Bronchodilator responsiveness in wheezy infants and toddlers is not associated with asthma risk factors

Background There are limited data assessing bronchodilator responsiveness (BDR) in infants and toddlers with recurrent wheezing, and factors associated with a positive response. Objectives In a multicenter study of children ≤ 36 months old, we assessed the prevalence of and factors associated with BDR among infants/toddlers with recurrent episodes of wheezing. Methods Forced expiratory flows and volumes using the raised‐volume rapid thoracic compression method were measured in 76 infants/toddlers [mean (SD) age 16.8 (7.6) months] with recurrent wheezing before and after administration of albuterol. Prior history of hospitalization or emergency department treatment for wheezing, use of inhaled or systemic corticosteroids, physician treatment of eczema, environmental tobacco smoke exposure, and family history of asthma or allergic rhinitis were ascertained. Results Using the published upper limit of normal for post bronchodilator change (FEV 0.5  ≥ 13% and/or FEF 25–75  ≥ 24%) in healthy infants, 24% (n = 18) of children in our study exhibited BDR. The BDR response was not associated with any clinical factor other than body size. Dichotomizing subjects into responders (defined by published limits of normal) or by quartile to identify children with the greatest change from baseline (4th quartile vs. other) did not identify any other factor associated with BDR. Conclusions Approximately one quarter of infants/toddlers with recurrent wheezing exhibited BDR at their clinical baseline. However, BDR in wheezy infants/toddlers was not associated with established clinical asthma risk factors. Pediatr Pulmonol. 2012; 47:421–428. © 2011 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91214/1/21567_ftp.pd

The human milk proteome and allergy of mother and child: Exploring associations with protein abundances and protein network connectivity

BackgroundThe human milk proteome comprises a vast number of proteins with immunomodulatory functions, but it is not clear how this relates to allergy of the mother or allergy development in the breastfed infant. This study aimed to explore the relation between the human milk proteome and allergy of both mother and child.MethodsProteins were analyzed in milk samples from a subset of 300 mother-child dyads from the Canadian CHILD Cohort Study, selected based on maternal and child allergy phenotypes. For this selection, the definition of “allergy” included food allergy, eczema, allergic rhinitis, and asthma. Proteins were analyzed with non-targeted shotgun proteomics using filter-aided sample preparation (FASP) and nanoLC-Orbitrap-MS/MS. Protein abundances, based on label-free quantification, were compared using multiple statistical approaches, including univariate, multivariate, and network analyses.ResultsUsing univariate analysis, we observed a trend that milk for infants who develop an allergy by 3 years of age contains higher abundances of immunoglobulin chains, irrespective of the allergy status of the mother. This observation suggests a difference in the milk’s immunological potential, which might be related to the development of the infant’s immune system. Furthermore, network analysis showed overall increased connectivity of proteins in the milk of allergic mothers and milk for infants who ultimately develop an allergy. This difference in connectivity was especially noted for proteins involved in the protein translation machinery and may be due to the physiological status of the mother, which is reflected in the interconnectedness of proteins in her milk. In addition, it was shown that network analysis complements the other methods for data analysis by revealing complex associations between the milk proteome and mother-child allergy status.ConclusionTogether, these findings give new insights into how the human milk proteome, through differences in the abundance of individual proteins and protein-protein associations, relates to the allergy status of mother and child. In addition, these results inspire new research directions into the complex interplay of the mother-milk-infant triad and allergy

Progression of Lung Disease in Preschool Patients with Cystic Fibrosis

RATIONALE: Implementation of intervention strategies to prevent lung damage in early cystic fibrosis (CF) requires objective outcome measures that capture and track lung disease. OBJECTIVES: To define the utility of the Lung Clearance Index (LCI), measured by multiple breath washout, as a means to track disease progression in preschool children with CF. METHODS: Children with CF between the ages of 2.5 and 6 years with a confirmed diagnosis of CF and age-matched healthy control subjects were enrolled at three North American CF centers. Multiple breath washout tests were performed at baseline, 1, 3, 6, and 12 months to mimic time points chosen in clinical care and interventional trials; spirometry was also conducted. A generalized linear mixed-effects model was used to distinguish LCI changes associated with normal growth and development (i.e., healthy children) from the progression of CF lung disease. MEASUREMENTS AND MAIN RESULTS: Data were collected on 156 participants with 800 LCI measurements. Although both LCI and spirometry discriminated health from disease, only the LCI identified significant deterioration of lung function in CF over time. The LCI worsened during cough episodes and pulmonary exacerbations, whereas similar symptoms in healthy children were not associated with increased LCI values. CONCLUSIONS: LCI is a useful marker to track early disease progression and may serve as a tool to guide therapies in young patients with CF

Comparison of Questionnaire Responses with Biomarkers of Tobacco Smoke Exposure in A Canadian Birth Cohort at Three Months of Age

Background Exposure to tobacco smoke increases the risk for several adverse health effects in children including wheeze, asthma, and asthma exacerbation. Accurately assessing tobacco smoke exposure is important for understanding and preventing these health effects. Questionnaires are a flexible and relatively inexpensive method of assessing exposure, but biomarkers of tobacco smoke exposure are considered more accurate. We developed questionnaire-based exposure models predicting urinary levels of biomarkers cotinine and trans-3’-hydroxycotinine (3HC) (metabolites of nicotine) in 3-month old infants using parent-reported questionnaire responses about tobacco smoke exposure from the Canadian Healthy Infant Longitudinal Development (CHILD) Study. Methods We used a manual model building process to build multiple linear regression models predicting urinary concentrations of cotinine, 3HC, and the sum of cotinine and 3HC on a molar basis (Cot+3HC) for 987, 1003, and 983 infants, respectively. Questions were included on the infant’s exposure assessed at 3 months of age and tobacco smoke odour in the home. We also included questions on maternal smoking status and history, passive exposure, and family socio-economic status assessed during pregnancy, as potential indirect measures of the infant’s exposure at 3 months. Adjusted R2 values were maximized in the final models. Results During pregnancy, the prevalence of maternal smoking was 2.4 %, and 115 (11.4 %) mothers reported smoking by at least 1 person at home. Of the 144 (14.3 %) infants whose mothers reported that smoking occurred at home when their child was 3 months, 129 (89.6%) and 136 (94.4%) had cotinine and 3HC levels above the detection limit (0.03 ng/mL), respectively. Of the 811 infants who had no parent-reported exposure at 3 months, 538 (66.3%) and 715 (88.2%) had detectable cotinine and 3HC levels, respectively. After correcting for urine dilution, the geometric mean levels were 0.085 ng/mL for cotinine, 0.20 ng/mL for 3HC, and 1.62 picomole/mL for Cot+3HC. The final questionnaire models explained 43.4%, 41.0%, and 42.9% of the variance in cotinine, 3HC, and Cot+3HC levels, respectively. Conclusions Our results indicate that exposure of these infants to tobacco smoke is not completely captured by questionnaires, suggesting that exposure assessment could be improved by using a combination of biomarker and questionnaire methods. Though more detectable, the inclusion of 3HC did not increase the ability of the questionnaires to explain variance in metabolite levels, but 3HC may be important since the ratio of 3HC to cotinine can be used to quantify the rate of nicotine metabolism and variation within population

Ethnic differences in maternal diet in pregnancy and infant eczema

Background The global prevalence of childhood eczema has increased over the last few decades, with a marked increase in high-income countries. Differences in prevalence of childhood eczema between countries and ethnicities suggest that genetic and early modifiable environmental factors, such as dietary intake, may underlie this observation. To investigate the association between pregnancy diet and infant eczema in a consortium of prospective Canadian birth cohorts predominantly comprised of white Europeans and South Asians. Methods We evaluated the association of maternal dietary patterns reported during pregnancy (assessed at 24–28 weeks gestation using a semi-quantitiative food-frequency questionnaire) with parent-reported physician-diagnosed infant eczema at 1-year from 2,160 mother-infant pairs. Using three dietary patterns (“Western”, “plant-based”, and “Balanced”) previously derived in this cohort using principal component analysis, we used multivariable logistic regression to determine the association of these dietary patterns with infant eczema, adjusted for potential confounders. Results We observed a lower odds of eczema in the full sample combining white Europeans and South Asians with greater adherence to a plant-based (OR = 0.65; 95% CI: 0.55, 0.76; <0.001) and Western dietary pattern (OR = 0.73; 95% CI: 0.60, 0.89; P<0.01), after adjusting for other known predictors of eczema, including ethnicity, which was not significant. No associations were observed for the balanced diet. An interaction between the Western diet and ethnicity was observed (P<0.001). Following stratification by ethnicity, a protective association between the plant-based diet and infant eczema was confirmed in both white Europeans (OR = 0.59; 95% CI: 0.47, 0.74; P<0.001) and South Asians (OR = 0.77; 95% CI: 0.61, 0.97; P = 0.025). In white Europeans only, a Western diet was associated with a lower odds of infant eczema (OR = 0.69; 95% CI: 0.56, 0.87; P = 0.001) while a balanced diet increased the odds of infant eczema (OR = 1.23; 95% CI: 1.02, 1.49; P = 0.03). Beyond a plant-based diet, no significant associations with other dietary patterns were observed in South Asians. Conclusion A plant-based diet during pregnancy is associated with a lowered odds of infant eczema at 1 year in all participants. Future studies of the components of plant-based diet which underlie the lower risk of eczema are needed

The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study: Assessment of environmental exposures

The Canadian Healthy Infant Longitudinal Development birth cohort was designed to elucidate interactions between environment and genetics underlying development of asthma and allergy. Over 3600 pregnant mothers were recruited from the general population in four provinces with diverse environments. The child is followed to age 5 years, with prospective characterization of diverse exposures during this critical period. Key exposure domains include indoor and outdoor air pollutants, inhalation, ingestion and dermal uptake of chemicals, mold, dampness, biological allergens, pets and pests, housing structure, and living behavior, together with infections, nutrition, psychosocial environment, and medications. Assessments of early life exposures are focused on those linked to inflammatory responses driven by the acquired and innate immune systems. Mothers complete extensive environmental questionnaires including time-activity behavior at recruitment and when the child is 3, 6, 12, 24, 30, 36, 48, and 60 months old. House dust collected during a thorough home assessment at 3–4 months, and biological specimens obtained for multiple exposure-related measurements, are archived for analyses. Geo-locations of homes and daycares and land-use regression for estimating traffic-related air pollution complement time-activity-behavior data to provide comprehensive individual exposure profiles. Several analytical frameworks are proposed to address the many interacting exposure variables and potential issues of co-linearity in this complex data set

Integrated Analysis of Human Milk Microbiota With Oligosaccharides and Fatty Acids in the CHILD Cohort

Background: Human milk contains many bioactive components that are typically studied in isolation, including bacteria. We performed an integrated analysis of human milk oligosaccharides and fatty acids to explore their associations with milk microbiota.Methods: We studied a sub-sample of 393 mothers in the CHILD birth cohort. Milk was collected at 3–4 months postpartum. Microbiota was analyzed by 16S rRNA gene V4 sequencing. Oligosaccharides and fatty acids were analyzed by rapid high-throughput high performance and gas liquid chromatography, respectively. Dimension reduction was performed with principal component analysis for oligosaccharides and fatty acids. Center log-ratio transformation was applied to all three components. Associations between components were assessed using Spearman rank correlation, network visualization, multivariable linear regression, redundancy analysis, and structural equation modeling. P-values were adjusted for multiple comparisons. Key covariates were considered, including fucosyltransferase-2 (FUT2) secretor status of mother and infant, method of feeding (direct breastfeeding or pumped breast milk), and maternal fish oil supplement use.Results: Overall, correlations were strongest between milk components of the same type. For example, FUT2-dependent HMOs were positively correlated with each other, and Staphylococcus was negatively correlated with other core taxa. Some associations were also observed between components of different types. Using redundancy analysis and structural equation modeling, the overall milk fatty acid profile was significantly associated with milk microbiota composition. In addition, some individual fatty acids [22:6n3 (docosahexaenoic acid), 22:5n3, 20:5n3, 17:0, 18:0] and oligosaccharides (fucosyl-lacto-N-hexaose, lacto-N-hexaose, lacto-N-fucopentaose I) were associated with microbiota α diversity, while others (C18:0, 3′-sialyllactose, disialyl-lacto-N-tetraose) were associated with overall microbiota composition. Only a few significant associations between individual HMOs and microbiota were observed; notably, among mothers using breast pumps, Bifidobacterium prevalence was associated with lower abundances of disialyl-lacto-N-hexaose. Additionally, among non-secretor mothers, Staphylococcus was positively correlated with sialylated HMOs.Conclusion: Using multiple approaches to integrate and analyse milk microbiota, oligosaccharides, and fatty acids, we observed several associations between different milk components and microbiota, some of which were modified by secretor status and/or breastfeeding practices. Additional research is needed to further validate and mechanistically characterize these associations and determine their relevance to infant gut and respiratory microbiota development and health

Polygenic risk score for atopic dermatitis in the Canadian population

Atopic dermatitis (AD) is characterized by a damaged skin barrier that allows allergens to penetrate the body, leading to sensitization and a higher risk of developing food allergies (relative risk [RR], 33.79), asthma (RR, 7.04), and/or rhinitis (RR, 11.75), all features of the atopic march.1 Recent evidence has shown that the atopic march can be modified in high-risk infants with early interventions directed at reestablishing and/or maintaining skin barrier function with intense use of simple emollients, and introducing food allergens early into the diet.2, 3, 4, 5 Although these constitute examples of low-intensity, high-impact interventions for health care systems, their successful and indiscriminate implementation in the whole population is neither feasible nor realistic. In this context, building a predictive tool to identify children at high risk of developing moderate to severe AD (MSAD) would allow targeted interventions with maximized impact. In this study, a polygenic risk score (PRS) with an area under the curve (AUC) of 88% and explaining 37% of MSAD variance was established for the Canadian population