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Background: Phenotypes of asthma and allergic diseases are mainly studied separately for children and adults. To explore the role of adolescence and young adulthood, we investigated symptom trajectories at the transition from childhood into adulthood., Methods: Latent class analysis (LCA) was conducted in a population initially recruited for the German arm of Phase II of the International Study of Asthma and Allergies in Childhood and followed-up three times until their early 30s (N=2267). Indicators included in LCA were 12-month prevalences of symptoms of wheeze, rhinoconjunctivitis, and eczema. Latent classes were further characterised regarding important traits such as skin prick tests. Logistic regression models were used to investigate associations with environmental determinants such as smoking and occupational exposures., Results: Six latent classes were identified: an asymptomatic one as well as three with single and two with co-occurring symptoms. All trajectories essentially established between baseline assessment at around 10 years and the first follow-up at around 17 years. Probabilities for symptoms increased from childhood to adolescence, especially for wheeze-related latent classes, while they remained constant in adulthood. Wheeze-related latent classes were also positively associated with exposures during adolescence (e.g. active smoking)., Conclusion: Distinct trajectories of asthma and allergy symptoms establish from childhood through adolescence and stabilize during early adulthood. This pattern was most notable in wheeze-related latent classes which also showed the strongest positive associations with environmental exposures in adolescence/young adulthood. Therefore, not only childhood but also adolescence is relevant for disease development and offers considerable potential for prevention and health promotion., (© 2021 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Introduction: Epidemiological cohort studies have consistently found associations between long-term exposure to outdoor air pollution and a range of morbidity and mortality endpoints. Recent evaluations by the World Health Organization and the Global Burden of Disease study have suggested that these associations may be nonlinear and may persist at very low concentrations. Studies conducted in North America in particular have suggested that associations with mortality persisted at concentrations of particulate matter with an aerodynamic diameter of less than 2.5 μm (PM 2.5 ) well below current air quality standards and guidelines. The uncertainty about the shape of the concentration-response function at the low end of the concentration distribution, related to the scarcity of observations in the lowest range, was the basis of the current project. Previous studies have focused on PM 2.5 , but increasingly associations with nitrogen dioxide (NO 2 ) are being reported, particularly in studies that accounted for the fine spatial scale variation of NO 2 . Very few studies have evaluated the effects of long-term exposure to low concentrations of ozone (O 3 ). Health effects of black carbon (BC), representing primary combustion particles, have not been studied in most large cohort studies of PM 2.5 . Cohort studies assessing health effects of particle composition, including elements from nontailpipe traffic emissions (iron, copper, and zinc) and secondary aerosol (sulfur) have been few in number and reported inconsistent results. The overall objective of our study was to investigate the shape of the relationship between long-term exposure to four pollutants (PM 2.5 , NO 2 , BC, and O 3 ) and four broad health effect categories using a number of different methods to characterize the concentration-response function (i.e., linear, nonlinear, or threshold). The four health effect categories were (1) natural- and cause-specific mortality including cardiovascular and nonmalignant as well as malignant respiratory and diabetes mortality; and morbidity measured as (2) coronary and cerebrovascular events; (3) lung cancer incidence; and (4) asthma and chronic obstructive pulmonary disease (COPD) incidence. We additionally assessed health effects of PM 2.5 composition, specifically the copper, iron, zinc, and sulfur content of PM 2,5 ., Methods: We focused on analyses of health effects of air pollutants at low concentrations, defined as less than current European Union (EU) Limit Values, U.S. Environmental Protection Agency (U.S. EPA), National Ambient Air Quality Standards (NAAQS), and/or World Health Organization (WHO) Air Quality Guideline values for PM 2.5 , NO 2 , and O 3 . We address the health effects at low air pollution levels by performing new analyses within selected cohorts of the ESCAPE study (European Study of Cohorts for Air Pollution Effects; Beelen et al. 2014a) and within seven very large European administrative cohorts. By combining well-characterized ESCAPE cohorts and large administrative cohorts in one study the strengths and weaknesses of each approach can be addressed. The large administrative cohorts are more representative of national or citywide populations, have higher statistical power, and can efficiently control for area-level confounders, but have fewer possibilities to control for individual-level confounders. The ESCAPE cohorts have detailed information on individual confounders, as well as country-specific information on area-level confounding. The data from the seven included ESCAPE cohorts and one additional non-ESCAPE cohort have been pooled and analyzed centrally. More than 300,000 adults were included in the pooled cohort from existing cohorts in Sweden, Denmark, Germany, the Netherlands, Austria, France, and Italy. Data from the administrative cohorts have been analyzed locally, without transfer to a central database. Privacy regulations prevented transfer of data from administrative cohorts to a central database. More than 28 million adults were included from national administrative cohorts in Belgium, Denmark, England, the Netherlands, Norway, and Switzerland as well as an administrative cohort in Rome, Italy. We developed central exposure assessment using Europewide hybrid land use regression (LUR) models, which incorporated European routine monitoring data for PM 2.5 , NO 2 , and O 3 , and ESCAPE monitoring data for BC and PM 2.5 composition, land use, and traffic data supplemented with satellite observations and chemical transport model estimates. For all pollutants, we assessed exposure at a fine spatial scale, 100 × 100 m grids. These models have been applied to individual addresses of all cohorts including the administrative cohorts. In sensitivity analyses, we applied the PM 2.5 models developed within the companion HEI-funded Canadian MAPLE study (Brauer et al. 2019) and O 3 exposures on a larger spatial scale for comparison with previous studies. Identification of outcomes included linkage with mortality, cancer incidence, hospital discharge registries, and physician-based adjudication of cases. We analyzed natural-cause, cardiovascular, ischemic heart disease, stroke, diabetes, cardiometabolic, respiratory, and COPD mortality. We also analyzed lung cancer incidence, incidence of coronary and cerebrovascular events, and incidence of asthma and COPD (pooled cohort only). We applied the Cox proportional hazard model with increasing control for individual- and area-level covariates to analyze the associations between air pollution and mortality and/or morbidity for both the pooled cohort and the individual administrative cohorts. Age was used as the timescale because of evidence that this results in better adjustment for potential confounding by age. Censoring occurred at the time of the event of interest, death from other causes, emigration, loss to follow-up for other reasons, or at the end of follow-up, whichever came first. A priori we specified three confounder models, following the modeling methods of the ESCAPE study. Model 1 included only age (time axis), sex (as strata), and calendar year of enrollment. Model 2 added individual-level variables that were consistently available in the cohorts contributing to the pooled cohort or all variables available in the administrative cohorts, respectively. Model 3 further added area-level socioeconomic status (SES) variables. A priori model 3 was selected as the main model. All analyses in the pooled cohort were stratified by subcohort. All analyses in the administrative cohorts accounted for clustering of the data in neighborhoods by adjusting the variance of the effect estimates. The main exposure variable we analyzed was derived from the Europewide hybrid models based on 2010 monitoring data. Sensitivity analyses were conducted using earlier time periods, time-varying exposure analyses, local exposure models, and the PM 2.5 models from the Canadian MAPLE project. We first specified linear single-pollutant models. Two-pollutant models were specified for all combinations of the four main pollutants. Two-pollutant models for particle composition were analyzed with PM 2.5 and NO 2 as the second pollutant. We then investigated the shape of the concentration-response function using natural splines with two, three, and four degrees of freedom; penalized splines with the degrees of freedom determined by the algorithm and shape-constrained health impact functions (SCHIF) using confounder model 3. Additionally, we specified linear models in subsets of the concentration range, defined by removing concentrations above a certain value from the analysis, such as for PM 2.5 25 μg/m 3 (EU limit value), 20, 15, 12 μg/m 3 (U.S. EPA National Ambient Air Quality Standard), and 10 μg/m 3 (WHO Air Quality Guideline value). Finally, threshold models were evaluated to investigate whether the associations persisted below specific concentration values. For PM 2.5 , we evaluated 10, 7.5, and 5 μg/m 3 as potential thresholds. Performance of threshold models versus the corresponding no-threshold linear model were evaluated using the Akaike information criterion (AIC)., Results: In the pooled cohort, virtually all subjects in 2010 had PM 2.5 and NO 2 annual average exposures below the EU limit values (25 μg/m 3 and 40 μg/m 3 , respectively). More than 50,000 had a residential PM 2.5 exposure below the U.S. EPA NAAQS (12 μg/m 3 ). More than 25,000 subjects had a residential PM 2.5 exposure below the WHO guideline (10 μg/m 3 ). We found significant positive associations between PM 2.5 , NO 2 , and BC and natural-cause, respiratory, cardiovascular, and diabetes mortality. In our main model, the hazard ratios (HRs) (95% [confidence interval] CI) were 1.13 (CI = 1.11, 1.16) for an increase of 5 μg/m 3 PM 2.5 , 1.09 (CI = 1.07, 1.10) for an increase of 10 μg/m 3 NO 2 , and 1.08 (CI = 1.06, 1.10) for an increase of 0.5 × 10 -5 /m BC for natural-cause mortality. The highest HRs were found for diabetes mortality. Associations with O 3 were negative, both in the fine spatial scale of the main ELAPSE model and in large spatial scale exposure models. For PM 2.5 , NO 2 , and BC, we generally observed a supralinear association with steeper slopes at low exposures and no evidence of a concentration below which no association was found. Subset analyses further confirmed that these associations remained at low levels: below 10 μg/m 3 for PM 2.5 and 20 μg/m 3 for NO 2 . HRs were similar to the full cohort HRs for subjects with exposures below the EU limit values for PM 2.5 and NO 2 , the U.S. NAAQS values for PM 2.5 , and the WHO guidelines for PM 2.5 and NO 2 . The mortality associations were robust to alternative specifications of exposure, including different time periods, PM 2.5 from the MAPLE project, and estimates from the local ESCAPE model. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. HRs in two-pollutant models were attenuated but remained elevated and statistically significant for PM 2.5 and NO 2 . In two-pollutant models of PM 2.5 and NO 2 HRs for natural-cause mortality were 1.08 (CI = 1.05, 1.11) for PM 2.5 and 1.05 (CI = 1.03, 1.07) for NO 2 . Associations with O 3 were attenuated but remained negative in two-pollutant models with NO 2 , BC, and PM 2.5 . We found significant positive associations between PM 2.5 , NO 2 , and BC and incidence of stroke and asthma and COPD hospital admissions. Furthermore, NO 2 was significantly related to acute coronary heart disease and PM 2.5 was significantly related to lung cancer incidence. We generally observed linear to supralinear associations with no evidence of a threshold, with the exception of the association between NO 2 and acute coronary heart disease, which was sublinear. Subset analyses documented that associations remained even with PM 2.5 below 20 μg/m 3 and possibly 12 μg/m 3 . Associations remained even when NO 2 was below 30 μg/m 3 and in some cases 20 μg/m 3 . In two-pollutant models, NO 2 was most consistently associated with acute coronary heart disease, stroke, asthma, and COPD hospital admissions. PM 2.5 was not associated with these outcomes in two-pollutant models with NO 2 . PM 2.5 was the only pollutant that was associated with lung cancer incidence in two-pollutant models. Associations with O 3 were negative though generally not statistically significant. In the administrative cohorts, virtually all subjects in 2010 had PM 2.5 and NO 2 annual average exposures below the EU limit values. More than 3.9 million subjects had a residential PM 2.5 exposure below the U.S. EPA NAAQS (12 μg/m 3 ) and more than 1.9 million had residential PM 2.5 exposures below the WHO guideline (10 μg/m 3 ). We found significant positive associations between PM 2.5 , NO 2 , and BC and natural-cause, respiratory, cardiovascular, and lung cancer mortality, with moderate to high heterogeneity between cohorts. We found positive but statistically nonsignificant associations with diabetes mortality. In our main model meta-analysis, the HRs (95% CI) for natural-cause mortality were 1.05 (CI = 1.02, 1.09) for an increase of 5 μg/m 3 PM 2.5 , 1.04 (CI = 1.02, 1.07) for an increase of 10 μg/m 3 NO 2 , and 1.04 (CI = 1.02, 1.06) for an increase of 0.5 × 10 -5 /m BC, and 0.95 (CI = 0.93, 0.98) for an increase of 10 μg/m 3 O 3 . The shape of the concentration-response functions differed between cohorts, though the associations were generally linear to supralinear, with no indication of a level below which no associations were found. Subset analyses documented that these associations remained at low levels: below 10 μg/m 3 for PM 2.5 and 20 μg/m 3 for NO 2 . BC and NO 2 remained significantly associated with mortality in two-pollutant models with PM 2.5 and O 3 . The PM 2.5 HR attenuated to unity in a two-pollutant model with NO 2 . The negative O 3 association was attenuated to unity and became nonsignificant. The mortality associations were robust to alternative specifications of exposure, including time-varying exposure analyses. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. Effect estimates in the youngest participants (<65 years at baseline) were much larger than in the elderly (>65 years at baseline). Effect estimates obtained with the ELAPSE PM 2.5 model did not differ from the MAPLE PM 2.5 model on average, but in individual cohorts, substantial differences were found., Conclusions: Long-term exposure to PM 2.5 , NO 2 , and BC was positively associated with natural-cause and cause-specific mortality in the pooled cohort and the administrative cohorts. Associations were found well below current limit values and guidelines for PM 2.5 and NO 2 . Associations tended to be supralinear, with steeper slopes at low exposures with no indication of a threshold. Two-pollutant models documented the importance of characterizing the ambient mixture with both NO 2 and PM 2.5 . We mostly found negative associations with O 3 . In two-pollutant models with NO 2 , the negative associations with O 3 were attenuated to essentially unity in the mortality analysis of the administrative cohorts and the incidence analyses in the pooled cohort. In the mortality analysis of the pooled cohort, significant negative associations with O 3 remained in two-pollutant models. Long-term exposure to PM 2.5 , NO 2 , and BC was also positively associated with morbidity outcomes in the pooled cohort. For stroke, asthma, and COPD, positive associations were found for PM 2.5 , NO 2 , and BC. For acute coronary heart disease, an increased HR was observed for NO 2 . For lung cancer, an increased HR was found only for PM 2.5 . Associations mostly showed steeper slopes at low exposures with no indication of a threshold., (© 2021 Health Effects Institute. All rights reserved.)

Background: Long-term exposure to ambient air pollution has been linked to childhood-onset asthma, although evidence is still insufficient. Within the multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), we examined the associations of long-term exposures to particulate matter with a diameter <2.5 µm (PM 2.5 ), nitrogen dioxide (NO 2 ) and black carbon (BC) with asthma incidence in adults., Methods: We pooled data from three cohorts in Denmark and Sweden with information on asthma hospital diagnoses. The average concentrations of air pollutants in 2010 were modelled by hybrid land-use regression models at participants' baseline residential addresses. Associations of air pollution exposures with asthma incidence were explored with Cox proportional hazard models, adjusting for potential confounders., Results: Of 98 326 participants, 1965 developed asthma during a mean follow-up of 16.6 years. We observed associations in fully adjusted models with hazard ratios of 1.22 (95% CI 1.04-1.43) per 5 μg·m -3 for PM 2.5 , 1.17 (95% CI 1.10-1.25) per 10 µg·m -3 for NO 2 and 1.15 (95% CI 1.08-1.23) per 0.5×10 -5  m -1 for BC. Hazard ratios were larger in cohort subsets with exposure levels below the European Union and US limit values and possibly World Health Organization guidelines for PM 2.5 and NO 2 . NO 2 and BC estimates remained unchanged in two-pollutant models with PM 2.5 , whereas PM 2.5 estimates were attenuated to unity. The concentration-response curves showed no evidence of a threshold., Conclusions: Long-term exposure to air pollution, especially from fossil fuel combustion sources such as motorised traffic, was associated with adult-onset asthma, even at levels below the current limit values., Competing Interests: Conflict of interest: S. Liu has nothing to disclose. Conflict of interest: J.T. Jørgensen has nothing to disclose. Conflict of interest: P. Ljungman has nothing to disclose. Conflict of interest: G. Pershagen has nothing to disclose. Conflict of interest: T. Bellander has nothing to disclose. Conflict of interest: K. Leander has nothing to disclose. Conflict of interest: P.K.E. Magnusson has nothing to disclose. Conflict of interest: D. Rizzuto has nothing to disclose. Conflict of interest: U.A. Hvidtfeldt has nothing to disclose. Conflict of interest: O. Raaschou-Nielsen has nothing to disclose. Conflict of interest: K. Wolf has nothing to disclose. Conflict of interest: B. Hoffmann has nothing to disclose. Conflict of interest: B. Brunekreef has nothing to disclose. Conflict of interest: M. Strak has nothing to disclose. Conflict of interest: J. Chen has nothing to disclose. Conflict of interest: A. Mehta has nothing to disclose. Conflict of interest: R.W. Atkinson has nothing to disclose. Conflict of interest: M. Bauwelinck has nothing to disclose. Conflict of interest: R. Varraso has nothing to disclose. Conflict of interest: M-C. Boutron-Ruault has nothing to disclose. Conflict of interest: J. Brandt has nothing to disclose. Conflict of interest: G. Cesaroni has nothing to disclose. Conflict of interest: F. Forastiere has nothing to disclose. Conflict of interest: D. Fecht has nothing to disclose. Conflict of interest: J. Gulliver has nothing to disclose. Conflict of interest: O. Hertel has nothing to disclose. Conflict of interest: K. de Hoogh has nothing to disclose. Conflict of interest: N.A.H. Janssen has nothing to disclose. Conflict of interest: K. Katsouyanni has nothing to disclose. Conflict of interest: M. Ketzel has nothing to disclose. Conflict of interest: J.O. Klompmaker has nothing to disclose. Conflict of interest: G. Nagel has nothing to disclose. Conflict of interest: B. Oftedal has nothing to disclose. Conflict of interest: A. Peters has nothing to disclose. Conflict of interest: A. Tjønneland has nothing to disclose. Conflict of interest: S.P. Rodopoulou has nothing to disclose. Conflict of interest: E Samoli has nothing to disclose. Conflict of interest: D.T. Kristoffersen has nothing to disclose. Conflict of interest: T. Sigsgaard has nothing to disclose. Conflict of interest: M. Stafoggia has nothing to disclose. Conflict of interest: D. Vienneau has nothing to disclose. Conflict of interest: G. Weinmayr has nothing to disclose. Conflict of interest: G. Hoek has nothing to disclose. Conflict of interest: Z.J. Andersen has nothing to disclose., (Copyright ©ERS 2021.)

Background: Long-term effectiveness of asthma control medication has been shown in clinical trials but results from observational studies with children and adolescents are lacking. Marginal structural models estimated using targeted maximum likelihood methods are a novel statistiscal approach for such studies as it allows to account for time-varying confounders and time-varying treatment. Therefore, we aimed to calculate the long-term risk of reporting asthma symptoms in relation to control medication use in a real-life setting from childhood to adulthood applying targeted maximum likelihood estimation., Methods: In the prospective cohort study SOLAR (Study on Occupational Allergy Risks) we followed a German subsample of 121 asthmatic children (9-11 years old) of the ISAAC II cohort (International Study of Asthma and Allergies in Childhood) until the age of 19 to 24. We obtained self-reported questionnaire data on asthma control medication use at baseline (1995-1996) and first follow-up (2002-2003) as well as self-reported asthma symptoms at baseline, first and second follow-up (2007-2009). Three hypothetical treatment scenarios were defined: early sustained intervention, early unsustained intervention and no treatment at all. We performed longitudinal targeted maximum likelihood estimation combined with Super Learner algorithm to estimate the relative risk (RR) to report asthma symptoms at SOLAR I and SOLAR II in relation to the different hypothetical scenarios., Results: A hypothetical intervention of early sustained treatment was associated with a statistically significant risk increment of asthma symptoms at second follow-up when compared to no treatment at all (RR: 1.51, 95% CI: 1.19-1.83) or early unsustained intervention (RR:1.38, 95% CI: 1.11-1.65)., Conclusions: While we could confirm the tagerted maximum likelihood estimation to be a usable and robust statistical tool, we did not observe a beneficial effect of asthma control medication on asthma symptoms. Because of potential due to the small sample size, lack of data on disease severity and reverse causation our results should, however, be interpreted with caution.

Objectives: This study analyzes the association of work-related stress with incident asthma and rhinitis in young adults with a special focus on gender-specific differences., Methods: Incident asthma, wheezing and rhinitis were measured in a cohort of 2051 young German adults (aged 16-18 years at baseline) recruited by the prospective population-based SOLAR study (Study of Occupational Allergy Risks). Work-related stress was measured by the Trier Inventory for the Assessment of Chronic Stress (TICS). Two TICS scales, work overload and work discontent, were analysed. Logistic regression was conducted to calculate odds ratios (OR) and 95% confidence intervals (CI)., Results: In females, the odds for incident asthma were found to be 17% higher for each increase of the work discontent score by one point (OR 1.17, 95% CI 1.04-1.31). In males, no association was statistically significant. Incident rhinitis showed no association with any exposure variable., Conclusion: This study shows a link between work-related stress and incident asthma which seems to be confined to women. This study adds evidence about the association of work-related stress and asthma in young adults and can contribute to prevention for that particular age group.

Asthma prevalence in children varies substantially around the world, but the contribution of known risk factors to this international variation is uncertain. The International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two studied 8-12 year old children in 30 centres worldwide with parent-completed symptom and risk factor questionnaires and aeroallergen skin prick testing. We used multilevel logistic regression modelling to investigate the effect of adjustment for individual and ecological risk factors on the between-centre variation in prevalence of recent wheeze. Adjustment for single individual-level risk factors changed the centre-level variation from a reduction of up to 8.4% (and 8.5% for atopy) to an increase of up to 6.8%. Modelling the 11 most influential environmental factors among all children simultaneously, the centre-level variation changed little overall (2.4% increase). Modelling only factors that decreased the variance, the 6 most influential factors (synthetic and feather quilt, mother's smoking, heating stoves, dampness and foam pillows) in combination resulted in a 21% reduction in variance. Ecological (centre-level) risk factors generally explained higher proportions of the variation than did individual risk factors. Single environmental factors and aeroallergen sensitisation measured at the individual (child) level did not explain much of the between-centre variation in wheeze prevalence.

Background: Childhood obesity and asthma are increasing worldwide. A possible link between the two conditions has been postulated., Methods: Cross-sectional studies of stratified random samples of 8-12-year-old children (n = 10 652) (16 centres in affluent and 8 centres in non-affluent countries) used the standardized methodology of ISAAC Phase Two. Respiratory and allergic symptoms were ascertained by parental questionnaires. Tests for allergic disease were performed. Height and weight were measured, and overweight and obesity were defined according to international definitions. Prevalence rates and prevalence odds ratios were calculated., Results: Overweight (odds ratio = 1.14, 95%-confidence interval: 0.98; 1.33) and obesity (odds ratio = 1.67, 95%-confidence interval: 1.25; 2.21) were related to wheeze. The relationship was stronger in affluent than in non-affluent centres. Similar results were found for cough and phlegm, rhinitis and eczema but the associations were mostly driven by children with wheeze. There was a clear association of overweight and obesity with airways obstruction (change in FEV1/FVC, -0.90, 95%-confidence interval: -1.33%; -0.47%, for overweight and -2.46%, 95%-confidence interval: -3.84%; -1.07%, for obesity) whereas the results for the other objective markers, including atopy, were null., Conclusions: Our data from a large international child population confirm that there is a strong relation of body mass index with wheeze especially in affluent countries. Moreover, body mass index is associated with an objective marker of airways obstruction (FEV1/FVC) but no other objective markers of respiratory and allergic disorders.

Although work-related asthma and allergies are a huge burden for society, investigation of occupational exposures in early work life using an unexposed reference group is rare. Thus, the present analyses aimed to assess the potential impact of occupational exposure and other risk factors on the prevalence of work-related sensitisation and incidence of allergic rhinitis/asthma using a population-based approach and taking into account an unexposed reference group. In SOLAR (Study on Occupational Allergy Risks) II, German participants of ISAAC (International Study of Asthma and Allergies in Childhood) phase II were followed from childhood (9-11 years) until early adulthood (19-24 years). Data on 1570 participants were available to fit predictive models. Occupational exposure was not statistically significantly associated with disease prevalence/incidence. Sensitisation in childhood, parental asthma, environmental tobacco smoke exposure during puberty, sex and study location were statistically significant predictors of outcome. Our results indicate that occupational exposure is of little relevance for work-related sensitisation prevalence and allergic rhinitis/asthma incidence in early work life, while other risk factors can be used to improve career guidance for adolescents. Further research on the role of a potential healthy hire effect and the impact of longer exposure duration is needed., (©ERS 2014.)

Background: Pertussis and measles infection as well as vaccination have been suspected as possible mediating factors of allergic disease in childhood., Methods: Between 1995 and 2005 cross-sectional studies were performed in 29 centers in 21 countries. Parental questionnaires were used to collect information on allergic diseases and exposures. We analyzed data from 54,943 randomly selected schoolchildren aged 8-12 yr. A subgroup of 31,759 children was also skin prick tested (SPT) to common environmental allergens. Combined odds ratios were calculated by random effect models for meta-analysis., Results: Pertussis and measles vaccination were not significantly associated with any of the allergy outcomes or SPT positivity. However, pertussis infection was associated with wheeze (OR(ad) 1.68; 95% CI 1.44-1.97) and rhinoconjunctivitis (OR(ad) 1.63; 95% 1.33-2.00). Pertussis infection was also significantly associated with a higher prevalence of reported eczema during the past year in non-affluent countries. Measles infection was associated with a higher prevalence of wheeze (OR(ad) 1.26; 95% 1.10-1.43) and reported eczema (OR(ad) 1.22; 95% 1.08-1.39). No association with SPT positivity was found, suggesting that these associations are unlikely to be mediated by an allergic component., Conclusions: Associations of pertussis and measles infection with symptoms of asthma, rhinoconjunctivitis and eczema were found in both affluent and non-affluent countries and are unlikely to be mediated by IgE., (© 2012 John Wiley & Sons A/S.)

Some have suggested a protective effect of tuberculosis (TB) infection on allergic disease risk, but few studies have examined the association between the two. We therefore investigated whether TB disease and bacillus Calmette-Guérin (BCG) vaccination in early life protect against allergic disease. Information on allergic disease symptoms, past TB disease, and BCG vaccination as well as potential confounding factors was gathered by parental questionnaire from a randomly selected subset of 23,901 8- to 12-yr-old schoolchildren in 20 centers in both developed and developing countries. Children were also physically examined for flexural eczema and underwent skin prick testing. Pooled odds ratio (OR) estimates and corresponding 95% confidence intervals (CIs) across study centers were calculated, using random effects meta-analysis models. There were 245 (1.0%) reported cases of TB disease, and 66.3% (15,857) of all children received the BCG vaccine. Asthma, hay fever, and flexural eczema symptoms in the past year as well as flexural eczema on skin examination were all positively linked to a history of TB (adjusted pooled OR 'wheeze in the past year' = 2.27, 95% CI 1.52-3.41; adjusted pooled OR 'hay fever symptoms in the past year' = 2.23, 1.22-4.09; adjusted pooled OR 'flexural eczema symptoms in the past year' = 3.21, 2.01-5.12; adjusted pooled OR 'flexural eczema on skin examination' = 4.04, 1.71-9.56). Even higher risk estimates were seen for severe asthma and eczema symptoms [adjusted OR = 4.02 (2.17-7.47) and adjusted OR = 6.31 (2.19-18.17), respectively]. There was no significant association between past TB and skin prick test positivity (adjusted pooled OR = 1.32, 0.87-2.02). BCG vaccination during the first year of life was also not associated with any of the allergy outcomes. We found a uniform positive association between TB and all allergic disease outcomes, including eczema on skin examination. As this was a cross-sectional study, it is unclear whether this positive association is attributable to a causal relationship, and further longitudinal studies are required., (© 2011 John Wiley & Sons A/S.)

Rationale: Bronchial responsiveness is an objectively measurable trait related to asthma. Its prevalence and association with asthma symptoms among children in many countries are unknown., Objectives: To investigate international variations in bronchial responsiveness (BR) and their associations with asthma symptoms and atopic sensitization., Methods: Bronchial challenge tests were conducted in 6,826 schoolchildren (aged 8-12 years) in 16 countries using hypertonic (4.5%) saline. FEV(1) was measured at baseline and after inhalation for 0.5, 1, 2, 4, and 8 min. BR was analyzed both as a dichotomous (bronchial hyperreactivity, BHR, at least 15% decline in FEV(1)) and as a continuous variable (time-response slope, BR slope, individual decline in FEV(1) per log(min))., Results: Prevalence of wheeze last year ranged from 4.4% in Tirana (Albania) to 21.9% in Hawkes Bay (New Zealand) and of BHR from 2.1% in Tirana to 48% in Mumbai (India). The geometric mean BR slope varied between 3.4%/log(min) in Tirana and 12.8%/log(min) in Mumbai and Rome (Italy). At the individual level, BHR was positively associated with wheeze during the past 12 months both in affluent countries (OR = 3.6; 95% CI: 2.7-5.0) and non-affluent countries (OR = 3.0; 1.6-5.5). This association was more pronounced in atopic children. There was a correlation (rho = 0.64, P = 0.002) between center-specific mean BR slope and wheeze prevalence in atopic, but not in non-atopic children., Conclusions: BR to saline in children varied considerably between countries. High rates of BR were not confined to affluent countries nor to centers with high prevalences of asthma symptoms. The association between wheeze and BHR at the individual level differed across centers and this heterogeneity can be largely explained by effect modification by atopy. Pediatr. Pulmonol. 2010; 45:796-806. (c) 2010 Wiley-Liss, Inc., (Copyright 2010 Wiley-Liss, Inc.)

Background: The increasing prevalence of asthma and allergy might be related to diet, particularly in Western countries. A study was undertaken to assess the association between dietary factors, asthma and allergy in a large international study including objective measurements of atopy., Methods: Between 1995 and 2005, cross-sectional studies were performed in 29 centres in 20 countries. Parental questionnaires were used to collect information on allergic diseases and exposure factors and data from 50 004 randomly selected schoolchildren (8-12 years, 29 579 with skin prick testing) were analysed. Random effect models for meta-analysis were applied to calculate combined ORs., Results: Fruit intake was associated with a low prevalence of current wheeze in affluent (OR(adj) 0.86, 95% CI 0.73 to 1.02) and non-affluent countries (OR(adj) 0.71, 95% CI 0.57 to 0.88). Consumption of fish in affluent countries (OR(adj) 0.85, 95% CI 0.74 to 0.97) and of cooked green vegetables in non-affluent countries (OR(adj) 0.78, 95% CI 0.65 to 0.95) was associated with a lower prevalence of current wheeze. Overall, more frequent consumption of fruit, vegetables and fish was associated with a lower lifetime prevalence of asthma, whereas high burger consumption was associated with higher lifetime asthma prevalence. None of the food items was associated with allergic sensitisation. Except for fruit juice and fruit consumption, no associations were found with atopic wheeze. Food selection according to the 'Mediterranean diet' was associated with a lower prevalence of current wheeze and asthma ever (p(trend)=0.03)., Conclusion: Diet is associated with wheeze and asthma but not with allergic sensitisation in children. These results provide further evidence that adherence to the 'Mediterranean diet' may provide some protection against wheeze and asthma in childhood.

Objective: Our goal was to quantify the short-term effects of particulate matter with aerodynamic diameter < or = 10 microm (PM10) and nitrogen dioxide (NO2) on respiratory health of asthmatic children from published panel studies, and to investigate the influence of study and population characteristics as effect modifiers., Data Extraction: After a systematic literature review, we extracted quantitative estimates of the association of PM10 and/or NO2 with respiratory symptoms and peak expiratory flow (PEF). Combined effect estimates for an increase of 10 microg/m3 were calculated by random effects meta-analysis for all studies and for different strata defined by study characteristics. The effect of publication bias was investigated with Egger's and Begg's tests and "trim-and-fill" analyses., Data Synthesis: We identified 36 studies; 14 were part of the European Pollution Effects on Asthmatic Children in Europe (PEACE) study. Adverse associations of PM10 with asthma symptoms were statistically significant [odds ratio (OR) = 1.028; 95% confidence interval (CI), 1.006-1.051]. There were also associations, although not statistically significant, of PM10 with cough (OR = 1.012; 95% CI, 0.997-1.026) and on PEF (decrease of -0.082 L/min; 95% CI, -0.214 to 0.050). NO2 had statistically significant associations with asthma symptoms in the overall analysis considering all possible lags (OR = 1.031; 95% CI, 1.001-1.062), but not when we evaluated only the 0-1 lag. We found no publication bias, although it appeared when excluding the PEACE studies. When we applied the trim-and-fill method to the data set without the PEACE studies, the results were similar to the overall estimates from all studies. There was an indication for stronger PM10 associations for studies conducted in summer, outside of Europe, with longer lags, and in locations with higher NO2 concentrations., Conclusions: We found clear evidence of effects of PM10 on the occurrence of asthma symptom episodes, and to a lesser extent on cough and PEF. The results for NO2 are more difficult to interpret because they depend on the lag times examined. There was an indication of effect modification by several study conditions.

Rationale: Atopic sensitization has long been known to be related to asthma in children, but its role in determining asthma prevalence remains to be elucidated further., Objectives: To investigate the role of atopic sensitization in the large international variation in the prevalence of childhood asthma., Methods: Cross-sectional studies of random samples of 8- to 12-year-old children (n = 1,000 per center) were performed according to the standardized methodology of Phase Two of the International Study of Asthma and Allergy in Childhood (ISAAC). Thirty study centers in 22 countries worldwide participated and reflect a wide range of living conditions, from rural Africa to urban Europe. Data were collected by parental questionnaires (n = 54,439), skin prick tests (n = 31,759), and measurements of allergen-specific IgE levels in serum (n = 8,951). Economic development was assessed by gross national income per capita (GNI)., Measurements and Main Results: The prevalence of current wheeze (i.e., during the past year) ranged from 0.8% in Pichincha (Ecuador) to 25.6% in Uruguaiana (Brazil). The fraction of current wheeze attributable to atopic sensitization ranged from 0% in Ankara (Turkey) to 93.8% in Guangzhou (China). There were no correlations between prevalence rates of current wheeze and atopic sensitization, and only weak correlations of both with GNI. However, the fractions and prevalence rates of wheeze attributable to skin test reactivity correlated strongly with GNI (Spearman rank-order coefficient rho = 0.50, P = 0.006, and rho = 0.74, P < 0.0001, respectively). In addition, the strength of the association between current wheeze and skin test reactivity, assessed by odds ratios, increased with GNI (rho = 0.47, P = 0.01)., Conclusions: The link between atopic sensitization and asthma symptoms in children differs strongly between populations and increases with economic development.

Measurement of bronchial responsiveness to hypertonic saline was applied in 22 study centers worldwide as part of Phase Two of the International Study of Asthma and Allergies in Childhood (ISAAC Phase Two). Because the amount of inhaled saline was difficult to standardize during the stepwise protocol with inhalation periods of increasing duration, we evaluated different statistical procedures based on inhalation time in relation to wheeze and current asthma. Data on random samples on 9 to 11-year-old children (n = 1,418) from two German centers were analyzed. The following statistical approaches were evaluated: (1) bronchial hyperreactivity (BHR) defined dichotomously as a fall in FEV1 (forced expiratory volume in 1 s) >or=15%; (2) PT15: the provocation time causing BHR using survival-analyses methods; (3) time-response-slope (continuous) of the individual FEV1-courses calculated by a linear model after comparing different mathematical models. The sensitivity and specificity of BHR versus current asthma were 47% and 87%, respectively. Analyses of the provocation time indicated an increased risk (adjusted hazard-ratio: 4.3; 95% CI: 2.8-6.5) for a fall in FEV1 >or= 15% among children with current asthma in comparison to those without. The time-response-slope differed markedly between children with and without wheeze and current asthma (P < 0.0001). BHR is meaningful and relatively easy to use, but has low sensitivity. Time-response-slopes utilize the available information from the stepwise protocol better than BHR and survival-analysis based on PT15. Response parameters based on inhalation time discriminate well between children with and without asthma and will be compared in the analyses of ISAAC Phase Two data., ((c) 2006 Wiley-Liss, Inc.)

Background: SOLAR II is the 2nd follow-up of a population-based cohort study that follows the participants of ISAAC Phase Two recruited in Munich and Dresden in 1995/6. A first follow-up study was conducted 2002 and 2003 (SOLAR I). The aims of SOLAR II were to investigate the course of atopic diseases over puberty taking environmental and occupational risk factors into account. This paper describes the methods of the 2nd follow-up carried out from 2007 to 2009 and the challenges we faced while studying a population-based cohort of young adults. Methods: Wherever possible, the same questionnaire instruments were used throughout the studies. They included questions on respiratory and allergic diseases, domestic and occupational exposure and work related stress. Furthermore, clinical examinations including skin prick tests, spirometry and bronchial challenge with methacholine, exhaled nitric oxide (FeNO) and blood samples were employed at baseline and 2nd follow-up. As information from three studies was available, multiple imputation could be used to handle missing data. Results: Of the 3053 SOLAR I study participants who had agreed to be contacted again, about 50% had moved in the meantime and had to be traced using phone directories and the German population registries. Overall, 2904 of these participants could be contacted on average five years after the first follow-up. From this group, 2051 subjects (71%) completed the questionnaire they received via mail. Of these, 57% participated at least in some parts of the clinical examinations. Challenges faced included the high mobility of this age group. Time constraints and limited interest in the study were substantial. Analysing the results, selection bias had to be considered as questionnaire responders (54%) and those participating in the clinical part of the study (63%) were more likely to have a high parental level of education compared to non-participants (42%). Similarly, a higher prevalence of parental atopy (e. g. allergic rhinitis) at baseline was found for participants in the questionnaire part (22%) and those participating in the clinical part of the study (27%) compared to non-participants (11%). Conclusions: In conclusion, a 12-year follow-up from childhood to adulthood is feasible resulting in a response of 32% of the baseline population. However, our experience shows that researchers need to allocate more time to the field work when studying young adults compared to other populations. [ABSTRACT FROM AUTHOR]

Objective: Our goal was to quantify the short-term effects of particulate matter with aerodynamic diameter = 10 μm (PM10) and nitrogen dioxide (NO2) on respiratory health of asthmatic children from published panel studies, and to investigate the influence of study and population characteristics as effect modifiers. Data extraction: After a systematic literature review, we extracted quantitative estimates of the association of PM10 and/or NO2 with respiratory symptoms and peak expiratory flow (PEF). Combined effect estimates for an increase of 10 μg/m3 were calculated by random effects meta-analysis for all studies and for different strata defined by study characteristics. The effect of publication bias was investigated with Egger's and Begg's tests and "trim-and-fill" analyses. Data synthesis: We identified 36 studies; 14 were part of the European Pollution Effects on Asthmatic Children in Europe (PEACE) study. Adverse associations of PM10 with asthma symptoms were statistically significant [odds ratio (OR) = 1.028; 95% confidence interval (CI), 1.006- 1.051]. There were also associations, although not statistically significant, of PM10 with cough (OR = 1.012; 95% CI, 0.997-1.026) and on PEF (decrease of -0.082 L/min; 95% CI, -0.214 to 0.050). NO2 had statistically significant associations with asthma symptoms in the overall analysis considering all possible lags (OR = 1.031; 95% CI, 1.001-1.062), but not when we evaluated only the 0-1 lag. We found no publication bias, although it appeared when excluding the PEACE studies. When we applied the trim-and-fill method to the data set without the PEACE studies, the results were similar to the overall estimates from all studies. There was an indication for stronger PM10 associations for studies conducted in summer, outside of Europe, with longer lags, and in locations with higher NO2 concentrations. Conclusions: We found clear evidence of effects of PM10 on the occurrence of asthma symptom episodes, and to a lesser extent on cough and PEF. The results for NO2 are more difficult to interpret because they depend on the lag times examined. There was an indication of effect modification by several study conditions. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusions Using disinfectants and cleaning products (DCPs) at home and work is known to influence both the onset and course of asthma, but most epidemiological studies did not consider the multiplicity and correlations of exposures to DCPs. We aimed to identify exposure profiles for the long‐term weekly use of DCPs by latent class analysis (LCA) and assess their associations with asthma.LCA was conducted on data from 1143 young adults initially recruited in the German centers of Phase II of the International Study of Asthma and Allergies in Childhood (ISAAC) and followed up three times. In our LCA model, we included the use of cleaning sprays, disinfectant sprays, and nonspray disinfection methods, measured at ages 19–24 (first assessment) and 29–34 years (second assessment). Associations between identified exposure profiles and current as well as incident asthma/wheeze were evaluated by logistic regression.We identified five long‐term exposure profiles to DCPs (latent classes): no weekly use of DCPs (55% of participants), use in first assessment (7%), use in second assessment (18%), persistent use (8%), and persistent cleaning sprays use (12%). Compared to “no weekly use,” being in the “persistent use” profile was associated with both current asthma (OR = 1.68, 95% CI = [0.48–5.88]) and current wheeze (OR = 1.71, 95% CI = [0.75–3.90]). For incident asthma/wheeze, interval estimates were very wide.Our study identified five distinct long‐term exposure profiles to DCPs. Among those, only a persistent weekly use of multiple DCPs over time seemed to have an adverse effect on asthma. However, large confidence intervals indicate considerable uncertainty. [ABSTRACT FROM AUTHOR]