratory disease outcomes) multicenter study of severe asthma, all receiving severity-appropriate treatment, were examined using 16S ribosomal RNA gene sequencing. Bacterial taxa were defined as amplicon sequence variants. Results: We analyzed 241 samples from four cohorts: A) 86 school-age children with severe asthma; B) 39 school-age children with mild/moderate asthma; C) 65 preschool children with severe wheeze; and D) 51 preschool children with mild/moderate wheeze. The most common bacteria were Streptococcus (mean relative abundance, 33.5%), Veillonella (10.3%), Haemophilus (7.0%), Prevotella (5.9%), and Rothia (5.5%). Age group (school-age vs. preschool) was associated with the microbiota in ß-diversity analysis (F = 3.32, P = 0.011) and in a differential abundance analysis (28 significant amplicon sequence variants). Among all children, we found no significant difference in the microbiota between children with severe and mild/moderate asthma/wheeze in univariable ß-diversity analysis (F = 1.99, P = 0.08, N = 241), but a significant difference in a multivariable model (F = 2.66, P = 0.035), including the number of exacerbations in the previous year. Age was also significant when expressed as a microbial maturity score (Spearman Rho, 0.39; P = 4.6 × 10-10); however, this score was not associated with asthma/wheeze severity. Conclusions: There was a modest difference in the oropharyngeal airway microbiota between children with severe and mild/moderate asthma/wheeze across all children but not in individual age groups, and a strong association between the microbiota and age. This suggests the oropharyngeal airway microbiota as an interesting entity in studying asthma severity, but probably without the strength to serve as a biomarker for targeted intervention.
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Asma , Microbiota , Humanos , Adolescente , Preescolar , Ruidos Respiratorios , Microbiota/genética , Asma/microbiología , Orofaringe/microbiología , Bacterias/genéticaRESUMEN
Relapse of neonatal meningitis is most commonly caused by Escherichia coli. Management to prevent relapse varies and evidence is limited. We present four cases of relapsing neonatal E. coli meningitis in Denmark in 2016-2017 and review the current literature on this subject. During the primary episodes, our patients received cephalosporin for 3 weeks and gentamicin for the first 3 days. The only identified risk factor was delayed CSF sterilization in three of four cases and no repeated lumbar puncture. Relapse occurred after 2-28 days; one case with ventriculitis and one with empyema. Relapses were treated for 6-14 weeks with monotherapy. No children had an underlying disease predisposing to E. coli meningitis. There is generally a trend towards reducing invasive procedures, e.g., lumbar puncture and the length of intravenous antibiotics in pediatric infectious diseases, but our cases highlight a condition where the opposite might be needed.
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Antimicrobial resistance in Pseudomonas aeruginosa is a threat to children with cancer. We explored the association between P. aeruginosa resistance and previous antibiotic exposure. All children with cancer and P. aeruginosa bacteremia in 2007 to 2016 in Denmark, a country with an overall resistance rate of â¼3%, were included. Twenty percent (10/49) of isolates from children previously exposed to meropenem were meropenem nonsusceptible. The only significant risk factor of meropenem nonsusceptibility was previous meropenem therapy (P=0.03). On the basis of these results, we suggest that meropenem should be reserved as a last resort for children with febrile neutropenia in countries with low antimicrobial resistance.
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Antibacterianos/efectos adversos , Neutropenia Febril/tratamiento farmacológico , Meropenem/efectos adversos , Infecciones por Pseudomonas/epidemiología , Pseudomonas aeruginosa/aislamiento & purificación , Adolescente , Niño , Preescolar , Dinamarca/epidemiología , Neutropenia Febril/patología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Pruebas de Sensibilidad Microbiana , Pronóstico , Infecciones por Pseudomonas/inducido químicamente , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/efectos de los fármacos , Estudios RetrospectivosRESUMEN
RATIONALE: Experimental evidence suggests that CDHR3 (cadherin-related family member 3) is a receptor for rhinovirus (RV)-C, and a missense variant in this gene (rs6967330) is associated with childhood asthma with severe exacerbations. OBJECTIVES: To determine whether rs6967330 influences RV-C infections and illnesses in early childhood. METHODS: We studied associations between rs6967330 and respiratory infections and illnesses in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) and COAST (Childhood Origins of Asthma Birth Cohort Study) birth cohorts, where respiratory infections were monitored prospectively for the first 3 years of life. Nasal samples were collected during acute infections in both cohorts and during asymptomatic periods in COAST and analyzed for RV-A, RV-B, and RV-C, and other common respiratory viruses. MEASUREMENTS AND MAIN RESULTS: The CDHR3 asthma risk allele (rs6967330-A) was associated with increased risk of respiratory tract illnesses (incidence risk ratio [IRR] = 1.14 [95% confidence interval, 1.05-1.23]; P = 0.003). In particular, this variant was associated with risk of respiratory episodes with detection of RV-C in COPSAC2010 (IRR = 1.89 [1.14-3.05]; P = 0.01) and in COAST (IRR = 1.37 [1.02-1.82]; P = 0.03) children, and in a combined meta-analysis (IRR = 1.51 [1.13-2.02]; P = 0.006). In contrast, the variant was not associated with illnesses related to other viruses (IRR = 1.07 [0.92-1.25]; P = 0.37). Consistent with these observations, the CDHR3 variant was associated with increased detection of RV-C, but not of other viruses during scheduled visits at specific ages. CONCLUSIONS: The CDHR3 asthma risk allele is associated specifically with RV-C illnesses in two birth cohorts. This clinical evidence supports earlier molecular evidence indicating that CDHR3 functions as an RV-C receptor, and raises the possibility of preventing RV-C infections by targeting CDHR3.
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Asma/genética , Cadherinas/genética , Infecciones por Enterovirus/genética , Enterovirus/genética , Proteínas de la Membrana/genética , Adulto , Alelos , Proteínas Relacionadas con las Cadherinas , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring. METHODS: We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization. RESULTS: A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization. CONCLUSIONS: Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lundbeck Foundation and others; ClinicalTrials.gov number, NCT00798226 .).
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Asma/prevención & control , Suplementos Dietéticos , Ácidos Grasos Omega-3/administración & dosificación , Ruidos Respiratorios/efectos de los fármacos , Asma/epidemiología , Preescolar , Método Doble Ciego , Ácidos Grasos Omega-3/sangre , Femenino , Aceites de Pescado/administración & dosificación , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Cumplimiento de la Medicación , Aceite de Oliva/administración & dosificación , Embarazo , Tercer Trimestre del Embarazo , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/prevención & control , RiesgoRESUMEN
More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N = 5758) followed by replication (N = 3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.
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Diarrea/genética , Fucosiltransferasas/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Alelos , Preescolar , Diarrea/patología , Femenino , Genotipo , Humanos , Lactante , Masculino , Polimorfismo de Nucleótido Simple , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
IMPORTANCE: Observational studies have suggested that increased dietary vitamin D intake during pregnancy may protect against wheezing in the offspring, but the preventive effect of vitamin D supplementation to pregnant women is unknown. OBJECTIVE: To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, single-center, randomized clinical trial conducted within the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort. Enrollment began March 2009 with a goal of 708 participants, but due to delayed ethical approval, only 623 women were recruited at 24 weeks of pregnancy. Follow-up of the children (N = 581) was completed when the youngest child reached age 3 years in March 2014. INTERVENTIONS: Vitamin D3 (2400 IU/d; n = 315) or matching placebo tablets (n = 308) from pregnancy week 24 to 1 week postpartum. All women received 400 IU/d of vitamin D3 as part of usual pregnancy care. MAIN OUTCOMES AND MEASURES: Age at onset of persistent wheeze in the first 3 years of life. Secondary outcomes included number of episodes of troublesome lung symptoms, asthma, respiratory tract infections, and neonatal airway immunology. Adverse events were assessed. RESULTS: Of the 581 children, persistent wheeze was diagnosed during the first 3 years of life in 47 children (16%) in the vitamin D3 group and 57 children (20%) in the control group. Vitamin D3 supplementation was not associated with the risk of persistent wheeze, but the number of episodes of troublesome lung symptoms was reduced, and the airway immune profile was up-regulated (principal component analysis, P = .04). There was no effect on additional end points. Intrauterine death was observed in 1 fetus (<1%) in the vitamin D3 group vs 3 fetuses (1%) in the control group and congenital malformations in 17 neonates (5%) in the vitamin D3 group vs 23 neonates (8%) in the control group. [table: see text]. CONCLUSIONS AND RELEVANCE: The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years. However, interpretation of the study is limited by a wide CI that includes a clinically important protective effect. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00856947.
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Colecalciferol/administración & dosificación , Ruidos Respiratorios , Vitaminas/administración & dosificación , Adulto , Asma/diagnóstico , Asma/prevención & control , Preescolar , Método Doble Ciego , Femenino , Humanos , Lactante , Recién Nacido , Embarazo , Tercer Trimestre del Embarazo , Vitamina D/análogos & derivados , Vitamina D/sangreRESUMEN
BACKGROUND: Bacteria and viruses are equally associated with the risk of acute episodes of asthma-like symptoms in young children, suggesting antibiotics as a potential treatment for such episodes. We aimed to assess the effect of azithromycin on the duration of respiratory episodes in young children with recurrent asthma-like symptoms, hypothesising that it reduces the duration of the symptomatic period. METHODS: In this randomised, double-blind, placebo-controlled trial, we recruited children aged 1-3 years, who were diagnosed with recurrent asthma-like symptoms from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort; a birth cohort consisting of the general Danish population of Zealand, including Copenhagen. Exclusion criteria were macrolide allergy, heart, liver, neurological, and kidney disease, and, before each treatment, one or more clinical signs of pneumonia (respiratory frequency of ≥50 breaths per min; fever of ≥39°C; C-reactive protein concentration of ≥476·20 nmol/L [≥50 mg/L]). Each episode of asthma-like symptoms lasting at least 3 days was randomly allocated to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo after thorough examination by a study physician at the Copenhagen Prospective Studies on Asthma research unit. Each episode was randomly allocated independently of previous treatment from a computer-generated list of random numbers in blocks of ten (generated at the Pharmacy of Glostrup). Investigators and children were masked until the youngest child turned 3 years of age and throughout the data validation and analysis phases. The primary outcome was duration of the respiratory episode after treatment, verified by prospective daily diaries and analysed with Poisson regression. Analyses were per protocol (excluding those without a primary outcome measure or who did not receive treatment). This trial is registered with ClinicalTrials.gov, number NCT01233297. FINDINGS: Between Nov 17, 2010, and Jan 28, 2014, we randomly allocated 158 asthma-like episodes in 72 children (79 [50%] to azithromycin and 79 [50%] to placebo). The mean duration of the episode after treatment was 3·4 days for children receiving azithromycin compared with 7·7 days for children receiving placebo. Azithromycin caused a significant shortening of the episode of 63·3% (95% CI 56·0-69·3; p<0·0001). The effect size increased with early initiation of treatment, showing a reduction in episode duration of 83% if treatment was initiated before day 6 of the episode compared with 36% if initiated on or after day 6 (p<0·0001). We noted no differences in clinical adverse events between the azithromycin (18 [23%] of 78 episodes included in final analysis) and placebo (24 [30%] of 79) groups (p=0·30), but we did not investigate bacterial resistance patterns after treatment. INTERPRETATION: Azithromycin reduced the duration of episodes of asthma-like symptoms in young children, suggesting that this drug could have a role in acute management of exacerbations. Further research is needed to disentangle the inflammatory versus antimicrobial aspects of this relation. FUNDING: Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation.
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Antibacterianos/uso terapéutico , Asma/tratamiento farmacológico , Azitromicina/uso terapéutico , Tos/tratamiento farmacológico , Disnea/tratamiento farmacológico , Ruidos Respiratorios , Corticoesteroides/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Asma/inmunología , Proteína C-Reactiva/inmunología , Preescolar , Tos/inmunología , Dinamarca , Método Doble Ciego , Disnea/inmunología , Intervención Médica Temprana , Femenino , Hospitalización , Humanos , Lactante , Masculino , Factores de TiempoRESUMEN
U-BIOPRED aims to characterise paediatric and adult severe asthma using conventional and innovative systems biology approaches. A total of 99 school-age children with severe asthma and 81 preschoolers with severe wheeze were compared with 49 school-age children with mild/moderate asthma and 53 preschoolers with mild/moderate wheeze in a cross-sectional study. Despite high-dose treatment, the severe cohorts had more severe exacerbations compared with the mild/moderate ones (annual medians: school-aged 3.0 versus 1.1, preschool 3.9 versus 1.8; p<0.001). Exhaled tobacco exposure was common in the severe wheeze cohort. Almost all participants in each cohort were atopic and had a normal body mass index. Asthma-related quality of life, as assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) and the Paediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), was worse in the severe cohorts (mean±se school-age PAQLQ: 4.77±0.15 versus 5.80±0.19; preschool PACQLQ: 4.27±0.18 versus 6.04±0.18; both p≤0.001); however, mild/moderate cohorts also had significant morbidity. Impaired quality of life was associated with poor control and airway obstruction. Otherwise, the severe and mild/moderate cohorts were clinically very similar. Children with severe preschool wheeze or severe asthma are usually atopic and have impaired quality of life that is associated with poor control and airflow limitation: a very different phenotype from adult severe asthma. In-depth phenotyping of these children, integrating clinical data with high-dimensional biomarkers, may help to improve and tailor their clinical management.
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Corticoesteroides/uso terapéutico , Asma/tratamiento farmacológico , Asma/epidemiología , Contaminación por Humo de Tabaco/efectos adversos , Adolescente , Niño , Preescolar , Costo de Enfermedad , Estudios Transversales , Europa (Continente) , Femenino , Humanos , Hipersensibilidad Inmediata , Masculino , Pediatría , Estudios Prospectivos , Calidad de Vida , Ruidos Respiratorios/diagnóstico , Índice de Severidad de la Enfermedad , Espirometría , Encuestas y CuestionariosRESUMEN
BACKGROUND: Wheezy episodes in young children are often triggered by viral and bacterial respiratory tract infections, but there is little evidence supporting the hypothesis that symptom duration depends on the specific microbial trigger. OBJECTIVE: We sought to investigate whether the duration of wheezy episodes in young children depends on the microbial trigger. METHODS: Two hundred eighty-three children from the Copenhagen Prospective Study on Asthma in Childhood2000 at-risk birth cohort were prospectively examined for common airway pathogenic bacteria and viruses during acute wheezy episodes in the first 3 years of life. Findings were related to symptomatic duration of episodes, as monitored in daily diary cards from birth. RESULTS: Eight hundred thirty-seven samples were investigated for viruses, bacteria, or both. Both viruses and bacteria were identified in 55% of episodes, bacteria were identified exclusively in 31% of episodes, and viruses were identified exclusively in 10% of episodes. The median duration of acute symptoms was 9 days (interquartile range, 5-16 days), and duration was independent of bacterial or viral species. CONCLUSIONS: The duration of wheezy episodes was independent of pathogenic airway bacterial or viral species. This suggests that symptom burden from infections is dependent on other factors, such as environmental exposures or host factors. The common term viral wheeze seems inappropriate in view of the finding of pathogenic bacteria in 86% of wheezy episodes.
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Asma/epidemiología , Infecciones Bacterianas/epidemiología , Ruidos Respiratorios , Infecciones del Sistema Respiratorio/epidemiología , Virosis/epidemiología , Asma/fisiopatología , Infecciones Bacterianas/fisiopatología , Preescolar , Dinamarca/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estudios Prospectivos , Ruidos Respiratorios/fisiopatología , Infecciones del Sistema Respiratorio/fisiopatología , Factores de Tiempo , Virosis/fisiopatologíaRESUMEN
BACKGROUND: It is recommended to vaccinate pregnant women against influenza. A possible impact on the immune expression of the fetus has never been studied. We aim to study the immune signature in the upper airways and the incidence of infections in neonates born to mothers receiving Influenza A(H1N1)pnd09 vaccination during pregnancy. METHODS: One hundred and fifty-six women from the unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC2010) received Influenza A(H1N1)pnd09-vaccination during the 2009 pandemic. Fifty-one mothers received the vaccine during pregnancy and 105 after pregnancy; 332 neonates of nonvaccinated mothers were included as secondary controls. Nasal mucosal lining fluid was sampled in 488 neonates and assessed for interleukin (IL)-12p70, IP-10, interferon-gamma (IFN)-γ, tumor necrosis factor-alpha (TNF)-α, MIP-1ß, MCP-1, MCP-4, IL-4, IL-5, IL-13, eotaxin-1, eotaxin-3, TARC, MDC, IL-17, IL-1ß, IL-8, transforming growth factor beta (TGF)-ß1, IL-10 and IL-2. Infections were monitored the first year of life by daily diary cards and clinical controls. RESULTS: Neonates of mothers vaccinated during pregnancy had significant up-regulation of TGF-ß1 [ratio = 1.52 (1.22-1.90), P = 0.0002], and corresponding down-regulation (P < 0.05) of IL-12p70, IFN-γ, IL-5, eotaxin-1, TARC, MDC, IL-8 in comparison to those vaccinated after pregnancy. The lag-time from vaccination during pregnancy to assessment of the immune signature showed significant and positive association to up-regulation of TGF-ß1 levels (P = 0.0003) and significant negative association to other mediators. The study was not powered to study differences in the incidence of infections in early infancy which did not differ between the study groups. CONCLUSION: Influenza A(H1N1)pnd09 vaccination during pregnancy up-regulates TGF-ß1 and down-regulates key mediators of the protective immunity.
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Tolerancia Inmunológica , Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/epidemiología , Vacunación/métodos , Estudios de Cohortes , Citocinas/análisis , Femenino , Humanos , Recién Nacido , Vacunas contra la Influenza/administración & dosificación , Madres , Mucosa Nasal/inmunología , Embarazo , Estudios ProspectivosAsunto(s)
Antiasmáticos/administración & dosificación , Asma/tratamiento farmacológico , Beclometasona/administración & dosificación , Etanolaminas/administración & dosificación , Administración por Inhalación , Adolescente , Antiasmáticos/efectos adversos , Antiasmáticos/farmacocinética , Antiasmáticos/uso terapéutico , Asma/sangre , Beclometasona/efectos adversos , Beclometasona/farmacocinética , Beclometasona/uso terapéutico , Disponibilidad Biológica , Estudios Cruzados , Combinación de Medicamentos , Quimioterapia Combinada , Inhaladores de Polvo Seco , Etanolaminas/efectos adversos , Etanolaminas/farmacocinética , Etanolaminas/uso terapéutico , Femenino , Fumarato de Formoterol , Humanos , Masculino , Cooperación del PacienteAsunto(s)
Infecciones Asintomáticas/epidemiología , Tos/etiología , Nasofaringe/microbiología , Ruidos Respiratorios/etiología , Preescolar , Infecciones por Haemophilus/complicaciones , Infecciones por Haemophilus/epidemiología , Haemophilus influenzae , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Moraxella catarrhalis , Infecciones por Moraxellaceae/complicaciones , Infecciones por Moraxellaceae/epidemiología , Infecciones Neumocócicas/complicaciones , Infecciones Neumocócicas/epidemiología , Modelos de Riesgos Proporcionales , Reacción en Cadena en Tiempo Real de la Polimerasa , Streptococcus pneumoniaeRESUMEN
RATIONALE: The frequency of pneumonia and bronchiolitis exhibits considerable variation in otherwise healthy children, and suspected risk factors explain only a minor proportion of the variation. We hypothesized that alterations in the airway microbiome in early life may be associated with susceptibility to pneumonia and bronchiolitis in young children. OBJECTIVES: To investigate the relation between neonatal airway colonization and pneumonia and bronchiolitis during the first 3 years of life. METHODS: Participants comprised children of the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) cohort, a prospective birth cohort study of 411 children born to mothers with asthma. Aspirates from the hypopharynx at age 4 weeks were cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Clinical information on pneumonia and bronchiolitis within the first 3 years of life was prospectively collected by the research physicians at the center. Analyses were adjusted for covariates associated with pneumonia and bronchiolitis and bacterial airway colonization. MEASUREMENTS AND MAIN RESULTS: Hypopharyngeal aspirates and full clinical follow-up until 3 years of age were available for 265 children. Of these, 56 (21%) neonates were colonized with S. pneumoniae, H. influenzae, and/or M. catarrhalis at 4 weeks of age. Colonization with at least one of these microorganisms (but not S. aureus) was significantly associated with increased incidence of pneumonia and bronchiolitis (adjusted incidence rate ratio, 1.79 [1.29-2.48]; P < 0.005) independently of concurrent or later asthma. CONCLUSIONS: Neonatal airway colonization with S. pneumoniae, H. influenzae, or M. catarrhalis is associated with increased risk of pneumonia and bronchiolitis in early life independently of asthma. This suggests a role of pathogenic bacterial colonization of the airways in neonates for subsequent susceptibly to pneumonia and bronchiolitis.
Asunto(s)
Bronquiolitis/microbiología , Hipofaringe/microbiología , Microbiota , Neumonía/microbiología , Asma/diagnóstico , Asma/epidemiología , Asma/microbiología , Bronquiolitis/diagnóstico , Bronquiolitis/epidemiología , Preescolar , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Haemophilus influenzae/aislamiento & purificación , Humanos , Incidencia , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Moraxella catarrhalis/aislamiento & purificación , Neumonía/diagnóstico , Neumonía/epidemiología , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores de Riesgo , Staphylococcus aureus/aislamiento & purificación , Streptococcus pneumoniae/aislamiento & purificaciónRESUMEN
AIM: The fixed combination of beclomethasone (BDP) and formoterol pressurized metered dose inhaler (pMDI) (Foster®, Chiesi Farmaceutici) is being developed in the lower strength (BDP/formoterol: 50/6 µg) to provide an appropriate dosage for children with asthma. The aim of this work was to investigate the systemic bioavailability of beclomethasone-17-monoproprionate (B17MP, the active metabolite of BDP) and formoterol after single inhalation of Foster® pMDI 50/6 µg vs. the free combination of BDP and formoterol pMDIs in asthmatic children. METHODS: Children aged 5-11 years old inhaled BDP 200 µg and formoterol 24 µg as fixed vs. free combination in an open label, randomized, two way crossover single dose study. Blood was collected pre-dose up to 8 h post-dose for pharmacokinetic evaluation (AUC(0,t), AUC(0,∞), AUC(0,0.5 h, Cmax , tmax , t1/2 ). Pharmacodynamics included heart rate, plasma potassium, urinary glucose and cortisol excretion. Peak expiratory flow and adverse events were monitored. RESULTS: Twenty subjects were evaluable. The systemic exposure of B17MP and formoterol administered as fixed combination did not exceed the free combination: B17MP AUC(0,t) (pg ml(-1) h) ratio test : reference (90% CI), 0.81 (0.697, 0.948) and formoterol AUC(0,t) (pg ml(-1) h) ratio test : reference 0.97 (0.85, 1.10). All pharmacokinetic and pharmacodynamic end points showed non-superiority in favour of the test drug. One adverse event (vertigo) occurred but was not considered treatment-related. CONCLUSION: BDP and formoterol pharmacokinetic and pharmacodynamic effects are non-superior after administration of the two actives as fixed vs. the free combination in 5-11-year-old asthmatic children.