Background Asthma has its origins in early childhood, but different patterns of childhood wheezing vary in their associations with subsequent asthma, atopy, and bronchial hyperresponsiveness (BHR). ...Novel wheezing phenotypes have been identified on the basis of analyses of longitudinal data from the Avon Longitudinal Study of Parents And Children (ALSPAC). It is unclear whether these phenotypes can be replicated in other birth cohorts. Objective To compare wheezing phenotypes identified in the first 8 years of life in the ALSPAC study and the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study. Methods We used longitudinal latent class analysis to identify phenotypes on the basis of repeated reports of wheezing from 0 to 8 years in 5760 children from the ALSPAC study and 2810 children from the PIAMA study. Phenotypes were compared between cohorts. Associations with asthma, atopy, BHR, and lung function were analyzed by using weighted regression analyses. Results The model with the best fit to PIAMA data in the first 8 years of life was a 5-class model. Phenotypes identified in the PIAMA study had wheezing patterns that were similar to those previously reported in ALSPAC, adding further evidence to the existence of an intermediate-onset phenotype with onset of wheeze after 2 years of age. Associations with asthma, atopy, BHR, and lung function were remarkably similar in the 2 cohorts. Conclusion Wheezing phenotypes identified by using longitudinal latent class analysis were comparable in 2 large birth cohorts. Study of genetic and environmental factors associated with different phenotypes may help elucidate the origins of asthma.
Background Genome-wide association studies identified IL33 and IL-1 receptor–like 1 ( IL1RL1 )/ IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. ...Objective In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll–IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor–associated kinase 1, IL-1 receptor–associated kinase 4, and TNF receptor–associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction. Methods Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated. Results Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC. Conclusions IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood.
Background Maternal psychological distress during pregnancy might affect fetal lung development and subsequently predispose children to childhood asthma. Objective We sought to assess the ...associations of maternal psychological distress during pregnancy with early childhood wheezing. Methods We performed a population-based prospective cohort study among 4848 children. We assessed maternal and paternal psychological distress at the second trimester of gestation and 3 years after delivery and maternal psychological distress at 2 and 6 months after delivery by using the Brief Symptom Inventory questionnaire. Wheezing in the children was annually examined by using questionnaires from 1 to 4 years. Physician-diagnosed ever asthma was reported at 6 years. Results Mothers with psychological distress during pregnancy had increased odds of wheezing in their children from 1 to 4 years of life (overall distress: odds ratio OR, 1.60 95% CI, 1.32-1.93; depression: OR, 1.46 95% CI, 1.20-1.77; and anxiety: OR, 1.39 95% CI, 1.15-1.67). We observed similar positive associations with the number of wheezing episodes, wheezing patterns, and physician-diagnosed asthma at 6 years. Paternal distress during pregnancy and maternal and paternal distress after delivery did not affect these results and were not associated with childhood wheezing. Conclusion Maternal psychological distress during pregnancy is associated with increased odds of wheezing in their children during the first 6 years of life independent of paternal psychological distress during pregnancy and maternal and paternal psychological distress after delivery. These results suggest a possible intrauterine programming effect of maternal psychological distress leading to respiratory morbidity.
Background Data from asthma diaries are frequently used as an end point in asthma studies; however, data on the validity of Web-based diaries are scarce. Objectives First, we examined the validity of ...a Web-based diary in assessing asthma control. Second, we determined the cutoff points for well-controlled asthma of the Childhood Asthma Control Test (C-ACT) and the Asthma Control Test (ACT), and calculated the minimal important difference for both tests. Methods Children with asthma, ages 4-18 years (n = 228) completed a 4-week Web-based diary, C-ACT, ACT, and an asthma-related quality-of-life questionnaire at baseline and after 1-year follow-up. Results The completion rate of the Web-based diaries was 89%. The diary scores correlated strongly with C-ACT and ACT scores ( r = −0.73, P < .01; r = −0.64, P < .01, respectively) and the changes in diary scores correlated well with changes in C-ACT and ACT scores. The best cutoff points for well-controlled asthma were C-ACT ≥ 22 and ACT ≥ 23. The minimal important differences were 1.9 (95% CI, 1.3-2.5) for ACT and 1.6 (95% CI, 1.1-2.1) for C-ACT, and −0.7 points/d (95% CI, −1.1 to −0.4) for the Web-based diary. Conclusions Our Web-based diary was valid for recording asthma symptoms. Cutoff points of ≥22 (C-ACT) and ≥23 (ACT) define well-controlled asthma. We recommend a 2 C-ACT and ACT points difference as minimally important.
Background Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results. ...Objectives We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years). Methods First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes. Results Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma ( P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio OR, 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio pOR, 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27). Conclusion Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth.
Background The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) risk score predicts the probability of having asthma at school age among preschool children with suggestive symptoms. ...Objective We sought to externally validate the PIAMA risk score at different ages and in ethnic and socioeconomic subgroups of children in addition to updating it. Methods We studied 2877 children with preschool asthma-like symptoms participating in the multiethnic, prospective, population-based cohort study Generation R. The PIAMA risk score was assessed at preschool age, and asthma was predicted at age 6 years. Discrimination (concordance index C-index) and calibration were calculated. The PIAMA risk score was updated, and its performance was similarly analyzed. Results At age 6 years, 6% (168/2877) of the children had asthma. The discriminative ability of the original PIAMA risk score to predict asthma in Generation R was similar compared with that in the PIAMA cohort (C-index = 0.74 vs 0.71). The predicted risks by using the original PIAMA risk score for having asthma at the age of 6 years tended to be slightly higher than the observed risks (8% vs 6%). No differences in discriminative ability were found at different ages or in ethnic and socioeconomic subgroups ( P > .05). The updated PIAMA risk score had a C-index of 0.75. Conclusions The PIAMA risk score showed good external validity. The discriminative ability was similar at different ages and in ethnic and socioeconomic subgroups of preschool children, which suggests good generalizability. Further studies are needed to reproduce the predictive performance of the updated PIAMA risk score in other populations and settings and to assess its clinical relevance.
Background Clinicians have difficulty in diagnosing asthma in preschool children with suggestive symptoms. Objective We sought to develop a clinical asthma prediction score for preschool children who ...have asthma-like symptoms for the first time. Methods The Prevalence and Incidence of Asthma and Mite Allergy birth cohort followed 3,963 children for 8 years. Between 0 and 4 years of age, 2,171 (55%) children reported “wheezing,” “coughing at night without a cold,” or both. In these children possible predictor variables for asthma were assessed at the age respiratory symptoms were first reported. Asthma was defined as wheezing, inhaled steroid prescription, or a doctor's diagnosis of asthma at both age 7 and 8 years of age. Results Eleven percent of children with symptoms at 0 to 4 years of age had asthma at 7 to 8 years of age. Eight clinical parameters independently predicted asthma at 7 to 8 years of age: male sex, postterm delivery, parental education and inhaled medication, wheezing frequency, wheeze/dyspnea apart from colds, respiratory infections, and eczema. In 72% of the cases, the model accurately discriminated between asthmatic and nonasthmatic children. A clinical risk score was developed (range, 0-55 points). Symptomatic children with a score of less than 10 points had a 3% risk, whereas children with a score of 30 points or greater had a 42% risk of asthma. Conclusion A risk score based on 8 readily available clinical parameters at the time preschool children first reported asthma-like symptoms predicted the risk of asthma at 7 to 8 years of age.
Background It has been hypothesized that a disturbed early lung development underlies the susceptibility to chronic obstructive pulmonary disease (COPD). Little is known about whether subjects ...genetically predisposed to COPD show their first symptoms or reduced lung function in childhood. Objective We investigated whether replicated genes for COPD associate with transient early wheeze (TEW) and lung function levels in 6- to 8-year-old children and whether cigarette smoke exposure in utero and after birth (environmental tobacco smoke ETS) modifies these effects. Methods The association of COPD-related genotypes of 20 single nucleotide polymorphisms in 15 genes with TEW, FEV1 , forced vital capacity (FVC), and FEV1 /FVC ratio was studied in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort (n = 1996) and replicated in the Child, parents and health: lifestyle and genetic constitution (KOALA) and Avon Longitudinal Study of Parents and Children (ALSPAC) cohorts. Results AGER showed replicated association with FEV1 /FVC ratio. TNS1 associated with more TEW in PIAMA and lower FEV1 in ALSPAC. TNS1 interacted with ETS in PIAMA, showing lower FEV1 in exposed children. HHIP rs1828591 interacted with cigarette smoke exposure in utero in PIAMA and with ETS in ALSPAC, with lower lung function in nonexposed children. SERPINE2 , FAM13A , and MMP12 associated with higher FEV1 and FVC, and SERPINE2 , HHIP , and TGFB1 interacted with cigarette smoke exposure in utero in PIAMA only, showing adverse effects of exposure on FEV1 being limited to children with genotypes conferring the lowest risk of COPD. Conclusion Our findings indicate relevant involvement of at least 3 COPD genes in lung development and lung growth by demonstrating associations pointing toward reduced airway caliber in early childhood. Furthermore, our results suggest that COPD genes are involved in the infant's lung response to smoke exposure in utero and in early life.
Background Evidence on the long-term effects of air pollution exposure on childhood allergy is limited. Objective We investigated the association between air pollution exposure and allergic ...sensitization to common allergens in children followed prospectively during the first 10 years of life. Methods Five European birth cohorts participating in the European Study of Cohorts for Air Pollution Effects project were included: BAMSE (Sweden), LISAplus and GINIplus (Germany), MAAS (Great Britain), and PIAMA (The Netherlands). Land-use regression models were applied to assess the individual residential outdoor levels of particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5 ), the mass concentration of particles between 2.5 and 10 μm in size, and levels of particulate matter with an aerodynamic diameter of less than 10 μm (PM10 ), as well as measurement of the blackness of PM2.5 filters and nitrogen dioxide and nitrogen oxide levels. Blood samples drawn at 4 to 6 years of age, 8 to 10 years of age, or both from more than 6500 children were analyzed for allergen-specific serum IgE against common allergens. Associations were assessed by using multiple logistic regression and subsequent meta-analysis. Results The prevalence of sensitization to any common allergen within the 5 cohorts ranged between 24.1% and 40.4% at the age of 4 to 6 years and between 34.8% and 47.9% at the age of 8 to 10 years. Overall, air pollution exposure was not associated with sensitization to any common allergen, with odds ratios ranging from 0.94 (95% CI, 0.63-1.40) for a 1 × 10−5 ∙ m−1 increase in measurement of the blackness of PM2.5 filters to 1.26 (95% CI, 0.90-1.77) for a 5 μg/m3 increase in PM2.5 exposure at birth address. Further analyses did not provide consistent evidence for a modification of the air pollution effects by sex, family history of atopy, or moving status. Conclusion No clear associations between air pollution exposure and development of allergic sensitization in children up to 10 years of age were revealed.
Background Obesity and asthma often coexist. We hypothesized that detailed body fat distribution measures might be more strongly associated than body mass index (BMI) with childhood asthma. Objective ...We examined the associations of total body and abdominal fat measures with respiratory resistance (Rint), fractional exhaled nitric oxide (F eno ), and risks of wheezing and asthma in school-aged children. Methods In a population-based prospective cohort study among 6178 children aged 6 years, we measured BMI, fat mass index, android/gynoid ratio, and preperitoneal and subcutaneous fat mass by physical examinations, dual-energy x-ray absorptiometry, and ultrasound, respectively. We performed Rint and F eno measurements, and assessed physician-diagnosed wheezing and asthma by questionnaires. Results A higher BMI was associated with a higher Rint ( Z score 95% CI, 0.06 0.01-0.12) and increased risk of wheezing (odds ratio 95% CI, 1.07 1.00-1.14, per Z score BMI increase), but not with F eno or asthma. A high fat mass index was associated with a higher Rint ( Z score 95% CI, 0.40 0.13-0.68). A high android/gynoid fat mass ratio was associated with a lower F eno (Sym% 95% CI, −9.8 −16.3 to −3.4), whereas a high preperitoneal fat mass was associated with a higher F eno (Sym% 95% CI, 6.5 0.1-12.9). Subcutaneous fat mass was not associated with any respiratory outcome. Conclusions Studying detailed body fat distribution measures might provide better insight into the obesity-asthma paradigm.
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