Key risk factors of asthma-like symptoms are mediated through infection burden in early childhood.

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.

Oropharyngeal Microbiota Clusters in Children with Asthma or Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways, and Exacerbation Risk.

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.

Fungi and bacteria in the beds of rural and urban infants correlate with later risk of atopic diseases.

INTRODUCTION: Rural children have a lower risk of asthma and atopic diseases than urban children. However, whether indoor microbiota in non-farming rural homes provides protection is unclear. METHODS: Here, we examine if microbes in the beds of rural and urban infants are associated with later development of atopic diseases. We studied fungi and bacteria in the beds of 6-month-old infants (n = 514) in association with the risk of asthma, allergic rhinitis, eczema and aeroallergen sensitization at 6 years of age in the prospective COPSAC2010 cohort. RESULTS: Both fungal and bacterial diversity were lower in the beds of children, who later developed allergic rhinitis (-0.22 [-0.43,-0.01], padj = .04 and -.24 [-0.42,-0.05], padj = .01 respectively) and lower bacterial richness was discovered in beds of children later developing asthma (-41.34 [-76.95,-5.73], padj = .02) or allergic rhinitis (-45.65 [-81.19,-10.10], padj = .01). Interestingly, higher fungal diversity and richness were discovered in the beds of children developing eczema (0.23 [0.02,0.43], padj = .03 and 29.21 [1.59,56.83], padj = .04 respectively). We defined a limited set of fungal and bacterial genera that predicted rural/urban environment. Some rural-associated bacterial genera such as Romboutsia and Bacillus and fungal genera Spegazzinia and Physcia were also associated with reduced risk of diseases, including eczema. These fungal and bacterial fingerprints predicting the living environment were associated with asthma and allergic rhinitis, but not eczema, with rural compositions being protective. The bed dust bacteria mediated 27% of the protective association of a rural living environment for allergic rhinitis (p = .04). CONCLUSIONS: Bed dust microbes can be differentially associated with airway- and skin-related diseases. The differing bed dust microbiota between rural and urban infants may influence their later risk of asthma and allergic rhinitis.

Increasing severity of early-onset atopic dermatitis, but not late-onset, associates with development of aeroallergen sensitization and allergic rhinitis in childhood.

BACKGROUND: Early exposure to allergens through a defect skin barrier has been proposed as a mechanism for inducing sensitization and development of allergic diseases. We hypothesized that early-onset, severe atopic dermatitis (AD) is associated with development of aeroallergen sensitization and allergic rhinitis. METHODS: We included 368 children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000 ) at-risk mother-child cohort. AD was diagnosed prospectively based on Hanifin&Rajka's criteria and severity assessed using the Scoring Atopic Dermatitis (SCORAD) index. Early-onset AD was defined as debut ≤1 year, late-onset as debut from 1-6 years. Aeroallergen sensitization and allergic rhinitis were diagnosed at ages 6-7 and 12 years. Associations between early-onset and late-onset AD and allergy endpoints were calculated using general estimating equations (GEE) models to compute the overall odds ratios (OR) for both time points. RESULTS: Early-onset AD (yes/no) and severity (SCORAD) were associated with development of aeroallergen sensitization during childhood; GEE OR = 1.68 [1.08; 2.62], p = .02 and 1.08 [1.03; 1.12], p < .001, whereas late-onset AD showed a borderline significant association and late-onset severity showed no association; GEE OR = 1.65 [0.92; 2.94], p = .08 and 1.01 [0.97; 1.06], p = .55. The same trend was seen for allergic rhinitis with significant association between early-onset AD and allergic rhinitis; GEE OR = 1.56 [1.01; 2.41], p = .04 and severity; GEE OR = 1.09 [1.05; 1.13], p < .001, whereas late-onset AD showed no association. The effects on sensitization and rhinitis of early-onset versus late-onset AD severity were significantly different: p-interactionsensitization  = .03 and p-interactionrhinitis  < .01. CONCLUSION: Increasing severity of early-onset AD, but not late-onset AD, associates with aeroallergen sensitization and allergic rhinitis later in childhood.

Asthma-like symptoms in young children increase the risk of COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) may originate in early life and share disease mechanisms with asthma-like symptoms in early childhood. This possibility remains unexplored on account of the lack of long-term prospective studies from infancy to the onset of COPD. OBJECTIVE: We aimed to investigate the relationship between asthma-like symptoms in young children and development of COPD. METHODS: In a population-based cohort of women who gave birth at the central hospital in Copenhagen during period from 1959 to 1961, we investigated data from 3290 mother-child pairs who attended examinations during pregnancy and when the children were aged 1, 3, and 6 years. COPD was assessed from the Danish national registries on hospitalizations and prescription medication since 1994. A subgroup of 930 individuals underwent spirometry testing at age 50 years. RESULTS: Of the 3290 children, 1 in 4 had a history of asthma-like symptoms in early childhood. The adjusted hazard ratio for hospitalization for COPD was 1.88 (95% CI = 1.32-2.68), and the odds ratio for prescription of long-acting muscarinic antagonists was 2.27 (95% CI = 1.38-3.70). Asthma-like symptoms in early childhood were also associated with a reduced FEV1 percent predicted and an FEV1-to-forced vital capacity ratio at age 50 years (-3.36% [95% CI = -5.47 to -1.24] and -1.28 [95% CI = -2.17 to -0.38], respectively) and with COPD defined according to Global Initiative for Chronic Obstructive Lung Disease stage higher than 1 (odds ratio = 1.96 [95% CI = 1.13-3.34]). CONCLUSION: This 60-year prospective follow-up of a mother-child cohort demonstrated a doubled risk for COPD from childhood asthma-like symptoms.

Urbanized microbiota in infants, immune constitution, and later risk of atopic diseases.

BACKGROUND: Urbanization is linked with an increased burden of asthma and atopic traits. A putative mechanism is insufficient exposure to beneficial microbes early in life, leading to immune dysregulation, as was previously shown for indoor microbial exposures. OBJECTIVE: Our aim was to investigate whether urbanization is associated with the microbiota composition in the infants' body and early immune function, and whether these contribute to the later risk of asthma and atopic traits. METHODS: We studied the prospective Copenhagen Prospective Studies on Asthma in Childhood 20102010 mother-child cohort of 700 children growing up in areas with different degrees of urbanization. During their first year of life, airway and gut microbiotas, as well as immune marker concentrations, were defined. When the children were 6 years of age, asthma and atopic traits were diagnosed by pediatricians. RESULTS: In adjusted analyses, the risk of asthma and aeroallergen sensitization were increased in urban infants. The composition of especially airway but also gut microbiotas differed between urban and rural infants. The living environment-related structure of the airway microbiota was already associated with immune mediator concentrations at 1 month of age. An urbanized structure of the airway and gut microbiotas was associated with an increased risk of asthma coherently during multiple time points and also with the risks of eczema and sensitization. CONCLUSION: Our findings suggest that urbanization-related changes in the infant microbiota may elevate the risk of asthma and atopic traits, probably via cross talk with the developing immune system. The airways may facilitate this effect, as they are open for colonization by environmental airborne microbes and serve as an immune interface.

Parent-specific effects on risk of developing allergic sensitization and asthma in childhood.

BACKGROUND: Parent's history of atopic traits increases the risk of the same traits in their children, but mother's history may confer an increased risk compared to father's history. OBJECTIVE: To investigate parent-specific effects on risk of developing allergic sensitization and asthma in childhood. METHODS: We included 685 parent-child trios from the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort. Parent's asthma was assessed by structured interviews and child's asthma was diagnosed prospectively at regular visits to the COPSAC clinic until age 6. Specific IgE and total IgE levels were measured in parents and children by age 0.5, 1.5 and 6 years. Associations between parent and child disease traits were analyzed using general estimating equations model adjusted for breastfeeding and maternal smoking during 3rd trimester. RESULTS: Maternal compared to paternal elevated specific IgE increased the child's risk of elevated specific IgE from 0-6 years: adjusted odds ratio (aOR)mother = 1.49 [1.09-2.03], P = .01 and aORfather = 1.32 [0.96-1.82], P = .08. Maternal elevated total IgE also increased the child's risk of elevated total IgE: adjusted relative risk (aOR)mother = 4.32 [1.51-10.8], P < .01, while a trend was observed for paternal total IgE: aORfather = 2.01 [0.76-4.82], P = .13. Individual time point analyses showed that the maternal effect was strongest in early life, whereas the parental effects were comparable by age 6. A similar parent-specific pattern was observed for the child's risk of asthma. CONCLUSIONS AND CLINICAL RELEVANCE: The effect of mother's history of atopic traits on the child's risk of developing the same traits in early childhood was stronger than the effect from father's history, which was not evident before age 6. This suggests that maternal non-genetic factors seem to confer an added disease risk to the child, particularly in early life.

Airway obstruction and bronchial reactivity from age 1 month until 13 years in children with asthma: A prospective birth cohort study.

BACKGROUND: Studies have shown that airway obstruction and increased bronchial reactivity are present in early life in children developing asthma, which challenges the dogma that airway inflammation leads to low lung function. Further studies are needed to explore whether low lung function and bronchial hyperreactivity are inherent traits increasing the risk of developing airway inflammation and asthmatic symptoms in order to establish timely primary preventive initiatives. METHODS AND FINDINGS: We investigated 367 (89%) of the 411 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort born to mothers with asthma, who were assessed by spirometry and bronchial reactivity to methacholine from age 1 month, plethysmography and bronchial reversibility from age 3 years, cold dry air hyperventilation from age 4 years, and exercise challenge at age 7 years. The COPSAC pediatricians diagnosed and treated asthma based on symptom load, response to inhaled corticosteroid, and relapse after treatment withdrawal according to a standardized algorithm. Repeated measures mixed models were applied to analyze lung function trajectories in children with asthma ever or never at age 1 month to 13 years. The number of children ever versus never developing asthma in their first 13 years of life was 97 (27%) versus 270 (73%), respectively. Median age at diagnosis was 2.0 years (IQR 1.2-5.7), and median remission age was 6.2 years (IQR 4.2-7.8). Children with versus without asthma had reduced lung function (z-score difference, forced expiratory volume, -0.31 [95% CI -0.47; -0.15], p < 0.001), increased airway resistance (z-score difference, specific airway resistance, +0.40 [95% CI +0.24; +0.56], p < 0.001), increased bronchial reversibility (difference in change in forced expiratory volume in the first second [ΔFEV1], +3% [95% CI +2%; +4%], p < 0.001), increased reactivity to methacholine (z-score difference for provocative dose, -0.40 [95% CI -0.58; -0.22], p < 0.001), decreased forced expiratory volume at cold dry air challenge (ΔFEV1, -4% [95% CI -7%; -1%], p < 0.01), and decreased forced expiratory volume after exercise (ΔFEV1, -4% [95% CI -7%; -1%], p = 0.02). Both airway obstruction and bronchial hyperreactivity were present before symptom debut, independent of disease duration, and did not improve with symptom remission. The generalizability of these findings may be limited by the high-risk nature of the cohort (all mothers had a diagnosis of asthma), the modest study size, and limited ethnic variation. CONCLUSIONS: Children with asthma at some point at age 1 month to 13 years had airway obstruction and bronchial hyperreactivity before symptom debut, which did not worsen with increased asthma symptom duration or attenuate with remission. This suggests that airway obstruction and bronchial hyperreactivity are stable traits of childhood asthma since neonatal life, implying that symptomatic disease may in part be a consequence of these traits but not their cause.

Single and multiple time-point allergic sensitization during childhood and risk of asthma by age 13.

BACKGROUND: The relationship between allergic sensitization during childhood and risk of developing asthma remains unclear. OBJECTIVE: To analyze single time-point and temporal patterns of sensitization in childhood in relation to asthma at age 13. METHODS: Specific IgE (sIgE) level and skin prick test (SPT) toward 22 food allergens and aeroallergens were assessed at 6, 18 months, 4, 6, and 13 years in children from the high-risk Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000 ) mother-child cohort. We analyzed the association between single time-point monosensitization, polysensitization, and quantitative assessment of sensitization, that is, sum of all sIgE levels and SPT wheal sizes, against asthma at age 13. In addition, we analyzed the association between three temporal patterns of sensitization: (a) early-transient, (b) late-onset, and (c) persistent sensitization and asthma. RESULTS: Polysensitization status measured by SPT or sIgE was at all single time-points associated with increased risk of asthma at age 13: OR range, SPT = 3.0-15.7, and sIgE = 2.6-15.7, respectively, whereas monosensitization status was inconsistently associated with asthma. Quantitative assessment of both sIgE and SPT results was associated with asthma at all single time-points: OR range, SPT = 1.3-3.6, and sIgE = 1.1-1.7. Persistent sensitization, but not early-transient or late-onset sensitization was associated with asthma by age 13: OR [95% CI], SPT = 8.9 [2.8-28.23], and sIgE = 2.9 [1.1-7.6], respectively. CONCLUSION: Sensitization to multiple allergens at single time-points, increasing sIgE levels and SPT wheal sizes, and persistent sensitization during childhood were associated with increased risk of asthma at age 13, suggesting the use of quantitative and repetitive sensitization measurements when assessing risk of developing asthma.

Atopic endotype in childhood.

BACKGROUND: The term atopic disorder is an early attempt to define specific endotypes of children with asthma, eczema, or both and increased IgE levels. OBJECTIVE: We performed a longitudinal analysis of the relevance of the atopic endotype from birth to age 13 years. METHODS: Allergic sensitization against 28 inhalant and food allergens was assessed at ½, 1½, 4, 6, and 13 years of age in 399 children from the Copenhagen Prospective Study on Asthma in Childhood2000 birth cohort by using both skin prick test responses and specific IgE levels. Asthma and eczema were diagnosed longitudinally by strictly adhering to predefined algorithms. Associations between allergic sensitization, asthma, and eczema were estimated by means of logistic regression, and a machine learning approach was used to identify temporal phenotype clusters of these traits. RESULTS: Allergic sensitization showed no association with asthma through early childhood (0-6 years) when analyzed as any sensitization (odds ratio [OR] range, 0.78-1.29; P ≥ .48). However, at 13 years of age, any sensitization was associated with asthma (OR range, 4.02-5.94; all P < .001). In contrast, any sensitization was associated with eczema at ½, 1½, and 6 years of age (OR range, 2.06-6.02; P ≤ .01) and borderline associated at 4 years of age (OR, 1.61 [95% CI, 0.96-2.69]; P = .07) but not at 13 years of age (OR, 1.57 [95% CI, 0.78-3.16]; P = .21). We identified 4 latent patterns of disease development that were either dominated by sensitization (37%), eczema (26%), asthma (14%), or healthy status (24%). CONCLUSION: We found very little interdependency between asthma, eczema, and allergic sensitization through childhood. The associations between those entities were strongly dependent on age, type of allergens, and method of testing for sensitization. Therefore, atopy in children is unlikely to represent a true endotype.

New time-saving predictor algorithm for multiple breath washout in adolescents.

BACKGROUND: Multiple breath washout (MBW) is an informative but time-consuming test. This study evaluates the uncertainty of a time-saving predictor algorithm in adolescents. METHODS: Adolescents were recruited from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC2000) birth cohort. MBW trials were performed at 13 y of age with Innocor model Inn00400 using sulfur hexafluoride (SF6) as tracer gas. Measurements were analyzed using a mixed model focusing on two prediction points doubling (t5%) and quadrupling (t10%) the standard end point (t2.5%). RESULTS: One hundred and seventy-two MBW trials conducted in 78 adolescents with and without asthma from COPSAC2000 were included. At t10%, the washout time (WoT) was reduced by 41%, and an uncertainty of 0.159 lung clearance index (LCI) units was introduced (±2 SD), ±1.27). At t5%, the WoT was reduced by 25%, with an uncertainty of 0.083 LCI units (±0.558). The optimal prediction point, which led to most saved time and least uncertainty was t5%. CONCLUSION: The predictor algorithm is capable of shortening the MBW test time but introduces an increasing uncertainty with earlier prediction points. This first-of-a-kind prediction algorithm holds promise in shortening the MBW test in children but should be used with caution in subjects with normal LCI values.

Burden and Subtypes of Early Life Infections Increase the Risk of Asthma.

BACKGROUND: Early life respiratory tract infections have been linked to the development of asthma, but studies on the burden and subtypes of common infections in asthma development are sparse. OBJECTIVE: To examine the association between burden of early life infections, including subtypes, with the risk of asthma from age 3 to 10 years and lung function at age 10 years. METHODS: We included 662 children from the Copenhagen Prospective Studies on Asthma in Childhood 2010 birth cohort, for whom infections such as colds, acute tonsillitis, acute otitis media, pneumonia, gastroenteritis, and fever were registered prospectively in daily diaries at age 0 to 3 years and asthma was diagnosed longitudinally from age 3 to 10 years. The association between the burden of infection and subtypes and risk of asthma was analyzed by generalized estimating equations. RESULTS: The children experienced a median of 16 infections (interquartile range, 12-23 infections) at age 0 to 3 years. Children with a high burden of infections (above the median) had an increased risk of asthma at age 3 to 10 years (adjusted odds ratio = 3.61; 95% CI, 2.39-5.45; P < .001), which was driven by colds, pneumonia, gastroenteritis, and fever episodes (P < .05) but not by acute otitis media and tonsillitis. Lower lung function measures at age 10 years were associated with the burden of pneumonia but not the overall infection burden. The association between colds and the risk of asthma was significantly higher in children with allergic rhinitis at age 6 years (P interaction = .032). CONCLUSION: A high burden of early life infections in terms of colds, pneumonia, gastroenteritis, and fever is associated with an increased risk of developing asthma, particularly in children with respiratory allergy. Strategies to diminish these early life infections may offer a path for the primary prevention of childhood asthma.

Risk Factors and Age-Related Patterns of Asthma-Like Symptoms in Early Childhood.

BACKGROUND: Episodes of asthma-like symptoms in young children are common, but little is known about risk factors and their patterns for the daily symptom burden. OBJECTIVE: We investigated a variety of possible risk factors and their age-related impact on the number of asthma-like episodes during age 0 to 3 years. METHODS: The study population included 700 children from the Copenhagen Prospective Studies on Asthma in Childhood2010 mother-child cohort followed prospectively from birth. Asthma-like symptoms were recorded until age 3 by daily diaries. Risk factors were analyzed by quasi-Poisson regressions, and interaction with age was explored. RESULTS: Diary data were available in 662 children. Male sex, maternal asthma, low birth weight, maternal antibiotic use, high asthma exacerbation polygenic risk score, and high airway immune score were associated with a higher number of episodes in a multivariable analysis. Maternal asthma, preterm birth, caesarean section, and low birth weight showed an increasing impact with age, whereas sibling(s) at birth showed a decreased association with age. The remaining risk factors had a stable pattern during age 0 to 3 years. For every additional clinical risk factor (male sex, low birth weight, and maternal asthma) a child had, we found 34% more episodes (incidence rate ratio: 1.34, 95% confidence interval: 1.21-1.48; P < .001). CONCLUSION: Using unique day-to-day diary recordings, we identified risk factors for the burden of asthma-like symptoms in the first 3 years of life and described their unique age-related patterns. This provides novel insight into the origin of asthma-like symptoms in early childhood that potentially pave a path for personalized prognostics and treatment.

Elevated eosinophil protein X in urine from healthy neonates precedes development of atopy in the first 6 years of life.

RATIONALE: Biomarkers predicting development of atopic disease are needed for targeted preventive measures and to study if disease pathology may be active before onset of symptoms. OBJECTIVES: To investigate whether eosinophil protein X, leukotriene-C4/D4/E4, and 11ß-prostaglandin (PG) F2α (PGD2 metabolite) assessed in urine from healthy at-risk neonates precede development of atopic disease during the first 6 years of life. METHODS: We measured eosinophil protein X (n = 369), leukotriene-C4/D4/E4 (n = 367), and 11ß-PGF2α (n = 366) in urine from 1-month-old children participating in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort. Clinical data on development of allergic sensitization, allergic rhinitis, nasal eosinophilia, blood eosinophilia, eczema, troublesome lung symptoms (significant cough or wheeze or dyspnea), and asthma were collected prospectively until age 6 years. Associations between urinary biomarkers and development of atopic traits were investigated using general estimating equations, logistic regression, and Cox regression. MEASUREMENTS AND MAIN RESULTS: Eosinophil protein X in the urine of the asymptomatic 1-month-old neonates was significantly associated with development of allergic sensitization (odds ratio, 1.49; 95% confidence interval [CI], 1.08­1.89), nasal eosinophilia (odds ratio, 3.2; 95% CI, 1.2­8.8), and eczema (hazard ratio, 1.4; 95% CI, 1.0­2.0), but not with allergic rhinitis, asthma, or blood eosinophilia. Neither leukotriene-C4/D4/E4 nor 11ß-PGF2α was associated with any of the atopic phenotypes. CONCLUSIONS: Eosinophil protein X in urine from asymptomatic neonates is a biomarker significantly associated with later development of allergic sensitization, nasal eosinophilia, and eczema during the first 6 years of life. These findings suggest activation of eosinophil granulocytes early in life before development of atopy-related symptoms.

Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age.

BACKGROUND: Changes in the human microbiome have been suggested as a risk factor for a number of lifestyle-related disorders, such as atopic diseases, possibly through a modifying influence on immune maturation in infancy. OBJECTIVES: We aimed to explore the association between neonatal fecal flora and the development of atopic disorders until age 6 years, hypothesizing that the diversity of the intestinal microbiota influences disease development. METHODS: We studied the intestinal microbiota in infants in the Copenhagen Prospective Study on Asthma in Childhood, a clinical study of a birth cohort of 411 high-risk children followed for 6 years by clinical assessments at 6-month intervals, as well as at acute symptom exacerbations. Bacterial flora was analyzed at 1 and 12 months of age by using molecular techniques based on 16S rRNA PCR combined with denaturing gradient gel electrophoresis, as well as conventional culturing. The main outcome measures were the development of allergic sensitization (skin test and specific serum IgE), allergic rhinitis, peripheral blood eosinophil counts, asthma, and atopic dermatitis during the first 6 years of life. RESULTS: We found that bacterial diversity in the early intestinal flora 1 and 12 months after birth was inversely associated with the risk of allergic sensitization (serum specific IgE P = .003; skin prick test P = .017), peripheral blood eosinophils (P = .034), and allergic rhinitis (P = .007). There was no association with the development of asthma or atopic dermatitis. CONCLUSIONS: Reduced bacterial diversity of the infant's intestinal flora was associated with increased risk of allergic sensitization, allergic rhinitis, and peripheral blood eosinophilia, but not asthma or atopic dermatitis, in the first 6 years of life. These results support the general hypothesis that an imbalance in the intestinal microbiome is influencing the development of lifestyle-related disorders, such as allergic disease.

Safety of High-Dose Vitamin D Supplementation Among Children Aged 0 to 6 Years: A Systematic Review and Meta-analysis.

Importance: Several health benefits of vitamin D have been suggested; however, the safety of high-dose supplementation in early childhood is not well described. Objective: To systematically assess the risk of adverse events after high-dose supplementation with vitamin D reported in published randomized clinical trials. Data Sources: PubMed and ClinicalTrials.gov were searched through August 24, 2021. Study Selection: Randomized clinical trials of high-dose vitamin D supplementation in children aged 0 to 6 years, defined as greater than 1000 IU/d for infants (aged 0-1 year) and greater than 2000 IU/d for children aged 1 to 6 years. Data Extraction and Synthesis: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, 2 reviewers independently extracted the data from the eligible studies. Summary risk ratio (RR), 95% CI, and P values were derived from random-effects meta-analysis. Main Outcomes and Measures: Adverse events, serious adverse events (SAEs), and/or levels of 25-hydroxyvitamin D, calcium, alkaline phosphatase, phosphate, parathyroid hormone, and/or the ratio of urine calcium to creatinine levels. Results: A total of 32 randomized clinical trials with 8400 unique participants were included. Different clinical outcomes of children receiving high-dose vitamin D supplements ranging from 1200 to 10 000 IU/d and bolus doses from 30 000 IU/week to a single dose of 600 000 IU were evaluated. Eight studies with 4612 participants were eligible for meta-analysis using a control group receiving either low-dose vitamin D supplementation (≤400 IU/d) or placebo when investigating the risk of SAEs such as hospitalization or death. No overall increased risk of SAEs in the high-dose vitamin D vs control groups was found (RR, 1.01 [95% CI, 0.73-1.39]; P = .89, I2 = 0%). In addition, risk of hypercalcemia (n = 726) was not increased (RR, 1.18 [95% CI, 0.72-1.93]; P = .51). Clinical adverse events potentially related to the vitamin D supplementation reported in the studies were rare. Conclusions and Relevance: This meta-analysis and systematic review found that high-dose vitamin D supplementation was not associated with an increased risk of SAEs in children aged 0 to 6 years, and that clinical adverse events potentially related to the supplementation were rare. These findings suggest that vitamin D supplementation in the dose ranges of 1200 to 10 000 IU/d and bolus doses to 600 000 IU to young children may be well tolerated.

Children with allergic and nonallergic rhinitis have a similar risk of asthma.

BACKGROUND: Both allergic and nonallergic rhinitis have been associated with increased prevalence of asthma. OBJECTIVE: To characterize asthma and intermediary asthma endpoints in young children with allergic and nonallergic rhinitis. METHODS: Thirty-eight 7-year-old children with allergic rhinitis, 67 with nonallergic rhinitis, and 185 without rhinitis from the Copenhagen Prospective Study on Asthma in Childhood birth cohort were compared for prevalence of asthma, eczema, food sensitization, filaggrin null-mutations, total IgE, blood eosinophil count, fractional exhaled nitric oxide (FeNO), lung function, and bronchial responsiveness. RESULTS: Children with allergic rhinitis compared with asymptomatic controls had increased prevalence of asthma (21% vs 5%; P = .002), food sensitization (47% vs 13%; P < .001), and eczema (66% vs 43%; P = .01) and increased total IgE (155 kU/L vs 41 kU/L; P < .001), blood eosinophil count (0.46 x 10(9)/L vs 0.30 x 10(9)/L; P = .01), FeNO (15.9 ppb vs 6.6 ppb; P < .001), and bronchial hyperresponsiveness (23% vs 9%; P = .008). Filaggrin null-mutations were associated with allergic rhinitis (odds ratio, 3.3; 95% CI, 1.3-8.3) but did not modify these associations. Children with nonallergic rhinitis also had increased asthma prevalence (20% vs 5%; P = .001) but showed no association with filaggrin null-mutations, eczema, food sensitization, total IgE, blood eosinophil count, FeNO, or bronchial responsiveness. CONCLUSION: Asthma is similarly associated with allergic and nonallergic rhinitis, suggesting a link between upper and lower airways beyond allergy associated inflammation. Only children with allergic rhinitis had increased bronchial responsiveness and elevated FeNO, suggesting different endotypes of asthma symptoms in young children with allergic and nonallergic rhinitis.

Cost of Illness in Young Children: A Prospective Birth Cohort Study.

Childhood illness is extremely common and imposes a considerable economic burden on society. We aimed to quantify the overall economic burden of childhood illness in the first three years of life and the impact of environmental risk factors. The study is based on the prospective, clinical mother-child cohort Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) of 700 children with embedded randomized trials of fish-oil and vitamin D supplementations during pregnancy. First, descriptive analyses were performed on the total costs of illness, defined as both the direct costs (hospitalizations, outpatient visits, visit to the practitioner) and the indirect costs (lost earnings) collected from the Danish National Health Registries. Thereafter, linear regression analyses on log-transformed costs were used to investigate environmental determinants of the costs of illness. The median standardized total cost of illness at age 0-3 years among the 559 children eligible for analyses was EUR 14,061 (IQR 9751-19,662). The exposures associated with reduced costs were fish-oil supplementation during pregnancy (adjusted geometric mean ratio (GMR) 0.89 (0.80; 0.98), p = 0.02), gestational age in weeks (aGMR = 0.93 (0.91; 0.96), p < 0.0001), and birth weight per 100 g (aGMR 0.98 (0.97; 0.99), p = 0.0003), while cesarean delivery was associated with higher costs (aGMR = 1.30 (1.15; 1.47), p < 0.0001). In conclusion, common childhood illnesses are associated with significant health-related costs, which can potentially be reduced by targeting perinatal risk factors, including maternal diet during pregnancy, cesarean delivery, preterm birth and low birth weight.

Children Monosensitized to Can f 5 Show Different Reactions to Male and Female Dog Allergen Extract Provocation: A Randomized Controlled Trial.

BACKGROUND: Dog dander consists of several allergenic molecules including Can f 5, which is a protein expressed in the prostate of male dogs. OBJECTIVE: To investigate whether children monosensitized to Can f 5 show different reactions to provocation tests with male versus female dog dander in a double-blind randomized clinical trial. METHODS: Twenty-two children (15-18 years) with a history of dog sensitization were enrolled from the COpenhagen Prospective Studies on Asthma in Childhood2000 mother-child cohort. Skin prick test, specific IgE levels to dog dander (e5), and dog components Can f 1, 2, 3, and 5 were first assessed. We subsequently performed skin prick test and conjunctival allergen provocation test using dog dander collected separately from male and female dogs. RESULTS: Seven of the 22 children were monosensitized to Can f 5. Eight were sensitized to a mix of the dog components, and 7 were no longer sensitized to dog. Of the children monosensitized to Can f 5, all had a positive skin prick test result to male dog extract and 1 of 7 was also positive to female dog extract (P = .01). Furthermore, 5 of 7 had a positive conjunctival allergen provocation test result to male dog extract and 1 of 7 also reacted to the female dog extract (P = .03). There was no difference between reactions to male and female dog extract provocation in children sensitized to a mix of the dog components. CONCLUSIONS: Children monosensitized to Can f 5 show different reactions to male and female dog extract provocation using both skin prick test and conjunctival allergen provocation test, suggesting tolerance to female dogs.

Delayed Motor Milestones Achievement in Infancy Associates with Perturbations of Amino Acids and Lipid Metabolic Pathways.

The relationship between developmental milestone achievement in infancy and later cognitive function and mental health is well established, but underlying biochemical mechanisms are poorly described. Our study aims to discover pathways connected to motor milestone achievement during infancy by using untargeted plasma metabolomic profiles from 571 six-month-old children in connection with age of motor milestones achievement (Denver Developmental Index) in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) mother-child cohort. We used univariate regression models and multivariate modelling (Partial Least Squares Discriminant Analysis: PLS-DA) to examine the associations and the VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort for validation. The univariate analyses showed 62 metabolites associated with gross-motor milestone achievement (p < 0.05) as well as the PLS-DA significantly differentiated between slow and fast milestone achievers (AUC = 0.87, p = 0.01). Higher levels of tyramine-O-sulfate in the tyrosine pathway were found in the late achievers in COPSAC (p = 0.0002) and in VDAART (p = 0.02). Furthermore, we observed that slow achievers were characterized by higher levels of fatty acids and products of fatty acids metabolism including acyl carnitines. Finally, we also observed changes in the lysine, histidine, glutamate, creatine and tryptophan pathways. Observing these metabolic changes in relation to gross-motor milestones in the first year of life, may be of importance for later cognitive function and mental health.