Risk Of Childhood Asthma Research Articles

Early infancy microbial and metabolic alterations affect risk of childhood asthma.

Asthma is the most prevalent pediatric chronic disease and affects more than 300 million people worldwide. Recent evidence in mice has identified a "critical window" early in life where gut microbial changes (dysbiosis) are most influential in experimental asthma. However, current research has yet to establish whether these changes precede or are involved in human asthma. We compared the gut microbiota of 319 subjects enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study, and show that infants at risk of asthma exhibited transient gut microbial dysbiosis during the first 100 days of life. The relative abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This reduction in bacterial taxa was accompanied by reduced levels of fecal acetate and dysregulation of enterohepatic metabolites. Inoculation of germ-free mice with these four bacterial taxa ameliorated airway inflammation in their adult progeny, demonstrating a causal role of these bacterial taxa in averting asthma development. These results enhance the potential for future microbe-based diagnostics and therapies, potentially in the form of probiotics, to prevent the development of asthma and other related allergic diseases in children.

Timing and Duration of Traffic-related Air Pollution Exposure and the Risk for Childhood Wheeze and Asthma.

The timing and duration of traffic-related air pollution (TRAP) exposure may be important for childhood wheezing and asthma development. We examined the relationship between TRAP exposure and longitudinal wheezing phenotypes and asthma at age 7 years. Children completed clinical examinations annually from age 1 year through age 4 years and age 7 years. Parental-reported wheezing was assessed at each age, and longitudinal wheezing phenotypes (early-transient, late-onset, persistent) and asthma were defined at age 7 years. Participants' time-weighted exposure to TRAP, from birth through age 7 years, was estimated using a land-use regression model. The relationship between TRAP exposure and wheezing phenotypes and asthma was examined. High TRAP exposure at birth was significantly associated with both transient and persistent wheezing phenotypes (adjusted odds ratio [aOR] = 1.64; 95% confidence interval [CI], 1.04-2.57 and aOR = 2.31; 95% CI, 1.28-4.15, respectively); exposure from birth to age 1 year and age 1 to 2 years was also associated with persistent wheeze. Only children with high average TRAP exposure from birth through age 7 years were at significantly increased risk for asthma (aOR = 1.71; 95% CI, 1.01-2.88). Early-life exposure to TRAP is associated with increased risk for persistent wheezing, but only long-term exposure to high levels of TRAP throughout childhood was associated with asthma development.

Prenatal antibiotic use and risk of childhood wheeze/asthma: A meta-analysis.

Existing body of knowledge suggests that antibiotic use during pregnancy was inconsistently associated with childhood wheeze/asthma. The aim of this study was to determine whether exposure to antibiotic during pregnancy could increase the risk for childhood wheeze/asthma using a comprehensive meta-analysis. PubMed, MEDLINE, and China National Knowledge Infrastructure (CNKI) were systematically searched for studies up to September 10, 2014, and additional studies were found by searching reference lists of relevant articles. Forthis meta-analysis, cohort studies and case-control studies assessing the association between antibiotic use during pregnancy and risk of childhood wheeze/asthma were included. Extracted data were mainly pooled using random-effects model. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). Ten studies were identified in final analysis. Pooling analysis of these studies showed an OR of 1.20 (95% CI, 1.13-1.27) for wheeze/asthma. After excluding case-control studies and prospective studies without achieving high scores on the NOS, the pooled OR was 1.18 (95% CI, 1.11-1.26). We found the risk of antibiotic use and pooled ORs of wheeze/asthma were 1.09 (95% CI, 0.92-1.29) for the first trimester, 1.14 (95% CI, 1.01-1.29) for the second trimester, and 1.33 (95% CI, 1.11-1.60) for the third trimester, respectively. This meta-analysis suggests that antibiotic exposure during pregnancy may increase the risk of wheeze/asthma in childhood. Besides, the risk of developing wheeze/asthma in childhood was marked during last two trimesters of pregnancy. Future studies of large-size and prospective cohorts which adequately address concerns for confounder bias are needed to examine the relationship between antibiotic use and risk of childhood asthma.

Genes associated with RSV lower respiratory tract infection and asthma: the application of genetic epidemiological methods to understand causality.

Infants with respiratory syncytial virus (RSV) lower respiratory tract infections (LRIs) are at increased risk for childhood asthma. The objectives of this article are to review the genes associated with both RSV LRI and asthma, review analytic approaches to assessing shared genetic risk and propose a future perspective on how these approaches can help us to understand the role of infant RSV infection as both an important risk factor for asthma and marker of shared genetic etiology between the two conditions. The review of shared genes and thus pathways associated with severity of response to RSV infection and asthma risk can help us to understand mechanisms of disease and ultimately propose new and novel targets for primary prevention of both diseases.

Is the Relationship Between Breastfeeding and Childhood Risk of Asthma and Obesity Mediated by Infant Antibiotic Treatment?

Studies of the protective effect of breastfeeding on asthma have not brought unequivocal results, and thus this issue remains controversial. Antibiotic use, known to increase asthma risk, may be involved in this relationship. The objective of this study was to assess the influence of breastfeeding duration on obesity and asthma risk in childhood and to test a mediating role of antibiotic use in infancy. A cross-sectional anthropometric and questionnaire study was conducted on 1,277 schoolchildren 8 years of age. Data on weight status, asthma, breastfeeding duration, antibiotic administration in infancy, socioeconomic status, and lifestyle were analyzed. Multivariate standard and logistic regression and mediation analyses, controlling for confounders, were applied. Total duration of breastfeeding was negatively related to the child's body mass index (p=0.038), fat percentage (p=0.030), and obesity risk (p=0.032). Dropping the variable of antibiotic use from the model made the breastfeeding duration a significant predictor of low asthma risk (p=0.027). Antibiotic treatment mediated the relationship between breastfeeding duration and asthma risk (Sobel's z=-2.61, p=0.009). Our findings support protective effects of longer duration of breastfeeding against obesity and asthma. We propose a new mechanism for a relationship between breastfeeding and asthma: shorter breastfeeding compromises infant health and thereby leads to antibiotic treatment, which in turn increases the risk of asthma.

Peak weight velocity in infancy is negatively associated with lung function in adolescence.

Rapid weight gain during infancy increases childhood asthma risk, which might be related to impaired lung function. This study investigated associations between peak weight velocity (PWV) during the first two years of life and spirometric lung function indices at 15 years of age. Data from 1842 children participating in the GINIplus German birth cohort who underwent spirometry at age 15 were analysed. PWV was calculated from weight measurements obtained between birth and two years of age. Generalised additive models were fitted after adjustment for potential confounding factors (birth weight, height, and age at lung function testing). Results are presented per interquartile range increase (3.5 kg/year) in PWV. PWV was negatively associated with pre-bronchodilation flow rates after extensive adjustment for potential confounders including asthma: forced expiratory flow at 50% of forced vital capacity (FEF50 ) decreased by 141 ml/s (95%CI = [-225;-57]), FEF75 by 84 ml/s [-144;-24] and FEF25-75 by 118 ml/s [-192;-44]. FEV1 /FVC was also negatively associated with PWV (-0.750% [-1.273;-0.226]) whereas forced expiratory volume in 1s (FEV1 ) and forced vital capacity (FVC) were not. Similar results were found for measurements post-bronchodilation. Early life weight gain was negatively associated with flow indices in adolescence, suggesting structural changes in peripheral lungs.

Neonatal urinary tract infection may increase the risk of childhood asthma.

The aim of this population-based retrospective cohort study was to investigate the onset of urinary tract infection in newborns and the associated risks of childhood asthma. Children with neonatal UTI (n = 3,312) and randomly selected controls (n = 13,243) were enrolled for our analysis. We calculated the follow-up person-years for each participant from the index date until the diagnosis of asthma, the end of 2008, or withdrawal from the insurance system (because of death or loss to follow-up). Furthermore, we compared the risk of asthma between non-UTI and UTI cohorts by using Cox proportional hazards model analysis, the adjusted hazard ratio (aHR), and a 95 % confidence interval (95 % CI). The overall asthma incidence rate was found to be 1.53-fold significantly higher in the UTI cohort than in the non-UTI cohort (70.3 vs 45.8 per 1000 person-years). After we adjusted for potential risk factors, the overall risk of asthma remained higher in the UTI cohort (aHR = 1.47, 95 % CI = 1.35-1.59). The incidence rate was higher in boys than in girls. Overall, patients suffering from UTI may have a greater risk of developing asthma than patients without UTI. This nationwide retrospective cohort study demonstrates that neonatal UTI may increase the risk of childhood asthma.

Maternal vitamin D levels are inversely related to allergic sensitization and atopic diseases in early childhood.

There are few studies addressing the impact of maternal vitamin D status on the vitamin D levels in offspring, their sensitization to common allergens and atopic disease development. Children aged 0 through 4 yr from a birth cohort in the Prediction of Allergies in Taiwanese Children (PATCH) study were enrolled. Time series of serum 25-hydroxyvitamin D (25(OH)D) levels were measured in maternal blood before delivery, cord blood, and at age 1.5, 3, and 4 using an electrochemiluminescence-based assay. Specific IgE antibodies against food and inhalant allergens were measured at 6 months, and 1, 1.5, 2, 3, and 4 yr of age. A total of 164 mother-child pairs from a birth cohort were recruited in this study. The mean levels of maternal 25(OH)D were 23.2 ± 7.7 ng/ml with a high (up to 80%) prevalence of insufficient vitamin D status (< 30 ng/ml). A significant correlation was seen between maternal and cord blood 25(OH)D levels (p < 0.001), and a persistent lower 25(OH)D level was found in children born to mothers with deficient 25(OH)D levels. Deficient maternal 25(OH)D levels (<20 ng/ml) appeared to be associated with a higher prevalence of allergen sensitization before age 2. Higher maternal 25(OH)D levels were significantly associated with lower risk of eczema (OR 0.12; 95% CI 0.02-0.63; p = 0.012) and asthma (OR 0.22; 95% CI 0.06-0.92; p = 0.038) at age 4. Low maternal 25(OH)D levels appear not only to be associated with an increase in the prevalence of allergic sensitization but also the risk of eczema and asthma in early childhood.

Mode of delivery and childhood fractional exhaled nitric oxide, interrupter resistance and asthma: the Generation R study.

Previous studies suggest that caesarean section may influence the risk of childhood asthma. We examined the associations of different modes of delivery with childhood wheezing patterns, asthma, fractional exhaled nitric oxide (FeNO) and airway interrupter resistance (Rint) up to school age. This study among 6,128 children was embedded in a population-based prospective cohort study. Information on mode of delivery was obtained from midwives and hospital registries. Wheezing patterns from birth onwards and ever physician-diagnosed asthma at age 6 yr were assessed by questionnaires. FeNO and Rint were measured at age 6 yr. We used multivariate polynomial, logistic and linear regression models. Compared with vaginal delivery, caesarean section was associated with increased risks of early and persistent wheezing up to school age [odds ratios (95% confidence interval): 1.36 (1.06, 1.75) and 1.73 (1.24, 2.40), respectively]. The effect sizes of elective and emergency caesarean section with wheezing outcomes were similar. Only elective caesarean section was associated with a higher FeNO level [sympercent (95% CI): 12.7 (0.6, 24.8)]. We did not observe associations of mode of delivery with asthma or Rint. Also, vacuum- or forceps-assisted vaginal delivery was not associated with any asthma or related outcome. Both elective and emergency caesarean sections are associated with increased risks of early and persistent wheezing up to school age. This might be explained by increased airway inflammation reflected by higher FeNO levels.

Mode of delivery and childhood hospitalizations for asthma and other wheezing disorders.

Observationally, delivery by Caesarean section is associated with higher risk of childhood asthma and wheeze in developed Western settings, but associations are less consistent in other settings. To examine the association of mode of delivery with hospitalizations for asthma and other wheezing disorders in a developed non-Western setting with high rates of Caesarean section. Using Cox regression, we examined the adjusted association of mode of delivery with public hospital admissions for asthma, bronchitis, and bronchiolitis (International Classification of Diseases, Ninth Version Clinical Modification 466, 490 and 493) from 9days to 12years of age in a population-representative prospective birth cohort of 8327 Chinese children in Hong Kong. Confounders included sex, birth and parental characteristics, and socio-economic position (SEP). Delivery by Caesarean section accounted for 27% of all births and was not clearly associated with hospitalizations for asthma and other wheezing disorders to 12years [hazard ratio (HR) 1.11, 95% confidence interval (CI) 0.91 to 1.36] compared to vaginal delivery. Similarly, there were no clear associations to 2years (HR 1.07, 95% CI 0.83 to 1.38) or 6years (HR 1.12, 95% CI 0.91 to 1.37), although we cannot rule out residual confounding by SEP. We cannot rule out an association, but our findings suggest that the observed associations of delivery by Caesarean section with childhood wheezing disorders may vary with setting and may not be biologically mediated. Further studies with different designs are needed to clarify the role of the microbiome and mode of delivery in the aetiology of asthma and other childhood wheezing disorders.

Food consumption and risk of childhood asthma.

The consumption of foods rich in n-3 polyunsaturated fatty acids has been proposed to protect against childhood asthma. This study explores the association of food consumption (including cow's milk (CM)-free diet) in early life and the risk of atopic and non-atopic asthma. Food intake of 182 children with asthma and 728 matched controls was measured using 3-day food records, within the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study cohort. The diagnoses of food allergies came both from the written questionnaire and from the registers of the Social Insurance Institution. Conditional logistic regression with generalized estimating equations framework was used in the analyses. The diagnosis of cow's milk allergy (CMA) led to multiple dietary restrictions still evident at 4yr of age. Even after adjusting for CMA, higher consumption of CM products was inversely associated with the risk of atopic asthma and higher consumption of breast milk and oats inversely with the risk of non-atopic asthma. Early consumption of fish was associated with a decreased risk of all asthma. Dietary intake in early life combined with atopy history has a clear impact on the risk of developing asthma. Our results indicate that CM restriction due to CMA significantly increases and mediates the association between food consumption and childhood asthma risk.

Objectives, design and enrollment results from the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure Study (INSPIRE).

BackgroundRespiratory syncytial virus (RSV) lower respiratory tract infection (LRI) during infancy has been consistently associated with an increased risk of childhood asthma. In addition, evidence supports that this relationship is causal. However, the mechanisms through which RSV contributes to asthma development are not understood. The INSPIRE (Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure) study objectives are to: 1) characterize the host phenotypic response to RSV infection in infancy and the risk of recurrent wheeze and asthma, 2) identify the immune response and lung injury patterns of RSV infection that are associated with the development of early childhood wheezing illness and asthma, and 3) determine the contribution of specific RSV strains to early childhood wheezing and asthma development. This article describes the INSPIRE study, including study aims, design, recruitment results, and enrolled population characteristics.Methods/designThe cohort is a population based longitudinal birth cohort of term healthy infants enrolled during the first months of life over a two year period. Respiratory infection surveillance was conducted from November to March of the first year of life, through surveys administered every two weeks. In-person illness visits were conducted if infants met pre-specified criteria for a respiratory illness visit. Infants will be followed annually to ages 3-4 years for assessment of the primary endpoint: wheezing illness. Nasal, urine, stool and blood samples were collected at various time points throughout the study for measurements of host and viral factors that predict wheezing illness. Nested case-control studies will additionally be used to address other primary and secondary hypotheses.DiscussionIn the INSPIRE study, 1952 infants (48% female) were enrolled during the two enrollment years and follow-up will continue through 2016. The mean age of enrollment was 60 days. During winter viral season, more than 14,000 surveillance surveys were carried out resulting in 2,103 respiratory illness visits on 1189 infants. First year follow-up has been completed on over 95% percent of participants from the first year of enrollment.With ongoing follow-up for wheezing and childhood asthma outcomes, the INSPIRE study will advance our understanding of the complex causal relationship between RSV infection and early childhood wheezing and asthma.

Predicting risk for childhood asthma by pre-pregnancy, perinatal, and postnatal factors.

Symptoms of atopic disease start early in human life. Predicting risk for childhood asthma by early-life exposure would contribute to disease prevention. A birth cohort study was conducted to investigate early-life risk factors for childhood asthma and to develop a predictive model for the development of asthma. National representative samples of newborn babies were obtained by multistage stratified systematic sampling from the 2005 Taiwan Birth Registry. Information on potential risk factors and children's health was collected by home interview when babies were 6 months old and 5 yr old, respectively. Backward stepwise regression analysis was used to identify the risk factors of childhood asthma for predictive models that were used to calculate the probability of childhood asthma. A total of 19,192 children completed the study satisfactorily. Physician-diagnosed asthma was reported in 6.6% of 5-yr-old children. Pre-pregnancy factors (parental atopy and socioeconomic status), perinatal factors (place of residence, exposure to indoor mold and painting/renovations during pregnancy), and postnatal factors (maternal postpartum depression and the presence of atopic dermatitis before 6 months of age) were chosen for the predictive models, and the highest predicted probability of asthma in 5-yr-old children was 68.1% in boys and 78.1% in girls; the lowest probability in boys and girls was 4.1% and 3.2%, respectively. This investigation provides a technique for predicting risk of childhood asthma that can be used to developing a preventive strategy against asthma.

Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life

BackgroundCurrent data concerning maternal paracetamol intake during pregnancy, or intake during infancy and risk of wheezing or asthma in childhood is inconclusive based on epidemiological studies. We have investigated whether...

Caesarean Section has no impact on lung function at the age of 15 years

Epidemiological studies and meta-analyses have shown an increased risk of childhood asthma for children born by Caesarean Section (C-Section). To investigate the effect of delivery by C-Section on lung function and asthma in adolescence in a population-based prospective birth cohort of healthy full term newborns. Questionnaire data on mode of delivery and asthma as well as spirometric measurements were available for 1850 adolescents at the age of 15 years, who participated in a follow-up examination of the GINIplus study. Linear regression models were used to examine associations between mode of delivery and lung function parameters. Two reference populations (Lunokid and GLI) were used to calculate the standardized z-scores of lung function parameters. The mean difference in lung function parameters for adolescents born by C-Section, compared to vaginal delivery was not statistically significant. The risk for developing asthma by the age of 15 years was not higher in children born by C-Section-OR: 0.87 (95% CI: 0.57, 1.33) adjusted for sex, age, study center, and parental education level. C-Section was not associated with impaired lung function or an increased risk of asthma at the age of 15 years in our birth cohort of healthy full term neonates.

Is there an association between acetaminophen use and the risk of asthma?

Evidence-Based Answer There is a correlation between acetaminophen use and a diagnosis of asthma in children and adults. There is also a correlation between prenatal use of acetaminophen and the risk of asthma in children. This risk appears to increase with dose (SOR: B, meta-analysis of observational studies and individual observational studies). Study structures, however, do not allow a cause-and-effect assessment.

690 Exposure to Acid-Suppressing Drugs During Pregnancy and the Risk of Asthma in Childhood

690 Exposure to Acid-Suppressing Drugs During Pregnancy and the Risk of Asthma in Childhood

ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis

The ORM1 (Saccharomyces cerevisiae)-like proteins (ORMDLs) and their yeast orthologs, the Orms, are negative homeostatic regulators of the initiating enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT). Genome-wide association studies have established a strong correlation between elevated expression of the endoplasmic reticulum protein ORMDL3 and risk for childhood asthma. Here we test the notion that elevated levels of ORMDL3 decrease sphingolipid biosynthesis. This was tested in cultured human bronchial epithelial cells (HBECs) (an immortalized, but untransformed, airway epithelial cell line) and in HeLa cells (a cervical adenocarcinoma cell line). Surprisingly, elevated ORMDL3 expression did not suppress de novo biosynthesis of sphingolipids. We determined that ORMDL is expressed in functional excess relative to SPT at normal levels of expression. ORMDLs and SPT form stable complexes that are not increased by elevated ORMDL3 expression. Although sphingolipid biosynthesis was not decreased by elevated ORMDL3 expression, the steady state mass levels of all major sphingolipids were marginally decreased by low level ORMDL3 over-expression in HBECs. These data indicate that the contribution of ORMDL3 to asthma risk may involve changes in sphingolipid metabolism, but that the connection is complex.

Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation.

BackgroundPhthalates may increase the asthma risk in children. Mechanisms underlying this association remain to be addressed. This study assesses the effect of phthalate exposures on epigenetic changes and the role of epigenetic changes for asthma. In the first step, urine and blood samples from 256 children of the Childhood Environment and Allergic diseases Study (CEAS) were analyzed. Urine 5OH-MEHP levels were quantified as an indicator of exposure, and asthma information was collected. DNA methylation (DNA-M) was measured by quantitative PCR. In the screening part of step 1, DNA-M of 21 potential human candidate genes suggested by a toxicogenomic data were investigated in 22 blood samples. Then, in the testing part of step 1, positively screened genes were tested in a larger sample of 256 children and then validated by protein measurements. In step 2, we replicated the association between phthalate exposure and gene-specific DNA-M in 54 children in the phthalate contaminated food event. In step 3, the risk of DNA-M for asthma was tested in 256 children from CEAS and corroborated in 270 children from the Isle of Wight (IOW) birth cohort.ResultsDifferential methylation in three genes (AR, TNFα, and IL-4) was identified through screening. Testing in 256 children showed that methylation of the TNFα gene promoter was lower when children had higher urine 5OH-MEHP values (β = −0.138, P = 0.040). Functional validation revealed that TNFα methylation was inversely correlated with TNFα protein levels (β = −0.18, P = 0.041). In an additional sample of 54 children, we corroborated that methylation of the TNFα gene promoter was lower when urine 5OH-MEHP concentrations were higher. Finally, we found that a lower methylation of 5′CGI region of TNFα was associated with asthma in 256 CEAS children (OR = 2.15, 95% CI = 1.01 to 4.62). We replicated this in 270 children from the IOW birth cohort study. Methylation of the CpG site cg10717214 was negatively associated with asthma, when children had ‘AA’ or ‘AG’ genotype of the TNFα single nucleotide rs1800610.ConclusionsEffects of phthalate exposure on asthma may be mediated through alterations in DNA methylation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0060-x) contains supplementary material, which is available to authorized users.

Maternal waterpipe smoke exposure and the risk of asthma and allergic diseases in childhood: A post hoc analysis.

This analysis was conducted with the objective of evaluating association between waterpipe passive smoking exposure and asthma, and allergies among Lebanese children. Data were taken from a crosssectional study on children from public and private schools. A sample of 22 schools participated in the study, where standardized written core questionnaires were distributed. From 5 to 12-year-old students filled in the questionnaires at home, while 13-14-year-old students filled it in in the class. In total, 5522 children were evaluated for the prevalence of asthma, allergic rhinitis and atopic eczema, and their associated factors, including waterpipe exposure due to parents' smoking. The descriptive results of parental smoking were, as follows: among mothers: 1609 (29%) mothers smoked cigarettes, 385 (7%) smoked waterpipe and 98 (1.8%) smoked both; among fathers: 2449 (44.2%) smoked cigarettes, 573 (10.3%) smoked waterpipe and 197 (3.5%) smoked both. Maternal waterpipe smoking was significantly and moderately associated with allergic diseases (p < 0.001; ORa = 1.71), including probable asthma, rhinitis and dermatitis (p < 0.001 for all). Quite on the opposite, father's waterpipe smoking was not associated with any of the diseases. Parental cigarette smoking demonstrated some positive effects: father's cigarette smoking did not show association with dermatitis or asthma diagnosed by a physician, while mother's cigarette smoking showed a positive association only with probable asthma. Moreover, no interactions between cigarette and waterpipe smoking were observed. Maternal waterpipe smoking should be regarded as a high risk behavior; however, additional studies are necessary to confirm this finding.