Early Childhood Asthma Research Articles

Maternal Vitamin D Status and Development of Asthma and Allergy in Early Childhood.

Vitamin D has an indisputable immunodulatory role in both lung and immune system development, which is initiated during fetal life and is mainly accomplished in the first years of extrauterine life. Several published studies have shown that low levels of vitamin D may increase the risk of developing asthma and allergic diseases. Moreover, vitamin D deficiency epidemic reported over the last decades coincides with an increase in the prevalence of asthma and allergies in westernized societies. Since placental transfer of 25(OH)D is the major source of vitamin D in the developing fetus, important questions concerning the impact of maternal vitamin D status on the outcome of pregnancy have arisen. The aim of this review is to present the current evidence regarding the determinants of vitamin D status in pregnancy as well as its role in the development of asthma and allergies in early childhood.

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.

Antibiotics in Fetal and Early Life and Subsequent Childhood Asthma

Objective To investigate the association between exposure to antibiotics in fetal and early life and asthma in childhood, with adjustment for confounding factors. Design Nationwide prospective population based cohort study, including sibling control design. Setting Swedish population identified from national demographic and health registers. Participants 493 785 children born 2006-10; 180 894 of these were eligible for sibling analyses. Main outcome measure Asthma defined as having both an asthma diagnosis and dispensed asthma drugs. The association between antibiotic exposure and asthma was investigated in the whole cohort with Cox proportional hazard regression. A stratified proportional hazards model conditional on sibling group was used to adjust for shared factors within families. Confounding by respiratory infections was assessed by investigating whether specific groups of antibiotics were associated with asthma. Results Antibiotic exposure in fetal life was associated with an increased risk of asthma in cohort analyses (hazard ratio 1.28, 95% confidence interval 1.25 to 1.32), but not in sibling analyses (0.99, 0.92 to 1.07). In cohort analyses, antibiotics used to treat respiratory infections in childhood were associated with a more pronounced increased risk of asthma (4.12, 3.78 to 4.50) than antibiotics used for urinary tract and skin infections (1.54, 1.24 to 1.92). In sibling analyses, the excess risks after exposure to antibiotics for respiratory infections decreased (2.36, 1.78 to 3.13) and disappeared for antibiotics for urinary tract and skin (0.85, 0.47 to 1.55). Conclusions Previous positive associations between exposure to antibiotics in fetal and early life and subsequent childhood asthma could have been caused by confounding by shared familial factors, in addition to confounding by respiratory infections.

Maternal depressive symptoms across early childhood and asthma in school children: findings from a Longitudinal Australian Population Based Study.

There is a growing body of evidence attesting to links between early life exposure to stress and childhood asthma. However, available evidence is largely based on small, genetically high risk samples. The aim of this study was to explore the associations between the course of maternal depressive symptoms across early childhood and childhood asthma in a nationally representative longitudinal cohort study of Australian children. Participants were 4164 children and their biological mothers from the Longitudinal Study of Australian Children. Latent class analysis identified three trajectories of maternal depressive symptoms across four biennial waves from the first postnatal year to when children were 6–7 years: minimal symptoms (74.6%), sub-clinical symptoms (20.8%), and persistent and increasing high symptoms (4.6%). Logistic regression analyses revealed that childhood asthma at age 6–7 years was associated with persistent and increasing high depressive symptoms after accounting for known risk factors including smoking during pregnancy and maternal history of asthma (adjusted OR 2.36, 95% CI 1.61–3.45), p.001). Our findings from a nationally representative sample of Australian children provide empirical support for a relationship between maternal depressive symptoms across the early childhood period and childhood asthma. The burden of disease from childhood asthma may be reduced by strengthening efforts to promote maternal mental health in the early years of parenting.

Antibiotic use in early life and childhood asthma: causation or confounding?

The prevalence of childhood asthma has been increased yearly.Based on the hygiene hypothesis, the antibiotic use may increase the risk of the allergic disease by reducing microbial exposure.In the last decade, a number of epidemiological studies have been conducted on the association between early exposure of antibiotic and childhood asthma, and the results are not consistent.The majority retrospective studies have found a positive association but the prospective studies have showed a null or weak association.Reverse causation and confounding-by-indication may partly explain the relation.But it is difficult to deny a causal link between antibiotic use and asthma. Key words: Antibiotics; Asthma; Early life

Piecewise Mixed Effects Model to Compare the Weight-gain Patter ns Before and After Diagnosis of Asthma in Children Younger than 5 Years.

Asthma and obesity are two significant public health problems that both originate in early childhood and have shared risk factors and manifestations. Studies suggest a strong association between asthma development and subsequent accelerated weight gain. Children are diagnosed with asthma in early childhood and are often exposed to factors associated with rapid weight gain. This article intends to demonstrate an innovative application of the piecewise mixed effects model to characterize the difference in the temporal rate of change in BMIz, the standardized scores of body mass index and weight-for-length that measure weight status, before and after asthma diagnosis in children younger than 5 years. The data consist of unique sequences from 1194 children's clinic visits during the first 5 years of life. We used a knot at the time of diagnosis and detected a differential weight-gain pattern before and after asthma diagnosis. The pre- and post-asthma-diagnosis weight-gain patterns further differ by sex and race-ethnicity. After asthma diagnosis, female children showed a higher increase in the rate of change in BMIz than males. Non-Hispanic African Americans and Hispanics had higher post-diagnosis rates of change in BMIz than Caucasians. The differential weight-gain patterns between male and female children were mainly contributed by Caucasian children. These findings could have important implications in the clinical care of children after asthma diagnosis.

Higher cord blood 25-hydroxyvitamin D concentrations reduce the risk of early childhood eczema: in children with a family history of allergic disease

Background In recent years the role of vitamin D status in early life on the development of allergic disease has generated much interest. The aim of this study was to determine whether cord blood vitamin D concentrations were associated with risk of early childhood allergic disease.Methods Measurements of cord blood 25-hydroxyvitamin D [25(OH)D] concentrations were available in 270 mother-child pairs who were participating in the allergy follow-up (n = 706) of the Docosahexaenoic Acid to Optimise Mother Infant Outcome randomised controlled trial. All of the children had a hereditary risk of allergic disease. The diagnosis of allergic disease was made during medical assessments at 1 and 3 years of age.Results The mean (standard deviation) standardised cord blood 25(OH)D concentration was 57.0 (24.1) nmol/L. The cumulative incidence of eczema to 3 years of age, n = 101/250 (40 %) was associated with standardised cord blood 25(OH)D concentration, with a 10 nmol/L rise in 25(OH)D concentration reducing the risk of eczema by 8 % (relative risk 0.92, 95 % confidence interval 0.86–0.97; P = 0.005). This association was stronger at 1 year of age, when a 10 nmol/L rise in standardised cord blood 25(OH)D concentration reduced the risk of eczema by 12 % (relative risk 0.88, 95 % confidence interval 0.81–0.96; P = 0.002). No associations between cord blood 25(OH)D concentrations and development of allergic sensitisation, allergic rhinitis or asthma in early childhood were found.Conclusion In children with a family history of allergic disease, a higher cord blood 25(OH)D concentration appears to be associated with reduced risk of eczema in early childhood.Trial registration Australian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial: ACTRN12605000569606).

Is parent-child bed-sharing a risk for wheezing and asthma in early childhood?

Household crowding can place young children at risk for respiratory infections which subsequently provoke asthma symptoms. However, crowding might also protect against asthma, in accordance with the hygiene hypothesis. We tested if parent-infant bed-sharing, an important dimension of household crowding, increases or decreases the risk for asthma. In a population-based prospective cohort (N = 6160) we assessed bed-sharing at 2 and 24 months; wheezing between 1 and 6 years of age; and asthma at 6 years of age. Generalised estimating equation models were used to assess repeated measures of wheezing and asthma. We found no association between bed-sharing in early infancy and wheezing or diagnosis of asthma. By contrast, we found a positive association between bed-sharing in toddlerhood and both wheezing (OR 1.42, 95% CI 1.15-1.74) and asthma (OR 1.57, 95% CI 1.03-2.38). Wheezing was not associated with bed-sharing when using cross-lagged modelling. This study suggests that bed-sharing in toddlerhood is associated with an increased risk of asthma at later ages, and not vice versa. Further studies are needed to explore the underlying causal mechanisms.

Low cord blood vitamin D levels are associated with increased milk sensitization in early childhood.

The association between vitamin D status at birth and allergen sensitizations is uncertain. The aim of this study was to investigate the relationship between cord blood vitamin D status with allergen sensitizations and the development of atopic diseases in early childhood. Children aged 0 through 4 yr from a birth cohort in the Prediction of Allergies in Taiwanese Children (PATCH) study were enrolled. Serum levels of 25-hydroxyvitamin D (25(OH)D) in cord blood were measured by a new automated 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 186 children were regular followed up at clinics for a 4-yr follow-up period. The mean level of cord blood 25(OH)D was 23.8 ± 9.5 ng/ml with a high prevalence of low vitamin D status (<20 ng/ml) at birth (42%). There was a tendency of low cord blood 25(OH)D levels being associated with higher risk of food sensitization throughout childhood. Cord blood 25(OH)D levels were inversely associated with the risk of milk sensitization at age 2, at which age a higher prevalence of milk sensitization was significantly associated with the risk of allergic rhinitis, and asthma development at age 4. Low cord blood vitamin D levels appear to be associated with increased milk sensitization but not with asthma, eczema, or allergic rhinitis in early childhood.

Antibiotics in fetal and early life and subsequent childhood asthma: nationwide population based study with sibling analysis

Objective To investigate the association between exposure to antibiotics in fetal and early life and asthma in childhood, with adjustment for confounding factors.Design Nationwide prospective population based cohort study, including...

Breast-feeding and hospitalization for asthma in early childhood: a nationwide longitudinal survey in Japan.

Whether or not breast-feeding is protective against asthma among children is still controversial. Therefore, we examined the effects of breast-feeding on hospitalization for asthma in early childhood. Secondary data analyses of a nationwide longitudinal survey of children in Japan ongoing since 2001, with results collected from 2001 to 2004. We used logistic regression models to evaluate the associations of breast-feeding with hospitalization for asthma in children between the ages of 6 and 42 months, adjusting for children's factors (sex, day-care attendance and presence of older siblings) and maternal factors (educational attainment and smoking habit). Setting All over Japan. Term singleton children with information on feeding practices during infancy (n 43367). After adjusting for maternal factors and children's factors, exclusive breast-feeding at 6-7 months of age was associated with decreased risk of hospitalization for asthma in children. The adjusted odds ratio was 0.77 (95% CI 0.56, 1.06). One-month longer duration of breast-feeding was associated with a 4% decreased risk of hospitalization for asthma (OR = 0.96; 95% CI 0.92, 0.99). The protective effects of breast-feeding on hospitalization for asthma were observed in children between the ages of 6 and 42 months.

Prenatal and infant exposure to acetaminophen and ibuprofen and the risk for wheeze and asthma in children

Several studies have reported an association between use of over-the-counter antipyretics during pregnancy or infancy and increased asthma risk. An important potential limitation of these observational studies is confounding by indication. We investigated the association of antipyretic intake during pregnancy and during the first year of life (infancy) with asthma-related outcomes before and after controlling for early-life respiratory tract infections. We included 1490 mother-child pairs in Project Viva, a longitudinal prebirth cohort study. We categorized prenatal acetaminophen exposure as the maximum intake (never, 1-9 times, or ≥10 times) in early pregnancy or midpregnancy and ibuprofen intake as presence or absence in early pregnancy. We expressed intake of antipyretics in infancy as never, 1 to 5 times, 6 to 10 times, or more than 10 times. We examined the associations of acetaminophen and ibuprofen (per unit increase in exposure category) during pregnancy and infancy with wheeze, asthma, and allergen sensitization in early childhood (3-5 years of age, n = 1419) and midchildhood (7-10 years of age, n = 1220). Unadjusted models showed an increased asthma risk in early childhood for higher infant acetaminophen (odds ratio [OR], 1.21; 95% CI 1.04-1.41) and ibuprofen (OR, 1.35; 95% CI, 1.19-1.52) intake. Controlling for respiratory tract infections attenuated estimates for acetaminophen (OR, 1.03; 95% CI, 0.88-1.22) and ibuprofen (OR, 1.19; 95% CI, 1.05-1.36). Prenatal acetaminophen was associated with increased asthma (OR, 1.26; 95% CI, 1.02-1.58) in early childhood but not midchildhood. Adjustment for respiratory tract infections in early life substantially diminished associations between infant antipyretic use and early childhood asthma. Respiratory tract infections should be accounted for in studies of antipyretics and asthma to mitigate bias caused by confounding by indication.

Early life environmental predictors of asthma age-of-onset.

Prevention strategies that delay the onset of asthma may improve clinical outcomes. To identify early life environmental exposures associated with asthma age-of-onset and potential genetic modifiers of these exposures, we studied 1085 subjects with physician-diagnosed asthma and disease onset at or after age two. Subjects reported retrospectively on their exposure to 17 environmental factors before the age of two. The presence of individual or combinations of these early life exposures was then tested for association with variation in asthma age-of-onset. For exposures significantly associated with age-of-onset, we tested if 26 single nucleotide polymorphisms (SNP) with an established association with allergic disease significantly modified the effect of the exposure. Five environmental exposures were significantly associated with variation in asthma age-of-onset after correction for multiple testing: carpet at home (P = 6 × 10−5), a serious chest illness (P = 10−4), father a cigarette smoker (P = 6 × 10−4) and direct exposure to father's smoking (P = 3 × 10−4). Individuals with early childhood asthma onset, between the ages of two and six, were 1.4-fold (CI 1.1–1.9) more likely to report having lived in a house with carpet and 2.1-fold (CI 1.3–3.5) more likely to report suffering a serious chest illness before the age of two, than asthmatics with later disease onset. We further found these individual risks to increase to 3.2-fold (CI 1.7–6.0) if carpet exposure and suffering a serious chest illness co-occurred before age two. Paternal smoking exposures were less likely to be reported by asthmatics with early when compared to later disease onset (OR 0.5, CI 0.3–0.7). There were no significant SNP interactions with these environmental exposures after correction for multiple testing. Our results suggest that disease onset in individuals at a high-risk of developing asthma can potentially be delayed by avoiding exposure to carpet at home and preventing serious chest illnesses during the first 2 years of life.

Protocadherin-1: epithelial barrier dysfunction in asthma and eczema

Asthma and eczema result from the interaction between genetic susceptibility and environmental exposures. Over the last two decades, genetic studies have led to the identification of multiple susceptibility genes, increasing our understanding of the biological pathways leading to these diseases. Many asthma and eczema susceptibility genes are expressed in epithelial cells of airway mucosa and skin [1]. The epithelium constitutes the first line of defence against allergens and invading microbes. Recently, loss of epithelial integrity has been implicated as an important mechanism leading to both asthma [2] and eczema [3]. In this issue of the European Respiratory Journal , Mortensen et al. [4] report the association of genetic variants in the gene encoding protocadherin-1 ( PCDH1 ) with asthma, wheeze and eczema in (early) childhood in the Danish birth cohort study COPSAC (Copenhagen Studies on Asthma in Childhood). Their studies also suggest a gene–environment interaction of PCDH1 with passive smoke exposure in early childhood in asthma development. These studies expand on previous data reporting a role for PCDH1 polymorphisms in the susceptibility to both asthma [4–7] and eczema [4, 6, 8]. Given the replicated association of PCDH1 with both diseases, this gene might contribute to a biological pathway that constitutes a shared cause for both diseases. Here, we will summarise the cumulative data on PCDH1 polymorphisms in asthma and eczema, and make an attempt to interpret these genetic data in light of PCDH1 expression and function as a contributor to epithelial integrity. In 1993, PCDH1 was originally identified by Sano et al. [9] as protocadherin-42 and was reported to induce cell adhesion upon ectopic membrane expression in a mouse fibroblast L-cell assay. PCDH1 is a member of the δ1 subfamily of the …

Allergen challenge in vivo alters rhinovirus-induced chemokine secretion from human airway macrophages

Allergen challenge in vivo alters rhinovirus-induced chemokine secretion from human airway macrophages

Peanut, milk, and wheat intake during pregnancy is associated with reduced allergy and asthma in children

Maternal diet during pregnancy may affect childhood allergy and asthma. We sought to examine the associations between maternal intake of common childhood food allergens during early pregnancy and childhood allergy and asthma. We studied 1277 mother-child pairs from a US prebirth cohort unselected for any disease. Using food frequency questionnaires administered during the first and second trimesters, we assessed maternal intake of common childhood food allergens during pregnancy. In mid-childhood (mean age, 7.9 years), we assessed food allergy, asthma, allergic rhinitis, and atopic dermatitis by questionnaire and serum-specific IgE levels. We examined the associations between maternal diet during pregnancy and childhood allergy and asthma. We also examined the cross-sectional associations between specific food allergies, asthma, and atopic conditions in mid-childhood. Food allergy was common (5.6%) in mid-childhood, as was sensitization to at least 1 food allergen (28.0%). Higher maternal peanut intake (each additional z score) during the first trimester was associated with 47% reduced odds of peanut allergic reaction (odds ratio [OR], 0.53; 95% CI, 0.30-0.94). Higher milk intake during the first trimester was associated with reduced asthma (OR, 0.83; 95% CI, 0.69-0.99) and allergic rhinitis (OR, 0.85; 95% CI, 0.74-0.97). Higher maternal wheat intake during the second trimester was associated with reduced atopic dermatitis (OR, 0.64; 95% CI, 0.46-0.90). Peanut, wheat, and soy allergy were each cross-sectionally associated with increased childhood asthma, atopic dermatitis, and allergic rhinitis (ORs, 3.6 to 8.1). Higher maternal intake of peanut, milk, and wheat during early pregnancy was associated with reduced odds of mid-childhood allergy and asthma.

Combination corticosteroid/β-agonist inhaler as reliever therapy: A solution for intermittent and mild asthma?

The recommended treatment of mild asthma is regular maintenance inhaled corticosteroids (ICSs) with a short-acting β-agonist as a separate inhaler used when needed for symptom relief. However, the benefits of regular ICS use in actual clinical practice are limited by poor adherence and low prescription rates. An alternative strategy would be the symptom-driven (as-required or "prn") use of a combination ICS/short-acting β-agonist or ICS/long-acting β-agonist inhaler as a reliever rather than regular maintenance use. The rationale for this approach is to titrate both the ICS and β-agonist dose according to need and enhance ICS use in otherwise poorly adherent patients who overrely on their reliever β-agonist inhaler. This strategy will only work if the β-agonist component has a rapid onset of action for symptom relief. There is evidence to suggest that this regimen has advantages over regular ICS therapy and might represent an effective, safe, and novel therapy for the treatment of intermittent and mild asthma. In this commentary we review this evidence and propose that randomized controlled trials investigating different combination ICS/β-agonist inhaler products prescribed according to this regimen in intermittent and mild asthma are an important priority.

A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL1RL1, were previously reported as asthma susceptibility loci, but the effect sizes for these loci in our cohort were considerably larger than in the previous genome-wide association studies of asthma. We also obtained strong evidence for a new susceptibility gene, CDHR3 (encoding cadherin-related family member 3), which is highly expressed in airway epithelium. These results demonstrate the strength of applying specific phenotyping in the search for asthma susceptibility genes.

Use of Antibiotics During Pregnancy Increases the Risk of Asthma in Early Childhood

To investigate whether maternal use of antibiotics during pregnancy influences the development of asthma and eczema early in life.The Copenhagen Prospective Study on Asthma in Childhood (COPSAC), a birth cohort of 411 infants born between 1998 and 2001 to mothers with a history of asthma. The COPSAC data were supplemented by data from the Danish National Birth Cohort (DNBC) consisting of 101 042 pregnant women and their children recruited between 1997 and 2003. Both cohorts were followed prospectively for 5 years.History of maternal exposure to antibiotics in the third trimester was obtained during the first COPSAC enrollment visit. Asthma exacerbations were defined as need for oral prednisolone, high-dose inhaled corticosteroids (ICS), or asthma hospitalization. In the DNBC data, investigators defined maternal antibiotic use as at least 1 filled antibiotic prescription during pregnancy. Asthma was defined as either an asthma hospitalization or an ICS prescription filled at least once.In the COPSAC birth cohort, children of mothers who used antibiotics during the third trimester were at a significantly increased risk of developing early asthma exacerbation (hazard ratio [HR]: 1.98). Maternal use of antibiotics in the third trimester did not influence the child’s risk of eczema. An increased risk of asthma after maternal antibiotic exposure was confirmed via DNBC analysis: children of mothers exposed to antibiotics during pregnancy were at a higher risk of asthma hospitalization (HR: 1.17) and ICS use (HR: 1.18). For each additional antibiotic prescription filled during pregnancy, a progressively increased risk of asthma was demonstrated (adjusted P = .01).An increased risk of asthma was found in a prospectively followed cohort of children whose mothers received antibiotics during the third trimester of pregnancy. This finding was confirmed in an unselected national birth cohort of mothers. No increased risk of eczema was detected in either cohort.Perturbing the native microbiome in the lungs has been increasingly shown to affect both asthma development and clinical control. This study adds to the mounting evidence suggesting that changing the balance between beneficial and pathogenic bacteria may play a role in the development of asthma. In a prospective analysis, these investigators implicate in utero exposure to maternal antibiotics as a significant risk factor in early asthma pathogenesis.

Frequency dependence of capnography in anesthetized rabbits

Aspirative capnography may be of help to diagnose early childhood asthma, but clinical usefulness in young children is limited by the relatively high respiratory rate. This study aimed to characterize the FCO2 time course during airway constriction in 8 anesthetized rabbits, artificially ventilated at 30, 60 and 80breaths/min. Methacholine was inhaled to double the respiratory resistance measured at 8Hz by the forced oscillation technique. The capnogram shape changed in response to both methacholine and ventilatory frequency. Slope of phase II, the peak of first-order time derivative and trough of the second-order time derivative of the FCO2 signal, were significantly attenuated after methacholine compared with baseline at all breathing rates (p<0.02). Moreover, significant correlations between respiratory reactance and resistance were observed with the phase III slope and the angle described by phase II and phase III (p<0.01). It is concluded that capnography may be useful to identify acute airway changes related to bronchoconstriction, even at high breathing frequencies.