TNS1 and NRXN1 Genes Interacting With Early-Life Smoking Exposure in Asthma-Plus-Eczema Susceptibility.

PURPOSE: Numerous genes have been associated with allergic diseases (asthma, allergic rhinitis, and eczema), but they explain only part of their heritability. This is partly because most previous studies ignored complex mechanisms such as gene-environment (G-E) interactions and complex phenotypes such as co-morbidity. However, it was recently evidenced that the co-morbidity of asthma-plus-eczema appears as a sub-entity depending on specific genetic factors. Besides, evidence also suggest that gene-by-early life environmental tobacco smoke (ETS) exposure interactions play a role in asthma, but were never investigated for asthma-plus-eczema. To identify genetic variants interacting with ETS exposure that influence asthma-plus-eczema susceptibility. METHODS: To conduct a genome-wide interaction study (GWIS) of asthma-plus-eczema according to ETS exposure, we applied a 2-stage strategy with a first selection of single nucleotide polymorphisms (SNPs) from genome-wide association meta-analysis to be tested at a second stage by interaction meta-analysis. All meta-analyses were conducted across 4 studies including a total of 5,516 European-ancestry individuals, of whom 1,164 had both asthma and eczema. RESULTS: Two SNPs showed significant interactions with ETS exposure. They were located in 2 genes, NRXN1 (2p16) and TNS1 (2q35), never reported associated and/or interacting with ETS exposure for asthma, eczema or more generally for allergic diseases. TNS1 is a promising candidate gene because of its link to lung and skin diseases with possible interactive effect with tobacco smoke exposure. CONCLUSIONS: This first GWIS of asthma-plus-eczema with ETS exposure underlines the importance of studying sub-phenotypes such as co-morbidities as well as G-E interactions to detect new susceptibility genes.

Continuous Rather Than Solely Early Farm Exposure Protects From Hay Fever Development.

BACKGROUND: An important window of opportunity for early-life exposures has been proposed for the development of atopic eczema and asthma. OBJECTIVE: However, it is unknown whether hay fever with a peak incidence around late school age to adolescence is similarly determined very early in life. METHODS: In the Protection against Allergy-Study in Rural Environments (PASTURE) birth cohort potentially relevant exposures such as farm milk consumption and exposure to animal sheds were assessed at multiple time points from infancy to age 10.5 years and classified by repeated measure latent class analyses (n = 769). Fecal samples at ages 2 and 12 months were sequenced by 16S rRNA. Hay fever was defined by parent-reported symptoms and/or physician's diagnosis of hay fever in the last 12 months using questionnaires at 10.5 years. RESULTS: Farm children had half the risk of hay fever at 10.5 years (adjusted odds ratio [aOR] 0.50; 95% CI 0.31-0.79) than that of nonfarm children. Whereas early life events such as gut microbiome richness at 12 months (aOR 0.66; 95% CI 0.46-0.96) and exposure to animal sheds in the first 3 years of life (aOR 0.26; 95% CI 0.06-1.15) were determinants of hay fever, the continuous consumption of farm milk from infancy up to school age was necessary to exert the protective effect (aOR 0.35; 95% CI 0.17-0.72). CONCLUSIONS: While early life events determine the risk of subsequent hay fever, continuous exposure is necessary to achieve protection. These findings argue against the notion that only early life exposures set long-lasting trajectories.

Surveillance of Acute SARS-CoV-2 Infections in Elementary Schools and Daycare Facilities in Bavaria, Germany (09/2020-03/2021).

Introduction: Here we report our results of a multi-center, open cohort study ("COVID-Kids-Bavaria") investigating the distribution of acute SARS-CoV-2 infections among children and staff in 99 daycare facilities and 48 elementary schools in Bavaria, Germany. Materials and Methods: Overall, 2,568 children (1,337 school children, 1,231 preschool children) and 1,288 adults (466 teachers, 822 daycare staff) consented to participate in the study and were randomly tested in three consecutive phases (September/October 2020, November/December 2020, March 2021). In total, 7,062 throat swabs were analyzed for SARS-CoV-2 by commercial RT-PCR kits. Results: In phase I, only one daycare worker tested positive. In phase II, SARS-CoV-2 was detected in three daycare workers, two preschool children, and seven school children. In phase III, no sample tested positive. This corresponds to a positive test rate of 0.05% in phase I, 0.4% in phase II and 0% in phase III. Correlation of a positive PCR test result with the local-7-day incidence values showed a strong association of a 7-day-incidence of more than 100/100,000 as compared to <100/100,000 (OR = 10.3 [1.5-438], p < 0.005). After phase III, antibody testing was offered to 713 study participants in elementary schools. A seroprevalence rate of 7.7% (students) and 4.5% (teachers) was determined. Discussion: During the initial waves of the SARS-CoV-2 pandemic, the risk of a positive SARS-CoV-2 result correlated positively with the local 7-day incidence. Hence, the occurrence of SARS-CoV-2 infections were reflected in schools and daycare facilities. An increased risk of SARS-CoV-2 transmission in the setting of daycare and elementary schooling was unlikely.

IgA+ memory B-cells are significantly increased in patients with asthma and small airway dysfunction.

BACKGROUND: Comprehensive studies investigated the role of T-cells in asthma which led to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B-cells to this chronic inflammatory disease. In this study we investigated the contribution of various B-cell populations to specific clinical features in asthma. METHODS: In the All Age Asthma Cohort (ALLIANCE), a subgroup of 154 adult asthma patients and 28 healthy controls were included for B-cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B-cells using association studies and multivariate linear models. RESULTS: Patients with severe asthma showed decreased immature B-cell populations while memory B-cells were significantly increased compared with both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of IgA+ memory B-cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA+ memory B-cells, particularly in patients with mild-moderate asthma. Additionally, IgA+ memory B-cells significantly correlated with clinical features of SAD such as exacerbations. CONCLUSIONS: With this study we demonstrate for the first time a significant association of increased IgA+ memory B-cells with asthma and SAD, pointing towards future options for B-cell-directed strategies in preventing and treating asthma.

Early priming of asthma and respiratory allergies: Future aspects of prevention: A statement by the European Forum for Education and Research in Allergy and Airway Disease (EUFOREA) and the EAACI-Clemens von Pirquet Foundation.

In order to summarize recent research on the prevention of allergies-particularly asthma-and stimulate new activities for future initiatives, a virtual workshop sponsored by the EAACI Clemens von Pirquet foundation and EUFOREA was held in October 2021. The determinants of the "allergic march" as well as the key messages from intervention studies were reviewed by an international faculty of experts. Several unmet needs were identified, and a number of priorities for future studies were proposed.

T2-high asthma phenotypes across lifespan.

RATIONALE: In adults, personalised asthma treatment targets patients with type 2 (T2)-high and eosinophilic asthma phenotypes. It is unclear whether such classification is achievable in children. OBJECTIVES: To define T2-high asthma with easily accessible biomarkers and compare resulting phenotypes across all ages. METHODS: In the multicentre clinical All Age Asthma Cohort (ALLIANCE), 1125 participants (n=776 asthmatics, n=349 controls) were recruited and followed for 2 years (1 year in adults). Extensive clinical characterisation (questionnaires, blood differential count, allergy testing, lung function and sputum induction (in adults)) was performed at baseline and follow-ups. Interleukin (IL)-4, IL-5 and IL-13 were measured after stimulation of whole blood with lipopolysaccharide (LPS) or anti-CD3/CD28. MEASUREMENTS AND MAIN RESULTS: Based on blood eosinophil counts and allergen-specific serum IgE antibodies, patients were categorised into four mutually exclusive phenotypes: "atopy-only", "eosinophils-only", "T2-high" (eosinophilia + atopy) and "T2-low" (neither eosinophilia nor atopy). The T2-high phenotype was found across all ages, even in very young children in whom it persisted to a large degree even after 2 years of follow-up. T2-high asthma in adults was associated with childhood onset, suggesting early origins of this asthma phenotype. In both children and adults, the T2-high phenotype was characterised by excessive production of specific IgE to allergens (p<0.0001) and, from school age onwards, by increased production of IL-5 after anti-CD3/CD28 stimulation of whole blood. CONCLUSIONS: Using easily accessible biomarkers, patients with T2-high asthma can be identified across all ages delineating a distinct phenotype. These patients may benefit from therapy with biologicals even at a younger age.

Identification of OCA2 as a novel locus for the co-morbidity of asthma-plus-eczema.

BACKGROUND: Numerous genes have been associated with the three most common allergic diseases (asthma, allergic rhinitis or eczema) but these genes explain only a part of the heritability. In the vast majority of genetic studies, complex phenotypes such as co-morbidity of two of these diseases, have not been considered. This may partly explain missing heritability. OBJECTIVE: To identify genetic variants specifically associated with the co-morbidity of asthma-plus-eczema. METHODS: We first conducted a meta-analysis of four GWAS (Genome-Wide Association Study) of the combined asthma-plus-eczema phenotype (total of 8807 European-ancestry subjects of whom 1208 subjects had both asthma and eczema). To assess whether the association with SNP(s) was specific to the co-morbidity, we also conducted a meta-analysis of homogeneity test of association according to disease status ("asthma-plus-eczema" vs. the presence of only one disease "asthma only or eczema only"). We then used a joint test by combining the two test statistics from the co-morbidity-SNP association and the phenotypic heterogeneity of SNP effect meta-analyses. RESULTS: Seven SNPs were detected for specific association to the asthma-plus-eczema co-morbidity, two with significant and five with suggestive evidence using the joint test after correction for multiple testing. The two significant SNPs are located in the OCA2 gene (Oculocutaneous Albinism II), a new locus never detected for significant evidence of association with any allergic disease. This gene is a promising candidate gene, because of its link to skin and lung diseases, and to epithelial barrier and immune mechanisms. CONCLUSION: Our study underlines the importance of studying sub-phenotypes as co-morbidities to detect new susceptibility genes.

Trajectories of asthma and allergy symptoms from childhood to adulthood.

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.

Excessive Unbalanced Meat Consumption in the First Year of Life Increases Asthma Risk in the PASTURE and LUKAS2 Birth Cohorts.

A higher diversity of food items introduced in the first year of life has been inversely related to subsequent development of asthma. In the current analysis, we applied latent class analysis (LCA) to systematically assess feeding patterns and to relate them to asthma risk at school age. PASTURE (N=1133) and LUKAS2 (N=228) are prospective birth cohort studies designed to evaluate protective and risk factors for atopic diseases, including dietary patterns. Feeding practices were reported by parents in monthly diaries between the 4th and 12th month of life. For 17 common food items parents indicated frequency of feeding during the last 4 weeks in 4 categories. The resulting 153 ordinal variables were entered in a LCA. The intestinal microbiome was assessed at the age of 12 months by 16S rRNA sequencing. Data on feeding practice with at least one reported time point was available in 1042 of the 1133 recruited children. Best LCA model fit was achieved by the 4-class solution. One class showed an elevated risk of asthma at age 6 as compared to the other classes (adjusted odds ratio (aOR): 8.47, 95% CI 2.52-28.56, p = 0.001) and was characterized by daily meat consumption and rare consumption of milk and yoghurt. A refined LCA restricted to meat, milk, and yoghurt confirmed the asthma risk effect of a particular class in PASTURE and independently in LUKAS2, which we thus termed unbalanced meat consumption (UMC). The effect of UMC was particularly strong for non-atopic asthma and asthma irrespectively of early bronchitis (aOR: 17.0, 95% CI 5.2-56.1, p < 0.001). UMC fostered growth of iron scavenging bacteria such as Acinetobacter (aOR: 1.28, 95% CI 1.00-1.63, p = 0.048), which was also related to asthma (aOR: 1.55, 95% CI 1.18-2.03, p = 0.001). When reconstructing bacterial metabolic pathways from 16S rRNA sequencing data, biosynthesis of siderophore group nonribosomal peptides emerged as top hit (aOR: 1.58, 95% CI 1.13-2.19, p = 0.007). By a data-driven approach we found a pattern of overly meat consumption at the expense of other protein sources to confer risk of asthma. Microbiome analysis of fecal samples pointed towards overgrowth of iron-dependent bacteria and bacterial iron metabolism as a potential explanation.

Asthma in farm children is more determined by genetic polymorphisms and in non-farm children by environmental factors.

BACKGROUND: The asthma syndrome is influenced by hereditary and environmental factors. With the example of farm exposure, we study whether genetic and environmental factors interact for asthma. METHODS: Statistical learning approaches based on penalized regression and decision trees were used to predict asthma in the GABRIELA study with 850 cases (9% farm children) and 857 controls (14% farm children). Single-nucleotide polymorphisms (SNPs) were selected from a genome-wide dataset based on a literature search or by statistical selection techniques. Prediction was assessed by receiver operating characteristics (ROC) curves and validated in the PASTURE cohort. RESULTS: Prediction by family history of asthma and atopy yielded an area under the ROC curve (AUC) of 0.62 [0.57-0.66] in the random forest machine learning approach. By adding information on demographics (sex and age) and 26 environmental exposure variables, the quality of prediction significantly improved (AUC = 0.65 [0.61-0.70]). In farm children, however, environmental variables did not improve prediction quality. Rather SNPs related to IL33 and RAD50 contributed significantly to the prediction of asthma (AUC = 0.70 [0.62-0.78]). CONCLUSIONS: Asthma in farm children is more likely predicted by other factors as compared to non-farm children though in both forms, family history may integrate environmental exposure, genotype and degree of penetrance.

Maturation of the gut microbiome during the first year of life contributes to the protective farm effect on childhood asthma.

Growing up on a farm is associated with an asthma-protective effect, but the mechanisms underlying this effect are largely unknown. In the Protection against Allergy: Study in Rural Environments (PASTURE) birth cohort, we modeled maturation using 16S rRNA sequence data of the human gut microbiome in infants from 2 to 12 months of age. The estimated microbiome age (EMA) in 12-month-old infants was associated with previous farm exposure (ß = 0.27 (0.12-0.43), P = 0.001, n = 618) and reduced risk of asthma at school age (odds ratio (OR) = 0.72 (0.56-0.93), P = 0.011). EMA mediated the protective farm effect by 19%. In a nested case-control sample (n = 138), we found inverse associations of asthma with the measured level of fecal butyrate (OR = 0.28 (0.09-0.91), P = 0.034), bacterial taxa that predict butyrate production (OR = 0.38 (0.17-0.84), P = 0.017) and the relative abundance of the gene encoding butyryl-coenzyme A (CoA):acetate-CoA-transferase, a major enzyme in butyrate metabolism (OR = 0.43 (0.19-0.97), P = 0.042). The gut microbiome may contribute to asthma protection through metabolites, supporting the concept of a gut-lung axis in humans.

The Beneficial Effect of Farm Milk Consumption on Asthma, Allergies, and Infections: From Meta-Analysis of Evidence to Clinical Trial.

The low prevalence of asthma and allergies in farm children has partially been ascribed to the consumption of raw cow's milk. A literature search identified 12 publications on 8 pertinent studies. A meta-analysis corroborated the protective effect of raw milk consumption early in life (<1 to 5 years, according to study) on asthma (odds ratio [OR], 0.58; 95% CI, 0.49-0.69), current wheeze (OR, 0.66; 95% CI, 0.55-0.78), hay fever or allergic rhinitis (OR, 0.68; 95% CI, 0.57-0.82), and atopic sensitization (OR, 0.76; 95% CI, 0.62-0.95). The effect particularly on asthma was observed not only in children raised on farms (OR, 0.62; 95% CI, 0.58-0.82) but also in children living in rural areas but not on a farm (OR, 0.60; 95% CI, 0.48-0.74). This demonstrates that the effect of farm milk consumption is independent of other farm exposures and that children not living on a farm can theoretically profit from this effect. Because of the minimal but real risk of life-threatening infections, however, consumption of raw milk and products thereof is strongly discouraged. Raw farm milk and industrially processed milk differ in many instances including removal of cellular components, manipulation of the fat fraction, and various degrees of heating. Preliminary evidence attributes the effect to heat-labile molecules and components residing in the fat fraction. The Milk Against Respiratory Tract Infections and Asthma (MARTHA) trial is currently testing the protective effect of microbiologically safe, minimally processed cow's milk against standard ultra-heat-treated milk in children from 6 months to 3 years with the primary outcome of an asthma diagnosis until age 5 years. If successful, this approach might provide a simple but effective prevention strategy.

Correction to: Analysis of the Fungal Flora in Environmental Dust Samples by PCR-SSCP Method.

The original version of this article contained a mistake in the co-author's conflict of interest statement. Erika von Mutius wishes to add the following disclosures: "E. von Mutius is listed as an inventor on the following patents: publication number EP 1411977, composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases, granted on 18 April 2007; publication number EP1637147, stable dust extract for allergy protection, granted on 10 December 2008; publication number EP 1964570, pharmaceutical compound to protect against allergies and inflammatory diseases, granted on 21 November 2012. E. von Mutius is listed as inventor and has received royalties on the following patent: publication number EP2361632, specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders, granted on 19 March 2014".

Genome-wide interaction study of early-life smoking exposure on time-to-asthma onset in childhood.

BACKGROUND: Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma. OBJECTIVE: Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood. METHODS: We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totalling 8273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analysed. RESULTS: The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P = 4.3 × 10-8 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P < 5 × 10-6 ) were found at three other loci: 20p12 (rs13037508 within MACROD2; P = 4.9 × 10-7 ), 14q22 (rs7493885 near NIN; P = 2.9 × 10-6 ) and 2p22 (rs232542 near CYP1B1; P = 4.1 × 10-6 ). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings. CONCLUSIONS AND CLINICAL RELEVANCE: We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms.

Parents know it best: Prediction of asthma and lung function by parental perception of early wheezing episodes.

BACKGROUND: Childhood asthma is often preceded by early wheeze. Usually, wheezing episodes are recorded retrospectively, which may induce recall bias. AIMS AND OBJECTIVES: The aim of this study was to investigate true-positive recall of parent-reported wheeze at 1 year of age, its determinants, and its implications for asthma and lung function at 6 years of age. METHODS: The PASTURE (Protection Against Allergy-Study in Rural Environments) study followed 880 children from rural areas in 5 European countries from birth to age 6 years. Wheeze symptoms in the first year were asked weekly. At age 6, parent-reported asthma diagnosis was ascertained and lung function measurements were conducted. Correct parental recall of wheeze episodes at the end of the first year was assessed for associations with lung function, asthma, and the asthma risk locus on chromosome 17q21. RESULTS: Parents correctly recalled wheeze after the first year in 54% of wheezers. This true-positive recall was determined by number of episodes, timing of the last wheeze episode, and parental asthma. Independently from these determinants, true-positive recall predicted asthma at age 6 years (odds ratio 4.54, 95% confidence interval (CI) [1.75-14.16]) and impaired lung function (ß = -0.62, 95% CI [-1.12; -0.13], P-value = .02). Associations were stronger in children with asthma risk SNPs on chromosome 17q21. CONCLUSION: Correct parental recall of wheezing episodes may reflect clinical relevance of early wheeze and its impact on subsequent asthma and lung function impairment. Questions tailored to parental perception of wheezing episodes may further enhance asthma prediction.

Author Correction: Farm-like indoor microbiota in non-farm homes protects children from asthma development.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Farm-like indoor microbiota in non-farm homes protects children from asthma development.

Asthma prevalence has increased in epidemic proportions with urbanization, but growing up on traditional farms offers protection even today1. The asthma-protective effect of farms appears to be associated with rich home dust microbiota2,3, which could be used to model a health-promoting indoor microbiome. Here we show by modeling differences in house dust microbiota composition between farm and non-farm homes of Finnish birth cohorts4 that in children who grow up in non-farm homes, asthma risk decreases as the similarity of their home bacterial microbiota composition to that of farm homes increases. The protective microbiota had a low abundance of Streptococcaceae relative to outdoor-associated bacterial taxa. The protective effect was independent of richness and total bacterial load and was associated with reduced proinflammatory cytokine responses against bacterial cell wall components ex vivo. We were able to reproduce these findings in a study among rural German children2 and showed that children living in German non-farm homes with an indoor microbiota more similar to Finnish farm homes have decreased asthma risk. The indoor dust microbiota composition appears to be a definable, reproducible predictor of asthma risk and a potential modifiable target for asthma prevention.

Development of atopic sensitization in Finnish and Estonian children: A latent class analysis in a multicenter cohort.

BACKGROUND: The prevalence of atopy is associated with a Western lifestyle, as shown by studies comparing neighboring regions with different socioeconomic backgrounds. Atopy might reflect various conditions differing in their susceptibility to environmental factors. OBJECTIVE: We sought to define phenotypes of atopic sensitization in early childhood and examine their association with allergic diseases and hereditary background in Finland and Estonia. METHODS: The analysis included 1603 Finnish and 1657 Estonian children from the DIABIMMUNE multicenter young children cohort. Specific IgE levels were measured at age 3, 4, and 5 years, respectively, and categorized into 3 CAP classes. Latent class analysis was performed with the statistical software package poLCA in R software. RESULTS: Both populations differed in terms of socioeconomic status and environmental determinants, such as pet ownership, farm-related exposure, time spent playing outdoors, and prevalence of allergic diseases (all P < .001). Nevertheless, we found similar latent classes in both populations: an unsensitized class, a food class, 2 inhalant classes differentiating between seasonal and perennial aeroallergens, and a severe atopy class. The latter was characterized by high total and specific IgE levels and strongly associated with wheeze (odds ratio [OR], 5.64 [95% CI, 3.07-10.52] and 4.56 [95% CI, 2.35-8.52]), allergic rhinitis (OR, 22.4 [95% CI, 11.67-44.54] and 13.97 [95% CI, 7.33-26.4]), and atopic eczema (OR, 9.39 [95% CI, 4.9-19.3] and 9.5 [95% CI, 5.2-17.5] for Finland and Estonia, respectively). Environmental differences were reflected in the larger seasonal inhalant atopy class in Finland, although composition of classes was comparable between countries. CONCLUSION: Despite profound differences in environmental exposures, there might exist genuine patterns of atopic sensitization. The distribution of these patterns might determine the contribution of atopic sensitization to disease onset.