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Background: Rhinovirus (RV) positive bronchiolitis episodes in infancy confer a higher risk to develop asthma in later childhood with associated lung function impairments. We aimed to investigate the association between the type of virus causing a bronchiolitis hospitalization episode and lung ventilation inhomogeneities at preschool age., Methods: Infants hospitalized with a clinical diagnosis of moderate (ward admission) or severe (pediatric intensive care ward admission) bronchiolitis were prospectively followed-up at preschool age to assess nitrogen (N 2 ) multiple breath washout (MBW). Lung clearance index (LCI), functional residual capacity (FRC), and concentration normalized phase III slope analysis (Sn III ) indices were reported from ≥2 technically acceptable trials. Differences between groups were calculated using logistic and linear regression and adjusted for confounders (sex, age at bronchiolitis admission, height at visit, maternal asthma, and doctor-diagnosed asthma, including interaction terms between the latter three). An interaction term was included in a regression model to test for an interaction between RV bronchiolitis severity and MBW parameters at preschool age., Results: One hundred and thirty-nine subjects attended preschool follow-up, of which 84 out of 103 (82%) performing MBW had technically acceptable data. Children with a history of RV positive bronchiolitis (n = 39) had increased LCI (adjusted β-coefficient [aβ] = 0.33, 95% confidence interval [CI] 0.02-0.65, p = 0.040) and conductive airways ventilation inhomogeneity [S cond ] (aβ = 0.016, CI 0.004-0.028, p = 0.011) when compared with those with a RV negative bronchiolitis history (n = 45). In addition, we found a statistical interaction between RV bronchiolitis and bronchiolitis severity strengthening the association with LCI (aβ = 0.93, CI 0.20-1.58, p = 0.006)., Conclusion: Children with a history of hospital admission for RV positive bronchiolitis in infancy might be at a higher risk of lung ventilation inhomogeneities at preschool age, arising from the peripheral conducting airways., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Exhaled nitric oxide is a marker of airway inflammation. Air pollution induces airway inflammation and oxidative stress. Little is known about the impact of air pollution on exhaled nitric oxide in young infants., Methods: The Breathing for Life Trial recruited pregnant women with asthma into a randomised controlled trial comparing usual clinical care versus inflammometry-guided asthma management in pregnancy. Four hundred fifty-seven infants from the Breathing for Life Trial birth cohort were assessed at six weeks of age. Exhaled nitric oxide was measured in unsedated, sleeping infants. Its association with local mean 24-h and mean seven-day concentrations of ozone, nitric oxide, nitrogen dioxide, carbon monoxide, sulfur dioxide, ammonia, particulate matter less than 10 μm (PM10) and less than 2.5 μm (PM2.5) in diameter was investigated. The air pollutant data were sourced from local monitoring sites of the New South Wales Air Quality Monitoring Network. The association was assessed using a 'least absolute shrinkage and selection operator' (LASSO) approach, multivariable regression and Spearman's rank correlation., Results: A seasonal variation was evident with higher median exhaled nitric oxide levels (13.6 ppb) in warmer months and lower median exhaled nitric oxide levels (11.0 ppb) in cooler months, P = 0.008. LASSO identified positive associations for exhaled nitric oxide with 24-h mean ammonia, seven-day mean ammonia, seven-day mean PM10, seven-day mean PM2.5, and seven-day mean ozone; and negative associations for eNO with seven-day mean carbon monoxide, 24-h mean nitric oxide and 24-h mean sulfur dioxide, with an R-square of 0.25 for the penalized coefficients. These coefficients selected by LASSO (and confounders) were entered in multivariable regression. The achieved R-square was 0.27., Conclusion: In this cohort of young infants of asthmatic mothers, exhaled nitric oxide showed seasonal variation and an association with local air pollution concentrations., (© 2023. The Author(s).)

Background: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear., Methods: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points., Results: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N)., Conclusions: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Little is known about the association of newborn DNA methylation (DNAm) with asthma acquisition across adolescence and early adult life., Objective: We aim to identify epigenetic biomarkers in newborns for asthma acquisition during adolescence or young adulthood., Methods: The Isle of Wight Birth Cohort (IOWBC) (n = 1456) data at ages 10, 18 and 26 years were assessed. To screen cytosine-phosphate-guanine site (CpGs) potentially associated with asthma acquisition, at the genome scale, we examined differentially methylated regions (DMR) using dmrff R package and individual CpG sites using linear regression on such associations. For CpGs that passed screening, we examined their enrichment in biological pathways using their mapping genes and tested their associations with asthma acquisitions using logistic regressions. Findings in IOWBC were tested in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort., Results: In total, 2636 unique CpGs passed screening, based on which we identified one biological pathway linked to asthma acquisition during adolescence in females (FDR adjusted p-value = .003 in IOWBC). Via logistic regressions, for females, four CpGs were shown to be associated with asthma acquisition during adolescence, and another four CpGs with asthma acquisition in young adulthood (FDR adjusted p-value < .05 in IOWBC) and these eight CpGs were replicated in ALSPAC (all p-values < .05). DNAm at all the identified CpGs was shown to be temporally consistent, and at six of the CpGs was associated with expressions of adjacent or mapping genes in females (all p-values < .05). For males, 622 CpGs were identified in IOWBC (FDR = 0.01), but these were not tested in ALSPAC due to small sample sizes., Conclusion and Clinical Relevance: Eight CpGs on LHX5, IL22RA2, SOX11, CBX4, ACPT, CFAP46, MUC4, and ATP1B2 genes have the potential to serve as candidate epigenetic biomarkers in newborns for asthma acquisition in females during adolescence or young adulthood., (© 2022 John Wiley & Sons Ltd.)

Background: Children with a history of rhinovirus (RV) positive bronchiolitis have a high risk of developing subsequent asthma. Maternal asthma might also increase this risk. The aim of this study was to investigate the combined effects of hospitalization for RV positive bronchiolitis in infancy and a history of maternal asthma on the development of asthma at preschool age., Methods: This is a prospective cohort study of 139 preschool-aged children, with a history of hospital admission for bronchiolitis in infancy, followed-up to ascertain asthma and asthma-like symptoms, skin prick allergy test positivity, and lung function measured pre- and post-bronchodilator using impulse oscillometry., Results: Children with a past hospitalization for RV positive bronchiolitis (42.4% of all) and a history of maternal asthma (36.7% of all) had the greatest prevalence and risk ratio (RR) for doctor-diagnosed asthma (prevalence 81.8% and RR 2.10, 95% confidence interval [CI] 1.37-3.19, p = .001), use of inhaled corticosteroids (68.2% and RR 2.17, 95% CI 1.19-3.99, p = .001) and short-acting β-agonists in the last 12 months (95.2% and RR 1.49, 95% CI 1.17-1.89, p = .001), as compared to those with RV negative bronchiolitis and no maternal asthma history. More children in this group had an abnormal airway resistance (33.3% and adjusted risk ratio [aRR] 3.11, 95% CI 1.03-9.47, p = .045) and reactance (27.8% and aRR 2.11, 95% CI 1.06-4.26, p = .035) at 5 Hz, as compared to those with RV negative bronchiolitis and no maternal asthma history., Conclusion: Hospitalization for RV positive bronchiolitis in early life combined with a history of maternal asthma identifies a subgroup of children with a high asthma burden while participants with only one of the two risk factors had intermediate risk for asthma., (© 2020 Wiley Periodicals LLC.)

Background: Underlying biological mechanisms involved in sex differences in asthma status changes from pre- to post-adolescence are unclear. DNA methylation (DNAm) has been shown to be associated with the risk of asthma., Objective: We hypothesized that asthma acquisition from pre- to post-adolescence was associated with changes in DNAm during this period at asthma-associated cytosine-phosphate-guanine (CpG) sites and such an association was sex-specific., Methods: Subjects from the Isle of Wight birth cohort (IOWBC) with DNAm in blood at ages 10 and 18 years (n = 124 females, 151 males) were studied. Using a training-testing approach, epigenome-wide CpGs associated with asthma were identified. Logistic regression was used to examine sex-specific associations of DNAm changes with asthma acquisition between ages 10 and 18 at asthma-associated CpGs. The ALSPAC birth cohort was used for independent replication. To assess functional relevance of identified CpGs, association of DNAm with gene expression in blood was assessed., Results: We identified 535 CpGs potentially associated with asthma. Significant interaction effects of DNAm changes and sex on asthma acquisition in adolescence were found at 13 of the 535 CpGs in IOWBC (P-values <1.0 × 10 -3 ). In the replication cohort, consistent interaction effects were observed at 10 of the 13 CpGs. At 7 of these 10 CpGs, opposite DNAm changes across adolescence were observed between sexes in both cohorts. In both cohorts, cg20891917, located on IFRD1 linked to asthma, shows strong sex-specific effects on asthma transition (P-values <.01 in both cohorts)., Conclusion and Clinical Relevance: Gender reversal in asthma acquisition is associated with opposite changes in DNAm (males vs females) from pre- to post-adolescence at asthma-associated CpGs. These CpGs are potential biomarkers of sex-specific asthma acquisition in adolescence., (© 2020 John Wiley & Sons Ltd.)

We investigated associations of asthma and smoking with lung function and airway reversibility from childhood to early adulthood.The population-based Isle of Wight Birth Cohort (n=1456) was assessed at birth, and at 1, 2, 4, 10, 18 and 26 years. Asthma was defined as physician diagnosis plus current wheeze and/or treatment. Spirometry was conducted at 10 (n=981), 18 (n=839) and 26 years (n=547). Individuals were subdivided into nonsmokers without asthma, nonsmokers with asthma, smokers without asthma and smokers with asthma, based on asthma and smoking status at 26 years. Their lung function trajectories from 10 to 26 years were examined using longitudinal models.Nonsmokers with asthma had smaller forced expiratory volume in 1 s (FEV 1 ), FEF 25-75% (forced expiratory flow at 25-75% of forced vital capacity (FVC)) and FEV 1 /FVC ratio compared to nonsmokers without asthma at age 10 and 18 years, with differences reduced after bronchodilator (pre-bronchodilator FEV 1 at 26 years 3.75 L versus 4.02 L, p<0.001; post-bronchodilator 4.02 L versus 4.16 L, p=0.08). This lung function deficit did not worsen after 18 years. Smokers without asthma had smaller FEF 25-75% and FEV 1 /FVC ratio (but not FEV 1 ) at 26 years compared to nonsmokers without asthma, with the deficit appearing after 18 years and persisting despite bronchodilator response (for FEV 1 /FVC ratio at 26 years 0.80 versus 0.81, p=0.002; post-bronchodilator 0.83 versus 0.85, p=0.005). Smokers with asthma had worse lung function compared to other groups.Lung function deficits associated with asthma and smoking occur early in life. They are not fully responsive to bronchodilators, indicating a risk for long-term lung health, which highlights the need to institute preventive measures in adolescence and early adult life before irreversible damage occurs., Competing Interests: Conflict of interest: S.H. Arshad has nothing to disclose. Conflict of interest: C. Hodgekiss has nothing to disclose. Conflict of interest: J.W. Holloway has nothing to disclose. Conflict of interest: R. Kurukulaaratchy has nothing to disclose. Conflict of interest: W. Karmaus has nothing to disclose. Conflict of interest: H. Zhang has nothing to disclose. Conflict of interest: G. Roberts has nothing to disclose., (Copyright ©ERS 2020.)

Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis., Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma., Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions., Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2., Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium., (Published by Elsevier Inc.)

Background: Epidemiologic studies have demonstrated associations between acetaminophen use and asthma. This investigation sought to determine whether sex modifies the acetaminophen-asthma association and whether leptin (LEP) and leptin receptor (LEPR) gene polymorphisms modulate the sex-specific associations., Methods: Data from the Isle of Wight birth cohort (IOW; n = 1456, aged 18 years) and Kuwait University Allergy (KUA; n = 1154, aged 18-26 years) studies were analyzed. Acetaminophen use and current asthma were self-reported. Genotype information for eighteen polymorphisms in LEP and LEPR genes were available in the IOW study. Associations between acetaminophen use and asthma were stratified by sex and genotype. Poisson regression models with robust variance estimation were evaluated to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI)., Results: Acetaminophen use was dose-dependently associated with an increased prevalence of current asthma in the IOW and KUA studies. In both studies, sex-stratified analysis showed that acetaminophen use was associated with asthma among males, but not in females (P interaction  <  0.05). Moreover, a sex- and genotype-stratified analysis of the IOW data indicated that acetaminophen was associated with asthma to a similar extent among males and females carrying two common alleles of LEPR polymorphisms. In contrast, among those carrying at least one copy of the minor allele of LEPR polymorphisms, the magnitude of association between acetaminophen use and asthma was pronounced among males (aPR = 6.83, 95% CI: 2.87-16.24), but not among females (aPR = 1.22, 95% CI: 0.61-2.45)., Conclusions: The identified sex-related effect modification of the acetaminophen-asthma association varied across LEPR genotypes, indicating that the sex-specific association was confined to individuals with certain genetic susceptibility. If the acetaminophen-asthma association is causal, then our findings will aid susceptibility-based stratification of at-risk individuals and augment preventive public health efforts.

Background: Allergic sensitization is associated with eczema, asthma, and rhinitis. However, it is unknown whether and how allergic sensitization is associated over time with acquisition, remission, and persistence of these diseases and their comorbidity., Objective: To gain a better understanding of factors including allergic sensitization transitions that influence the temporal pattern of asthma, eczema, and rhinitis and their comorbidity during childhood., Methods: In the Isle of Wight birth cohort, information on allergic sensitization to common allergens was collected at ages 4, 10, and 18 years along with asthma, rhinitis, and eczema status determined by clinical diagnosis. Logistic regressions were used to estimate subsequent and concurrent odds ratios of diseases transition with allergic sensitization transition status as the main independent variable. Two transition periods were considered, 4 to 10 years of age and 10 to 18 years of age., Results: The odds of new diagnosis of allergic disease (no-yes) was increased among subjects with acquired or persistent allergic sensitization to common allergens compared to subjects with no sensitization (acquisition of sensitization odds ratio [OR]=3.22, P < .0001; persistence of sensitization, OR=6.33, P < .0001). The odds of remission of allergic diseases (yes-no) was lower among subjects with acquired or sustained allergic sensitization (acquisition, OR=0.18, P = .0001; persistence, OR=0.085, P < .0001), compared to subjects not sensitized. Subjects with acquired or persistent allergic sensitization were also had higher odds for persistence of disease (yes-yes) than subjects not sensitized (acquisition, OR=5.49, P = .0001; persistence, OR=11.79, P < .0001)., Conclusion: Transition of allergic sensitizations to common allergens is a prognostic factor for subsequent or concurrent transition of eczema, asthma, and rhinitis. Prevention or reduction in allergic sensitization has a potential to lead to remission of these conditions., (© 2018 John Wiley & Sons Ltd.)

Recent observations that disease risk can be transmitted across generations without the need for direct exposure of the child to the index environmental insult has sparked interest in transgenerational inheritance. Epigenetics describes processes that modify gene expression without a change in the nucleotide sequence. Epigenetic processes can be induced in response to environmental exposures, can influence disease risk, and might explain these multigenerational effects. In experimental models a number of epigenetic mechanisms have been identified that could mediate vertical transmission of epigenetic inheritance. However, relevance of these findings to human disease is not yet clear. An alternative model is one in which transgenerational inheritance of disease risk requires the presence of exposure-related diseases in the mother during pregnancy (termed induced epigenetic transmission model). A number of cross-sectional studies have investigated multigenerational effects in allergy and asthma. However, given the early-life origins of asthma and allergy, birth cohort studies are ideal to investigate the effect of genetic predisposition, epigenetics, and environmental exposures, avoiding pitfalls, such as recall bias and confounding by ongoing exposures, disease, and treatment. The well-characterized 3 generations of the Isle of Wight cohort include 2 consecutive birth cohorts, providing longitudinal data that can be studied for epigenetic transfer of information, such as the effect of grand parental smoking or exposure to other toxic compounds. Further large multigenerational birth cohorts are needed to establish the clinical relevance of this phenomenon and differentiate between vertical and induced transmission models, which might influence future preventive strategies., Competing Interests: statement None of the authors have any conflicts of interests to declare., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Vaccinations have been suggested to be associated with increased risk of allergic diseases. Tetanus vaccination is one of the most frequently administered vaccines as a part of wound management and was also found to be associated with increased serum IgE levels. We hypothesized that the vaccination modifies the risk of allergic diseases through epigenetic changes such as DNA methylation., Method: Data on tetanus vaccination between 10 and 18years of age was collected from a birth cohort established on the Isle of Wight UK in 1989. DNA methylation data were collected from individuals at different ages (at birth [n=30], age 10 [n=34], age 18 [n=245] and during pregnancy [n=121]) using the Illumina Infinium HumanMethylation450K array. Firstly, we performed an epigenome-wide screening to identify cytosine-phosphate-guanine sites (CpGs) associated with tetanus vaccination in 18-year-olds. Secondly, we tested their association with asthma, allergic sensitization, eczema, serum IgE and pulmonary lung function (FVC, FEV1, FEV1/FVC, and FEF25-75%). We then described changes in the methylation of the selected CpG sites over age, and by vaccination status., Results: Tetanus vaccination was found to be associated with decreased methylation of cg14472551 (p value 0.5×10 - 5 ) and increased methylation of cg01669161 (p value 0.0007, FDR-adjusted p value 0.014). Both CpGs, in turn, were associated with decreased risk of asthma at 18years of age. Cg14472551 is located in an intron of KIAA1549L, whose protein binds to a B-cell commitment transcription factor; cg01669161 is located between an antisense regulator of the proteasome assembly chaperone PSMG3, and TFAMP1, a pseudogene. Increased methylation of cg01669161 was also associated with decreased serum IgE levels.- 4 ) and increased methylation of cg01669161 (p value 0.0007, FDR-adjusted p value 0.014). Both CpGs, in turn, were associated with decreased risk of asthma at 18years of age. Cg14472551 is located in an intron of KIAA1549L, whose protein binds to a B-cell commitment transcription factor; cg01669161 is located between an antisense regulator of the proteasome assembly chaperone PSMG3, and TFAMP1, a pseudogene. Increased methylation of cg01669161 was also associated with decreased serum IgE levels., Conclusion: DNA methylation changes following tetanus vaccination may offer a novel prospect to explain a differential occurrence of asthma in adolescence., Competing Interests: The authors declare that they have no conflicts of interests., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Rhinitis affects many young adults and often shows comorbidity with asthma., Objective: We hypothesized that young adult rhinitis, like asthma, exhibits clinical heterogeneity identifiable by means of cluster analysis., Methods: Participants in the Isle of Wight birth cohort (n = 1456) were assessed at 1, 2, 4, 10, and 18 years of age. Cluster analysis was performed on those with rhinitis at age 18 years (n = 468) by using 13 variables defining clinical characteristics., Results: Four clusters were identified. Patients in cluster 1 (n = 128 [27.4%]; ie, moderate childhood-onset rhinitis) had high atopy and eczema prevalence and high total IgE levels but low asthma prevalence. They showed the best lung function at 18 years of age, with normal fraction of exhaled nitric oxide (Feno), low bronchial hyperresponsiveness (BHR), and low bronchodilator reversibility (BDR) but high rhinitis symptoms and treatment. Patients in cluster 2 (n = 199 [42.5%]; ie, mild-adolescence-onset female rhinitis) had the lowest prevalence of comorbid atopy, asthma, and eczema. They had normal lung function and low BHR, BDR, Feno values, and total IgE levels plus low rhinitis symptoms, severity, and treatment. Patients in cluster 3 (n = 59 [12.6%]; ie, severe earliest-onset rhinitis with asthma) had the youngest rhinitis onset plus the highest comorbid asthma (of simultaneous onset) and atopy. They showed the most obstructed lung function with high BHR, BDR, and Feno values plus high rhinitis symptoms, severity, and treatment. Patient 4 in cluster 4 (n = 82 [17.5%]; ie, moderate childhood-onset male rhinitis with asthma) had high atopy, intermediate asthma, and low eczema. They had impaired lung function with high Feno values and total IgE levels but intermediate BHR and BDR. They had moderate rhinitis symptoms., Conclusion: Clinically distinctive adolescent rhinitis clusters are apparent with varying sex and asthma associations plus differing rhinitis severity and treatment needs., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Adolescence is a period of change, which coincides with disease remission in a significant proportion of subjects with childhood asthma. There is incomplete understanding of the changing characteristics underlying different adolescent asthma transitions. We undertook pathophysiological characterization of transitional adolescent asthma phenotypes in a longitudinal birth cohort., Methods: The Isle of Wight Birth Cohort (N = 1456) was reviewed at 1, 2, 4, 10 and 18-years. Characterization included questionnaires, skin tests, spirometry, exhaled nitric oxide, bronchial challenge and (in a subset of 100 at 18-years) induced sputum. Asthma groups were "never asthma" (no asthma since birth), "persistent asthma" (asthma at age 10 and 18), "remission asthma" (asthma at age 10 but not at 18) and "adolescent-onset asthma" (asthma at age 18 but not at age 10)., Results: Participants whose asthma remitted during adolescence had lower bronchial reactivity (odds ratio (OR) 0.30; CI 0.10 -0.90; p = 0.03) at age 10 plus greater improvement in lung function (forced expiratory flow 25-75% gain: 1.7 L; 1.0-2.9; p = 0.04) compared to persistent asthma by age 18. Male sex (0.3; 0.1-0.7; p < 0.01) and lower acetaminophen use (0.4; 0.2-0.8; p < 0.01) independently favoured asthma remission, when compared to persistent asthma. Asthma remission had a lower total sputum cell count compared to never asthma (31.5 [25-75 centiles] 12.9-40.4) vs. 47.0 (19.5-181.3); p = 0.03). Sputum examination in adolescent-onset asthma showed eosinophilic airway inflammation (3.0%, 0.7-6.6), not seen in persistent asthma (1.0%, 0-3.9), while remission group had the lowest sputum eosinophil count (0.3%, 0-1.4) and lowest eosinophils/neutrophils ratio of 0.0 (Interquartile range: 0.1)., Conclusion: Asthma remission during adolescence is associated with lower initial BHR and greater gain in small airways function, while adolescent-onset asthma is primarily eosinophilic.

Background: Knowledge on the long-term development of adiposity throughout childhood/adolescence and its prenatal determinants and health sequelae is lacking. We sought to (1) identify trajectories of Body Mass Index (BMI) from 1 to 18 years of age, (2) examine associations of maternal gestational smoking and early pregnancy overweight with offspring BMI trajectories and (3) determine whether BMI trajectories predict health outcomes: asthma, lung function parameters (forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio), and blood pressure, at 18 years., Methods: The Isle of Wight birth cohort, a population-based sample of 1456 infants born between January 1989 and February 1990, was prospectively assessed at ages 1, 2, 4, 10 and 18 years. Group-based trajectory modelling was applied to test for the presence of latent BMI trajectories. Associations were assessed using log-binomial and linear regression models., Results: Four trajectories of BMI were identified: 'normal', 'early persistent obesity', 'delayed overweight', and 'early transient overweight'. Risk factors for being in the early persistent obesity trajectory included maternal smoking during pregnancy (RR 2.16, 95% CI 1.02 to 4.68) and early pregnancy overweight (3.16, 1.52 to 6.58). When comparing the early persistent obesity to the normal trajectory, a 2.15-fold (1.33 to 3.49) increased risk of asthma, 3.2% (0.4% to 6.0%) deficit in FEV1/FVC ratio, and elevated systolic 11.3 mm Hg (7.1 to 15.4) and diastolic 12.0 mm Hg (8.9 to 15.1) blood pressure were observed at age 18 years., Conclusions: Maternal prenatal exposures show prolonged effects on offspring's propensity towards overweight-obesity. Distinct morbid BMI trajectories are evident during the first 18 years of life that are associated with higher risk of asthma, reduced FEV1/FVC ratio, and elevated blood pressure., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Associations of variants of the filaggrin gene, i.e. FLG with asthma and rhinitis have been shown to be modulated by eczema status. However, it is unknown whether allergic sensitization status modifies this association. The aim of this study was to determine whether FLG variants need eczema and/or allergic sensitization as a necessary component to execute adverse effects on coexisting and subsequent asthma and rhinitis., Methods: In the Isle of Wight birth cohort, repeated measurements of asthma, rhinitis, eczema and allergic sensitization (documented by skin-prick tests) were taken in 1,456 children at the ages of 1, 2, 4, 10 and 18 years. Filaggrin haploinsufficiency was defined as having at least the minor allele of R501X, 2282del4 or S3247X variants. log-binomial regression models were used to test associations and statistical interactions., Results: FLG variants increased the risk of asthma [risk ratio (RR) 1.39, 95% confidence interval (CI) 1.06-1.80] and rhinitis (RR 1.37, 95% CI 1.16-1.63). In the delayed-effects models, 'FLG variants plus allergic sensitization' and 'FLG variants plus eczema' increased the risk of subsequent asthma by 4.93-fold (95% CI 3.61-6.71) and 3.33-fold (95% CI 2.45-4.51), respectively, during the first 18 years of life. In contrast, neither eczema nor allergic sensitization in combination with FLG variants increased the risk of later rhinitis., Conclusions: Allergic sensitization and eczema modulated the association between FLG variants and asthma but not rhinitis. Our results imply that the mechanisms and pathways through which FLG variants predispose to an increased risk of asthma and rhinitis may be different., (© 2014 S. Karger AG, Basel.)

Background: Maternal allergy and gestational exposures can alter the concentration of type-1/type-2/T-regulatory markers in breast milk. We tested whether maternal risk factors are related to breast milk immune markers., Methods: Expecting mothers were enrolled in 2008-2010 in South Carolina in prenatal clinics and classes. Interferon (IFN)-γ-induced protein 10 (CXCL10), CCL11, interleukin (IL)-1β, IL-4, IL-5, IL-6, CXCL8, IL-10, IL-12(p70), IL-13, transforming growth factor (TGF)-β1, and immunoglobulin (Ig)A in 115 whey samples were measured by immunoassays. Maternal asthma, eczema, rhinitis, smoking, urogenital infections during gestation, pet exposure, education, race/ethnicity, age, body mass, and the child's birth date and sex were ascertained. The effects of these risk factors on immune markers were estimated using general linear models., Results: Maternal asthma was linked to higher levels of IL-5, rhinitis to lower levels of IL-5 and INF-γ, and eczema to lower levels of IL-6. Gestational smoking was related to increased concentrations of CXCL8 and IL-6. African-American mothers had markedly higher levels of IL-6, IFN-γ, and CXCL8. Urogenital infections, maternal age, body mass, child's sex, and season of birth contributed to the variation., Conclusion: The impact of maternal allergies on immune markers in breast milk was small compared with that of maternal nondisease characteristics.

Purpose of Review: Epigenetic mechanisms have the ability to alter the phenotype without changing the genetic code. The science of epigenetics has grown considerably in recent years, and future epigenetically based treatments or prevention strategies are likely. Epigenetic associations with asthma have received growing interest because genetic and environmental factors have been unable to independently explain the cause of asthma., Recent Findings: Recent findings suggest that both the environment and underlying genetic sequence variation influence DNA methylation, which in turn seems to modify the risk conferred by genetic variants for various asthma phenotypes. In particular, DNA methylation may act as an archive of a variety of early developmental exposures, which then can modify the risk related to genetic variants., Summary: Current asthma treatments may control the symptoms of asthma but do not modify its natural history. Epigenetic mechanisms and novel explanatory models provide burgeoning approaches to significantly increase our understanding of the initiation and progression of asthma. Due to the inheritance of epigenetics, we anticipate a rapid emergence of critical information that will provide novel treatment strategies for asthma in the current generation and ultimately the prevention of asthma in future generations.

Background: In settings in which diseases wax and wane, there is a need to measure disease dynamics in longitudinal studies. Traditional measures of disease occurrence (eg, cumulative incidence) do not address change or stability or are limited to stable cohorts (eg, incidence) and may thus lead to erroneous conclusions. To illustrate how different measures can be used to detect disease dynamics, we investigated sex differences in the occurrence of asthma and wheezing, using a population-based study cohort that covered the first 18 years of life., Methods: In the Isle of Wight birth cohort (n = 1456), prevalence, incidence, cumulative incidence, positive and negative transitions, and remission were determined at ages 1 or 2, 4, 10, and 18 years. Latent transition analysis was used to simultaneously identify classes of asthma and wheezing (related phenotypes) and characterize transition probabilities over time. Trajectory analysis was used to characterize the natural history of asthma and wheezing., Results: Regarding time-specific changes, positive and negative transition probabilities were more informative than other measures of associations because they revealed a sex switchover in asthma prevalence (P < 0.05). Transition probabilities were able to identify the origin of a sex-specific dynamic; in particular, prior wheezing transitioned to asthma at age 18 years among girls but not among boys. In comparison with latent transition analysis, trajectory analysis did not directly identify a switchover in prevalence among boys and girls., Conclusions: In longitudinal analyses, transition analyses that impose minimal restrictions on data are needed in order to produce appropriate information on disease dynamics.

Objective: The relationship between fatty acids (FAs) in breast milk and the risk of childhood allergies is controversial. We prospectively investigated the relationship between FAs in colostrum and breast milk and asthma-like symptoms (AS) and atopy in infancy., Methods: Pregnant women were recruited in Columbia and Charleston, South Carolina. Colostrum and mature milk samples were collected. The concentrations of n-3 FAs (eicosapentaenoic acid, α-linolenic acid, docosapentaenoic acid, and docosahexaenoic acid) and n-6 FAs (linoleic acid, arachidonic acid, and eicosadienoic acid) were determined by gas chromatography. AS were ascertained at 6 and 12 months of age and atopy (skin prick test) at 12 months. FAs were dichotomized (high vs. median and low). Generalized estimating equations were used to determine the effect of FAs on repeated AS, compensating for intra-individual correlations and adjusting for confounders. Log-linear regression was used to analyze atopy., Results: FAs were analyzed in 24 colostrum and 78 breast milk samples. High levels of total n-6 (lipid based) FAs in breast milk were associated with an increased risk of AS in infants (risk ratio (RR) = 2.91; 95% confidence interval (CI): 1.37, 6.18), even after controlling for total n-3 FAs (RR = 2.07, 95% CI: 1.12, 3.85). High levels of total n-3 FAs controlling for n-6 FAs decreased the risk of atopy at the age of 12 months., Conclusions: High levels of total n-6 polyunsaturated fatty acids (PUFAs) in breast milk are associated with an increased risk for AS, whereas high levels of total n-3 PUFAs decreased the risk of atopy. These data suggest that the effects of n-3 and n-6 PUFAs on allergic disorders should be further explored.

Background: The parent-of-origin effect is important in understanding the genetic basis of childhood allergic diseases and improving our ability to identify high-risk children., Objective: We sought to investigate the parent-of-origin effect in childhood allergic diseases., Methods: The Isle of Wight Birth Cohort (n= 1456) has been examined at 1, 2, 4, 10, and 18 years of age. Information on the prevalence of asthma, eczema, rhinitis, and environmental factors was obtained by using validated questionnaires. Skin prick tests were carried out at ages 4, 10, and 18 years, and total IgE measurement was carried out at 10 and 18 years. Parental history of allergic disease was assessed soon after the birth of the child, when maternal IgE levels were also measured. Prevalence ratios (PRs) and their 95% CIs were estimated, applying log-linear models adjusted for confounding variables., Results: When stratified for sex of the child, maternal asthma was associated with asthma in girls (PR, 1.91; 95% CI, 1.34-2.72; P= .0003) but not in boys (PR, 1.29; 95% CI, 0.85-1.96; P= .23), whereas paternal asthma was associated with asthma in boys (PR, 1.99; 95% CI, 1.42-2.79; P< .0001) but not in girls (PR, 1.03; 95% CI, 0.59-1.80; P= .92). Maternal eczema increased the risk of eczema in girls (PR, 1.92; 95% CI, 1.37-2.68; P= .0001) only, whereas paternal eczema did the same for boys (PR, 2.07; 95% CI, 1.32-3.25; P = .002). Similar trends were observed when the effect of maternal and paternal allergic disease was assessed for childhood atopy and when maternal total IgE levels were related to total IgE levels in children at ages 10 and 18 years., Conclusions: The current study indicates a sex-dependent association of parental allergic conditions with childhood allergies, with maternal allergy increasing the risk in girls and paternal allergy increasing the risk in boys. This has implications for childhood allergy prediction and prevention., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Asthma is a common disease of children with a complex genetic origin. Understanding the genetic basis of asthma susceptibility will allow disease prediction and risk stratification., Objective: We sought to identify asthma susceptibility genes in children., Methods: A nested case-control genetic association study of children of Caucasian European ancestry from a birth cohort was conducted. Single nucleotide polymorphisms (SNPs, n = 116,024) were genotyped in pools of DNA samples from cohort children with physician-diagnosed asthma (n = 112) and normal controls (n = 165). A genomic region containing the ATPAF1 gene was found to be significantly associated with asthma. Additional SNPs within this region were genotyped in individual samples from the same children and in 8 independent study populations of Caucasian, African American, Hispanic, or other ancestries. SNPs were also genotyped or imputed in 2 consortia control populations. ATPAF1 expression was measured in bronchial biopsies from asthmatic patients and controls., Results: Asthma was found to be associated with a cluster of SNPs and SNP haplotypes containing the ATPAF1 gene, with 2 SNPs achieving significance at a genome-wide level (P = 2.26 × 10(-5) to 2.2 × 10(-8)). Asthma severity was also found to be associated with SNPs and SNP haplotypes in the primary population. SNP and/or gene-level associations were confirmed in the 4 non-Hispanic populations. Haplotype associations were also confirmed in the non-Hispanic populations (P = .045-.0009). ATPAF1 total RNA expression was significantly (P < .01) higher in bronchial biopsies from asthmatic patients than from controls., Conclusion: Genetic variation in the ATPAF1 gene predisposes children of different ancestries to asthma., (Published by Mosby, Inc.)

Breastfeeding represents the continued exposure of the infant to the maternal immune environment.Uterine, perinatal, and postnatal exposure to immune factors may contribute to an infant’s risk of developing immune-mediated disorders, including allergies. A PubMed search was conducted to review studies in humans and analyze concentrations of immune markers (TGF-beta, IFN-gamma, eotaxin, CCL5, CXCL10, TNF-alpha, MCP-1, IL-1beta, IL-4, IL-5, IL-6,IL-8, IL-10, IL-12, IL-13, sCD14, sIgA, IgG4, IgM) found in maternal serum, amniotic fluid, cord serum, colostrum, transition and mature milk. Concentrations of immune markers showed large variations across samples and studies. Reports documented conflicting results. Small sample sizes, differences in population characteristics, inconsistent sample collection times, and various sample collection and measurement methods may have led to wide variations in the concentrations of immune markers. Studies analyzing the associations between immune markers in maternal fluids and infant allergies remain inconclusive because of gaps in knowledge and a lack of standardized methods.

Background: Asthma is considered to be associated with elevated levels of exhaled nitric oxide (FeNO). The nature of this relationship and how it is influenced by atopy are still not resolved., Methods: The Isle of Wight birth cohort (N=1456) was reassessed at 18 years of age. Participants able to attend the research centre were assessed by questionnaires, skin prick testing and FeNO in order to explore the interrelationship between asthma, atopy and FeNO., Results: Atopy was significantly associated with higher levels of FeNO. However, the level of FeNO for non-atopic asthmatic participants was no different to the non-atopic no-asthma group. The highest levels of FeNO were seen in subjects with both atopy and asthma. In addition, FeNO was positively associated with increasing atopic burden as evidenced by increasing FeNO with increasing skin prick testing positivity, and with increasing severity of atopic asthma as evidenced by the number of attacks of wheezing. FeNO and current inhaled corticosteroid use were not significantly associated., Conclusions: FeNO behaves as a biomarker of atopy and the "allergic asthma" phenotype rather than asthma itself. This may explain why FeNO-guided asthma treatment outcomes have proved to be of limited success where atopic status has not been considered and accounted for.

The effect of breastfeeding on asthma is controversial, which may be explained by related and interacting early childhood risk factors. We assessed the joint effects of a risk-triad consisting of maternal smoking during pregnancy, breastfeeding for less than 3 months, and recurrent lower respiratory tract infections (RLRTI) on physician-diagnosed childhood asthma. The association was assessed in the Isle of Wight birth cohort study (1989-1990) using a repeated measurement approach with data collection at birth, and at ages 1, 2, 4, and 10 years. The population consists of 1,456 children recruited between January 1989 and February 1990. Prenatal smoking, breastfeeding for less than 3 months, and recurrent lower respiratory infections (RLRTI) were combined into eight risk-triads. Relative risks (RR) and 95% confidence intervals were estimated with a log-linear model. The risk-triad involving RLRTI in infancy, maternal smoking during pregnancy, and breastfeeding for less than 3 months showed a stronger association with asthma at ages 4 and 10 compared to other risk-triads (RR of 5.79 for any asthma at ages 1, 2, 4, and 10; and 3.1 for asthma at ages 4 and 10). Of the three individual risk factors, RLRTI appeared to be the major driver of the combined effects in the risk-triads. The effect of RLRTI on asthma was modified by breastfeeding. Breastfeeding for > or = 3 months also attenuated the effect of prenatal smoking on asthma in children without RLRTI. A high proportion of asthma cases in childhood can be prevented by promoting breastfeeding, by preventing smoking during pregnancy, and by avoidance of recurrent lower respiratory tract infections in early childhood.

Background: Tobacco smoke and genetic susceptibility are risk factors for asthma and wheezing. The aim of this study was to investigate whether there is a combined effect of interleukin-13 gene (IL13) polymorphisms and tobacco smoke on persistent childhood wheezing and asthma., Methods: In the Isle of Wight birth cohort (UK, 1989-1999), five IL13 single nucleotide polymorphisms (SNPs): rs1800925 (-1112C/T), rs2066960, rs1295686, rs20541 (R130Q) and rs1295685 were genotyped. Parents were asked whether their children had wheezed in the last 12 months at ages 1, 2, 4 and 10 years. Children who reported wheeze in the first 4 years of life and also had wheezing at age 10 were classified as early-onset persistent wheeze phenotype; non-wheezers never wheezed up to age 10. Persistent asthma was defined as having a diagnosis of asthma both during the first four years of life and at age 10. Logistic regression methods were used to analyze data on 791 children with complete information. Potential confounders were gender, birth weight, duration of breast feeding, and household cat or dog present during pregnancy., Results: Maternal smoking during pregnancy was associated with early-onset persistent wheeze (OR 2.93, p < 0.0001); polymorphisms in IL13 were not (OR 1.15, p = 0.60 for the common haplotype pair). However, the effect of maternal smoking during pregnancy was stronger in children with the common IL13 haplotype pair compared to those without it (OR 5.58 and OR 1.29, respectively; p for interaction = 0.014). Single SNP analysis revealed a similar statistical significance for rs20541 (p for interaction = 0.02). Comparable results were observed for persistent childhood asthma (p for interaction = 0.03)., Conclusion: This is the first report that shows a combined effect of in utero exposure to smoking and IL13 on asthma phenotypes in childhood. The results emphasize that genetic studies need to take environmental exposures into account, since they may explain contradictory findings.

The effect of cow's milk consumption on childhood asthma has been debated for several years. This study attempts to provide further insight into this association through the use of a longitudinal study design. Newborns from parents with atopic history were recruited from Germany, Austria, and England (n = 696). For five repeated ascertainments, information was collected on cow's milk exposure, incidence of doctor-diagnosed asthma, and confounders. Generalized estimation equations, incorporating different models (concurrent, delayed, combined, and reverse causation), were used to determine this association. No association between cow's milk consumption and childhood asthma was found for the concurrent effects model (OR = 0.81, 95% confidence interval [CI]: 0.55, 1.20). In the delayed effects model, the direction of the association varied with time of follow-up. Thus, we stratified by period, which resulted in a significant protective delayed effect at 36 months (OR = 0.18, 95% CI = 0.06, 0.49). However, reverse causation negated this finding since the presence of asthma in prior months led to a reduction in further exposure to cow's milk (OR = 0.40, 95% CI = 0.16, 0.99). Hence, cow's milk consumption does not protect against childhood asthma. The apparent protection of cow's milk against asthma may result from parents of asthmatic children avoiding cow's milk, rather than actual prophylaxis.

The interleukin-1 receptor antagonist (IL1RN) is a potent anti-inflammatory cytokine. In the present study, association of the human IL1RN gene polymorphisms with asthma, bronchial hyperresponsiveness and forced expiratory volume in one second/forced vital capacity ratio was tested and the data was stratified by environmental tobacco smoke exposure in order to investigate a gene-smoking interaction. In an unselected subset (n = 921) of the Isle of Wight birth (UK) cohort, which has previously been evaluated for asthma and related manifestations at ages 1, 2, 4 and 10 yrs, three IL1RN single nucleotide polymorphisms (SNP) were genotyped. Logistic regression and repeated measurement models for tests of association using a representative SNP rs2234678 were used, as all SNPs tested were in strong linkage disequilibrium. In the overall analysis, the SNP rs2234678 was not associated with asthma. However, in the stratum with maternal smoking during pregnancy the rs2234678 GG genotype significantly increased the relative risk of asthma in children, both in analyses of repeated asthma occurrences and persistent asthma. In conclusion, the present results show that in the first decade of life, the gene-environment interaction of the interleukin-1 receptor antagonist gene polymorphism rs2234678 and maternal smoking during pregnancy increased the risk for childhood asthma.

Despite the numerous studies on the possible protective effect of breast feeding against the onset of atopic manifestations during childhood, this issue remains controversial. As part of an environmental epidemiological study, we investigated whether different blood concentrations of dichlorodiphenyl-dichloroethylene (DDE) modified the protective effect of breast feeding against atopic manifestations in 338 children. DDE concentration, duration of breast feeding and manifestation of atopic disorders were measured in 1994-95 at age 7-8 years. Information gathered on asthma, atopic eczema and hay fever was based on questionnaire data. We measured the total serum concentration of immunoglobulin E (IgE) and specific IgE levels against inhalant allergens. In 1997, we also determined bronchial hyper-reactivity with a hypertonic saline challenge test. To estimate odds ratios from our cross-sectional analysis, we applied logistic regressions, controlling for confounders. Breast feeding had a protective effect on the two asthma variables (e.g.> 12 weeks breast feeding for doctor-diagnosed asthma, OR = 0.32 [95% CI 0.11, 0.87]; for 'ever' asthma, OR = 0.13 [95% CI 0.02, 0.68]), but not on bronchial hyper-reactivity, hay fever, atopic eczema or the two IgE variables. The protective effect became stronger in children with DDE blood levels below the median of 0.29 micro g/L (e.g. doctor-diagnosed asthma,> 12 weeks breast feeding, OR = 0.24 [95% CI 0.06, 0.95]). Also, for specific IgE against inhalant allergens, the association gained statistical significance. For children with a DDE concentration of 0.29 micro g/L and higher, breast feeding did not show a significant protective effect. Our results suggest that contaminants such as DDE may modify the protective effect and may have contributed to inconsistent findings on the protective effect of breast feeding in previous studies. We recommend determining levels of breast milk contaminants in children when assessing the impact of breast feeding on atopic manifestations.

The authors investigated whether organochlorine exposure is associated with prevalence of otitis media, pneumonia, pertussis, asthma, and increased immunoglobulin E levels in children. Organochlorine concentrations and histories of infection and atopic manifestation were available for 343 children, and immunoglobulin E levels were available for 340 children. The authors applied logistic and linear regressions and controlled for confounders. In general, the prevalence of infections in children was not related to organochlorine exposure. However, for the combined effect of dichlorodiphenyldichloroethene with polychlorinated biphenyls or hexachlorobenzene, a significantly increased relative risk (odds ratios = 3.70 and 2.38, respectively) was found for otitis media. Exposure to dichlorodiphenyldichloroethene resulted in a significantly higher odds ratio for asthma (odds ratio = 3.71; 95% confidence interval = 1.10, 12.56) and in immunoglobulin E concentrations above 200 kU/l (odds ratio = 2.28; 95% confidence interval = 1.20, 4.31). This is the first study in which dichlorodiphenyldichloroethene has been identified as a substantial risk factor for asthma and for increased immunoglobulin E blood levels.

SUMMARY. To evaluate the importance of a past history of asthma-like symptoms over a period of 2 years and current bronchial hyperreactivity (BHR), 538 randomly selected schoolchildren, initially aged 7-8 years, were examined. At yearly intervals, three standardized questionnaires, including items from the ISAAC panel, were answered by parents. Following the last questionnaire, BHR to 4.5% hypertonic saline (HS) was recorded. In survey 1, lifetime prevalence of asthma was 4.9%. During the 12-month period, prevalence of wheeze and dyspnea ranged between 9.3 and 5.2% (Survey 1) and 5.9% and 4.4% (Survey 2). Among children with wheeze or dyspnea in Survey 3, BHR (defined as a fall of baseline FEV(1) > or = 15%) was significantly more frequent (50.0% and 60.7%, respectively) than among children without these symptoms (12.8%, P < 0.001, and 12.8%, P < 0.001, respectively). The negative predictive value of BHR to have neither wheeze nor dyspnea was about 88% and did not vary throughout the study (Survey 1, 87%; Survey 2, 88%; Survey 3, 88%). The relative risk of showing BHR was significantly increased in children with wheeze (survey 2, odds ratio (OR) 3.0 (95% confidence interval (CI) 1.0-8.7)) or dyspnea (Survey 1: OR 5.9 (95% CI 1.9-18.5), Survey 3: 5.2 (1.7-16.2), but not in children with dry cough or nocturnal cough (data not shown). Wheeze and dyspnea occurred repeatedly in the same individuals with BHR in a high percentage of children (83.3% and 76.5%, respectively). In conclusion, there is a strong association between recent and previous dyspnea and current BHR, and it indicates intraindividual persistence of symptom history., (Copyright 2001 Wiley-Liss, Inc.)

It has been suggested that the number of siblings in a family is a surrogate variable for exposure to early infections. Since there may be an association between early respiratory infections and impaired lung function in later life, the aim of this study was to elucidate the relationship between the number of siblings and pulmonary function. We analyzed pulmonary function data from 677 schoolchildren living in 431 nuclear families. Our results show that forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV(1)) expressed as a percentage of deviation from the predicted values (FVC%, FEV(1)%) increase significantly in line with the number of siblings in a family (FVC%: no sibling = reference, 1 sibling = +1.3%, 2 siblings = +1.9%, 3 siblings = +4.0%, 4 or more siblings = +5.1%; P-value for trend = 0.01; FEV(1)%: no sibling = reference, 1 sibling = +1.6%, 2 siblings = +2.0%, 3 siblings = +4.3%, 4 or more siblings = +6.5%; P-value for trend = 0.007). Pulmonary function values were no more strongly related to the number of older siblings than to the number of younger siblings (difference between the trend for older and younger siblings for FCV%: P = 0.7; FEV(1)%: P = 0.9). The association between pulmonary function and number of siblings can be explained neither by the child's atopic status, prevalence of asthma, or history of pneumonia, nor by former or current cigarette smoke exposure. This suggests that pulmonary function status of the child appears to be related to the number of siblings, and is unlikely to be explained solely by exposure to infections early in life. Our data therefore adds strength to the hypothesis that factors which cause the size of a sibship to influence a child's respiratory health have not yet been adequately explained., (Copyright 1999 Wiley-Liss, Inc.)

Background: To describe the natural history of asthma between the ages of 7 and 10 years and to analyze risk factors for prevalences, as well as new onset of asthma-like symptoms, a longitudinal study of 1812 children was conducted., Methods: In four surveys, each 1 year apart, four asthma-like symptoms and several hypothetical risk factors were ascertained through standardized questionnaires. Sensitization to seven common inhalant allergens was measured by skin prick testing. Exposure to mite allergens (Der p I, Der f I) was assessed by measuring the antigen concentrations in the dust of each child's mattress. Occurrence of more than one asthma-like symptom closely related to the practioner's diagnoses of bronchial asthma and recurrent wheezy bronchitis was used as the outcome variable., Results: After an initial prevalence of 14.5%, new onset of symptoms in children unaffected at the beginning was reported in 7.2% during the 3 years. Of the factors explaining prevalence and persistence of asthma-like symptoms (sensitization to mite allergens and animal danders, history of hay fever and eczema, low gestational age, male gender, parental atopy), only sensitization to mite allergens (odds ratio = 2.3, 95% confidence interval = 1.1-4.7) and parental atopy (odds ratio = 2.1, 95% confidence interval = 1.2-3.7) were also significantly associated with new onset. In a relatively small number of sensitized subjects with new onset of symptoms (n = 31), mite antigen concentration did not appear to be associated with incidence of symptoms., Conclusion: Sensitization to mite allergens antedated the onset of asthma-like symptoms, and no strong effect of allergen exposure on clinical development could be found. Thus the primary focus should be on preventing sensitization to mite allergens by implementing avoidance measures in infancy or at early school age in order to reduce the onset of asthma at a later stage.

In the course of a 2 1/2-year longitudinal study, the influence of outdoor NO2 and of the heating device at home on lung function was investigated in 467 children of school age in the urban area of Freiburg. Data were gathered in three surveys using standardized interviews, lung function measurements, skin prick tests with inhalant allergens, and NO2 measurements from October to April near the child's home. Regarding the lung function of a subpopulation with asthmatic symptoms (n = 106) in the three consecutive surveys, multivariate regression analyses adjusted for confounders indicate negative associations between five dependent variables, FEV1%FVC (P = 0.004), FEV1% (P = 0.02), MEF75% (P = 0.038), MEF50% (P = 0.052), and MEF25% (P = 0.002), on the one hand, and outdoor NO2 for average NO2 concentrations exceeding 40 micrograms/m3 on the other. The use of individual room heaters is associated with decreased lung function and is significant only for FEV1%FVC (P = 0.033). Neither NO2 nor individual room heating is significantly associated with one of the lung function parameters in the subpopulation without asthmatic symptoms (n = 361). In conclusion, children with asthmatic symptoms are identified as being susceptible to having reduced lung function under outdoor air pollution where average NO2 concentrations exceed 40 micrograms/m3.

Eosinophil inflammation is a common feature of allergic disorders and particularly in allergic asthma interest has been paid to related markers. In a community-based survey of 10-year-old children, the association of eosinophil count (EC) and serum eosinophil cationic protein (ECP) with allergic sensitization, clinical history and exposure to mite allergen was studied. Relying on the results of skin prick tests, the children were divided to three groups: (1) children showing no sensitization to one of the seven inhalant allergens (n = 16); (2) children with sensitization to at least one of five non-mite allergens (n = 16); and (3) children with sensitization to mite allergens (n = 75). Clinical history of asthma and hay fever was ascertained using standardized questionnaires. EC in peripheral blood and serum ECP were measured on one single occasion. Prior to blood sampling, mite allergen exposure at home had been assessed by taking dust samples and measuring the mite antigen concentration by means of an enzyme immunoassay. Compared to group 1, higher ECs were obvious in group 2 (P = 0.037) and in group 3 (P = 0.0013). Regarding serum ECP, higher levels occurred in group 2 (P = 0.0033) as well as in group 3 (P = 0.0001) when comparing them to the reference group. Sensitized children with neither asthma, nor asthma-like symptoms, nor hay fever (n = 28) did not have significantly lower ECs and serum ECP levels than those with hay fever (n = 15; P = 0.09, P = 0.17) and those with asthma (n = 22; P = 0.69, P = 0.64).(ABSTRACT TRUNCATED AT 250 WORDS)

The natural history of a bronchial response to exercise (BRE) was studied in a cohort of primary-school children, who were followed over a 2-year period. In 1,094 children, three free-running tests were performed in 1-year intervals. Children who responded in one of the tests were designated as "infrequent" responders (20.5%), whereas those responding at two or all three occasions were designated as "frequent" responders (7.4%). A frequent positive BRE was closely associated with atopy (defined as skin test positivity to 1 of 7 common aeroallergens) and respiratory symptom status. Compared to atopics without respiratory symptoms, an increased risk for a frequent positive BRE was seen for atopic children who were symptomatic during the whole study period [odds ratio (OR) 25.4; confidence interval (CI) 6.9-94.0], who had gained symptoms (OR, 11.0; CI, 2.8-43.2) or who had symptoms at the beginning of the study but had lost them during follow-up (OR, 4.6; CI, 1.0-20.6). A sensitization to dust mites (OR, 8.0; CI, 4.3-15.0) but not to animal dander (OR, 2.3; CI, 1.0-5.2) or pollen (OR, 0.7; CI, 0.3-1.6) was significantly related to a frequent positive BRE. Our findings support the notion that while "children grow out of asthma," they might maintain their bronchial hyperresponsiveness. Regarding specific sensitization, mite allergy seems to play the predominant role.

Diurnal variability of peak expiratory flow rates (PEFRs) was assessed in 1,237 children. The PEFR was measured twice daily over a 1-week period. As an index of variability, the log of a week's mean of daily amplitude was calculated. Linear regression analyses revealed a significant positive association between maternal smoking and the variability of PEFR for nonasthmatic children. For these children, exposure to maternal smoking was associated with a 13.7 percent increase (confidence interval [CI], 3.8 to 24.7 percent) in PEFR variability. For asthmatic children an effect was found for nonatopic (54.7 percent increase; CI, 5.5 to 226.8 percent) but not for atopic children (-8.5 percent change; CI, -41.2 to 42.3 percent). In the latter group, there was evidence that mothers changed their smoking habits subsequent to the development of disease in their children. We conclude that exposure to maternal smoking can increase the variability of PEFR and thus might contribute to the development of asthma.

Using cross-sectional data of an epidemiological study, risk factors for asthma and recurrent wheezy bronchitis were investigated in 1812 primary school children. Children with asthma (n = 63) had a similar pattern but a higher frequency of chronic respiratory symptoms than those with recurrent wheezy bronchitis (n = 136). Logistic regression analyses showed similar risk factors for both disorders, however, more pronounced for asthma. Prematurity was a significant risk factor for asthma and for recurrent wheezy bronchitis. Children with asthma more often had a family history of paternal or maternal asthma and their mothers tended to be younger. Effects of paternal asthma and prematurity were also found when the atopic status of the child (defined as skin test positivity to any of seven aero allergens) was taken into account. Next to genetic effects, adverse circumstances in early life seem to be important for the development of asthma. In school children recurrent wheezy bronchitis and asthma seem to be similar disorders which differ in quantitative but not qualitative aspects.

The coincidence of allergic sensitization was investigated in 302 school-aged children and their parents. Specific sensitization to four common inhalant allergens (grass and birch pollens, cat dander, Dermatophagoides pteronyssinus) was ascertained by means of skin-prick tests (SPT) carried out on the complete family unit at the beginning of a 22-month follow-up period. The same test procedure was then repeated on the children twice at 11-month intervals to provide cumulative prevalences of sensitization. A clinical history of atopy in the children (hay fever or asthma; n = 47), which was derived from an interview, is associated with sensitization (positive SPT in 89%). For three allergens (grass and birch pollens, cat dander) sensitization occurs significantly more frequently in the children of mothers who are sensitized to the same allergen (odds-ratios (ORs), 2.5-4.1). Additionally, in three of the four explanatory models related to a single antigen, maternal sensitization to one of the complementary allergens is of importance (ORs, 2.7-3.7). In contrast to this finding, none of the paternal sensitizations has statistical significance. Based on a reaction to at least one of the four allergens, the child's relative risk to be sensitized is increased in case of maternal (OR, 2.88; P = 0.001) but not of paternal (OR, 1.06; P = 0.83) sensitization. In conclusion, our data indicate that the maternal status is more predictive than that of the father with regard to the child's risk of sensitization.

Background: Variability in peak expiratory flow (PEF) has been proposed as a simple method of screening for asthma in epidemiological studies. This study was designed to assess whether the bronchial response to exercise and the diurnal variation in PEF identified the same subjects., Methods: Bronchial response to a free running exercise test was assessed in a cohort of 918 seven year old children and was compared with variability of PEF as assessed by twice daily recordings for a one week period. Mini Wright peak flow meters were used throughout the study., Results: Baseline PEFs of both tests were highly correlated but there was no significant correlation between a response to exercise and variability of PEF. Of 33 children with a physician's diagnosis of asthma, 18 had at least one abnormal test, but only five children were abnormal in both tests, showing that the tests did not identify the same subjects., Conclusion: Increased variability of PEF, as well as a response to exercise, was associated with respiratory symptoms, but only a response to exercise was closely associated with atopy (defined as a positive skin test to any of seven aero-allergens).

To examine the possibility of an effect of indoor and outdoor exposures on the prevalence of asthma in childhood we conducted a cross-sectional study in the area of Freiburg city and two communities in the Black Forest. The study group consists of 704 children aged 7 to 16 years. The children and their mothers took part in a standardized interview and a medical examination. Indoor exposures were assessed from information gathered in the interview by two different indices: (a) heating system and single room heating, and (b) the amount of indoor ventilation. The measurement of outdoor pollutants took into account weekly estimations of NO2 and combustion particles. The presence of asthma was recorded according to a previous medical diagnosis. Confounders were assessed during the interview (passive smoking, genetic predisposition to asthma etc.) or during the medical examination (cutaneous sensitization with a skin prick test). For the analysis of the data we applied logistic regression models and estimated odds-ratios. Only one of the four hypothesis variables displays a significant effect on the prevalence of asthma: Stoves as heating device carry a 4.8-fold relative risk for asthma compared to other types of heating. Among the confounding variables controlled for in the explanatory model, cutaneous reactions showed a relative risk of eight.