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.

We investigated the 10-year variation of asthma cost by the change of disease severity/control in adults from 11 European countries. We identified 562 adults (aged 29-56) with physician-diagnosed current asthma at the ECRHS II (1999-2003, baseline) and ECRHS III (2010-2013). At the two contacts, patients were classified as “intermittent” or “persistent” (GINA 2002); in addition, persistent asthmatics were classified as “controlled/partly controlled” (CP) or “uncontrolled” (U) (GINA 2016). The variation of disease status was considered “worsened” (from intermittent to persistent or from CP to U; n=98), “improved” (from persistent to intermittent or from U to CP; n=99) or “unchanged” (n=225). The annual cost per patient was computed from the societal perspective following the bottom-up approach, using rates/wages/prices obtained at national level in 2004 (ECRHS II; converted to a 2013 equivalent) and 2013 (ECRHS III). The variation of the annual cost per patient was estimated by the change in disease status using a 2-level random-intercept Laplace quantile regression model, adjusting for sex, age, ever smoking, low socio-economic status and cost at baseline (centre: level 2 unit). At baseline, the mean annual cost was €235, €501 and €2,247 Euro per patient with intermittent, CP persistent or U persistent asthma, respectively. Compared to patients whose disease status was unchanged, those with an improved or worsened asthma showed reduced [-143 (95%CI: -282, -5) €; p=0.043] and increased [267 (95%CI: 121, 414) €; p<0.001] annual costs, respectively. Our study suggests substantial cost savings if asthma severity/control improved among adult patients in Europe.

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.

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.

Component resolved diagnosis in relation to severity of hazelnut allergy across Europe MR Datema, L Zuidmeer, C Garino, J Marsh, A Lovegrove, M Clausen, D Gislason, R Dubakiene, I Reig, L Barreales, AC Knulst, T-M Le, ML Kowalski, M Jedvzejczak, J Lidholm, T Kralimarkova, T Popov, R Asero, S Seneviratne, N Sinaniotis, N Papadopoulos, A Purohit, F de Blay, P Bures, S Vieths, M Fernandez-Rivas, K Hoffmann-Sommergruber, R van Ree, B Ballmer-Weber

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: There are few published studies on geographical variation in prevalence of eczema in adults or its association with recognised risk factors for allergic disease.Objective: To describe the geographical variation in prevalence of eczema in adults, assess the associations with sociodemographic risk factors, serum-specific IgE and IgG, and exposure to allergen.Methods: A community-based sample of 8206 adults aged 27-56 years, in 25 European centres and Portland, USA, provided questionnaire information on symptoms of eczema. Serum-specific IgE to house dust mite (HDM), cat, grass and Cladosporium, and IgG and IgG4 to HDM and cat were measured. Mattress levels of mite and cat allergen were assessed.Results: Overall prevalence of eczema was 7.1% (range between countries of 2.2-17.6%). Eczema was associated with female gender [odds ratio (OR) 1.25; 95% confidence interval (CI) (1.01-1.55)], family history of atopic disease (OR 1.43; 95% CI 1.18-1.74), IgE sensitization to at least one allergen (OR 1.50; 95% CI 1.19-1.90), particularly Cladosporium (OR 3.65; 95% CI 1.81-7.37), and total IgE. Eczema was negatively associated with age and no clear associations were observed with sibship size, mattress mite and cat allergen levels or with cat and HDM-specific IgG or IgG4.Conclusions: There is geographical variation in the prevalence of eczema in adults both within and between countries. Although the disease is associated with IgE sensitization, in this study it was not related to mattress mite or cat allergen levels.

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BACKGROUND:An association between indoor dampness and respiratory symptoms has been reported, but dampness as a risk factor for the onset or remission of respiratory symptoms and asthma is not well documented.METHOD:This follow up study included 16 190 subjects from Iceland, Norway, Sweden, Denmark, and Estonia who had participated in the European Community Respiratory Health Survey (ECRHS I). Eight years later the same subjects answered a postal questionnaire that included questions on respiratory symptoms and indicators of indoor dampness.RESULTS:Subjects living in damp housing (18%) had a significantly (p<0.001) higher prevalence of wheeze (19.1% v 26.0%), nocturnal breathlessness (4.4% v 8.4%), nocturnal cough (27.2% v 36.5%), productive cough (16.6% v 22.3%) and asthma (6.0% v 7.7%). These associations remained significant after adjusting for possible confounders. Indoor dampness was a risk factor for onset of respiratory symptoms but not for asthma onset in the longitudinal analysis (OR 1.13, 95% CI 0.92 to 1.40). Remission of nocturnal symptoms was less common in damp homes (OR 0.84, 95% CI 0.73 to 0.97).CONCLUSIONS:Subjects living in damp housing had a higher prevalence of respiratory symptoms and asthma. Onset of respiratory symptoms was more common and remission of nocturnal respiratory symptoms was less common in subjects living in damp housing.

RATIONALE: Previous studies in Iceland show that 6-9% of young adults are sensitized to the house dust mite (HDM) Dermatophagoides pteronyssinus (D. pter). However, only small amounts of HDM and HDM allergens were detected in their homes. The study investigates this discrepancy. METHODS: We investigated all participants in the European Community Respiratory Health Surveys I and II (ECRHS I and II) with D. pter specific IgE, either in 1991-92 or nine years later. A D. pter negative but grass positive control group was recruited from the same cohort. A questionnaire was administered and the specific IgE (Pharmacia CAP system) against six D. pter cross-reactive allergens was measured. RESULTS: Out of 518 ECRHS I participants with available IgE results, 90% returned for ECRHS II 8.4 years later. Out of 50 individuals with D. pter specific IgE in ECRHS I, 25 had become negative in ECRHS II and four new individuals were detected. Compared to controls, HDM sensitive subjects were more often males, had lived on farms or kept goldfish in childhood. Of those with specific IgE against D. pter in ECRHS I and II, 75% had detectable IgE antibodies (≥0.35 kU/l) to cross-reactive allergens; Lepidoglyphus destructor (L. destructor)(67%), shrimp (58%), cockroach (33%), mosquito (17%), tropomyosin (17%) and blood worm (4%), compared to none in the control group (p<0.0001). CONCLUSIONS: Compared to controls, Icelanders with specific IgE to D. pter have higher prevalence of cross-reactive IgE antibodies and are more often males who spent time on farms in childhood.

Gene expression profiles were examined in freshly isolated peripheral blood mononuclear cells (PBMC) from two independent cohorts (training and test sets) of glucocorticoid (GC)-sensitive (n = 64) and GC-resistant (n = 42) asthma patients in search of genes that accurately predict responders and nonresponders to inhaled corticosteroids. A total of 11,812 genes were examined with high-density oligonucleotide microarrays in both resting PBMC (106 patients) and cells treated in vitro with IL-1 beta and TNF-alpha combined (88 patients), with or without GC. A total of 5,011 genes were expressed at significant levels in the PBMC, and 1,334 of those were notably up-regulated or down-regulated by IL-1 beta/TNF-alpha treatment. The expression changes of 923 genes were significantly reversed in GC responders in the presence of GC. The expression pattern of 15 of these 923 genes that most accurately separated GC responders (n = 26) from the nonresponders (n = 18) in the training set, based on the weighted voting algorithm, predicted the independent test set of equal size with 84% accuracy. The expression accuracy of these genes was confirmed by real-time-quantitative PCR, wherein 11 of the 15 genes predicted GC sensitivity at baseline with 84% accuracy, with one gene predicting at 81% in an independent cohort of 79 patients. We conclude that we have uncovered gene expression profiles in PBMC that predict clinical response to inhaled GC therapy with meaningful accuracy. Upon validation in an independent study, these results support the development of a diagnostic test to guide GC therapy in asthma patients.

The aim of this study was to describe changes in pharmacotherapy for asthma since the early 1990s in an international cohort of young and middle-aged adults. A total of 28 centres from 14 countries participated in a longitudinal study. The study included 8,829 subjects with a mean follow-up time of 8.7 yrs. Change in the prevalence of use for medication was expressed as absolute net change (95% confidence interval) standardised to a 10-yr period. The use of anti-asthmatics was found to have increased by 3.1% (2.4-3.7%) and the prevalence of symptomatic asthma by 4.0% (3.5-4.5%). In the sample with asthma in both surveys (n=423), the use of inhaled corticosteroids increased by 12.2% (6.6-17.8%). Despite this, only 17.2% were using inhaled corticosteroids on a daily basis at follow-up. Females with continuous asthma were more likely, compared with males, and smokers with asthma, to have started using inhaled corticosteroids since the first survey. The use of anti-asthmatics has increased in a pattern consistent with current consensus on treatment. However, despite increased use of inhaled corticosteroids, a large majority of subjects with symptomatic asthma do not use this treatment on a daily basis, particularly males and smokers with asthma.

Background: Hormone replacement therapy (HRT) and obesity both appear to increase the risk of asthma. A study was undertaken to investigate the association of HRT with asthma and hay fever in a population of perimenopausal women, focusing on a possible interaction with body mass index (BMI).Methods: A postal questionnaire was sent to population based samples in Denmark, Estonia, Iceland, Norway, and Sweden in 1999 - 2001, and 8588 women aged 25 - 54 years responded (77%). Pregnant women, women using oral contraceptives, and women,46 years were excluded. Analyses included 2206 women aged 46 - 54 years of which 884 were menopausal and 540 used HRT. Stratified analyses by BMI in tertiles were performed.Results: HRT was associated with an increased risk for asthma ( OR 1.57 (95% CI 1.07 to 2.30)), wheeze ( OR 1.60 ( 95% CI 1.22 to 2.10)), and hay fever ( OR 1.48 ( 95% CI 1.15 to 1.90)). The associations with asthma and wheeze were significantly stronger among women with BMI in the lower tertile ( asthma OR 2.41 ( 95% CI 1.21 to 4.77); wheeze OR 2.04 ( 95% CI 1.23 to 3.36)) than in heavier women ( asthma: p(interaction) = 0.030; wheeze: p(interaction) = 0.042). Increasing BMI was associated with more asthma ( OR 1.08 ( 95% CI 1.05 to 1.12) per kg/m(2)). This effect was only found in women not taking HRT ( OR 1.10 ( 95% CI 1.05 to 1.14) per kg/m(2)); no such association was detected in HRT users ( OR 1.00 ( 95% CI 0.92 to 1.08) per kg/m(2)) (p(interaction) = 0.046). Menopause was not significantly associated with asthma, wheeze, or hay fever.Conclusions: In perimenopausal women there is an interaction between HRT and BMI in the effects on asthma. Lean women who were HRT users had as high a risk for asthma as overweight women not taking HRT. It is suggested that HRT and overweight increase the risk of asthma through partly common pathways.

Background: High sensitivity C reactive protein (HsCRP) is an inflammatory marker known to be related to smoking, obesity, and cardiovascular disease. A study was undertaken to determine whether HsCRP is related to respiratory symptoms, asthma, atopy, and bronchial hyperresponsiveness in population samples from three countries. Methods: HsCRP was measured in 1289 subjects from three centres in ECRHS II: Reykjavik, Uppsala and Tartu. The HsCRP values ranged from <0.01 mg/l to 70.0 mg/l and were divided into four equal groups (⩽0.45, 0.46–0.96, 0.97–2.21, and >2.21 mg/l). Results: HsCRP increased with increasing body mass index (r = 0.41; p<0.0001) and was higher in smokers than in never smokers (p = 0.02). A significant relationship was found between increased HsCRP levels and respiratory symptoms such as wheeze, attacks of breathlessness after effort, and nocturnal cough (p<0.0001). The crude odds ratio (95% CI) for the probability of non-allergic asthma was 3.57 (1.83 to 6.96) for subjects in the 4th quartile compared with the 1st quartile of HsCRP. This association remained significant after adjusting for study centre, age, sex, body weight, and smoking history (OR 2.19 (95% CI 1.04 to 4.63)). No significant relationship was observed between HsCRP and allergic asthma or bronchial responsiveness. Conclusions: Raised levels of HsCRP are significantly associated with respiratory symptoms and non-allergic asthma but not with allergic asthma.