RESUMEN
In the pathogenesis of asthma in children there is a pivotal role for a type 2 inflammatory response to early life exposures or events. Interactions between infections, atopy, genetic susceptibility and environmental exposures (such as farmyard environment, air pollution and tobacco smoke exposure) influence the development of wheezing illness and the risk of progression to asthma. The immune system, lung function and the microbiome in gut and airways develop in parallel, and dysbiosis of the microbiome may be a critical factor in asthma development. Increased infant weight gain and preterm birth are other risk factors for development of asthma and reduced lung function. The complex interplay between these factors explains the heterogeneity of asthma in children. Subgroups of patients can be identified as phenotypes, based on clinical parameters, or endotypes, based on a specific pathophysiological mechanism. Paediatric asthma phenotypes and endotypes may ultimately help to improve diagnosis of asthma, prediction of asthma development and treatment of individual children, based on clinical, temporal, developmental or inflammatory characteristics. Unbiased, data-driven clustering, using a multidimensional or systems biology approach may be needed to better define phenotypes. The present knowledge on inflammatory phenotypes of childhood asthma has now been successfully applied in the treatment with biologicals of children with severe therapy-resistant asthma, and it is to be expected that more personalised treatment options may become available.
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Asma , Hipersensibilidad Inmediata , Nacimiento Prematuro , Niño , Femenino , Humanos , Recién Nacido , Fenotipo , Ruidos Respiratorios/etiologíaRESUMEN
RATIONALE: Severe fetal malnutrition has been related to an increased risk of respiratory diseases later in life, but evidence for the association of a suboptimal diet during pregnancy with respiratory outcomes in childhood is conflicting. We aimed to examine whether a pro-inflammatory or low-quality maternal diet during pregnancy was associated with child's respiratory health. METHODS: We performed an individual participant meta-analysis among 18â326 mother-child pairs from seven European birth cohorts. Maternal pro-inflammatory and low-quality diets were estimated by energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) scores. Preschool wheezing and school-age asthma were measured using questionnaires and lung function by spirometry. RESULTS: After adjustment for lifestyle and sociodemographic factors, we observed that a higher maternal E-DII score (a more pro-inflammatory diet) during pregnancy was associated only with a lower forced vital capacity (FVC) in children (z-score difference -0.05, 95% CI -0.08- -0.02, per interquartile range increase). No linear associations of the maternal E-DII or DASH score with child's wheezing or asthma were observed. In an exploratory examination of the extremes, a very low DASH score (<10th percentile) (a very low dietary quality) was associated with an increased risk of preschool wheezing and a low forced expiratory volume in 1â s/FVC (z-score <-1.64) (OR 1.20, 95% CI 1.06-1.36 and z-score difference 1.40, 95% CI 1.06-1.85, compared to ≥10th percentile), with corresponding population attributable risk fractions of 1.7% and 3.3%, respectively. CONCLUSION: The main results from this individual participant data meta-analysis do not support the hypothesis that maternal pro-inflammatory or low-quality diet in pregnancy are related to respiratory diseases in childhood.
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Asma , Ruidos Respiratorios , Asma/epidemiología , Asma/etiología , Preescolar , Dieta/efectos adversos , Femenino , Volumen Espiratorio Forzado , Humanos , Embarazo , Ruidos Respiratorios/etiología , Capacidad VitalRESUMEN
BACKGROUND: The relation of physical condition with respiratory outcomes in adolescents is unclear. We examined the hypothesis that adolescents with a lower physical condition represented by a lower cardiorespiratory fitness and physical activity, and a higher screen time have a lower lung function and higher risk of asthma. METHODS: In a population-based prospective cohort study on 4854 children aged 13 years, we assessed cardiorespiratory fitness by using the peak work rate measured by the steep ramp test. Information on physical activity and screen time was obtained by self-reported questionnaires. Lung function was measured by spirometry and current asthma was assessed by a parental-reported questionnaire. RESULTS: Taking sociodemographic, lifestyle, and growth-related confounders and multiple hypothesis testing into account, a 1 SD lower cardiorespiratory fitness was associated with a lower FEV1 , FVC, and FEF75 (Z-score difference (95% CI): -0.31 (-0.35, -0.28), -0.30 (-0.33, -0.26), -0.13 (-0.17, -0.10), respectively), and a higher risk of asthma (Odds Ratio (95% CI) 1.25 (1.06, 1.46)). A 1 SD higher screen time was associated with a lower FVC (Z-score difference (95% CI): -0.06 (-0.10, -0.03)). Physical activity and screen time were not related to asthma. Results did not materially change after additional adjustment for respiratory outcomes at an earlier age. CONCLUSION: Adolescents with a lower cardiorespiratory fitness had a lower lung function and a higher risk of asthma. Those with a higher screen time had a lower FVC. Further studies are needed to explore the effect of improvements in physical condition on long-term respiratory outcomes.
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Asma , Adolescente , Asma/epidemiología , Niño , Humanos , Pulmón , Estudios Prospectivos , Pruebas de Función Respiratoria , EspirometríaRESUMEN
The optimal dose regimen for intravenous (IV) treatment in children with severe acute asthma (SAA) is still a matter of debate. We assessed the efficacy of adding a salbutamol loading dose to continuous infusion with salbutamol in children admitted to a pediatric intensive care unit (PICU) with SAA. This multicentre, placebo-controlled randomized trial in the PICUs of four tertiary care children's hospitals included children (2-18 years) with SAA admitted between 2017 and 2019. Children were randomized to receive either a loading dose IV salbutamol (15 mcg/kg, max. 750 mcg) or normal saline while on continuous salbutamol infusion. The primary outcome was the asthma score (Qureshi) 1 h after the intervention. Analysis of covariance models was used to evaluate sensitivity to change in asthma scores. Serum concentrations of salbutamol were obtained. Fifty-eight children were included (29 in the intervention group). Median baseline asthma score was 12 (IQR 10-13) in the intervention group and 11 (9-12) in the control group (p = 0.032). The asthma score 1 h after the intervention did not differ significantly between the groups (p = 0.508, ß-coefficient = 0.283). The median increase in salbutamol plasma levels 10 min after the intervention was 13 µg/L (IQR 5-24) in the intervention group and 4 µg/L (IQR 0-7) in the control group (p = 0.001). Side effects were comparable between both groups. CONCLUSION: We found no clinical benefit of adding a loading dose IV salbutamol to continuous infusion of salbutamol, in children admitted to the PICU with SAA. Clinically significant side effects from the loading dose were not encountered. WHAT IS KNOWN: ⢠Pediatric asthma guidelines struggle with an evidence-based approach for the treatment of SAA beyond the initial steps of oxygen suppletion, repetitive administration of inhaled ß2-agonists, and systemic steroids. ⢠During an SAA episode, effective delivery of inhaled drugs is unpredictable due to severe airway obstruction. WHAT IS NEW: ⢠This study found no beneficial effect of an additional loading dose IV salbutamol in children admitted to the PICU. ⢠This study found no clinically significant side effects from the loading dose.
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Asma , Estado Asmático , Administración por Inhalación , Albuterol , Asma/tratamiento farmacológico , Broncodilatadores , Niño , Humanos , Unidades de Cuidado Intensivo Pediátrico , Oxígeno , Solución Salina/uso terapéuticoRESUMEN
BACKGROUND: Infants with less diverse gut microbiota seem to have higher risks of atopic diseases in early life, but any associations at school age are unclear. OBJECTIVES: This study sought to examine the associations of diversity, relative abundance, and functional pathways of stool microbiota with atopic diseases in school-age children. METHODS: We performed a cross-sectional study within an existing population-based prospective cohort among 1440 children 10 years of age. On stool samples, 16S ribosomal RNA gene sequencing was performed, and taxonomic and functional tables were produced. Physician-diagnosed eczema, allergy, and asthma were measured by questionnaires, allergic sensitization by skin prick tests, and lung function by spirometry. RESULTS: The α-diversity of stool microbiota was associated with a decreased risk of eczema (odds ratio [OR], 0.98; 95% CI, 0.97, 1.00), and ß-diversity was associated with physician-diagnosed inhalant allergy (R2 = 0.001; P = .047). Lachnospiraceae, Ruminococcaceae_UCG-005, and Christensenellaceae_R-7_group species were associated with decreased risks of eczema, inhalant allergic sensitization, and physician-diagnosed inhalant allergy (OR range, 0.88-0.94; 95% CI range, 0.79-0.96 to 0.88-0.98), while Agathobacter species were associated with an increased risk of physician-diagnosed inhalant allergy (OR, 1.23; 95% CI, 1.08-1.42). Functional pathways related to heme and terpenoid biosynthesis were associated with decreased risks of physician-diagnosed inhalant allergy and asthma (OR range, 0.89-0.86; 95% CI range, 0.80-0.99 to 0.73-1.02). No associations of stool microbiota with lung function were observed. CONCLUSIONS: The diversity, relative abundance and functional pathways of stool microbiota were most consistently associated with physician-diagnosed inhalant allergy in school-age children and less consistently with other atopic diseases.
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Bacterias , Eccema , Heces/microbiología , Microbioma Gastrointestinal/inmunología , Hipersensibilidad , Bacterias/clasificación , Bacterias/genética , Bacterias/inmunología , Niño , Estudios Transversales , Eccema/inmunología , Eccema/microbiología , Eccema/patología , Femenino , Humanos , Hipersensibilidad/inmunología , Hipersensibilidad/microbiología , Hipersensibilidad/patología , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: An association has been reported between early life Staphylococcus aureus nasal carriage and higher risk of childhood eczema, but it is unclear whether this relationship is causal and associations with other bacterial species are unclear. OBJECTIVE: To examine the associations of early life nasal and nasopharyngeal bacterial carriage with eczema phenotypes, and the direction of any associations identified. METHODS: Among 996 subjects of a population-based prospective cohort study, nasal swabs for Staphylococcus aureus, and nasopharyngeal swabs for Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae were collected and cultured from age 6 weeks to 6 years. Never, early, mid-, late transient and persistent eczema phenotypes were identified from parental-reported physician-diagnosed eczema from age 6 months until 10 years. Multinomial regression models and cross-lagged models were applied. RESULTS: Staphylococcus aureus nasal carriage at 6 months was associated with an increased risk of early transient and persistent eczema (OR (95% CI): 2.69 (1.34, 5.39) and 4.17 (1.12, 15.51)). The associations between Staphylococcus aureus nasal carriage and eczema were mostly cross-sectional, and not longitudinal. No associations of Staphylococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenza nasopharyngeal bacterial carriage with eczema and eczema phenotypes were observed (OR range (95% CI): 0.71 (0.35, 1.44) to 1.77 (0.84, 3.73)). CONCLUSIONS: Early life Staphylococcus aureus nasal carriage, but not Staphylococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenza nasopharyngeal carriage, was associated with early transient and persistent eczema. Staphylococcus aureus nasal carriage and eczema were mostly cross-sectionally associated, and not longitudinally, making a causal relationship in either direction unlikely.
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Portador Sano/epidemiología , Dermatitis Atópica/epidemiología , Nasofaringe/microbiología , Nariz/microbiología , Portador Sano/microbiología , Niño , Preescolar , Dermatitis Atópica/fisiopatología , Femenino , Haemophilus influenzae/aislamiento & purificación , Humanos , Lactante , Masculino , Moraxella catarrhalis/aislamiento & purificación , Staphylococcus aureus/aislamiento & purificación , Streptococcus pneumoniae/aislamiento & purificaciónRESUMEN
BACKGROUND: Cardio-metabolic risk factors might have an adverse effect on respiratory outcomes, but associations in children are unknown. We aimed to study the longitudinal associations of cardio-metabolic risk factors with lung function and asthma at school age. We also examined whether any association was explained by child's body mass index (BMI). METHODS: In a population-based cohort study among 4988 children, cardio-metabolic risk factors were measured at 6 and 10 years and included blood pressure, cholesterol, triglycerides, insulin, and C-reactive protein (CRP) concentrations. At age 10 years, lung function was measured by spirometry and current physician-diagnosed asthma was assessed by questionnaire. RESULTS: After adjustment for confounders, child's BMI, and multiple testing, we observed that a higher diastolic blood pressure at the age of 6 years was associated with a higher forced vital capacity (FVC) at the age of 10 years (Z-score difference (95% CI): 0.05 (0.01, 0.08), per SDS increase in diastolic blood pressure). Also, child's CRP concentrations above the 75th percentile at both ages 6 and 10 years were related to a lower FVC as compared to CRP concentrations below the 75th percentile at both ages (Z-score difference (95% CI) -0.21 (-0.36, -0.06)). No consistent associations of other cardio-metabolic risk factors with respiratory outcomes were observed. CONCLUSION: Blood pressure and CRP, but not lipids and insulin, were associated with lower lung function but not with asthma. The underlying mechanisms and long-term effects of these associations require further investigation.
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Asma , Asma/epidemiología , Índice de Masa Corporal , Niño , Estudios de Cohortes , Humanos , Pulmón , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Mutations in the filaggrin gene (FLG) affect epidermal barrier function and increase the risk of atopic dermatitis (AD). We hypothesized that FLG mutations affect immune cell composition in a general pediatric population. Therefore, we investigated whether school-aged children with and without FLG mutations have differences in T- and B-cell subsets. METHODS: This study was embedded in a population-based prospective cohort study, the Generation R Study, and included 523 children of European genetic ancestry aged 10 years. The most common FLG mutations in the European population (R501X, S1085CfsX36, R2447X, and S3247X) were genotyped. Additionally, 11-color flow cytometry was performed on peripheral blood samples to determine helper T (Th), regulatory T (Treg), and CD27+ and CD27- memory B cells. Subset analysis was performed in 358 non-AD and 102 AD cases, assessed by parental questionnaires. RESULTS: FLG mutations were observed in 8.4% of the total population and in 15.7% of the AD cases. Children with any FLG mutation had higher Th22 cell numbers compared to FLG wild-type children in the general and non-AD population. Children with and without FLG mutations had no difference in Th1, Th2, Th17, Treg, or memory B-cell numbers. Furthermore, in children with AD, FLG mutation carriership was not associated with differences in T- and B-cell subsets. CONCLUSIONS: School-aged children of a general population with FLG mutations have higher Th22 cell numbers, which reflects the immunological response to the skin barrier dysfunction. FLG mutations did not otherwise affect the composition of the adaptive immunity in this general pediatric population.
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Haploinsuficiencia , Proteínas de Filamentos Intermediarios , Recuento de Células , Niño , Proteínas Filagrina , Predisposición Genética a la Enfermedad , Humanos , Proteínas de Filamentos Intermediarios/genética , Mutación , Estudios ProspectivosRESUMEN
Rationale: Obesity has been implicated as a pathogenic factor in asthma, but the underlying role of general and organ fat is unclear.Objectives: We hypothesized that organ fat, rather than the total fat mass, increases the risk of asthma.Methods: In a population-based prospective cohort study among 5,421 children aged 10 years, we measured general fat including body mass index and fat mass index by dual-energy X-ray absorptiometry, and organ fat including subcutaneous fat index, visceral fat index, pericardial fat index, and liver fat fraction by magnetic resonance imaging. Lung function was measured by spirometry. Current asthma was assessed by questionnaire.Measurements and Main Results: Higher body mass index and fat mass index were associated with higher FEV1 (z-score difference [95% confidence interval (CI)], 0.16 [0.14 to 0.19] and z-score difference [95% CI], 0.06 [0.03 to 0.09] per SD score increase, respectively), higher FVC (z-score difference [95% CI], 0.19 [0.17 to 0.22] and z-score difference [95% CI], 0.07 [0.04 to 0.10]), and lower FEV1/FVC ratio (z-score difference [95% CI], -0.07 [-0.10 to -0.05] and z-score difference [95% CI], -0.03 [-0.06 to -0.00]) but not with forced expiratory flow after exhaling 75% of FVC or asthma. Higher visceral fat index, independent of fat mass index, was associated with higher FVC (z-score difference [95% CI], 0.07 [0.03 to 0.10]), lower FEV1/FVC (z-score difference [95% CI], -0.05 [-0.09 to -0.01]), and higher risk of asthma (odds ratio, 1.20; 95% CI, 1.01 to 1.43 per SD score increase). No other organ fat measures were independently associated with lung function or asthma.Conclusions: The obesity-asthma link is driven mainly by visceral fat, independent of total fat mass; therefore, abdominal fat might contribute to asthma development.
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Tejido Adiposo/diagnóstico por imagen , Asma/epidemiología , Imagen por Resonancia Magnética , Asma/etiología , Niño , Femenino , Humanos , Masculino , Estudios Prospectivos , Medición de RiesgoRESUMEN
BACKGROUND: Although maternal psychological distress during pregnancy is associated with increased risks of respiratory morbidity in preschool children, it is unknown whether this association persists into later childhood. OBJECTIVE: To examine the association between parental psychological distress during pregnancy and lung function and asthma in children of school age. METHODS: This study of 4231 children was embedded in a population-based prospective cohort. Parental psychological distress was assessed by the Brief Symptom Inventory during and 3 years after pregnancy, and in mothers also at 2 and 6 months after pregnancy. At age 10 years, lung function was obtained by spirometry and asthma by questionnaire. RESULTS: The prevalence of asthma was 5.9%. Maternal overall psychological distress during pregnancy was associated with a lower forced vital capacity (FVC) (z-score difference -0.10 (95% CI -0.20 to -0.01) per 1-unit increase), maternal depressive symptoms during pregnancy with a lower forced expiratory volume in the first second (FEV1) and FVC (-0.13 (95% CI -0.24 to -0.01) and -0.13 (95% CI -0.24 to -0.02) when using clinical cut-offs) in their children. All maternal psychological distress measures during pregnancy were associated with an increased risk of asthma (range OR: 1.46 (95% CI 1.12 to 1.90) to 1.91 (95% CI 1.26 to 2.91)). Additional adjustment for paternal psychological distress during pregnancy and parental psychological distress after pregnancy did not materially change the associations. Paternal psychological distress during pregnancy was not associated with childhood respiratory morbidity. CONCLUSION: Maternal, but not paternal, psychological distress during pregnancy is associated with an increased risk of asthma and partly lower lung function in children. This suggests intrauterine programming for the risk of later-life respiratory disease.
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Asma/epidemiología , Depresión/psicología , Pulmón/fisiopatología , Madres/psicología , Complicaciones del Embarazo/psicología , Distrés Psicológico , Adulto , Niño , Padre/psicología , Femenino , Volumen Espiratorio Forzado , Encuestas Epidemiológicas , Humanos , Masculino , Embarazo , Prevalencia , Estudios Prospectivos , Capacidad VitalRESUMEN
INTRODUCTION: Chlamydia trachomatis is the most commonly reported sexually transmitted disease and although infection during pregnancy is associated with neonatal complications, long-term respiratory consequences are unknown. We aimed to determine whether C. trachomatis infection during pregnancy is associated with asthma-related symptoms across childhood METHODS: This study among 2475 children and their mothers was embedded in a population-based prospective cohort study. Maternal urine samples were tested for C. trachomatis infection during pregnancy. Questionnaires provided information on childhood physician-attended lower respiratory tract infections and wheezing, and current asthma at age 10â years. Lung function was measured by spirometry at age 10â years. RESULTS: The prevalence of C. trachomatis infection during pregnancy was 3.2% (78 out of 2475). C. trachomatis infection during pregnancy was not associated with lower respiratory tract infections until age 6â years, but was associated with a higher odds of wheezing in children until age 10â years (OR 1.50 (95% CI 1.10-2.03)). C. trachomatis infection during pregnancy was associated with an increased odds of asthma (OR 2.29 (95% CI 1.02-5.13)), and with a lower forced expiratory volume in 1â s/forced vital capacity and forced expiratory flow at 75% of forced vital capacity (z-score difference -0.28 (95% CI -0.52-â-0.04) and -0.24 (95% CI -0.46-â-0.01), respectively) in children at age 10â years. The observed associations were only partly explained by mode of delivery, gestational age at birth or birthweight. CONCLUSIONS: C. trachomatis infection during pregnancy is associated with increased odds of wheezing, asthma and impaired lung function. The causality of the observed associations and potential underlying mechanisms need to be explored.
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Asma , Chlamydia trachomatis , Asma/epidemiología , Niño , Estudios de Cohortes , Femenino , Humanos , Recién Nacido , Morbilidad , Embarazo , Estudios ProspectivosRESUMEN
INTRODUCTION: Exhaled nitric oxide fraction (F ENO), a biomarker of eosinophilic airway inflammation, may be useful to guide asthma treatment. F ENO-guided treatment may be more effective in certain subgroups for improving asthma outcomes compared to standard treatment. METHODS: An individual patient data analysis was performed using data from seven randomised clinical trials (RCTs) which used F ENO to guide asthma treatment. The incidence of an asthma exacerbation and loss of control, and the time to first exacerbation and loss of control were described between five subgroups of RCT participants. RESULTS: Data were available in 1112 RCT participants. Among those not treated with leukotriene receptor antagonists (LTRA), but not among those who were treated with LTRA, F ENO-guided treatment was associated with reduced exacerbation risk (OR 0.68, 95% CI 0.49-0.94), longer time to first exacerbation (hazard ratio (HR) 0.76, 95% CI 0.57-0.99) and borderline reduced risk for loss of control (OR 0.70, 95% CI 0.49-1.00). Nonobese children, compared to obese children, were less likely to lose asthma control when treatment was guided by F ENO (OR 0.69, 95% CI 0.48-0.99) and time to loss of control was longer (HR 0.77, 95% CI 0.61-0.99). CONCLUSIONS: Asthma treatment guided by F ENO may be more effective in achieving better asthma outcomes for patients who are not treated with LTRA and who are not obese, compared to standard practice.
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Asma/fisiopatología , Óxido Nítrico/metabolismo , Adolescente , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Biomarcadores/metabolismo , Pruebas Respiratorias , Niño , Femenino , Volumen Espiratorio Forzado , Humanos , Estimación de Kaplan-Meier , Antagonistas de Leucotrieno/uso terapéutico , Masculino , Óxido Nítrico/análisis , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy.
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Antiasmáticos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Niño , Preescolar , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Farmacogenómica , Fenotipo , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection are common in early childhood. CMV infection favours a T-helper-1 and EBV infection a T-helper-2 cell response, possibly leading to disbalanced T-helper cell response, and subsequent risk of asthma or atopy. OBJECTIVE: To study the associations of EBV and CMV with lung function, asthma and inhalant allergic sensitization at school age. METHODS: This study among 3546 children was embedded in a population-based prospective cohort. At age 6 years, serum IgG levels against EBV and CMV were measured by ELISA. At age 10 years, lung function was measured by spirometry, asthma by questionnaire and inhalant allergic sensitization by skin prick test. RESULTS: Unadjusted models showed that seropositivity for EBV was associated with a higher FEV1 and FEF75 (Z-score difference (95% CI): 0.09 (0.02, 0.16) and 0.09 (0.02, 0.15)), while seropositivity for CMV was not. Specific combinations of viruses showed that seropositivity for EBV was only associated with FEV1 and FEF75 in the presence of seropositivity for CMV (0.12 (0.04, 0.20)) and 0.08 (0.01, 0.15)). Seropositivity for CMV in the absence of seropositivity for EBV was associated with an increased risk of inhalant allergic sensitization (OR (95% CI): 1.31 (1.02, 1.68)). All effect estimates attenuated into non-significant mainly after adjustment for child's ethnicity. Seropositivity for EBV or CMV was not associated with asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Associations of EBV and CMV infections in early childhood with school-age lung function and inhalant allergic sensitization are explained by ethnicity, or sociodemographic and lifestyle-related factors.
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Asma , Infecciones por Citomegalovirus , Citomegalovirus/inmunología , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4/inmunología , Adulto , Asma/etiología , Asma/inmunología , Asma/fisiopatología , Niño , Preescolar , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/fisiopatología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Estudios Prospectivos , Pruebas de Función RespiratoriaRESUMEN
BACKGROUND: We aimed to assess which sociodemographic factors are associated with current asthma and indicators of lung function in 10-year-old children. METHODS: We analysed data of 5237 children (Mean age: 9.7, SD: 0.3) from the Generation R Study (2012-2016), a population-based cohort study in the Netherlands. Indicators of sociodemographic factors included parental educational level, net household income, financial difficulties, parental employment status and child ethnic background. Current asthma (yes/no) was defined as ever doctor-diagnosed-asthma combined with wheezing symptoms or asthma-medication use in the past 12 months. Lung function was measured by spirometry and included forced expiratory volume in 1 second (FEV1 ), forced vital capacity (FVC), FEV1 /FVC, and forced expiratory flow after exhaling 75% of FVC (FEF75 ). Within-study sex-, height- and age-adjusted lung function measurements' z-scores were converted. RESULTS: After adjustment for all sociodemographic factors, an independent association was observed between ethnic background with current asthma and lung function. Compared with children with a Dutch background, children with a nonwestern ethnic background had a higher odds of having current asthma (OR: 1.61, 95% CI: 1.02, 2.53), lower FVC z-score (-0.25, 95% CI: -0.35, -0.14), higher FEV1 /FVC z-score (0.26, 95% CI: 0.14, 0.37) and higher FEF75% z-score (0.15, 95% CI: 0.04, 0.25). CONCLUSIONS: Among 10-year-old children, ethnic background was associated with current asthma and lung function after adjusting for a wide range of sociodemographic factors. No associations were found between socioeconomic status indicators and current asthma. Explanations for these associations such as language barriers, suboptimal care or pathophysiological differences require further investigation.
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Asma/epidemiología , Empleo , Etnicidad , Renta , Asma/etnología , Asma/fisiopatología , Niño , Escolaridad , Femenino , Flujo Espiratorio Forzado , Volumen Espiratorio Forzado , Humanos , Masculino , Países Bajos/epidemiología , Padres , Factores Socioeconómicos , Población Urbana , Capacidad VitalRESUMEN
BACKGROUND: New insights into immune cells could contribute to treatment and monitoring of atopic disease. Because nongenetic factors shape the human immune system, we here studied these immune cells in a large cohort with atopic children with adjustment for prenatal and postnatal confounders. METHODS: Information on atopic dermatitis, inhalant- and food-allergic sensitization, asthma lung function scores was obtained from 855 10-year-old children within the Generation R cohort. 11-color flow cytometry was performed to determine CD27+ and CD27- IgG+ , IgE+ and IgA+ memory B cells, Th1, Th2, Th17, and Treg-memory cells from venous blood. Associations between any atopic disease, the individual atopic diseases, and immune cell numbers were determined. RESULTS: Children with any atopic disease had higher Th2, Treg, Treg-memory, and CD27+ IgA+ memory B-cell numbers compared to children without atopic disease. When studying the individual diseases compared to children without the individual diseases, children with atopic dermatitis, inhalant-, and food-allergic sensitization had higher memory Treg cell numbers 12.3% (95% CI 4.2; 21.0), (11.1% (95% CI 3.0; 19.8), (23.7% (95% CI 7.9; 41.8), respectively. Children with food-allergic sensitization had higher total B and CD27+ IgA+ memory B-cell numbers (15.2% [95% CI 3.2; 28.7], 22.5% [95% CI 3.9; 44.3], respectively). No associations were observed between asthma and B- or T-cell numbers. CONCLUSION: Children with any atopic disease and children with inhalant- and food-allergic sensitization or atopic dermatitis had higher circulating memory Treg cells, but not higher IgE+ B-cell numbers. The associations of higher Treg and CD27+ IgA+ B-cell numbers in children with food-allergic sensitization are suggestive of TGF-ß-mediated compensation for chronic inflammation.
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Subgrupos de Linfocitos B/inmunología , Hipersensibilidad/inmunología , Inmunoglobulina A/inmunología , Memoria Inmunológica/inmunología , Subgrupos de Linfocitos T/inmunología , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Células Th2/inmunologíaRESUMEN
BACKGROUND: Airway bacterial carriage might play a role in respiratory disease. We hypothesize that nasal carriage with Staphylococcus aureus or nasopharyngeal carriage with Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae predisposes individuals to adverse respiratory health. OBJECTIVE: To examine the association of early-life airway bacterial carriage with respiratory tract infections and vice versa, and of early-life airway bacterial carriage with wheezing, lung function, and asthma in later childhood. METHODS: We collected upper airway swabs for bacterial culturing for S aureus, H influenzae, M catarrhalis, and H influenzae at six timepoints between the ages of 6 weeks and 6 years among 945 children participating in a population-based prospective cohort study. Information on respiratory tract infections and wheezing until age 6 years, and asthma at age 10 years was obtained by questionnaires. Lung function at age 10 years was measured by spirometry. We tested possible bidirectional associations between airway bacterial carriage and respiratory tract infections by cross-lagged models, and associations of repeatedly measured airway bacterial carriage with wheezing, lung function, and asthma by generalized estimating equations models and regression models. RESULTS: Cross-lagged modeling showed that early-life airway bacterial carriage was not consistently associated with upper and lower respiratory tract infections or vice versa. Nasopharyngeal carriage with any bacteria in infancy was associated with an increased risk of wheezing (OR [95% CI]: 1.66 [1.31, 2.10]). Airway bacterial carriage was not consistently associated with school-age lung function or asthma. CONCLUSION: Nasopharyngeal carriage with any bacteria is associated with wheezing, but not respiratory tract infections, asthma, or lung function.
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Bacterias/aislamiento & purificación , Portador Sano/microbiología , Cavidad Nasal/microbiología , Nasofaringe/microbiología , Infecciones del Sistema Respiratorio/epidemiología , Asma/epidemiología , Niño , Preescolar , Estudios de Cohortes , Femenino , Haemophilus influenzae/aislamiento & purificación , Humanos , Lactante , Masculino , Moraxella catarrhalis/aislamiento & purificación , Estudios Prospectivos , Pruebas de Función Respiratoria/métodos , Ruidos Respiratorios/etiología , Espirometría/métodos , Staphylococcus aureus/aislamiento & purificación , Streptococcus pneumoniae/aislamiento & purificación , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Fetal changes in DNA methylation may underlie associations of maternal smoking during pregnancy with adverse outcomes in children. We examined critical periods and doses of maternal smoking during pregnancy in relation to newborn DNA methylation, and associations of paternal smoking with newborn DNA methylation. AIMS AND METHODS: This study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We assessed parental smoking during pregnancy using questionnaires. We analyzed associations of prenatal smoke exposure with newborn DNA methylation at 5915 known maternal smoking-related cytosine-phosphate-guanine sites (CpGs) in 1261 newborns using linear regression. Associations with false discovery rate-corrected p-values < .05 were taken forward. RESULTS: Sustained maternal smoking was associated with newborn DNA methylation at 1391 CpGs, compared with never smoking. Neither quitting smoking early in pregnancy nor former smoking was associated with DNA methylation, compared with never smoking. Among sustained smokers, smoking ≥5, compared with <5, cigarettes/d was associated with DNA methylation at seven CpGs. Paternal smoking was not associated with DNA methylation, independent of maternal smoking status. CONCLUSIONS: Our results suggest that CpGs associated with sustained maternal smoking are not associated with maternal smoking earlier in pregnancy or with paternal smoking. Some of these CpGs show dose-response relationships with sustained maternal smoking. The third trimester may comprise a critical period for associations of smoking with newborn DNA methylation, or sustained smoking may reflect higher cumulative doses. Alternatively, maternal smoking limited to early pregnancy and paternal smoking may be associated with DNA methylation at specific other CpGs not studied here. IMPLICATIONS: Our results suggest that quitting maternal smoking before the third trimester of pregnancy, and possibly lowering smoking dose, may prevent differential DNA methylation in the newborns at CpGs associated with sustained smoking. If the relevance of DNA methylation for clinical outcomes is established, these results may help in counseling parents-to-be about quitting smoking.
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Metilación de ADN , Exposición Materna , Fumar , Femenino , Humanos , Recién Nacido , Embarazo , Efectos Tardíos de la Exposición Prenatal , Estudios Prospectivos , Factores de TiempoRESUMEN
RATIONALE: We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. METHODS: We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1â s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7-13â years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. RESULTS: We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. INTERPRETATION: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.