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BACKGROUND: Risk factors of asthma-like symptoms in childhood may act through an increased infection burden because infections often trigger these symptoms. OBJECTIVE: We sought to investigate whether the effect of established risk factors of asthma-like episodes in early childhood is mediated through burden and subtypes of common infections. METHODS: The study included 662 children from the Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort, in which infections were registered prospectively in daily diaries from age 0 to 3 years. The association between established risk factors of asthma-like episodes and infection burden was analyzed by quasi-Poisson regressions, and mediation analyses were performed for significant risk factors. RESULTS: In the first 3 years of life, the children experienced a median of 16 (interquartile range, 12-23) infectious episodes. We found that the infection burden significantly (PACME < .05) mediated the association of maternal asthma (36.6% mediated), antibiotics during pregnancy (47.3%), siblings at birth (57.7%), an asthma exacerbation polygenic risk score (30.6%), and a bacterial airway immune score (80.2%) with number of asthma-like episodes, whereas the higher number of episodes from male sex, low birth weight, low gestational age, and maternal antibiotic use after birth was not mediated through an increased infection burden. Subtypes of infections driving the mediation were primarily colds, pneumonia, gastroenteritis, and fever, but not acute otitis media or acute tonsillitis. CONCLUSIONS: Several risk factors of asthma-like symptoms in early childhood act through an increased infection burden in the first 3 years of life. Prevention of infectious episodes may therefore be beneficial to reduce the burden of asthma-like symptoms in early childhood.
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Asma , Neumonía , Recién Nacido , Femenino , Embarazo , Humanos , Masculino , Preescolar , Lactante , Estudios Prospectivos , Asma/etiología , Factores de Riesgo , Antibacterianos/uso terapéutico , Neumonía/tratamiento farmacológico , Ruidos RespiratoriosRESUMEN
BACKGROUND: Eicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs), and leukotrienes with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. This study aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease. METHODS: This study quantified the levels of 21 eicosanoids in urine from children from the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) (age 1 year, n = 450) and VDAART (Vitamin D Antenatal Asthma Reduction Trial) (age 3 years, n = 575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of type-2 inflammation, applying false discovery rate of 5% (FDR5%) multiple testing correction. RESULTS: In both cohorts, analyses adjusted for environmental determinants showed that higher TXA2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P < FDR5%) and type-2 inflammation (P < .05). In VDAART, lower PGE2 and PGI2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P < FDR5%). For wheeze/asthma, analyses in COPSAC2010 showed that lower isoprostanes and PGF2 eicosanoids and higher PGD2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (P < .05), whereas analyses in VDAART showed that lower PGE2 and higher TXA2 eicosanoids at age 3 years associated with an increased risk at 6 years (P < FDR5%). CONCLUSIONS: This study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases.
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BACKGROUND: Analysis of time-resolved postprandial metabolomics data can improve the understanding of metabolic mechanisms, potentially revealing biomarkers for early diagnosis of metabolic diseases and advancing precision nutrition and medicine. Postprandial metabolomics measurements at several time points from multiple subjects can be arranged as a subjects by metabolites by time points array. Traditional analysis methods are limited in terms of revealing subject groups, related metabolites, and temporal patterns simultaneously from such three-way data. RESULTS: We introduce an unsupervised multiway analysis approach based on the CANDECOMP/PARAFAC (CP) model for improved analysis of postprandial metabolomics data guided by a simulation study. Because of the lack of ground truth in real data, we generate simulated data using a comprehensive human metabolic model. This allows us to assess the performance of CP models in terms of revealing subject groups and underlying metabolic processes. We study three analysis approaches: analysis of fasting-state data using principal component analysis, T0-corrected data (i.e., data corrected by subtracting fasting-state data) using a CP model and full-dynamic (i.e., full postprandial) data using CP. Through extensive simulations, we demonstrate that CP models capture meaningful and stable patterns from simulated meal challenge data, revealing underlying mechanisms and differences between diseased versus healthy groups. CONCLUSIONS: Our experiments show that it is crucial to analyze both fasting-state and T0-corrected data for understanding metabolic differences among subject groups. Depending on the nature of the subject group structure, the best group separation may be achieved by CP models of T0-corrected or full-dynamic data. This study introduces an improved analysis approach for postprandial metabolomics data while also shedding light on the debate about correcting baseline values in longitudinal data analysis.
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Medicina , Metabolómica , Humanos , Simulación por Computador , Análisis de Datos , Estado de SaludRESUMEN
BACKGROUND: Infections in childhood remain a leading global cause of child mortality and environmental exposures seem crucial. We investigated whether urbanicity at birth was associated with the risk of infections and explored underlying mechanisms. METHODS: Children (n=633) from the COPSAC2010 mother-child cohort were monitored daily with symptom diaries of infection episodes during the first 3 years and prospectively diagnosed with asthma until age 6 years. Rural and urban environments were based on the CORINE land cover database. Child airway immune profile was measured at age 4 weeks. Maternal and child metabolomics profiling were assessed at pregnancy week 24 and at birth, respectively. RESULTS: We observed a mean (SD) total number of infections of 16.3 (8.4) consisting mainly of upper respiratory infections until age 3 years. Urban versus rural living increased infection risk (17.1 (8.7) vs 15.2 (7.9), adjusted incidence rate ratio; 1.15 (1.05-1.26), p=0.002) and altered the child airway immune profile, which increased infection risk (principal component 1 (PC1): 1.03 (1.00-1.06), p=0.038 and PC2: 1.04 (1.01-1.07), p=0.022). Urban living also altered the maternal and child metabolomic profiles, which also increased infection risk. The association between urbanicity and infection risk was partly mediated through the maternal metabolomic and child airway immune profiles. Finally, urbanicity increased the risk of asthma by age 6 years, which was mediated through early infection load (pACME<0.001). CONCLUSION: This study suggests urbanicity as an independent risk factor for early infections partly explained by changes in the early metabolic and immunological development with implications for later risk of asthma.
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BACKGROUND: We previously showed an association between neonatal bacterial airway colonisation and increased risk of persistent wheeze/asthma until age 5â years. Here, we study the association with persistent wheeze/asthma and allergy-related traits until age 18â years. METHODS: We investigated the association between airway colonisation with Streptococcus pneumoniae, Moraxella catarrhalis and/or Haemophilus influenzae in 1-month-old neonates from the COPSAC2000 mother-child cohort and the development of persistent wheeze/asthma and allergy-related traits longitudinally until age 18â years using generalised estimating equations. Replication was sought in the similarly designed COPSAC2010 cohort of 700 children. RESULTS: Neonatal airway colonisation was present in 66 (21%) out of 319 children and was associated with a 4-fold increased risk of persistent wheeze/asthma (adjusted OR 4.01 (95% CI 1.76-9.12); p<0.001) until age 7â years, but not from age 7 to 18â years. Replication in the COPSAC2010 cohort showed similar results using 16S data. Colonisation was associated with an increased number of exacerbations (adjusted incidence rate ratio 3.20 (95% CI 1.38-7.44); p<0.01) until age 7â years, but not from age 7 to 18â years. Colonisation was associated with increased levels of blood eosinophils (adjusted geometric mean ratio 1.24 (95% CI 1.06-1.44); p<0.01) and tumour necrosis factor (TNF)-α (adjusted geometric mean ratio 1.09 (95% CI 1.02-1.16); p=0.01) until age 12â years. There were no associations with lung function, bronchial reactivity, fractional exhaled nitric oxide, allergic sensitisation, total IgE or atopic dermatitis up to age 18â years. CONCLUSIONS: Neonatal airway colonisation was associated with early-onset persistent wheeze/asthma, exacerbations, elevated blood eosinophils and elevated TNF-α in blood, most prominent in early childhood, thereafter diminishing and no longer evident by age 18â years.
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Asma , Dermatitis Atópica , Hipersensibilidad , Recién Nacido , Humanos , Preescolar , Adolescente , Niño , Lactante , Asma/etiología , Hipersensibilidad/complicaciones , Sistema Respiratorio , Dermatitis Atópica/complicaciones , Streptococcus pneumoniae , Ruidos Respiratorios/etiologíaRESUMEN
BACKGROUND: High BMI is an established risk factor for asthma, but the underlying mechanisms remain unclear.Objective: To increase understanding of the BMI-asthma relationship by studying the association between genetic predisposition to higher body mass index (BMI) and asthma, infections, and other asthma-traits during childhood. METHODS: Data was obtained from the two ongoing COPSAC mother-child cohorts. Polygenic risk score (PRS) for adult BMI were calculated for each child. Replication was done in the large-scale iPSYCH cohort using data on hospitalization for asthma and infections. RESULTS: In the COPSAC cohorts (n=974), the adult BMI PRS was significantly associated with lower respiratory tract infections (LRTI) (IRR 1.20 95% CI 1.08-1.33, FDR=0.005) age 0-3â years and episodes of severe wheeze (IRR 1.30, 1.06-1.60, FDR=0.04) age 0-6â years. LRTI partly mediated the association between the adult BMI PRS and severe wheeze (proportion mediated: 0.59, 0.28-2.24, pACME 2E-16). In contrast, these associations were not mediated through the child's current BMI and the PRS was not associated with an asthma diagnosis or reduced lung function up to age 18. The associations were replicated in iPSYCH (n=114 283), where the adult BMI PRS significantly increased the risk of hospitalizations for LRTI and wheeze or asthma during childhood to age 18â years. CONCLUSION: Children with genetic predisposition to higher BMI had increased risk of LRTI and severe wheeze, independent of the child's current BMI. These results shed further light on the complex relationship between BMI and asthma.
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INTRODUCTION: Analysis of time-resolved postprandial metabolomics data can improve our understanding of the human metabolism by revealing similarities and differences in postprandial responses of individuals. Traditional data analysis methods often rely on data summaries or univariate approaches focusing on one metabolite at a time. OBJECTIVES: Our goal is to provide a comprehensive picture in terms of the changes in the human metabolism in response to a meal challenge test, by revealing static and dynamic markers of phenotypes, i.e., subject stratifications, related clusters of metabolites, and their temporal profiles. METHODS: We analyze Nuclear Magnetic Resonance (NMR) spectroscopy measurements of plasma samples collected during a meal challenge test from 299 individuals from the COPSAC2000 cohort using a Nightingale NMR panel at the fasting and postprandial states (15, 30, 60, 90, 120, 150, 240 min). We investigate the postprandial dynamics of the metabolism as reflected in the dynamic behaviour of the measured metabolites. The data is arranged as a three-way array: subjects by metabolites by time. We analyze the fasting state data to reveal static patterns of subject group differences using principal component analysis (PCA), and fasting state-corrected postprandial data using the CANDECOMP/PARAFAC (CP) tensor factorization to reveal dynamic markers of group differences. RESULTS: Our analysis reveals dynamic markers consisting of certain metabolite groups and their temporal profiles showing differences among males according to their body mass index (BMI) in response to the meal challenge. We also show that certain lipoproteins relate to the group difference differently in the fasting vs. dynamic state. Furthermore, while similar dynamic patterns are observed in males and females, the BMI-related group difference is observed only in males in the dynamic state. CONCLUSION: The CP model is an effective approach to analyze time-resolved postprandial metabolomics data, and provides a compact but a comprehensive summary of the postprandial data revealing replicable and interpretable dynamic markers crucial to advance our understanding of changes in the metabolism in response to a meal challenge.
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Metabolómica , Periodo Posprandial , Humanos , Periodo Posprandial/fisiología , Masculino , Femenino , Metabolómica/métodos , Adulto , Ayuno/metabolismo , Análisis de Componente Principal , Espectroscopía de Resonancia Magnética/métodos , Persona de Mediana Edad , Análisis de Datos , Metaboloma/fisiologíaRESUMEN
BACKGROUND: Infantile colic is a common condition with limited knowledge about later clinical manifestations. We evaluated the role of the early life gut microbiome in infantile colic and later development of atopic and gastrointestinal disorders. METHODS: Copenhagen Prospective Studies on Asthma in Childhood2010 cohort was followed with 6 years of extensive clinical phenotyping. The 1-month gut microbiome was analyzed by 16S rRNA sequencing. Infantile colic was evaluated at age 3 months by interviews. Clinical endpoints included constipation to age 3 years and prospectively diagnosed asthma and atopic dermatitis in the first 6 years of life, and allergic sensitization from skin prick tests, specific Immunoglobulin E, and component analyses. RESULTS: Of 695 children, 55 children (7.9%) had infantile colic. Several factors were associated with colic including race, breastfeeding, and pets. The 1-month gut microbiome composition and taxa abundances were not associated with colic, however a sparse Partial Least Squares model including combined abundances of nine species was moderately predictive of colic: median, cross-validated AUC = 0.627, p = .003. Children with infantile colic had an increased risk of developing constipation (aOR, 2.88 [1.51-5.35], p = .001) later in life, but also asthma (aHR, 1.69 [1.02-2.79], p = .040), atopic dermatitis (aHR, 1.84 [1.20-2.81], p = .005) and had a higher number of positive allergic components (adjusted difference, 116% [14%-280%], p = .012) in the first 6 years. These associations were not mediated by gut microbiome differences. CONCLUSIONS: We link infantile colic with risk of developing constipation and atopic disorders in the first 6 years of life, which was not mediated through an altered gut microbiome at age 1-month. These results suggest infantile colic to involve gastrointestinal and/or atopic mechanisms.
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BACKGROUND: While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship. METHODS: We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta-analyzed together. RESULTS: We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p-value range: 1.863E-04 to 2.24E-3], increased ceramide levels were associated with asthma risk factors [meta p-value range: 7.75E-5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes. CONCLUSION: This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.
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Asma , Esfingolípidos , Niño , Humanos , Esfingolípidos/metabolismo , Cromatografía Liquida , Espectrometría de Masas en Tándem , Ceramidas/metabolismo , Asma/etiología , Asma/genética , Factores de RiesgoRESUMEN
INTRODUCTION: Maternal inflammation during pregnancy may affect early neurodevelopment in offspring as suggested by preclinical and register data. However, clinical evidence for risk of aberrant neurodevelopment later in childhood is scarce. In the population-based COPSAC2010 mother-child cohort, we investigated associations between maternal inflammation levels during pregnancy and the risk of a diagnosis of ADHD as well as the load of ADHD symptoms in the children at age 10. METHODS: The COPSAC2010 cohort consists of 700 mother-child pairs followed prospectively since pregnancy week 24.Maternal high-sensitivity C-Reactive Protein (hs-CRP) level at week 24 of gestation was investigated in relation to child neurodevelopment by age 10 using logistic and linear regression models with extensive confounder adjustment, including socioeconomic status and maternal polygenic risk of ADHD. The children completed a comprehensive examination of neurodevelopment including categorical (i.e., diagnostic) and dimensional (i.e., symptom load) psychopathology using the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) and parental rated ADHD-Rating Scale (ADHD-RS). RESULTS: A total of 604 (86 %) of the 700 children in the COPSAC2010 cohort participated in the COPSYCH visit at age 10. Sixty-five (10.8 %) fulfilled a research diagnosis of ADHD (16 girls and 49 boys). Higher maternal hs-CRP level in pregnancy at week 24 (median 5.4 mg/L) was significantly associated with increased risk for a diagnosis of ADHD, adjusted OR 1.40, 95 %CI (1.16-1.70), p = 0.001. Additionally, higher maternal hs-CRP was associated with increased ADHD symptom load in the entire cohort, reflected by ADHD-RS raw scores. DISCUSSION: These clinical data demonstrated a robust association of prenatal maternal inflammation assessed by hs-CRP with a diagnosis of ADHD by age 10. Moreover, maternal inflammation was associated with ADHD symptom load in the complete cohort. Identifying inflammation as an important marker will provide a potential target for future increased awareness and prevention during pregnancy thereby ultimately improving neurodevelopmental outcomes in children.
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Trastorno por Déficit de Atención con Hiperactividad , Efectos Tardíos de la Exposición Prenatal , Masculino , Femenino , Embarazo , Humanos , Niño , Proteína C-Reactiva , Trastorno por Déficit de Atención con Hiperactividad/etiología , Efectos Tardíos de la Exposición Prenatal/psicología , Inflamación/complicaciones , PadresRESUMEN
Asthma is the most common chronic disease in childhood affecting the daily lives of many patients despite current treatment regimens. Therefore, the need for new therapeutic approaches is evident, where a primary prevention strategy is the ultimate goal. Studies of children born to mothers in farming environments have shown a lower risk of respiratory infections and asthma development. Already at birth, these newborns have demonstrated accelerated maturation and upregulation of host defense immune functions suggesting a prenatal transplacental training of the innate immune system through maternal microbial exposure. This mechanism could possibly be utilized to help prevent both respiratory infections and asthma in young children. Human studies exploring the potential preventative effects of pregnancy bacterial lysate treatment on asthma and respiratory infections are lacking, however, this has been studied in experimental studies using mice through administrations of the bacterial lysate OM-85. This review will present the current literature on the immunomodulatory effects relevant for respiratory infections and asthma in the offspring of mice treated with OM-85 throughout pregnancy. Further, the review will discuss the cellular and molecular mechanisms behind these effects. In conclusion, we found promising results of an accelerated immune competence and improved resistance to airway challenges as a result of prenatal bacterial lysate treatment that may pave the way for implementing this in human trials to prevent asthma and respiratory infections.
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Asma , Modelos Animales de Enfermedad , Efectos Tardíos de la Exposición Prenatal , Infecciones del Sistema Respiratorio , Animales , Asma/prevención & control , Asma/inmunología , Embarazo , Femenino , Humanos , Infecciones del Sistema Respiratorio/prevención & control , Infecciones del Sistema Respiratorio/inmunología , Ratones , Efectos Tardíos de la Exposición Prenatal/inmunología , Extractos Celulares/uso terapéutico , Lisados BacterianosRESUMEN
Preschool children with wheezing disorders pose diagnostic and therapeutic challenges and consume substantial healthcare resources. Peripheral eosinophil blood count (EBC) has been proposed as a potential indicator for future asthma development. This review by the European Academy of Allergy and Clinical Immunology (EAACI) Preschool Wheeze Task Force aimed to provide systematic evidence for the association between increased EBC and the risk of future asthma, as well as to identify potential cutoff values. In February 2023, a search of PubMed, EMBASE, and Cochrane Library databases was conducted to identify studies comparing EBCs in preschool children with wheezing who continued to wheeze later in life and those who did not. Included observational studies focused on children aged <6 years with a wheezing disorder, assessment of their EBCs, and subsequent asthma status. No language or publication date restrictions were applied. Among the initial 3394 studies screened, 10 were included in the final analysis, involving 1225 patients. The data from these studies demonstrated that high EBC in preschool children with wheezing is associated with future asthma development, with odds ratios of 1.90 (95% CI: 0.45-7.98, p = .38), 2.87 (95% CI: 1.38-5.95, p < .05), and 3.38 (95% CI: 1.72-6.64, p < .05) for cutoff values in the <300, 300-449, and ≥450 cells/µL ranges, respectively. Defining a specific cutoff point for an elevated EBC lacks consistency, but children with EBC >300 cells/µL are at increased risk of asthma. However, further research is needed due to the limitations of the included studies. Future investigations are necessary to fully elucidate the discussed association.
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Asma , Eosinófilos , Ruidos Respiratorios , Humanos , Eosinófilos/inmunología , Asma/diagnóstico , Asma/epidemiología , Preescolar , Recuento de Leucocitos , Factores de Riesgo , Lactante , Femenino , MasculinoRESUMEN
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
The Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) mother-child cohorts have provided a foundation of 25 years of research on the origins, prevention, and natural history of childhood asthma and related disorders. COPSAC's approach is characterized by clinical translational research with longitudinal deep phenotyping and exposure assessments from pregnancy, in combination with multi-omic data layers and embedded randomized controlled trials. One trial showed that fish oil supplementation during pregnancy prevented childhood asthma and identified pregnant women with the highest benefits from supplementation, thereby creating the potential for personalized prevention. COPSAC revealed that airway colonization with pathogenic bacteria in early life is associated with an increased risk of asthma. Further, airway bacteria were shown to be a trigger of acute asthma-like symptoms, with benefit from antibiotic treatment. COPSAC identified an immature gut microbiome in early life as a risk factor for asthma and allergy and further demonstrated that asthma can be predicted by infant lung function. At a molecular level, COPSAC has identified novel susceptibility genes, early immune deviations, and metabolomic alterations associated with childhood asthma. Thus, the COPSAC research program has enhanced our understanding of the processes causing childhood asthma and has suggested means of personalized prevention and treatment.
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Asma , Hipersensibilidad , Femenino , Humanos , Embarazo , Estudios Prospectivos , Investigación Biomédica Traslacional , Asma/genética , Hipersensibilidad/diagnóstico , Factores de RiesgoRESUMEN
BACKGROUND: Environmental, genetic, and microbial factors are independently associated with childhood asthma. OBJECTIVE: We sought to determine the roles of environmental exposures and 17q12-21 locus genotype in the maturation of the early-life microbiome in childhood asthma. METHODS: We analyzed fecal 16s rRNA sequencing at age 3 to 6 months and age 1 year to characterize microbial maturation of offspring of participants in the Vitamin D Antenatal Reduction Trial. We determined associations of microbial maturation and environmental exposures in the mediation of asthma risk at age 3 years. We examined 17q12-21 genotype and microbial maturation associations with asthma risk in Vitamin D Antenatal Reduction Trial and the replication cohort Copenhagen Prospective Studies on Childhood Asthma 2010. RESULTS: Accelerated fecal microbial maturation at age 3 to 6 months and delayed maturation at age 1 year were associated with asthma (P < .001). Fecal Bacteroides was reduced at age 3 to 6 months in association with subsequent asthma (P = .006) and among subjects with lower microbial maturation at age 1 year (q = 0.009). Sixty-one percent of the association between breast-feeding and asthma was mediated by microbial maturation at age 3 to 6 months. Microbial maturation and 17q12-21 genotypes exhibited independent, additive effects on childhood asthma risk. CONCLUSIONS: The intestinal microbiome and its maturation mediates associations between environmental exposures including breast-feeding and asthma. The intestinal microbiome and 17q12-21 genotype appear to exert additive and independent effects on childhood asthma risk.
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Asma , Microbioma Gastrointestinal , Humanos , Femenino , Embarazo , Lactante , Preescolar , Microbioma Gastrointestinal/genética , ARN Ribosómico 16S/genética , Estudios Prospectivos , Asma/genética , Vitamina DRESUMEN
BACKGROUND: Exposure to ambient air pollution has been linked to asthma, allergic rhinitis, and other inflammatory disorders, but little is known about the underlying mechanisms. OBJECTIVE: We studied the potential mechanisms leading from prenatal ambient air pollution exposure to asthma and allergy in childhood. METHODS: Long-term exposure to nitrogen dioxide (NO2) as well as to particulate matter with a diameter of ≤2.5 and ≤10 µm (PM2.5 and PM10) were modeled at the residence level from conception to 6 years of age in 700 Danish children followed clinically for development of asthma and allergy. Nasal mucosal immune mediators were assessed at age 4 weeks and 6 years, inflammatory markers in blood at 6 months, and nasal epithelial DNA methylation and gene expression at age 6 years. RESULTS: Higher prenatal air pollution exposure with NO2, PM2.5, and PM10 was associated with an altered nasal mucosal immune profile at 4 weeks, conferring an increased odds ratio [95% confidence interval] of 2.68 [1.58, 4.62] for allergic sensitization and 2.63 [1.18, 5.81] for allergic rhinitis at age 6 years, and with an altered immune profile in blood at age 6 months conferring increased risk of asthma at age 6 years (1.80 [1.18, 2.76]). Prenatal exposure to ambient air pollution was not robustly associated with immune mediator, epithelial DNA methylation, or gene expression changes in nasal cells at age 6 years. CONCLUSION: Prenatal exposure to ambient air pollution was associated with early life immune perturbations conferring risk of allergic rhinitis and asthma. These findings suggest potential mechanisms of prenatal exposure to ambient air pollution on the developing immune system.
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Contaminantes Atmosféricos , Asma , Efectos Tardíos de la Exposición Prenatal , Rinitis Alérgica , Niño , Embarazo , Femenino , Humanos , Lactante , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Dióxido de Nitrógeno/efectos adversos , Asma/etiología , Asma/inducido químicamente , Material Particulado/efectos adversos , Rinitis Alérgica/inducido químicamente , Exposición a Riesgos Ambientales/efectos adversosRESUMEN
BACKGROUND: Gestational vitamin D deficiency is implicated in development of respiratory diseases in offspring, but the mechanism underlying this relationship is unknown. OBJECTIVE: We sought to study the link between gestational vitamin D exposure and childhood asthma phenotypes using maternal blood metabolomics profiling. METHODS: Untargeted blood metabolic profiles were acquired using liquid chromatography-mass spectrometry at 1 week postpartum from 672 women in the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) mother-child cohort and at pregnancy weeks 32 to 38 from 779 women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) mother-child cohort. In COPSAC2010, we employed multivariate models and pathway enrichment analysis to identify metabolites and pathways associated with gestational vitamin D blood levels and investigated their relationship with development of asthma phenotypes in early childhood. The findings were validated in VDAART and in cellular models. RESULTS: In COPSAC2010, higher vitamin D blood levels at 1 week postpartum were associated with distinct maternal metabolome perturbations with significant enrichment of the sphingomyelin pathway (P < .01). This vitamin D-related maternal metabolic profile at 1 week postpartum containing 46 metabolites was associated with decreased risk of recurrent wheeze (hazard ratio [HR] = 0.92 [95% CI 0.86-0.98], P = .01) and wheeze exacerbations (HR = 0.90 [95% CI 0.84-0.97], P = .01) at ages 0 to 3 years. The same metabolic profile was similarly associated with decreased risk of asthma/wheeze at ages 0 to 3 in VDAART (odds ratio = 0.92 [95% CI 0.85-0.99], P = .04). Human bronchial epithelial cells treated with high-dose vitamin D3 showed an increased cytoplasmic sphingolipid level (P < .01). CONCLUSIONS: This exploratory metabolomics study in 2 independent birth cohorts demonstrates that the beneficial effect of higher gestational vitamin D exposure on offspring respiratory health is characterized by specific maternal metabolic alterations during pregnancy, which involves the sphingomyelin pathway.
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Asma , Vitamina D , Preescolar , Femenino , Humanos , Embarazo , Metaboloma , Estudios Prospectivos , Ruidos Respiratorios , Esfingomielinas , Ensayos Clínicos como AsuntoRESUMEN
BACKGROUND: We hypothesized that insufficient intake of fish oil-derived omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) during pregnancy is a contributing factor to gastroenteritis in early childhood. We examined the effect of n-3 LCPUFA supplementation on gastroenteritis symptoms in the offspring's first 3 years of life. METHODS: This was a double-blinded, randomized controlled trial whereby 736 mothers were administered n-3 LCPUFA or control from pregnancy week 24 until 1 week after birth. We measured the number of days with gastroenteritis, number of episodes with gastroenteritis, and the risk of having a gastroenteritis episode in the first 3 years of life. RESULTS: A median reduction of 2.5 days with gastroenteritis (Pâ =â .018) was shown, corresponding to a 14% reduction in the n-3 LCPUFA group compared with controls in the first 3 years of life (Pâ =â .037). A reduction in the number of gastroenteritis episodes (Pâ =â .027) and a reduced risk of having an episode (hazard ratio, 0.80 [95% confidence interval, .66-.97]; Pâ =â .023) were also shown. CONCLUSIONS: Fish oil supplementation from the 24th week of pregnancy led to a reduction in the number of days and episodes with gastroenteritis symptoms in the first 3 years of life. The findings suggest n-3 LCPUFA supplementation as a preventive measure against gastrointestinal infections in early childhood. CLINICAL TRIALS REGISTRATION: NCT00798226.
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Ácidos Grasos Omega-3 , Gastroenteritis , Embarazo , Femenino , Preescolar , Humanos , Aceites de Pescado/uso terapéutico , Suplementos Dietéticos , Ácidos Grasos Omega-3/uso terapéutico , Gastroenteritis/prevención & controlRESUMEN
BACKGROUND: We recently conducted a double-blinded randomised controlled trial showing that fish-oil supplementation during pregnancy reduced the risk of persistent wheeze or asthma in the child by 30%. Here, we explore the mechanisms of the intervention. METHODS: 736 pregnant women were given either placebo or n-3 long-chain polyunsaturated fatty acids (LCPUFAs) in the third trimester in a randomised controlled trial. Deep clinical follow-up of the 695 children in the trial was done at 12 visits until age 6 years, including assessment of genotype at the fatty acid desaturase (FADS) locus, plasma fatty acids, airway DNA methylation, gene expression, microbiome and metabolomics. RESULTS: Supplementation with n-3 LCPUFA reduced the overall risk of non-atopic asthma by 73% at age 6 (relative risk (RR) 0.27 (95% CI 0.06 to 0.85), p=0.042). In contrast, there was no overall effect on asthma with atopic traits (RR 1.42 (95% CI 0.63 to 3.38), p=0.40), but this was significantly modified by maternal FADS genotype and LCPUFA blood levels (interaction p<0.05), and supplementation did reduce the risk of atopic asthma in the subgroup of mothers with FADS risk variants and/or low blood levels of n-3 LCPUFA before the intervention (RR 0.31 (95% CI 0.11 to 0.75), p=0.016). Furthermore, n-3 LCPUFA significantly reduced the number of infections (croup, gastroenteritis, tonsillitis, otitis media and pneumonia) by 16% (incidence rate ratio 0.84 (95% CI 0.74 to 0.96), p=0.009). CONCLUSIONS: n-3 LCPUFA supplementation in pregnancy showed protective effects on non-atopic asthma and infections. Protective effects on atopic asthma depended on maternal FADS genotype and n-3 LCPUFA levels. This indicates that the fatty acid pathway is involved in multiple mechanisms affecting the risk of asthma subtypes and infections. TRIAL REGISTRATION NUMBER: NCT00798226.
Asunto(s)
Asma , Ácidos Grasos Omega-3 , Niño , Femenino , Humanos , Embarazo , Aceites de Pescado/uso terapéutico , Suplementos Dietéticos , Asma/prevención & control , Ácidos GrasosRESUMEN
BACKGROUND: Mixed and non-IgE-mediated food allergy is a subset of immune-mediated adverse food reactions that can impose a major burden on the quality of life of affected patients and their families. Clinical trials to study these diseases are reliant upon consistent and valid outcome measures that are relevant to both patients and clinicians, but the degree to which such stringent outcome reporting takes place is poorly studied. OBJECTIVE: As part of the Core Outcome Measures for Food Allergy (COMFA) project, we identified outcomes reported in randomized clinical trials (RCT) of treatments for mixed or non-IgE-mediated food allergy. DESIGN: In this systematic review, we searched the Ovid, MEDLINE and Embase databases for RCTs in children or adults investigating treatments for food protein-induced enterocolitis syndrome, food protein-induced allergic proctocolitis, food protein-induced enteropathy and eosinophilic gastrointestinal disorders including eosinophilic esophagitis [EoE], eosinophilic gastritis and eosinophilic colitis published until 14 October 2022. RESULTS: Twenty-six eligible studies were identified, with 23 focused on EoE (88%). Most interventions were corticosteroids or monoclonal antibodies. All EoE studies assessed patient-reported dysphagia, usually using a non-validated questionnaire. Twenty-two of 23 EoE studies used peak tissue eosinophil count as the primary outcome, usually using a non-validated assessment method, and other immunological markers were only exploratory. Thirteen (57%) EoE studies reported endoscopic outcomes of which six used a validated scoring tool recently recommended as a core outcome for EoE trials. Funding source was not obviously associated with likelihood of an RCT reporting mechanistic versus patient-reported outcomes. Only 3 (12%) RCTs concerned forms of food allergy other than EoE, and they reported on fecal immunological markers and patient-reported outcomes. CONCLUSIONS: Outcomes measured in clinical trials of EoE and non-IgE-mediated food allergy are heterogeneous and largely non-validated. Core outcomes for EoE have been developed and need to be used in future trials. For other forms of mixed or non-IgE-mediated food allergies, core outcome development is needed to support the development of effective treatments. SYSTEMATIC REVIEW REGISTRATION: OSF public registry DOI:10.17605/OSF.IO/AZX8S.