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Asthma often remains uncontrolled, despite the fact that the pharmacological treatment has undergone large changes. We studied changes in the treatment of asthma over a 20-year period and identified factors associated with the regular use of inhaled corticosteroid (ICS) treatment. Changes in the use of medication were determined in 4617 randomly selected subjects, while changes in adults with persistent asthma were analysed in 369 participants. The study compares data from three surveys in 24 centres in 11 countries. The use of ICSs increased from 1.7% to 5.9% in the general population and the regular use of ICSs increased from 19% to 34% among persistent asthmatic subjects. The proportion of asthmatic subjects reporting asthma attacks in the last 12 months decreased, while the proportion that had seen a doctor in the last 12 months remained unchanged (42%). Subjects with asthma who had experienced attacks or had seen a doctor were more likely to use ICSs on a regular basis. Although ICS use has increased, only one-third of subjects with persistent asthma take ICSs on a regular basis. Less than half had seen a doctor during the last year. This indicates that underuse of ICSs and lack of regular healthcare contacts remains a problem in the management of asthma.

Background: Pru p 3 and Pru p 7 have been implicated as risk factors for severe peach allergy. This study aimed to establish sensitization patterns to five peach components across Europe and in Japan, to explore their relation to pollen and foods and to predict symptom severity., Methods: In twelve European (EuroPrevall project) and one Japanese outpatient clinic, a standardized clinical evaluation was conducted in 1231 patients who reported symptoms to peach and/or were sensitized to peach. Specific IgE against Pru p 1, 2, 3, 4 and 7 and against Cup s 7 was measured in 474 of them. Univariable and multivariable Lasso regression was applied to identify combinations of parameters predicting severity., Results: Sensitization to Pru p 3 dominated in Southern Europe but was also quite common in Northern and Central Europe. Sensitization to Pru p 7 was low and variable in the European centers but very dominant in Japan. Severity could be predicted by a model combining age of onset of peach allergy, probable mugwort, Parietaria pollen and latex allergy, and sensitization to Japanese cedar pollen, Pru p 4 and Pru p 7 which resulted in an AUC of 0.73 (95% CI 0.73-0.74). Pru p 3 tended to be a risk factor in South Europe only., Conclusions: Pru p 7 was confirmed as a significant risk factor for severe peach allergy in Europe and Japan. Combining outcomes from clinical and demographic background with serology resulted in a model that could better predict severity than CRD alone., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: It is not well-understood why symptom severity varies between patients with peanut allergy (PA). Objective: To gain insight into the clinical profile of subjects with mild-to-moderate and severe PA, and investigate individual and collective predictive accuracy of clinical background and IgE to peanut extract and components for PA severity. Methods: Data on demographics, patient history and sensitization at extract and component level of 393 patients with probable PA (symptoms ≤ 2 h + IgE sensitization) from 12 EuroPrevall centers were analyzed. Univariable and penalized multivariable regression analyses were used to evaluate risk factors and biomarkers for severity. Results: Female sex, age at onset of PA, symptoms elicited by skin contact with peanut, family atopy, atopic dermatitis, house dust mite and latex allergy were independently associated with severe PA; birch pollen allergy with mild-to-moderate PA. The cross-validated AUC of all clinical background determinants combined (0.74) was significantly larger than the AUC of tests for sensitization to extract (0.63) or peanut components (0.54-0.64). Although larger skin prick test wheal size, and higher IgE to peanut extract, Ara h 1 and Ara h 2/6, were associated with severe PA, and higher IgE to Ara h 8 with mild-to-moderate PA, addition of these measurements of sensitization to the clinical background model did not significantly improve the AUC. Conclusions: Models combining clinical characteristics and IgE sensitization patterns can help establish the risk of severe reactions for peanut allergic patients, but clinical background determinants are most valuable for predicting severity of probable PA in an individual patient., Competing Interests: Outside of submitted work: MF-R reported grants and personal fees from Aimmune Therapeutics and Diater, personal fees from DBV, Allergy Therapeutics, GSK, HAL Allergy, Novartis, ThermoFisher Scientific, and SPRIM. BB-W reported personal fees from ThermoFisher Scientific. FB reported personal fees from Aimmune; grants from Stallergènes Greer, Chiesi, Mundipharma, Novartis, and Regeneron; and board membership for DVB, Stallergènes Greer, Novartis, ALK, Mundipharma, Boehringer, AstraZeneca, Medapharma, and Boston Scientific. JL was an employee of ThermoFisher Scientific. NP reported personal fees from Novartis, Nutricia, HAL Allergy BV, Menarine/Faes Farma, Sanofi, Mylan/Meda, Biomay, AstraZeneca, GSK, MSD, ASIT Biotech, Boehringer Ingelheim; and grants from Gerolymatos International SA, and Capricare. SV reported personal fees from Ärzteverband Deutscher Allergologen, Swiss Society for Allergy and Immunology, Schattauer Allergologie Handbuch, Elsevier Nahrungsmittelallergien und Intoleranzen, Karger Food Allergy: Molecular Basis and Clinical Practice, and Pharmacon. EM reported grants from Reacta Biotech; and was shareholder of Reacta Biotech Ltd. RR reported personal fees from HAL Allergy BV, Citeq BV, Angany Inc., and ThermoFisher Scientific. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Datema, Lyons, Fernández-Rivas, Ballmer-Weber, Knulst, Asero, Barreales, Belohlavkova, de Blay, Clausen, Dubakiene, Fernández-Perez, Fritsche, Gislason, Hoffmann-Sommergruber, Jedrzejczak-Czechowicz, Jongejan, Kowalski, Kralimarkova, Lidholm, Papadopoulos, Popov, Prado, Purohit, Reig, Seneviratne, Sinaniotis, Vassilopoulou, Versteeg, Vieths, Welsing, Mills, Le, Zwinderman and van Ree.)

Diseases connected with work in hay have been known in Iceland for a long time. In 1981 scientific studies of these diseases were started in Iceland at the request of the Farmers Union. The results of these studies are summarized in this article. In studies of hay a great amount of storage mites, moulds and thermophilic actinomycetes (microlyspora faeni) were found in addition to allergens from mice and pollen. Symptoms caused by hay dust were mainly from nose and eyes in people with positive skin tests, but cough, dyspnea and fever were equally common in those with negative skin tests. The most common causes of allergy in farming families were storage mites and cattle, but allergy to cats, dogs and grass pollen were less common rurally than in the Reykjavik area. When comparing individuals working in heavy hay dust with those working in cleaner air, the former group had a higher likelihood of having a positive precipitin test against micropolyspora faeni, fever after work in hay and airway obstruction. It was shown that Icelandic farmers were more likely to get emphysema than other people irrespective of smoking. In a large study of homes in the Reykjavik area almost no mites were found. In spite of this, positive specific IgE tests against dust mites were equally common as in Uppsala, Sweden, where dust mites were found in 16% of homes. In further studies it was found, that 57% of people in the study had been more and less exposed to hay dust. They had either been raised on a farm, been on a farm in the summer during childhood or owned horses and fed them with hay. We have argued that cross allergy to storage mites may be the cause of a rather common allergy to house dust mites. A new study of middle-aged individuals has shown that allergy to storage mites is a little more common in the Reykjavik area than in Aarhus, Bergen or Uppsala. The most likely explanation is that they have more often been exposed to hay dust.

Diseases connected with work in hay have existed in Iceland since its settlement late in the 9th century. Haymaking was probably easier in those days because of better climate and land quality but became more difficult later when these factors deteriorated. First data on diseases connected with hay are from the early 17th century where the word "haysickness" (in Icelandic "heysótt") is used in a book on treatment of diseases. Later in the century the word is found in a rhyme that says "short of breath due to haysickness". The word "haysickness" is also found in dictionaries from that time. In a book from 1730-40 says: "Haysickness sometimes causes illness and loss of appetite in those that loosen hay in a compressed haystack with a hayneedle or a hook." At the end of the 18th century Jón Pétursson writes a good description of hay diseases: "It cannot be denied that haysickness not taken seriously or long ignored can cause many deaths in this country." Jón Finsen mentions in his doctoral thesis in 1874 that the symptoms of haysickness are different from those of allergy to pollen (hay fever) that had been recently described. In 1870 the Director of Health writes directions for farmers on how to reduce the danger of getting haysickness by using a thin cloth facemask when loosing hay from a haystack.

Background: Walnut allergy is common across the globe, but data on the involvement of individual walnut components are scarce., Objectives: To identify geographical differences in walnut component sensitization across Europe, explore cosensitization and cross-reactivity, and assess associations of clinical and serological determinants with severity of walnut allergy., Methods: As part of the EuroPrevall outpatient surveys in 12 European cities, standardized clinical evaluation was conducted in 531 individuals reporting symptoms to walnut, with sensitization to all known walnut components assessed in 202 subjects. Multivariable Lasso regression was applied to investigate predictors for walnut allergy severity., Results: Birch-pollen-related walnut sensitization (Jug r 5) dominated in Northern and Central Europe and lipid transfer protein sensitization (Jug r 3) in Southern Europe. Profilin sensitization (Jug r 7) was prominent throughout Europe. Sensitization to storage proteins (Jug r 1, 2, 4, and 6) was detected in up to 10% of subjects. The walnut components that showed strong correlations with pollen and other foods differed between centers. The combination of determinants best predicting walnut allergy severity were symptoms upon skin contact with walnut, atopic dermatitis (ever), family history of atopic disease, mugwort pollen allergy, sensitization to cat or dog, positive skin prick test result to walnut, and IgE to Jug r 1, 5, 7, or carbohydrate determinants (area under the curve = 0.81; 95% CI, 0.73-0.89)., Conclusions: Walnut-allergic subjects across Europe show clear geographical differences in walnut component sensitization and cosensitization patterns. A predictive model combining results from component-based serology testing with results from extract-based testing and information on clinical background allows for good discrimination between mild to moderate and severe walnut allergy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Inhaled corticosteroids (ICSs) are the mainstay of asthma treatment, but response to medication is variable. Patients with allergic inflammation generally show a better short-term response to ICSs; however, studies on predictors of long-term response are few., Objective: To assess whether allergic sensitization can modify the association between ICS use and lung function decline over 20 years in adult asthma., Methods: We used data from the 3 clinical examinations of the European Community Respiratory Health Survey. We measured ICS use (no use, and use for <1.3, 1.3-8, and >8 years) and FEV 1 decline among subjects with asthma over the 2 periods between consecutive examinations. We conducted a cohort study combining data of the 2 periods (906 observations from 745 subjects) to assess whether the association between ICS use and FEV 1 decline was modified by allergic sensitization (IgE > 0.35 kU/L for any of house-dust mite, timothy grass, cat, or Cladosporium)., Results: FEV 1 decline was similar for non-ICS users, as well as ICS users for less than 1.3 years, with and without allergic sensitization. However, among subjects on ICSs for a longer period, sensitization was associated with an attenuated decline (P interaction  = .006): in the group treated for more than 8 years, FEV 1 decline was on average 27 mL/y (95% CI Bonferroni-adjusted , 11-42) lower for subjects with sensitization compared with nonsensitized subjects., Conclusions: Our study suggests that biomarkers of atopy can predict a more favorable long-term response to ICSs. Randomized controlled studies are needed to confirm these findings., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Allergic sensitization to storage mites has mostly been related to occupational exposures like farming, grain/cattle handling, whereas for non-occupational settings, storage mite sensitization has been attributed to cross-reactivity with house dust mite (HDM) allergens., Objective: We aimed to describe the prevalence of allergic sensitization to storage mites, co-sensitization to HDM allergens and respiratory symptoms in Denmark, Iceland, Norway and Sweden., Methods: The population comprised of 1180 participants born 1945-1972 of the third follow-up of the population-based cohort European Community Respiratory Health Survey (ECRHS) in Aarhus, Bergen, Reykjavik and Uppsala. A clinical examination included skin prick tests (SPT) to Lepidoglyphus destructor, Tyrophagus putrescentiae, Acarus siro and common inhalant allergens, as well as standardized interviews., Results: 8% were sensitized to HDM and 10% to storage mite, with some variation by study centre: Reykjavik 13%, Bergen 8% and Aarhus 7%. In Uppsala, only L destructor (3%) was measured. Storage mite sensitization was higher among men (11%) than women (8%). Among storage mite sensitized, 44% were also sensitized to HDM. Storage mite sensitization was associated with asthma and nasal allergies, but not with age, education, pet keeping or place of upbringing., Conclusions and Clinical Relevance: In this Northern European population-based study, allergic sensitization to storage mite was as common as HDM sensitization. Storage mite sensitization was, independently of HDM sensitization, associated with respiratory symptoms and asthma. Our findings suggest that storage mite sensitization should be evaluated with regard to inclusion into the common inhalant allergen panel in Northern Europe., (© 2019 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3' UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.

Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10 -27 , odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10 -8 , odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.

Background: Component-resolved diagnosis (CRD) has revealed significant associations between IgE against individual allergens and severity of hazelnut allergy. Less attention has been given to combining them with clinical factors in predicting severity., Aim: To analyze associations between severity and sensitization patterns, patient characteristics and clinical history, and to develop models to improve predictive accuracy., Methods: Patients reporting hazelnut allergy (n = 423) from 12 European cities were tested for IgE against individual hazelnut allergens. Symptoms (reported and during Double-blind placebo-controlled food challenge [DBPCFC]) were categorized in mild, moderate, and severe. Multiple regression models to predict severity were generated from clinical factors and sensitization patterns (CRD- and extract-based). Odds ratios (ORs) and areas under receiver-operating characteristic (ROC) curves (AUCs) were used to evaluate their predictive value., Results: Cor a 9 and 14 were positively (OR 10.5 and 10.1, respectively), and Cor a 1 negatively (OR 0.14) associated with severe symptoms during DBPCFC, with AUCs of 0.70-073. Combining Cor a 1 and 9 improved this to 0.76. A model using a combination of atopic dermatitis (risk), pollen allergy (protection), IgE against Cor a 14 (risk) and walnut (risk) increased the AUC to 0.91. At 92% sensitivity, the specificity was 76.3%, and the positive and negative predictive values 62.2% and 95.7%, respectively. For reported symptoms, associations and generated models proved to be almost identical but weaker., Conclusion: A model combining CRD with clinical background and extract-based serology is superior to CRD alone in assessing the risk of severe reactions to hazelnut, particular in ruling out severe reactions., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM&#95;001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.

The prevalence of atopy and asthma is relatively low in Iceland. The purpose of this study was to describe exhaled nitric oxide (FeNO) levels in the general population in correlation with demographic characteristics, smoking status, asthma, rhinitis, atopic status and lung function tests. Altogether 403 subjects, from the European Community Respiratory Health Survey (ECRHS) III who answered the main questionnaire and were checked by FeNO measurements, lung function testing, skin prick testing and measurement of total IgE and specific IgE were included. The geometric mean (95% CI) of FeNO was 16.2 ppb (15.2-17.1) and the prevalence of higher FeNO (⩾25 ppb) was 19.5% in the random sample. Subjects with higher FeNO levels were less likely to be current smokers and more likely to have asthma and rhinitis. Having higher FeNO values was also associated with higher total IgE, having specific IgE to at least one allergen and being skin prick test positive. Current smokers had significantly lower levels of FeNO, geometric mean (95% CI) 9.6 ppb (8.4-11.0), than ex-smokers 18.2 ppb (16.6-20.0) and never smokers 17.3 ppb (16.1-18.5). In multivariable models, having asthma (OR (95% CI) 2.10 (1.20-3.67)), having a specific IgE (OR 2.30 (1.25-4.23)) and being skin prick test positive (OR 2.06 (1.18-3.60)) were independently positively associated with a higher FeNO (⩾25) whereas current smoking was independently negatively associated with a higher FeNO (OR 0.19 (0.06-0.63)). Higher levels of FeNO (⩾25 ppb) were found in one out of five Icelanders; FeNO was positively associated with asthma and allergy and negatively with smoking.

Background: Hazelnut allergy is birch pollen-driven in Northern/Western Europe and lipid transfer protein-driven in Spain and Italy. Little is known about other regions and other allergens., Objective: Establishing a molecular map of hazelnut allergy across Europe., Methods: In 12 European cities, subjects reporting reactions to hazelnut (n = 731) were evaluated and sensitization to 24 foods, 12 respiratory allergen sources, and latex was tested by using skin prick test and ImmunoCAP. A subset (124 of 731) underwent a double-blind placebo-controlled food challenge to hazelnut. Sera of 423 of 731 subjects were analyzed for IgE against 7 hazelnut allergens and cross-reactive carbohydrate determinants by ImmunoCAP., Results: Hazelnut allergy was confirmed in 70% of those undergoing double-blind placebo-controlled food challenges. Birch pollen-driven hazelnut sensitization (Cor a 1) dominated in most cities, except in Reykjavik, Sofia, Athens, and Madrid, where reporting of hazelnut allergy was less frequent anyhow. In Athens, IgE against Cor a 8 dominated and strongly correlated with IgE against walnut, peach, and apple and against Chenopodium, plane tree, and mugwort pollen. Sensitization to seed storage proteins was observed in less than 10%, mainly in children, and correlated with IgE to nuts, seeds, and legumes. IgE to Cor a 12, observed in all cities (10% to 25%), correlated with IgE to nuts, seeds, and pollen., Conclusions: In adulthood, the importance of hazelnut sensitization to storage proteins, oleosin (Cor a 12), and Cor a 8 is diluted by the increased role of birch pollen cross-reactivity with Cor a 1. Cor a 8 sensitization in the Mediterranean is probably driven by diet in combination with pollen exposure. Hazelnut oleosin sensitization is prevalent across Europe; however, the clinical relevance remains to be established., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The EuroPrevall project aimed to develop effective management strategies in food allergy through a suite of interconnected studies and a multidisciplinary integrated approach. To address some of the gaps in food allergy diagnosis, allergen risk management and socio-economic impact and to complement the EuroPrevall population-based surveys, a cross-sectional study in 12 outpatient clinics across Europe was conducted. We describe the study protocol., Methods: Patients referred for immediate food adverse reactions underwent a consistent and standardized allergy work-up that comprised collection of medical history; assessment of sensitization to 24 foods, 14 inhalant allergens and 55 allergenic molecules; and confirmation of clinical reactivity and food thresholds by standardized double-blind placebo-controlled food challenges (DBPCFCs) to milk, egg, fish, shrimp, peanut, hazelnut, celeriac, apple and peach., Results: A standardized methodology for a comprehensive evaluation of food allergy was developed and implemented in 12 outpatient clinics across Europe. A total of 2121 patients (22.6% <14 years) reporting 8257 reactions to foods were studied, and 516 DBPCFCs were performed., Conclusions: This is the largest multicentre European case series in food allergy, in which subjects underwent a comprehensive, uniform and standardized evaluation including DBPCFC, by a methodology which is made available for further studies in food allergy. The analysis of this population will provide information on the different phenotypes of food allergy across Europe, will allow to validate novel in vitro diagnostic tests, to establish threshold values for major allergenic foods and to analyse the socio-economic impact of food allergy., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Asthma and rhinitis are common diseases in children often but not always caused by allergy. Gastroesophageal reflux is also prevalent in children and relationship with respiratory symptoms has been suggested. The aim of this study was to investigate this relationship in schoolchildren., Material and Methods: As a part of multi-centre cross-sectional food allergy study (Europrevall), a short questionnaire was sent out to 2895 schoolchildren in Reykjavik 7-10 year old. Of the 2346 (81%) children we received answers from we selected those that answered positively to questions regarding common foods and a random sample of those who denied any symptoms related to food. The selected children were invited to further study where they answered an extensive questionnaire that included questions regarding respiratory and gastrointestinal symptoms., Results: A significant correlation was found between a history of wheezing over the previous year and vomiting, (p<0.001) and feeling nauseous (p<0.001) in the past 6 months. There was also a correlation between asthma in the previous year and feeling nauseous (p<0.05), having a a burning or painful feeling in the middle of the chest (p<0.001) as well as nasal symptoms and vomiting (p<0.01), feeling nauseous (p<0.01), having a burning or painful feeling in the middle of the chest (p<0.01) and having a sour taste, like a taste of vomit in the mouth (p<0.001)., Conclusion: This study shows a significant correlation between symptoms of gastroesophageal reflux and respiratory and nasal symptoms. Clinicians should be aware of this association though the nature and direction of this association is still unclear.

Background: This study is aimed at providing a real-world evaluation of the economic cost of persistent asthma among European adults according to the degree of disease control [as defined by the 2006 Global Initiative for Asthma (GINA) guidelines]., Methods: A prevalence-based cost-of-illness study was carried out on 462 patients aged 30-54 years with persistent asthma (according to the 2002 GINA definition), who were identified in general population samples from 11 European countries and examined in clinical settings in the European Community Respiratory Health Survey II between 1999 and 2002. The cost estimates were computed from the societal perspective following the bottom-up approach on the basis of rates, wages and prices in 2004 (obtained at the national level from official sources), and were then converted to the 2010 values., Results: The mean total cost per patient was EUR 1,583 and was largely driven by indirect costs (i.e. lost working days and days with limited, not work-related activities 62.5%). The expected total cost in the population aged 30-54 years of the 11 European countries was EUR 4.3 billion (EUR 19.3 billion when extended to the whole European population aged from 15 to 64 years). The mean total cost per patient ranged from EUR 509 (controlled asthma) to EUR 2,281 (uncontrolled disease). Chronic cough or phlegm and having a high BMI significantly increased the individual total cost., Conclusions: Among European adults, the cost of persistent asthma drastically increases as disease control decreases. Therefore, substantial cost savings could be obtained through the proper management of adult patients in Europe., (Copyright © 2012 S. Karger AG, Basel.)

Background: Kiwifruit is a common cause of food allergy. Symptoms range from mild to anaphylactic reactions., Objective: We sought to elucidate geographic differences across Europe regarding clinical patterns and sensitization to kiwifruit allergens. Factors associated with the severity of kiwifruit allergy were identified, and the diagnostic performance of specific kiwifruit allergens was investigated., Methods: This study was part of EuroPrevall, a multicenter European study investigating several aspects of food allergy. Three hundred eleven patients with kiwifruit allergy from 12 countries representing 4 climatic regions were included. Specific IgE to 6 allergens (Act d 1, Act d 2, Act d 5, Act d 8, Act d 9, and Act d 10) and kiwifruit extract were tested by using ImmunoCAP., Results: Patients from Iceland were mainly sensitized to Act d 1 (32%), those from western/central and eastern Europe were mainly sensitized to Act d 8 (pathogenesis-related class 10 protein, 58% and 44%, respectively), and those from southern Europe were mainly sensitized to Act d 9 (profilin, 31%) and Act d 10 (nonspecific lipid transfer protein, 22%). Sensitization to Act d 1 and living in Iceland were independently and significantly associated with severe kiwifruit allergy (odds ratio, 3.98 [P = .003] and 5.60 [P < .001], respectively). Using a panel of 6 kiwifruit allergens in ImmunoCAP increased the diagnostic sensitivity to 65% compared with 20% for skin prick tests and 46% ImmunoCAP using kiwi extract., Conclusion: Kiwifruit allergen sensitization patterns differ across Europe. The use of specific kiwifruit allergens improved the diagnostic performance compared with kiwifruit extract. Sensitization to Act d 1 and living in Iceland are strong risk factors for severe kiwifruit allergy., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Introduction: In the year 1990 the European Community Respiratory Health Survey I (ECRHS I) demonstrated that the prevalence of these diseases was lowest in Iceland (www.ecrhs.org). In order to compare the prevalence of respiratory symptoms in Reykjavik over time, a new identical cross-sectional study was performed seventeen years later., Material and Methods: Both cohorts, were in the age group 20-44 years and randomly selected from the population in Reykjavik and suburbs. Both answered questionnaires about respiratory symptoms, nasal allergy and use of anti-asthmatic drugs. The second cohort was part of the EuroPrevall study (www.europrevall.org) performed in 2007., Results: Response rate was lower in 2007 (999 or 43.2%) than in 1990 (2.903 or 80.6%).The prevalence of attacks of asthma increased over time from 2.2% to 6.7% (p<0.0001), use of anti-asthmatic drugs increased from 2.4% to 7.2% (p<0.0001) and nasal allergy symptoms from 17.8% to 29.3% (p< 0.0001). There was an increase of all respiratory symptoms except wheezing or whistling, where the prevalence dropped from 18.0% to 14.4% (p<0.01). In the year 2007 women had more often been woken by attacks of coughing (p<0.0001), had more often attacks of asthma (p<0.05) and were more likely to use anti-asthmatic drugs (p<0.05) than men. Attacks of asthma and the use of anti-asthmatic drugs were more common among the younger age group in the year 2007. That was not seen in the year 1990., Conclusion: This study provides evidence of an increase in respiratory symptoms and use of anti-asthmatic drugs over a period of 17 years from 1990 among young adult Icelanders.

In this overview of investigations into mite allergy in Iceland and of the current understanding of the sources of exposure, 2 major categories of mite-induced allergies were encountered. The first was house dust mite allergy due to house dust mites from unknown sources, and the second was barn allergy caused by mites connected with the degradation of stored hay. Characteristics of these diseases have been obtained from surveys where skin prick tests were made with commercially available extracts of mites and from zoological investigations where mites had been found in different kinds of dusts relevant for the tested persons. The investigations uncovered a discrepancy between the capital Reykjavik and countryside farms. While the frequencies of sensitization to house dust mites and barn mites are rather similar in the capital area and in the rural area, the exposure to these mites is unexpectedly low in the capital area. Thus, sensitization appears to take place preferably in the rural area.

A sequence variant (rs7216389-T) near the ORMDL3 gene on chromosome 17q21 was recently found to be associated with childhood asthma. We sought to evaluate the effect of rs7216389-T on asthma subphenotypes and its correlation with expression levels of neighboring genes. The association of rs7216389-T with asthma was replicated in six European and one Asian study cohort (N=4917 cases N=34 589 controls). In addition, we found that the association of rs7216389-T was confined to cases with early onset of asthma, particularly in early childhood (age: 0-5 years OR=1.51, P=6.89.10(-9)) and adolescence (age: 14-17 years OR=1.71, P=5.47.10(-9)). A weaker association was observed for onset between 6 and 13 years of age (OR=1.17, P=0.035), but none for adult-onset asthma (OR=1.07, P=0.12). Cases were further stratified by sex, asthma severity and atopy status. An association with greater asthma severity was observed among early-onset asthma cases (P=0.0012), but no association with sex or atopy status was observed among the asthma cases. An association between sequence variants and the expression of genes in the 17q21 region was assessed in white blood cell RNA samples collected from Icelandic individuals (n=743). rs7216389 associated with the expression of GSDMB and ORMDL3 genes. However, other sequence variants showing a weaker association with asthma compared with that of rs7216389 were more strongly associated with the expression of both genes. Thus, the contribution of rs7216389-T to the development of asthma is unlikely to operate only through an impact on the expression of ORMDL3 or GSDMB genes.

Background: The identification of the factors associated with severe asthma may shed some light on its etiology and on the mechanisms of its development. We aimed to describe asthma severity using the Global Initiative for Asthma (GINA) classification and to investigate its determinants in a cross-sectional, population-based sample in Europe., Methods: In the European Community Respiratory Health Survey II (1999-2002), 1,241 adults with asthma were identified. Severity was assessed using the 2002 GINA classification (intermittent, mild persistent, moderate persistent, severe persistent) and it was related to potential determinants by a multinomial logistic model, using the intermittent group as the reference category for relative risk ratios., Results: About 30% of asthmatic subjects were affected by moderate-to-severe asthma. Sensitization to Cladosporium was associated with a more than 5-fold greater risk of having (mild, moderate or severe) persistent asthma than intermittent asthma. Persistent asthma was positively associated with sensitization to house dust mite, nonseasonal asthma, an older age at asthma onset, and chronic cough and phlegm. Sensitization to cat increased the risk of severe asthma only. Smoking was more strongly associated with asthma severity in men, while rhinitis was more strongly associated with asthma severity in women., Conclusions: One third of the asthmatic population have moderate-to-severe asthma. Sensitization to perennial indoor allergens, particularly Cladosporium, is strongly associated with asthma severity. The role of smoking and rhinitis in determining asthma severity may differ between the sexes, and it should be further investigated.

Background: Little is known about factors associated with lung function decline in asthma., Objective: To identify the determinants of FEV(1) decline in adults with asthma with and without airflow obstruction at baseline., Methods: An international cohort of 638 subjects with asthma (20-44 years old) was identified in the European Community Respiratory Health Survey (1991-1993) and followed up from 1998 to 2002. Spirometry was performed on both occasions. FEV(1) decline was related to potential determinants evaluated at baseline and during the follow-up by random intercept linear regression models. The analyses were stratified by the presence of airflow obstruction (FEV(1)/forced vital capacity < 0.70) at baseline., Results: In the group of individuals without airflow obstruction (n = 544), a faster FEV(1) decline was observed for subjects with intermediate body mass index (BMI) than for lean and obese subjects. FEV(1) decline was associated with weight gain independently of baseline BMI, and this association was stronger in men (20; 95% CI, 10-30, mL/y/kg gained) than in women (6; 95% CI, 1-11, mL/y). In the group of individuals with airflow obstruction (n = 94), the absence of allergen sensitization and a low BMI at baseline were associated with a faster FEV(1) decline, whereas weight gain was not associated with decline., Conclusions: The detrimental effect of weight gain on FEV(1) decline is particularly relevant in subjects with asthma who still do not have an established airflow obstruction. Our findings support the importance of weight management in asthma and recommend weight loss in overweight or obese individuals with asthma.

Background: In the European Community Respiratory Health Survey (ECRHS) I, the lowest prevalence of asthma and atopy was found in Reykjavík (Iceland) and Tartu (Estonia). The aim of this study was to compare home environments in Reykjavík and Tartu to a town with a higher prevalence of asthma and atopy (Uppsala, Sweden) in an attempt to identify factors in the indoor environment that could explain these differences., Method: A random sample of 129 ECRHS II participants was included in this analysis at each of the three study centres. The subjects answered a questionnaire, blood was analysed for specific immunoglobulin E, a methacholine test was performed and home indoor measurements were taken., Results: The prevalence of atopy was 11.9% in Reykjavík, 35.5% in Uppsala and 28.2% in Tartu (P < 0.04). The level of indoor cat allergen was significantly lower in Reykjavík compared with Uppsala (P = 0.05). No mite allergens were identified in the 41 homes investigated in Reykjavík, while this was the case in 16% and 72% of the households in Uppsala and Tartu, respectively (P = 0.001). A positive association was found between asthma symptoms and cat allergen levels [odds ratio 1.53 (95% confidence interval 1.04-2.24)], while the levels of viable moulds were significantly associated with increased bronchial responsiveness., Conclusions: Indoor exposure to allergens, moulds and bacteria was lower in Reykjavík than in the Swedish and Estonian centres. This finding indicates that the lower prevalence of allergic sensitization in Reykjavík may partly be related to lower indoor allergen exposure.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Background: There is uncertainty regarding the prevalence of allergies to plant food., Objective: To assess the prevalence of allergies to plant food according to the different subjective and objective assessment methods., Methods: Our systematic search of population-based studies (since 1990) in the literature database MEDLINE focused on fruits, vegetables/legumes, tree nuts, wheat, soy, cereals, and seeds. Prevalence estimates were categorized by food item and method used (food challenges, skin prick test, serum IgE, parent/self-reported symptoms), complemented by appropriate meta-analyses., Results: We included 36 studies with data from a total of over 250,000 children and adults. Only 6 studies included food challenge tests with prevalences ranging from 0.1% to 4.3% each for fruits and tree nuts, 0.1% to 1.4% for vegetables, and < 1% each for wheat, soy, and sesame. The prevalence of sensitization against any specific plant food item assessed by skin prick test was usually < 1%, whereas sensitization assessed by IgE against wheat ranged as high as 3.6% and against soy as high as 2.9%. For fruit and vegetables, prevalences based on perception were generally higher than those based on sensitization, but for wheat and soy in adults, sensitization was higher. Meta-analyses showed significant heterogeneity between studies regardless of food item or age group., Conclusion: Population-based prevalence estimates for allergies to plant products determined by the diagnostic gold standard are scarce. There was considerable heterogeneity in the prevalence estimates of sensitization or perceived allergic reactions to plant food.

Allergies to antibiotics are reported by 8-14% of the adult population out of which half is thought to be due to penicillins. Women are two thirds of those. It is estimated that 20.000 Icelanders believe they are allergic to beta-lactam drugs. Less than 10% of suspected penicillin allergy can be proved by allergy testing and challenge tests. The allergy to beta-lactam drugs can be of all types of allergy reactions, leading to clinical symptoms from mild to life threatening. The beta-lactam allergy is diagnosed by a precise history, measuring drug specific IgE, by prick- and intradermal skin tests and challenge tests with the drug in question. The purpose of this article is to draw the attention of Icelandic doctors to the importance of drug allergy with specific emphasis on beta-lactam drugs and the value of accurate recording of symptoms and signs in the patient's records. We also describe the diagnostic methods used and propose an algorithmic approach to diagnose beta-lactam allergy in Icelandic children and adults.

Viral infections have been associated with the aetiology of obesity in animal models. This study investigates the association between 7 serological markers of infections and body mass index (BMI) in a population based sample. Individuals (n=985, mean age 42+/-97 (28-55) y, mean BMI 25.594.2) from Iceland, Sweden and Estonia underwent a structured interview and blood sampling. IgG antibodies were measured against Helicobacter pylori and the cagA protein, hepatitis A virus, Toxoplasma gondii, herpes simplex virus 1, Chlamydia pneumoniae, Epstein-Barr virus and cytomegalovirus. High-sensitive C-reactive protein (CRP) was measured as a marker of systemic inflammation. A significant positive association between being overweight (BMI25 kg/m2) and IgG antibodies was found for Helicobacter pylori (OR 1.86, CI 1.34-2.60) and Chlamydia pneumoniae (OR 1.39, CI 1.03-1.88) and combined seropositivity had synergistic effect (OR 2.54 (1.62-3.97)). CRP was positively related to BMI (pB0.0001), whereas no significant association was found between CRP and IgG antibodies against Helicobacter pylori and/or Chlamydia pneumoniae and CRP. The results suggest that infections with Chlamydia pneumoniae and Helicobacter pylori are both significantly and synergistically associated with overweight and this association is not related to indicators of systemic inflammation.

Background: Few data are available on the asthma burden in the general population. We evaluated the level and the factors associated with the asthma burden in Europe., Methods: In 1999-2002, 1152 adult asthmatics were identified in the European Community Respiratory Health Survey (ECRHS)-II and the socio-economic burden (reduced activity days and hospital services utilization in the past 12 months) was assessed., Results: The asthmatics with a light burden (only a few reduced activity days) were 13.2% (95% CI: 11.4-15.3%), whereas those with a heavy burden (many reduced activity days and/or hospital services utilization) were 14.0% (95% CI: 12.1-16.1%). The burden was strongly associated with disease severity and a lower quality of life. Obese asthmatics had a significantly increased risk of a light [relative risk ratio (RRR) = 2.17; 95% CI: 1.18-4.00] or a heavy burden (RRR = 2.77; 95% CI: 1.52-5.05) compared with normal/underweight subjects. The asthmatics with frequent respiratory symptoms showed a threefold (RRR = 2.74; 95% CI: 1.63-4.61) and sixfold (RRR = 5.76; 95% CI: 3.25-10.20) increased risk of a light or a heavy burden compared with asymptomatic asthmatics, respectively. Moreover, the lower the forced expiratory volume in 1 s % predicted, the higher the risk of a heavy burden. The coexistence with chronic cough/phlegm only increased the risk of a heavy burden (RRR = 1.88; 95% CI: 1.16-3.06). An interaction was found between gender and IgE sensitization, with nonatopic asthmatic females showing the highest risk of a heavy burden (21.6%; 95% CI: 16.9-27.1%)., Conclusions: The asthma burden is substantial in Europe. A heavy burden is more common in asthmatics with obesity, frequent respiratory symptoms, low lung function, chronic cough/phlegm and in nonatopic females.

Background: Epidemiologic evidence related to asthma control in patients from the general population is scanty., Objectives: We sought to assess asthma control in several European centers according to the Global Initiative for Asthma (GINA) guidelines and to investigate its determinants., Methods: In the European Community Respiratory Health Survey II (1999-2002), 1241 adults with asthma were identified and classified into inhaled corticosteroid (ICS) users and non-ICS users in the last year. Control was assessed in both groups by using the GINA proposal (controlled, partly controlled, and uncontrolled asthma), and it was related to potential determinants., Results: Only 15% (95% CI, 12% to 19%) of subjects who had used ICSs in the last year and 45% (95% CI, 41% to 50%) of non-ICS users had their asthma under control; individuals with uncontrolled asthma accounted for 49% (95% CI, 44% to 53%) and 18% (95% CI, 15% to 21%), respectively. Among ICS users, the prevalence of uncontrolled asthma showed great variability across Europe, ranging from 20% (95% CI, 7% to 41%; Iceland) to 67% (95% CI, 35% to 90%; Italy). Overweight status, chronic cough and phlegm, and sensitization to Cladosporium species were associated with poor control in ICS users. About 65% and 87% of ICS users with uncontrolled and partly controlled asthma, respectively, were on a medication regimen that was less than recommended by the GINA guidelines., Conclusion: Six of 7 European asthmatic adults using ICSs in the last year did not achieve good disease control. The large majority of subjects with poorly controlled asthma were using antiasthma drugs in a suboptimal way. A wide variability in asthma control emerged across Europe., Clinical Implications: Greater attention should be paid to asthma management and to the implementation of the GINA guidelines.

Background: Epidemiologic reports on the effect of microbe exposure on the development of atopy and allergic asthma are inconsistent., Objectives: The study investigates the association between serologic markers of infections and occurrence of atopy, allergic asthma, and rhinitis among adults in Iceland, Sweden, and Estonia., Methods: Individuals (n = 1249; mean age, 42 years) from Iceland, Sweden, and Estonia underwent a structured interview and blood sampling. Specific IgE was measured against 4 allergens, and IgG antibodies were measured against Helicobacter pylori, Toxoplasmosis gondii, hepatitis A virus, herpes simplex virus 1, Chlamydia pneumoniae, EBV, and cytomegalovirus., Results: Nonatopic subjects more often had positive serology for Helicobacter pylori, herpes simplex virus 1, Chlamydia pneumoniae, and cytomegalovirus. Having a low number (

Background: There is uncertainty about the prevalence of food allergy in communities., Objective: To assess the prevalence of food allergy by performing a meta-analysis according to the method of assessment used., Methods: The foods assessed were cow's milk, hen's egg, peanut, fish, shellfish, and an overall estimate of food allergy. We summarized the information in 5 categories: self-reported symptoms, specific IgE positive, specific skin prick test positive, symptoms combined with sensitization, and food challenge studies. We systematically searched MEDLINE and EMBASE for publications since 1990. The meta-analysis included only original studies. They were stratified by age groups: infant/preschool, school children, and adults., Results: A total of 934 articles were identified, but only 51 were considered appropriate for inclusion. The prevalence of self-reported food allergy was very high compared with objective measures. There was marked heterogeneity between studies regardless of type of assessment or food item considered, and in most analyses this persisted after age stratification. Self-reported prevalence of food allergy varied from 1.2% to 17% for milk, 0.2% to 7% for egg, 0% to 2% for peanuts and fish, 0% to 10% for shellfish, and 3% to 35% for any food., Conclusion: There is a marked heterogeneity in the prevalence of food allergy that could be a result of differences in study design or methodology, or differences between populations., Clinical Implications: We recommend that measurements be made by using standardized methods, if possible food challenge. We need to be cautious in estimates of prevalence based only on self-reported food allergy.