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Objective: The impact of diagnostic work-up in asthma management on medication redemption and probably also drug adherence is largely unknown, but we hypothesized that a confirmed diagnosis of asthma in a hospital-based out-patient clinic increases the willingness to subsequent medication redemption in a real life setting. Methods: In a retrospective register-based study, 300 medical records of patients referred with possible asthma during one year were examined, of whom 171 had asthma (57%). One-year data on dispensed medicine was collected using the Danish Registry of Medicinal Product Statistics. Patients who had a positive asthma (e.g. bronchial challenge) were classified as verified asthma, whereas unverified asthma refers to doctor's diagnosis of asthma with negative or no diagnostic tests performed. Results: 111 (65%) had a verified diagnosis and patients with verified asthma were more frequently prescribed new therapy compared to those with unverified asthma (88.9% vs. 65.0%, respectively, p < 0.001). No difference was found in first time redemption of prescriptions (72% vs. 64%, respectively, p = 0.3), whereas the second (52% vs. 27%, p = 0.001) and third or more asthma redeemed prescriptions (37% vs. 17%, p = 0.006) showed increased redemption of prescription and probably adherence in the verified compared with the unverified patients with asthma. Furthermore, the use of inhaled corticosteroid (ICS) was calculated as Percent Days Covered (PDC), which was higher in the verified group compared with the non-verified asthma group (88% vs. 30%, p = 0.004). Conclusion: Objective verification of a diagnosis of asthma using asthma tests was associated with an improved redemption of prescription. [ABSTRACT FROM AUTHOR]

Due to a high prevalence of asthma and exercise‐induced bronchoconstriction in elite athletes, there is a high use of beta2‐adrenoceptor agonists (beta2‐agonists) in the athletic population. While anabolic in rodents, no study has been able to detect hypertrophy in humans after chronic beta2‐agonist inhalation. We investigated whether inhaled beta2‐agonist, terbutaline, alters body composition and metabolic rate with and without concurrent exercise training in healthy young men. Sixty‐seven participants completed a 4‐week intervention of daily terbutaline (8 × 0.5 mg) or placebo treatment without concurrent training (habitual; n = 23), with resistance (n = 23) or endurance (n = 21) training 3 times weekly. Before and after the interventions, participant's body composition was determined by dual‐energy X‐ray absorptiometry and resting metabolic rate and substrate oxidation by indirect calorimetry. Terbutaline increased lean body mass by 1.03 kg (95% CI 0.29‐1.76; P < .05) and 1.04 kg (95% CI 0.16‐1.93; P < .05) compared to placebo in the habitual and resistance training group, respectively, but had no effect compared to placebo in the endurance training group [−0.56 kg (95% CI −1.74‐0.62; P > .05)]. Fat mass, bone mineral content, and resting metabolic rate did not change differently between treatments with the intervention. Daily inhalation of terbutaline in near‐therapeutic doses induces skeletal muscle growth. This observation should be a concern for antidoping authorities. [ABSTRACT FROM AUTHOR]

Background: Obesity is increasing worldwide among children and adolescents, and has been associated with an increased incidence of asthma. However, the mechanisms underlying this association are incompletely understood.Objective: In this cohort study we aimed to investigate whether being overweight in childhood and adolescence is associated with an increased risk of airway hyperresponsiveness (AHR), a hallmark of asthma, in early adulthood.Methods: Of 527 subjects from a random population sample of children and adolescents (7–17 years) examined at baseline, a total of 184 subjects completed the follow-up visit 20 years later and were included in the present analysis. Both visits included assessment of height and weight, case history and spirometry. At both visits, bronchial provocation tests were performed using either histamine (baseline) or methacholine (follow-up). In addition, fractional exhaled nitric oxide (FeNO) was measured at follow-up.Results: No significant difference in the prevalence of AHR at follow-up was found between subjects who were overweight or obese at baseline visit (n = 26) (pediatric definition, body mass index ≥ 85%percentile) and normal weight subjects (n = 158) (positive bronchial provocation tests: 15.4% vs. 22.2%, respectively,p= 0.35). Likewise, follow-up FeNO levels did not differ significantly between subjects who were lean and those who were overweight or obese at baseline (geometric mean (95% confidence interval [CI]) 15.1 (13.7, 16.6) parts per billion (ppb) versus 13.0 (10.6, 15.9) ppb,p= 0.23).Conclusion: In children and adolescents, being obese or overweight seems not to be associated with an increased risk of AHR or increased FeNO levels in early adulthood. [ABSTRACT FROM PUBLISHER]

Background The major trigger of asthma exacerbations is infection with a respiratory virus, most commonly rhinovirus. Type 2 inflammation is known to be associated with an increased risk of exacerbations in general. Whether type 2 inflammation at baseline increases the risk of future virus-induced exacerbations is unknown. Objective To assess whether type 2 inflammation is associated with an increased risk of virus-induced exacerbations of asthma. Methods Stable asthmatics had spirometry, skin prick test, measurement of Fe NO and sputum induced for differential cell counts. Patients were followed up for 18 months, during which they were assessed at the research unit when they had symptoms of an exacerbation. Nasal swabs collected at these assessments underwent viral detection by PCR. Results A total of 81 asthma patients were recruited, of which 22 (27%) experienced an exacerbation during the follow-up period. Of these, 15 (68%) had a respiratory virus detected at exacerbation. Sputum eosinophils >1% at baseline increased the risk of having a subsequent virus-induced exacerbation ( HR 7.6 95% CI: 1.6-35.2, P=.010) as did having Fe NO >25 ppb ( HR 3.4 95% CI: 1.1-10.4, P=.033). Conclusion and Clinical Relevance Established type 2 inflammation during stable disease is a risk factor for virus-induced exacerbations in a real-life setting. Measures of type 2 inflammation, such as sputum eosinophils and Fe NO, could be included in the risk assessment of patients with asthma in future studies. [ABSTRACT FROM AUTHOR]

This study investigated the pharmacokinetics of inhaled terbutaline at rest and after exercise in normal and hot ambient conditions with respect to doping analysis. Thirteen trained young men participated in the study. Urine and blood samples were collected after inhalation of 4 mg terbutaline during three trials: exercise in hot ambient conditions (30-35 °C) ( EXH), exercise in normal ambient conditions (20-25 °C) ( EX), and rest (20-25 °C) (R). Exercise consisted of 130 min at various intensities. Adjustment of urine concentrations of terbutaline to a specific gravity ( USG) of 1.02 g/mL was compared with no adjustment. Area under the serum concentration-time curve within the first 6 h was higher for EX (27 ± 3 ng/mL/h) ( P ≤ 0.01) and EXH (25 ± 4 ng/mL/h) ( P ≤ 0.05) than for R (20 ± 3 ng/mL/h). When unadjusted for USG, urine concentrations of terbutaline after 4 h were different in the order EXH > EX > R ( P ≤ 0.01). When unadjusted for USG, urine concentrations of terbutaline were 299 ± 151 ng/mL higher ( P ≤ 0.001) after 4 h compared with adjusted concentrations in EXH. Excretion rate of terbutaline was higher ( P ≤ 0.001) for EX than for EXH and R within the first 0-1½ h. In conclusion, EXHs results in higher urine concentrations of terbutaline. This should be considered when evaluating doping cases of terbutaline. [ABSTRACT FROM AUTHOR]

Background: Asthma is a biologically heterogeneous disease and development of novel therapeutics requires understanding of pathophysiologic phenotypes. There is uncertainty regarding the stability of clinical characteristics and biomarkers in asthma over time. This report presents the longitudinal stability over 12 months of clinical characteristics and clinically accessible biomarkers from ADEPT.Methods: Mild, moderate, and severe asthma subjects were assessed at 5 visits over 12 months. Assessments included patient questionnaires, spirometry, bronchodilator reversibility, fractional exhaled nitric oxide (FENO), and biomarkers measured in induced sputum.Results: Mild (n = 52), moderate (n = 55), and severe (n = 51) asthma cohorts were enrolled from North America and Western Europe. For all clinical characteristics and biomarkers, group mean data showed no significant change from visit to visit. However, individual data showed considerable variability. FEV1/FVC ratio showed excellent reproducibility while pre-bronchodilator FEV1 and FVC were only moderately reproducible. Of note bronchodilator FEV1 reversibility showed low reproducibility, with the nonreversible phenotype much more reproducible than the reversible phenotype. The 7-item asthma control questionnaire (ACQ7) demonstrated moderate reproducibility for the combined asthma cohorts, but the uncontrolled asthma phenotype (ACQ7 > 1.5) was inconstant in mild and moderate asthma but stable in severe asthma. FENO demonstrated good reproducibility, with the FENO-low phenotype (FENO < 35 ppb) more stable than the FENO-high phenotype (FENO ≥ 35 ppb). Induced sputum inflammatory phenotypes showed marked variability across the 3 sputum samples taken over 6 months.Conclusions: The ADEPT cohort showed group stability, individual stability in some parameters e.g. low FEV1/FVC ratio, and low FENO, but marked individual variability in other clinical characteristics and biomarkers e.g. type-2 biomarkers over 12 months. This variability is possibly related to seasonal variations in climate and allergen exposure, medication changes and acute exacerbations. The implications for patient selection strategies based on clinical biomarkers may be considerable. [ABSTRACT FROM AUTHOR]

Background IL-33 represents a potential link between the airway epithelium and induction of a Th2-type inflammatory response in asthma. However, the association with markers of eosinophilic airway inflammation has not previously been reported in patients with steroid-free asthma. Aim To describe the relationship between airway IL-33 and markers of eosinophilic airway inflammation, as well potential triggers of IL-33, in mild, steroid-free asthma. Methods IL-33 mRNA expression and IL-33 immunoreactivity were measured in bronchial biopsies from patients with asthma untreated with inhaled steroids and healthy individuals. Furthermore, fractional exhaled nitric oxide (Fe NO) and eosinophils in sputum and BAL were measured, as well as airway hyperresponsiveness to mannitol and methacholine. Epithelial integrity was assessed by computerized image analysis on haematoxylin-stained sections, and TLR mRNA expression by PCR. Results A total of 23 patients with asthma and 10 healthy individuals were examined (age: 24 years (20-40); females: 53%). The level of IL-33 mRNA expression was significantly higher in patients with asthma compared to healthy individuals (Median ( IQR) 1.12 (0.78) vs. 0.86, P = 0.04). There was a positive correlation between IL-33 mRNA expression and the level of Fe NO ( r = 0.56, P = 0.01), whereas there was no association with airway or blood eosinophils. IL-33 expression was unrelated to loss of epithelial integrity, but correlated with an increased expression of TLR2 and TLR4 ( TLR2: r = 0.47, P = 0.04; TLR4: 0.68, P < 0.001), as well allergy to house dust mites ( HDMs). Conclusion In mild untreated asthma, the expression of IL-33 mRNA in bronchial mucosa is related to innate immune activation and allergic sensitization to HDM, rather than epithelial damage, and correlates with Fe NO. These findings suggest that in mild allergic asthma, IL-33 may represent a link between innate immune activation and Fe NO production. [ABSTRACT FROM AUTHOR]

Background Allergen-specific immunotherapy is the only curative treatment for type I allergy. It can be administered subcutaneously (SCIT) or sublingually (SLIT). The clinical efficacy of these two treatment modalities appears to be similar, but potential differences in the immunological mechanisms involved have not been fully explored. Objective To compare changes in the allergen-specific T cell response induced by subcutaneous vs. sublingual administration of allergen-specific immunotherapy (AIT). Methods Grass pollen-allergic patients were randomized into groups receiving either SCIT injections or SLIT tablets or neither. PBMCs were tested for Timothy grass (TG)-specific cytokine production by ELISPOT after in vitro expansion with TG-peptide pools. Phenotypic characterization of cytokine-producing cells was performed by FACS. Results In the SCIT group, decreased IL-5 production was observed starting 10 months after treatment commenced. At 24 months, T cell responses showed IL-5 levels significantly below the before-treatment baseline. No significant reduction of IL-5 was observed in the SLIT or untreated group. However, a significant transient increase in IL-10 production after 10 months of treatment compared to baseline was detected in both treatment groups. FACS analysis revealed that IL-10 production was associated with CD4+ T cells that also produced IFNγ and therefore may be associated with an IL-10-secreting type 1 cell phenotype. Conclusion and clinical relevance The most dominant immunological changes on a cellular level were a decrease in IL-5 in the SCIT group and a significant, transient increase of IL-10 observed after 10 months of treatment in both treated groups. The distinct routes of AIT administration may induce different immunomodulatory mechanisms at the cellular level. [ABSTRACT FROM AUTHOR]

One of the primary objectives in management of chronic obstructive pulmonary disease (COPD) is preventing decrease in lung function and reducing the annual number of acute exacerbations of COPD (AECOPD). An oral course of systemic corticosteroids is a commonly used treatment in AECOPD. We hypothesize that this treatment also increases exercise performance and decreases muscle fatigue. In a randomized double-blinded, parallel, placebo-controlled trial, we investigated 14 men (8 on prednisolone 37.5 mg vs. 6 on placebo) with severe and very severe COPD. For 5 consecutive days, the patients performed a submaximal endurance test measuring time to exhaustion (TTE, primary endpoint), spirometry, maximal inspiratory and expiratory pressure and maximal isometric contraction of the quadriceps femoris muscle (maximum voluntary contraction (MVC)). At visits 2, 3 and 4, a fatigue protocol was carried out after 40 minutes of cycling at 40% of maximal effort. No differences between groups were found for TTE, lung function or maximal inspiratory or expiratory pressure, however, patients on prednisolone showed significant increased MVC: median 5.15 [3.35; 9.15] against placebo: −2 [−5.57; 3.95] (p = 0.03). This finding indicates an impact of corticosteroids on muscle groups being exposed to submaximal endurance. [ABSTRACT FROM AUTHOR]

Background Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell-associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol. Methods Airway hyperresponsiveness to inhaled mannitol was measured in 23 non-smoking, corticosteroid-free asthmatic individuals and 10 healthy controls. Mast cells and eosinophils were identified in mucosal biopsies from all participants. Mast cells were divided into phenotypes based on the presence of chymase. mRNA expression of mast cell-associated genes was measured by real-time PCR. Results The proportion of submucosal MCTC was higher in asthmatic individuals with AHR to mannitol compared with asthmatic individuals without AHR (median: 40.3% vs. 18.7%, P = 0.03). Increased submucosal MCTC numbers were associated with increased levels of mRNA for thymic stromal lymphopoietin (TSLP) and CPA3 in asthmatics. Reactivity to mannitol correlated significantly with eosinophils in submucosa ( r(s): 0.56, P = 0.01). Conclusion Airway hyperresponsiveness to inhaled mannitol is associated with an altered submucosal mast cell profile in asthmatic individuals. This mast cell profile is associated with increased levels of TSLP and CPA3. The degree of AHR to mannitol is correlated with the degree of eosinophilic inflammation in the airway submucosa. [ABSTRACT FROM AUTHOR]

Our objective was to investigate effects of acute and 2-week administration of oral salbutamol on repeated sprint ability, exercise performance, and muscle strength in elite endurance athletes. Twenty male elite athletes [VO2max: 69.4 ± 1.8 (Mean ± SE) mL/min/kg], aged 25.9 ± 1.4 years, were included in a randomized, doubleblinded and placebo-controlled parallel study. At baseline, after acute administration, and again after 2-week administration of the study drugs (8 mg salbutamol or placebo), subjects' maximal voluntary contraction (MVC) of m. quadriceps and isometric endurance of m. deltoideus were measured, followed by three repeated Wingate tests. Exercise performance at 110% of VO2max was determined on a bike ergometer. Acute administration of salbutamol increased peak power during first Wingate test by 4.1 ± 1.7% (P < 0.05). Two-week administration of salbutamol increased (P < 0.05) peak power during first and second Wingate test by 6.4 ± 2.0 and 4.2 ± 1.0%. Neither acute nor 2-week administration of salbutamol had any effect on MVC, exercise performance at 110% of VO2max or on isometric endurance. No differences were observed in the placebo group. In conclusion, salbutamol benefits athletes' sprint ability. Thus, the present study supports the restriction of oral salbutamol in competitive sports. [ABSTRACT FROM AUTHOR]

Background: Asthma is a heterogeneous disease and development of novel therapeutics requires an understanding of pathophysiologic phenotypes. The purpose of the ADEPT study was to correlate clinical features and biomarkers with molecular characteristics, by profiling asthma (NCT01274507). This report presents for the first time the study design, and characteristics of the recruited subjects.Methods: Patients with a range of asthma severity and healthy non-atopic controls were enrolled. The asthmatic subjects were followed for 12 months. Assessments included history, patient questionnaires, spirometry, airway hyper-responsiveness to methacholine, fractional exhaled nitric oxide (FENO), and biomarkers measured in induced sputum, blood, and bronchoscopy samples. All subjects underwent sputum induction and 30 subjects/cohort had bronchoscopy.Results: Mild (n = 52), moderate (n = 55), severe (n = 51) asthma cohorts and 30 healthy controls were enrolled from North America and Western Europe. Airflow obstruction, bronchodilator response and airways hyperresponsiveness increased with asthma severity, and severe asthma subjects had reduced forced vital capacity. Asthma control questionnaire-7 (ACQ7) scores worsened with asthma severity. In the asthmatics, mean values for all clinical and biomarker characteristics were stable over 12 months although individual variability was evident. FENO and blood eosinophils did not differ by asthma severity. Induced sputum eosinophils but not neutrophils were lower in mild compared to the moderate and severe asthma cohorts.Conclusions: The ADEPT study successfully enrolled asthmatics across a spectrum of severity and non-atopic controls. Clinical characteristics were related to asthma severity and in general asthma characteristics e.g. lung function, were stable over 12 months. Use of the ADEPT data should prove useful in defining biological phenotypes to facilitate personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background/objective: Preservation of lung health requires understanding the modifiable risk factors of airflow limitation. This study investigates the association between diet and lung function in a population of Greenland Inuit residing in the Arctic (Greenland) or Western Europe (Denmark).Subjects/methods: Two unselected Inuit populations were recruited, one living in Greenland (Urban (Nuuk) n=358; Rural (Uummannaq) n=207) and the other in Denmark (n=539). Lung function was measured using spirometry and diet by a food frequency questionnaire. Factors associated with airflow limitation were assessed using multiple linear regression models.Results: The dietary composition differed significantly in the two regions, with higher whale, seal and wild meat intake and lower fruit and vegetable intake in the Arctic regions compared with Denmark. Consumption of vegetables (P=0.004) and whale and/or seal (P<0.0001) was significantly and positively associated with FEV1, as well as with FVC (vegetables: P=0.001, whale and/or seal: P=0.002). Regular fruit intake was included in the statistical models; however, it did not reach statistical significance (FEV1: P=0.053; FVC: P=0.055).Conclusions: High dietary intake of vegetables as well as intake of arctic marine mammals had independent positive associations with lung function in this cohort of Greenlandic Inuit. These findings suggest an additive role of dietary intake of antioxidants and unsaturated fatty acids in lung health, which warrants prospective evaluation. [ABSTRACT FROM AUTHOR]

Key points From animal models, it is well established that β2-adrenergic stimulation increases contractile force, rates of Ca2+ release and uptake from the sarcoplasmic reticulum, and Na+-K+-ATPase activity of skeletal muscles. However, these effects are unexplored in humans., Here we report that β2-adrenergic stimulation with the high dose selective β2-adrenoceptor agonist terbutaline elicits positive inotropic and lusitropic effects on non-fatigued m. quadriceps that are associated with enhanced rates of Ca2+ release and uptake from the sarcoplasmic reticulum in trained men., However, we also observed that the positive inotropic and lusitropic effects of β2-adrenergic stimulation on m. quadriceps were blunted when muscle fatigue developed., Furthermore, we show that β2-adrenergic stimulation counteracts exercise-induced reductions in Na+-K+-ATPase Vmax (maximum rate of activity) and elevates glycolytic activity during high intensity exercise., These findings are important for our understanding of the role of β2-adreceptor activation in regulation of ion handling and contractile properties of non-fatigued and fatigued skeletal muscles in humans., Abstract The aim of the present study was to examine the effect of β2-adrenergic stimulation on skeletal muscle contractile properties, sarcoplasmic reticulum (SR) rates of Ca2+ release and uptake, and Na+-K+-ATPase activity before and after fatiguing exercise in trained men. The study consisted of two experiments (EXP1, n = 10 males, EXP2, n = 20 males), where β2-adrenoceptor agonist (terbutaline) or placebo was randomly administered in double-blinded crossover designs. In EXP1, maximal voluntary isometric contraction (MVC) of m. quadriceps was measured, followed by exercise to fatigue at 120% of maximal oxygen uptake ( [ABSTRACT FROM AUTHOR]

Background Eosinophil cationic protein ( ECP) is one of four basic proteins of the secretory granules of eosinophils. It has a variety of functions associated with inflammatory responses. Little is known about the causes for variation in serum ECP levels. Aim To identify factors associated with variation in serum ECP and to determine the relative proportion of the variation in ECP due to genetic and non-genetic factors, in an adult twin sample. Methods A sample of 575 twins, selected through a proband with self-reported asthma, had serum ECP, lung function, airway responsiveness to methacholine, exhaled nitric oxide, and skin test reactivity, measured. Linear regression analysis and variance component models were used to study factors associated with variation in ECP and the relative genetic influence on ECP levels. Results Sex (regression coefficient = −0.107, P < 0.001), body mass index ( BMI) (0.007, P = 0.028), and airway responsiveness to methacholine (0.074, P = 0.001) were significantly associated with ECP. Adjusted for these factors, ECP correlated 0.53 ( P < 0.001) and 0.27 ( P = 0.001) in monozygotic and dizygotic twins, respectively ( P-value for difference = 0.05). According to the most parsimonious variance component model, genetic factors accounted for 57% ( CI: 42-72%, P < 0.001) of the variance in ECP levels, whereas the remainder (43%) was ascribable to non-shared environmental factors. The genetic correlation between ECP and airway responsiveness to methacholine was statistically non-significant ( r = −0.11, P = 0.50). Conclusion Around half of all variance in serum ECP is explained by genetic factors. Serum ECP is influenced by sex, BMI, and airway responsiveness. Serum ECP and airway responsiveness seem not to share genetic variance. [ABSTRACT FROM AUTHOR]

There is a high prevalence of asthma and airway hyperresponsiveness (AHR) in elite athletes, which leads to a major use of beta2-agonists. In a randomized double-blinded crossover study, we investigated the effects of combined inhalation of beta2-agonists (salbutamol, formoterol, and salmeterol), in permitted doses within the World Anti-Doping Agency 2013 prohibited list, in elite swimmers with (AHR, n = 13) or without (non-AHR, n = 17) AHR. Maximal voluntary isometric contraction of m. quadriceps (MVC), sprint performance on a swim ergometer and performance in an exhaustive swim test at 110% of VO2max were determined. Venous plasma interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured post-exercise. No improvement was observed in the exhaustive swim test, but swim ergometer sprint time was improved (P < 0.05) in both groups from 57 ± 1.7 to 56 ± 1.8 s in AHR and 58.3 ± 1 to 57.4 ± 1 s in non-AHR. MVC and post-exercise plasma IL-6 increased (P < 0.05) with beta2-agonists in both groups, whereas IL-8 only increased in AHR. In summary, inhalation of beta2-agonists, in permitted doses, did not improve swim performance in elite swimmers. However, swim ergometer sprint performance and MVC were increased, which should be considered when making future anti-doping regulations. [ABSTRACT FROM AUTHOR]

Background Smoking has been shown to have several detrimental effects on asthma, including poor symptom control, attenuated treatment response and accelerated decline in lung function. In spite of this, smoking is at least as common among asthma patients as in the rest of the population. The aggravations of smoking on asthma may be caused by effects on airway inflammation, which has been found to be changed in asthmatic smokers. It is not known whether these smoking-induced airway inflammation changes are reversible after smoking cessation. Objective The aim of this study was to assess airway changes in asthmatic smokers before and during smoking cessation. Methods Forty-six smokers with asthma, all steroid-free (age range: 19-40), were recruited. All participants attempted smoking cessation over a period of 3 months. Visits were performed at weeks 0, 6 and 12 and included induced sputum, Fe NO, methacholine challenge, lung function, Asthma Control Questionnaire ( ACQ6) and exhaled CO. Results Twenty-six of 46 patients succeeded in quitting smoking. In the quitters, improvements in methacholine AHR (77% before and 52% after smoking cessation, respectively, P = 0.016) and ACQ6 score (1.7-0.7, P = 0.034) and Fe NO (8.7-14.8 p.p.b., P = 0.002) were observed, whereas no significant changes were found regarding eosinophils or lung function. A small but significant decrease in neutrophils (54.1-52%, P = 0.003) was present in quitters compared with the non-quitters. Non-quitters experienced no changes in any parameters. Conclusion Smoking cessation improved asthma control, but the changes were not related to change in eosinophilic inflammation, and the reduction in neutrophils was small. Thus, airway inflammation with eosinophils and neutrophils may be less important drivers of asthma control in smokers than other factors. Clinical Relevance Smoking cessation may improve clinically important disease parameters such as AHR and symptom score, but likely unrelated to changes in airway inflammation. [ABSTRACT FROM AUTHOR]

Background IgE-mediated allergic rhinitis to grass pollen can successfully be treated with either allergen immunotherapy tablets ( SLIT tablet) or SQ-standardized subcutaneous immunotherapy ( SCIT). The efficacy of these two treatment modalities for grass allergy is comparable, but the immunological mechanisms may differ. ClinicalTrials.gov ID: NCT01889875. Objectives To compare the immunological changes induced by SQ-standardized SCIT and SLIT tablet. Methods We randomized 40 individuals with grass pollen rhinitis into groups receiving SCIT, SLIT tablet, or neither and followed them for 15 months with regular serum measurements of specific Ig E, Ig G4, Ig E-blocking factor, facilitated antigen presentation ( FAP), and basophil activation test ( BAT). Nasal challenges were used to assess changes in nasal sensitivity. Results After 15 months of treatment Ig G4, Ig E-blocking factor, FAP, and BAT values differed significantly in both SCIT and SLIT-tablet treatment groups when compared to the control group. Both SCIT and SLIT-tablet groups were significantly different from the control group after 1-3 months of treatment. In general, the changes induced by SCIT reached twice that of SLIT tablet, with the exception of specific Ig E where SLIT tablet induced initial threefold increase compared with SCIT. A slight but significant increase in Ig E and BAT after season was seen only in the control group. Significant differences between SCIT and SLIT tablet were observed early, but the differences diminished with the length of treatment, especially for FAP inhibition. Conclusions Both SCIT and SLIT tablet induce significant changes in specific antibodies ( Ig E and Ig G4) and competition assays ( Ig E-blocking factor, FAP, and BAT). Overall, SCIT induced larger (two- to threefold) changes than SLIT tablet, with the exception of FAP, where SLIT tablet showed a gradual increase ending at the same level as SCIT. Maximal change was generally reached after 3 months' treatment. [ABSTRACT FROM AUTHOR]

The function of cultured mast cells may depend on genetic or environmental influence on the stem cell donor. This study investigates whether asthma or atopy in the donor influenced the growth and sensitivity of mast cells cultured from patients with asthma and healthy controls under identical conditions. Mast cells were cultured from peripheral blood from twelve patients with an objectively confirmed asthma diagnosis and eight healthy subjects. During the last 2 weeks of culture, mast cells were incubated with IL-4 and 80 kU/l recombinant human Ig E containing two clones (7% + 7%) specific for mite allergen Der p2. The sensitivity of Ig E-mediated activation of mast cells was investigated as Fcε RI-mediated upregulation of CD63. Ten subjects were atopic, defined as a positive skin prick test (>3 mm) to at least one of ten common allergens. After activation with recombinant Der p2, the maximum CD63 median fluorescence intensity was 20 456 ± 1640 ( SE) for patients with asthma and 22 275 ± 1971 ( SE) for controls (ns). The fraction of CD63 positive cells was 54.4% in patients with asthma and 48.4% in controls (ns). The allergen concentration inducing 50% of the maximal CD63 response was similar in patients with asthma [−0.4795 log ng/ml ± 0.092 ( SE)] and controls (−0.6351 log ng/ml ± 0.083, ns) and in atopic and non-atopic subjects. When cultured, sensitized and activated under identical conditions, mast cells from allergic asthmatics and healthy controls respond similar. Activation of cultured mast cells appears to depend on culture conditions ( IL-4, Ig E) rather than on donor status as atopy and asthma. [ABSTRACT FROM AUTHOR]

We examined urine and serum concentrations after therapeutic use of single and repetitive doses of inhaled and supratherapeutic oral use of terbutaline. We compared the concentrations in 10 asthmatics and 10 healthy subjects in an open-label, cross-over study with 2 mg inhaled and 10 mg oral terbutaline on 2 study days. Further, 10 healthy subjects were administrated 1 mg inhaled terbutaline in 4 repetive doses with total 4 mg. Blood samples were collected at baseline and during 6 h after the first inhalations. Urine samples were collected at baseline and during 12 h after the first inhalations. Median (IQR) urine concentrations peaked in the period 0]4 h after inhalation with C max 472 (324) ng/mL in asthmatics and 661 (517) ng/mL in healthy subjects, and 4]8 h after oral use with C max 666 (877) ng/mL in asthmatic and 402 (663) ng/mL in healthy subjects. In conclusion we found no significant differences in urine and serum concentrations between asthmatic and healthy subjects. We compared urine and serum concentrations after therapeutic inhaled doses and supratherapeutic oral doses and observed significant statistical defenses in both groups but found it impossible to distinguish between therapeutic and prohibited use based on doping tests with urine and blood samples. [ABSTRACT FROM AUTHOR]

Background Worldwide, more than 400 million individuals have allergic rhinitis, which has a significant impact on the individual's general health. Most patients self-medicate with over-the-counter drugs, but severe cases need treatment with topical corticosteroids and/or immunotherapy ( SCIT). Although the ARIA guidelines discourage the use of systemic corticosteroids, this treatment is often used by general practitioners. Aims To investigate the use of systemic steroids to treat allergic rhinitis in Denmark and the role of SCIT as an alternative. Methods A retrospective study based on Danish National Registry databases 1995-2009. Steroid use was defined as a minimum of one steroid injection during April-July for at least three consecutive years. SCIT treatment against grass (Phleum pratense), birch (Betula verrucosa) or both was included. Results Overall, 39 173 individuals were treated with either SCIT or steroids; 93.1% received only steroids, and 6.9% received SCIT and/or steroids. The steroid-to- SCIT ratio was 14 : 1 ( P < 0.0001). The mean annual steroid injections were 1.6 in the steroid-only group and 1.0 in the SCIT group ( P < 0.0001). Of the SCIT-treated individuals, 84% did not need steroids after SCIT treatment ( P < 0.0001). The hazard ratios of receiving steroids after SCIT against grass, birch or both were 0.65, 0.83 and 0.72, respectively ( P < 0.0001), when compared with the steroids-only group. The maximum hazard reduction was obtained if patients responded well to SCIT treatment after one to 3 years. Conclusions Systemic steroid injections are still widely used to treat pollen allergy. Specific immunotherapy can greatly reduce the need for steroids. [ABSTRACT FROM AUTHOR]

The prevalence of asthma is higher among elite athletes than in the general population. This has resulted in the frequent use of anti-asthmatic medication such as beta2-agonists among asthmatic athletes. Beta2-agonists are on the prohibited list of WADA. The use of the beta2-agonist salbutamol is only permitted in therapeutic inhaled doses. Most studies have reported the lack of ergogenic effects of therapeutic doses of inhaled beta2-agonists measured in maximal oxygen uptake. No previous studies have examined any possible effects of high-dose inhaled salbutamol on oxygen uptake kinetics. We enrolled nine healthy well-trained men in a randomized, blinded, placebo-controlled crossover study. Subjects were randomized to inhalation of 40 puffs of 0.2 mg salbutamol or two placebo tablets and performed an incremental test to exhaustion and three submaximal tests at 75% of peak power to determine oxygen uptake kinetics. During the incremental test, there were no effects of inhaled salbutamol on VO2max in absolute or relative terms, and no effect on peak power and lactate threshold. During the submaximal test, we found no effects on the time constant, time delay, the mean response time or O2 deficit related to oxygen uptake kinetics. In conclusion, no ergogenic effect of a high dose of salbutamol on aerobic capacity was found. [ABSTRACT FROM AUTHOR]

Respiratory difficulties caused by exercise-induced laryngeal obstructions (EILOs) are reported with increasing frequency. The aim of this study was to assess the prevalence and symptoms of EILOs and their relation to airway hyperresponsiveness (AHR). In total, 556 randomly selected youths in Copenhagen aged 14-24 years were invited over a 2-year period. The study included a mailed questionnaire and two visits: day 1 (an interview-based questionnaire, methacholine bronchial provocation test and physical exertion test); and day 2 [an exercise test with continuous laryngoscopic recordings (CLE test)]. The diagnosis of EILOs was based on the CLE test. In total, 237 answered the mailed questionnaire and 150 participated on day 1 whereof 98 participated on day 2 also. AHR was verified in 23 (4.1% of invitees) and EILOs in 42 (7.5% of invitees). Co-morbidity was verified in 6 cases (26.1% of verified AHR cases). No symptoms were found specific for either AHR or EILOs. The minimum prevalence of EILOs in this cohort was 7.5%. EILOs were verified in 26.1% of participants with AHR. Questionnaires could not differentiate between AHR and EILOs. [ABSTRACT FROM AUTHOR]

We examined blood and urine concentrations of repetitive doses of inhaled salbutamol in relation to the existing cut-off value used in routine doping control. We compared the concentrations in asthmatics with regular use of beta2- agonists prior to study and healthy controls with no previous use of beta2-agonists. We enrolled 10 asthmatics and 10 controls in an open-label study in which subjects inhaled repetitive doses of 400 microgram salbutamol every second hour (total 1 600 microgram), which is the permitted daily dose by the World Anti-Doping Agency (WADA). Blood samples were collected at baseline, 30 min, 1, 2, 3, 4, and 6h after the first inhalations. Urine samples were collected at baseline, 0-4 h, 4-8h, and 8-12h after the first inhalations. Median urine concentrations peaked in the period 4-8 h after the first inhalations in the asthmatics and between 8-12h in controls and the median ranged from 268 to 611 ng×Ml1. No samples exceeded the WADA threshold value of 1 000 ng×mL1 when corrected for the urine specific gravity. When not corrected one sample exceeded the cut-off value with urine concentration of 1 082 ng×mL1. In conclusion we found no differences in blood and urine concentrations between asthmatic and healthy subjects. We found high variability in urine concentrations between subjects in both groups. The variability between subjects was still present after the samples were corrected for urine specific gravity. [ABSTRACT FROM AUTHOR]

Aim: To examine the relationship between asthma, type 2 diabetes and increased body mass index (BMI) in adult twins. Methods: We performed record linkage between questionnaire defined asthma and BMI, and hospital discharge diagnoses of type 2 diabetes in 34 782 Danish twins, 20–71 years of age. Results: The risk of asthma was increased in subjects with type 2 diabetes relative to nondiabetic subjects both in men (13.5% vs 7.5%), P = 0.001 and in women (16.6% vs 9.6%), P = 0.001. The result remained significant after adjustment for age, BMI, smoking, symptoms of chronic bronchitis, marital status and zygosity, men: OR = 1.70 (1.07–2.70), P = 0.026; women: OR = 1.88 (1.24–2.85), P = 0.003. In this analysis, BMI remained a highly significant predictor for asthma independently of diabetes status in women, P < 0.000 but not in men, P = 0.336. Significant positive genetic correlations were found between asthma and type 2 diabetes, 0.20 (0.01–0.40), P = 0.047; between asthma and BMI in women, 0.15 (0.07–0.22), P < 0.000; and between BMI and type 2 diabetes, 0.40 (0.29–0.43), P < 0.000. Conclusions: Asthma, type 2 diabetes and increased BMI are strongly associated in adults, particularly in women. These results suggest a common aetiology for asthma and metabolic syndrome. [ABSTRACT FROM AUTHOR]

To cite this article: Hansen JW, Thomsen SF, Nolte H, Backer V. Rhinitis: a complication to asthma. Allergy 2010; 65: 883–888. Background: Asthma and rhinitis often co-occur, and this potentially increases the disease severity and impacts negatively on the quality of life. We studied disease severity, airway responsiveness, atopy, quality of life and treatment in subjects with both asthma and rhinitis compared to patients with asthma or rhinitis alone. Methods: We examined 878 patients: 182 with asthma, 362 with rhinitis and 334 with both asthma and rhinitis. All had a clinical interview concerning severity of symptoms, treatment, and quality of life, a skin prick test, a lung function test and a bronchial provocation with methacholine. Results: Patients with both asthma and rhinitis had less severe asthma based on the frequency of respiratory symptoms compared to patients with asthma alone (55% vs 66% P = 0.01). On the contrary, they were more airway responsive ( P < 0.05) and had more perennial allergy ( P < 0.001). Asthmatics had poor perception of the general health, independent of rhinitis ( P < 0.001). No differences were found in asthma-specific quality of life, whereas rhinitis-specific quality of life was worse in those with both asthma and rhinitis compared to those with rhinitis alone ( P < 0.01). Subjects with both diseases were undertreated in 85% of the cases. Conclusion: We encourage that these observations be used in the evaluation and treatment of patients with asthma and rhinitis and that they contribute to the understanding of asthma and rhinitis as a uniform airways disease. [ABSTRACT FROM AUTHOR]

Background Asthma is a complex disease characterized by symptoms of wheezing, shortness of breath, chest tightness, and cough. Objective To study the relative contribution of genetic and environmental factors in the liability to asthma in a large sample of twins. Methods Data on asthma in 21 135 twin pairs, 3–71 years of age, from the Danish Twin Registry were collected via a multidisciplinary questionnaire survey. Heritability estimates were calculated using variance components models. Results A monozygotic twin had an approximately sixfold increased risk of asthma whereas a dizygotic twin only had an approximately threefold increased risk relative to the general population if his or her co-twin was affected. The difference was more pronounced among males. Familial aggregation of asthma in children and adolescents was explained mainly by additive genetic factors, but common environment was also important. The heritability of asthma was also substantial in adults aged 20–49 years. In older adults (aged 50–71 years), additive genetic factors did not significantly influence the disease risk. Conclusion Genetic influences on asthma are substantial throughout the life span but the proportion of the disease liability explained by genetic factors is decreased in older adults. Cite this as: S. F. Thomsen, S. van der Sluis, K. O. Kyvik, A. Skytthe, V. Backer, Clinical & Experimental Allergy, 2010 (40) 1054–1061. [ABSTRACT FROM AUTHOR]

To cite this article: Candelaria PV, Backer V, Khoo S-K, Bizzintino JA, Hayden CM, Baynam G, Laing IA, Zhang G, Porsbjerg C, Goldblatt J, LeSouëf PN, The Greenlandic Study Population Group. The importance of environment on respiratory genotype/phenotype relationships in the Inuit. Allergy 2010; 65: 229–237. Background: Genetic and environmental influences and their interactions are central to asthma pathogenesis. This study aimed to investigate the effects of different macro-environments on asthma genotype–phenotype associations in two geographically separated populations with common ancestry. Methods: To accomplish this, two unselected populations of Inuit were recruited, one living in Greenland ( n = 618) and the other in Denmark ( n = 739). Subjects were genotyped for CD14 C-159T, SCGB1A1 A38G, ADRB2 Arg16Gly and Gln27Glu. The resulting genetic data were analysed for relationships with asthma-related parameters including lung function, ever asthma, atopy, rhinitis and dermatitis. Results: The results showed contrasting magnitude and direction of genetic associations between the two geographically separate Inuit populations. In Greenland, the ADRB2 16Arg allele was associated with male-specific lower lung function, but in Denmark the same allele was associated with male-specific higher lung function. This allele was also associated with higher incidence of ever asthma in Denmark but not in Greenland. The SCGB1A1 38A allele was associated with lower rhinitis prevalence in Greenland but not in Denmark. Conclusions: These associations suggest that environment interacts with candidate asthma genes to modulate asthma pathogenesis in the Inuit. [ABSTRACT FROM AUTHOR]

BACKGROUND: Asthma is frequent in elite athletes and clinical studies in athletes have found increased airway inflammation. OBJECTIVE: To investigate asthma-like symptoms, airway inflammation, airway reactivity (AR) to mannitol and use of asthma medication in Danish elite athletes. METHODS: The study group consisted of 54 elite athletes (19 with doctor-diagnosed asthma), 22 non-athletes with doctor-diagnosed asthma (steroid naive for 4 weeks before the examination) and 35 non-athletes without asthma; all aged 18-35 years. Examinations (1 day): questionnaires, exhaled nitric oxide (eNO) in parts per billion, spirometry, skin prick test, AR to mannitol and blood samples. Induced sputum was done in subjects with asthma. RESULTS: No significant difference was found in values for eNO, AR and atopy between 42 elite athletes with and 12 without asthma-like symptoms. Elite athletes with doctor-diagnosed asthma had less AR (response dose ratio 0.02 (0.004) vs 0.08 (0.018) p<0.01) and fewer sputum eosinophils (0.8% (0-4.8) vs 6.0% (0-18.5), p<0.01) than non-athletes with doctor-diagnosed asthma. Use of inhaled corticosteroids was similar in the two groups (not significant). In all, 42 elite athletes had asthma-like symptoms but only 12 had evidence of current asthma. Elite athletes without asthma had asthma-like symptoms more frequently than non-athletes without asthma (68.6% vs 25.7%, p<0.001). CONCLUSION: Asthma-like symptoms in elite athletes are not necessarily associated with classic features of asthma and alone should not give a diagnosis of asthma. More studies are needed to further investigate if and how the asthma phenotype of elite athletes differs from that of classical asthma. [ABSTRACT FROM AUTHOR]

Background: Linkage studies have implicated the 2q33, 9p21, 11q13 and 20q13 regions in the regulation of allergic disease. The aim of this study was to test genetic variants in candidate genes from these regions for association with specific asthma traits. Methods: Ninety-five single nucleotide polymorphisms (SNP) located in eight genes ( CD28, CTLA4, ICOS, ADAM23, ADAMTSL1, MS4A2, CDH26 and HRH3) were genotyped in >5000 individuals from Australian ( n = 1162), Dutch ( n = 99) and Danish ( n = 303) families. Traits tested included doctor-diagnosed asthma, atopy, airway obstruction, total serum immunoglobulin (Ig) E levels and eosinophilia. Association was tested using both multivariate and univariate methods, with gene-wide thresholds for significance determined through simulation. Gene-by-gene and gene-by-environment analyses were also performed. Results: There was no overall evidence for association with seven of the eight genes tested when considering all genetic variation assayed in each gene. The exception was MS4A2 on chromosome 11q13, which showed weak evidence for association with IgE (gene-wide P < 0.05, rs502581). There were no significant gene-by-gene or gene-by-environment interaction effects after accounting for the number of tests performed. Conclusions: The individual variants genotyped in the 2q33, 9p21 and 20q13 regions do not explain a large fraction of the variation in the quantitative traits tested or have a major impact on asthma or atopy risk. Our results are consistent with a weak effect of MS4A2 polymorphisms on the variation of total IgE levels. [ABSTRACT FROM AUTHOR]

Background: Early detection and treatment of asthma is important to minimize morbidity and healthcare costs. The objective of this study was to investigate asthma awareness and management in a western society. Methods: In a random sample of 10 400 subjects aged 14–44 years, 686 (6.6%) reported symptoms of asthma in a standardized screening questionnaire. All 686 were evaluated by respiratory specialists and diagnosed by history, symptoms, lung function tests, bronchial challenges and allergy testing. Of these 686 participants, 69 (10%) had asthma alone, 205 (30%) had rhinitis alone and 217 (32%) had both asthma and rhinitis; 195 (28%) had nonasthmatic respiratory reports. Results: Awareness of asthma was found among 163 (57%) of the 286 asthmatics, and 204 (95%) had doctor-diagnosed rhinitis as well. In a multivariate regression analysis, comorbidity with rhinitis (β = 0.489, P < 0.001), smoking (β = −0.116, P < 0.01), doctor-diagnosed bronchitis (β = 0.086, P < 0.05), and earlier emergency visits at hospital (β = 0.147, P < 0.001) was significantly associated with awareness. A difference in awareness was found between those who had asthma and rhinitis (62.2%) and those who had asthma alone (40.6%) ( P < 0.01). Inhaled corticosteroids (ICS) were used by 27% of those with asthma, including 12% who used both ICS and long-acting beta-agonist. Conclusions: More than half of the persons with asthma were aware of their disorder; and the awareness was more likely in those with comorbidity of rhinitis. In general, asthma management was inadequate. [ABSTRACT FROM AUTHOR]

Aim To examine the airway response to inhaled mannitol performed before or after a methacholine challenge test in a group of asthmatics with different levels of disease. Methods A total of 48 asthmatics, 18–73 years of age, were included in the study. Two pairs of challenges were performed in a random order on two separate days ⩾24 h apart: either with mannitol performed first on day one, followed ⩾1 h by methacholine, and methacholine as the first on day two, followed ⩾1 h by mannitol or vice versa. A questionnaire-based interview was performed and lung function, exhaled nitric oxide, skin prick test, and blood eosinophil count were measured. Results A total of 44% of the asthmatics used inhaled corticosteroids and 48% were atopic. The airway response to mannitol was attenuated when mannitol was given after methacholine, compared with the response to mannitol when it was given first [log response dose ratio (RDR): 1.42 vs. 1.60 ( P=0.004)], whereas the response to methacholine was unchanged in the opposite test order [log RDR: 0.81 vs. 0.96 ( P=0.102)]. Conclusion Bronchial challenges with inhaled mannitol and methacholine may be performed on the same day but provocation with mannitol should be performed before methacholine. [ABSTRACT FROM AUTHOR]

RATIONALE: Severe respiratory syncytial virus (RSV) infection is associated with asthma but the nature of this association is imperfectly understood. OBJECTIVES: To examine the nature of the association between severe RSV infection and asthma in a population-based sample of twins. METHODS: Data on hospitalization due to RSV infection was gathered for all twins born in Denmark between 1994 and 2000 (8,280 pairs) and linked to information on asthma obtained from hospital discharge registries and parent-completed questionnaires. Genetic variance components models and direction of causation models were fitted to the observed data. MEASUREMENTS AND MAIN RESULTS: RSV hospitalization and asthma were positively associated (r = 0.43), and genetic determinants for the two disorders overlapped completely. Modeling the direction of causation between RSV hospitalization and asthma showed that a model in which asthma 'causes' RSV hospitalization fitted the data significantly better (P = 0.39 for deterioration in model fit) than a model in which RSV hospitalization 'causes' asthma (P < 0.001 for deterioration in model fit), even when sex, birth weight, and maternal smoking during pregnancy were accounted for. CONCLUSIONS: RSV infection that is severe enough to warrant hospitalization does not cause asthma but is an indicator of the genetic predisposition to asthma. [ABSTRACT FROM AUTHOR]

The objective was to determine the prevalence of asthma-like symptoms and asthma and the use of asthma medication in Danish elite athletes. A cross-sectional questionnaire survey of Danish elite athletes was conducted in 2006. All elite athletes ( N=418) financially supported by the national organization of elite athletes comprised the study group; 329 (79%) completed the questionnaire concerning their sport, asthma-like symptoms, asthma and use of asthma medication. Asthma-like symptoms at rest were reported by 41% of respondents; 55% reported asthma-like symptoms at rest or at exercise. Physician-diagnosed asthma was present in 16% and 14% had current asthma. Asthma medication was taken by 7% of the athletes, of whom 79% used inhaled corticosteroids and 21% used inhaled β2-agonists only. Athletes participating in endurance sports had higher prevalences of current asthma (24%) and use of asthma medication (15%) than all other athletes ( P<0.01). Athletes participating in endurance sports have a higher prevalence of asthma and use of asthma medication. The frequency of asthma medication is lower than the prevalence of current asthma indicating that there is no overuse of asthma medication among Danish elite athletes. [ABSTRACT FROM AUTHOR]

Aim: To study the relative contribution of genetic and environmental factors to the correlation between exhaled nitric oxide (FeNO), airway responsiveness, airway obstruction, and serum total immunoglobulin E (IgE). Methods: Within a sampling frame of 21 162 twin subjects, 20–49 years of age, from the Danish Twin Registry, a total of 575 subjects (256 intact pairs and 63 single twins) who either themselves and/or their co-twins reported a history of asthma at a nationwide questionnaire survey, were clinically examined. Traits were measured using standard techniques. Latent factor models were fitted to the observed data using maximum likelihood methods. Results: Additive genetic factors explained 67% of the variation in FeNO, 43% in airway responsiveness, 22% in airway obstruction, and 81% in serum total IgE. In general, traits had genetically and environmentally distinct variance structures. The most substantial genetic similarity was observed between FeNO and serum total IgE, genetic correlation (ρA) = 0.37, whereas the strongest environmental resemblance was observed between airway responsiveness and airway obstruction, specific environmental correlation (ρE) = −0.46, and between FeNO and airway responsiveness, ρE = 0.34. Conclusions: Asthma is a complex disease characterized by a set of etiologically heterogeneous biomarkers, which likely constitute diverse targets of intervention. [ABSTRACT FROM AUTHOR]

Background Airway hyperresponsiveness (AHR) to stimuli that cause bronchial smooth muscle (BSM) contraction indirectly through the release of endogenous mediators is thought to reflect airway inflammation more closely compared with AHR measured by stimuli that act directly on BSM. Methods Fifty-three adult non-smoking asthmatics (28 females, 18–56 years) who were not taking inhaled steroids were challenged with mannitol (up to 635 mg) and methacholine (up to 8 μmol). Induced sputum eosinophils, exhaled nitric oxide (eNO), peak flow variation and clinical severity of asthma according to the Global Initiative for Asthma guidelines were measured in addition to the health-related quality-of-life score using the Juniper asthma quality-of-life questionnaire. Findings Both AHR to mannitol as well as to methacholine was associated with elevated markers of airway inflammation: in 83% of asthma patients with AHR to mannitol, and in 88% of asthma patients with AHR to methacholine, the eNO level was >20 p.p.b. Sputum% eosinophils >1% was measured in 70% of asthma patients with AHR to mannitol and in 77% of asthma patients with AHR to methacholine. In asthma patients without AHR, 15% had an eNO level >20 p.p.b., but none had sputum% eosinophils >1%. AHR to mannitol was more closely associated with the percentage of sputum eosinophils (PD15 to mannitol vs. sputum% eosinophils: r: −0.52, P<0.05), compared with AHR to methacholine (PD20 to methacholine vs. sputum% eosinophils: r: −0.28, NS). Furthermore, there was a stronger correlation between AHR to mannitol and the level of eNO [PD15 to mannitol vs. eNO (p.p.b.): r: −0.63, P<0.001], compared with AHR to methacholine [PD20 to methacholine vs. eNO (p.p.b.): r: −0.43, P<0.05]. Interpretation In asthma patients not being treated with steroids, AHR to mannitol and to methacholine indicated the presence of airway inflammation. AHR to mannitol reflected the degree of airway inflammation more closely when compared with methacholine. [ABSTRACT FROM AUTHOR]

Asthma, exercise-induced bronchoconstriction, and airway hyper-responsiveness are often found in elite athletes, perhaps as a consequence of their sport or maybe because asthma is a common disorder in young adults. Inhaled β2-agonists (IBA) are frequently used in elite athletes, but due to regulations introduced by the International Olympic Committee, the use of anti-asthmatic therapy might change. Drugs that make ergogenic effect persist are prohibited in all athletes, whether or not they take part in competitions and systemic steroids and β2-agonists are among such drugs. On the other hand, opinion is more divided about the use of inhaled corticosteroids (ICS) and IBA. In humans, no effect has been found on the oxygen uptake, performance or distance run with therapeutic doses of IBA, either in asthmatics or non-asthmatics, whereas others report an ergogenic effect and better lung function of high doses of a β2-agonist in non-asthmatics. Anti-asthmatic treatment is necessary for asthmatics, but should not be used by non-asthmatic elite athletes due to both possible systemic effects and furthermore, side effects of both ICS and IBA. [ABSTRACT FROM AUTHOR]

Background: Obesity is linked to asthma in a yet poorly understood manner. We examined the relationship between obesity and asthma in a population-based sample of twins. Methods: From the cohorts born between 1953 and 1982, who were enrolled in The Danish Twin Registry, a total of 29 183 twin individuals participated in a nationwide questionnaire study, where data on height, weight and asthma were collected. Latent factor models of genetic and environmental effects were fitted using maximum likelihood methods. Results: The age-adjusted risk of asthma was increased both in obese females, OR = 1.96 (1.45–2.64), P ≤ 0.001 and in obese males, OR = 1.59 (1.08–2.33), P = 0.02. According to best-fitting models, the heritability for obesity was 81% in males and 92% in females, whereas the heritability for asthma was 78% and 68% in males and females respectively. The age-adjusted genetic liabilities to obesity and asthma were significantly correlated only in females, r = 0.28 (0.16–0.38). Conclusions: Obese subjects have an increased risk for asthma, which in females seems partly because of common genes. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to describe differences between allergic rhinitis (AR) and nonallergic rhinitis (NAR) in a large community-based sample of Danish adolescents and adults. Methods: A total of 1186 subjects, 14–44 years of age, who in a screening questionnaire had reported a history of airway symptoms suggestive of asthma and/or allergy, or who were taking any medication for these conditions were clinically examined. All participants were interviewed about respiratory symptoms and furthermore skin test reactivity, lung function and airway responsiveness were measured using standard techniques. Results: A total of 77% of the subjects with rhinitis had AR, whereas 23% had NAR. Subjects with NAR were more likely to be females, OR = 2.05 (1.31–3.20), P = 0.002, to have persistent symptoms within the last 4 weeks, OR = 1.88 (1.23–2.89), P = 0.003, and to have recurring headaches, OR = 1.94, (1.12–3.37), P = 0.019. On the other hand, subjects with NAR were less likely to have airway hyperresponsiveness, OR = 0.40, (0.24–0.66), P < 0.001, food allergy, OR = 0.40, (0.19–0.36), P = 0.009 and to have been treated with antihistamines in the last 4 weeks, OR = 0.22, (0.13–0.38), P < 0.001 compared with subjects with AR. Subjects with AR were symptomatically worse within their season in terms of sneezing ( P < 0.001) and itchy eyes ( P < 0.001), compared to subjects with NAR, whereas nasal congestion and rhinorrhea were equally frequent in the two groups ( P = 0.901 and P = 0.278, respectively). Conclusions: The proportion of subjects with NAR in an adolescent and adult population with rhinitis is around one-fourth. Women have NAR twice as often as men. In general, subjects with NAR have more persistent but equally severe symptoms compared to subjects with AR. However, subjects with AR have more sneezing and itchy eyes within their particular season of allergy compared to subjects with NAR. [ABSTRACT FROM AUTHOR]

Background Bronchial provocation using methacholine, a cholinergic agonist, causes airway narrowing directly by contraction of bronchial smooth muscle. While methacholine has a high sensitivity for identifying airway hyper-responsiveness (AHR), it does not have a high specificity to diagnose asthma and false-positive responses may be observed in non-asthmatics. Mannitol is an osmotic stimulus that acts indirectly to cause airway narrowing by release of endogenous bronchoconstricting mediators. Objectives We tested the hypothesis that subjects with asymptomatic AHR to methacholine would not have AHR to mannitol. Methods Sixteen subjects with a methacholine PD20 <8 μmol were challenged with mannitol. A positive response to mannitol was defined as a 15% decline in forced expiratory volume in 1 s (FEV1) after <635 mg (PD15). Expired nitric oxide (eNO) and blood eosinophils were also measured. Results The GM PD20 for methacholine was 2.25 μmol [95% confidence interval (CI): 2.19–5.29], the mean eNO was 14.7 p.p.b. (CI: 10.1–19.4) and the eosinophil count was 0.20 × 10−9/L (CI: 0.14–0.27 × 10−9/L). Only one subject (a smoker, 10 pack-years, FEV1 76% pred, non-allergic rhinitis, normal eNO and eosinophil count) also had a mild positive response to mannitol (PD15: 451 mg). Conclusions The response to mannitol was within the normal range in asymptomatic subjects with AHR to methacholine. Further evidence on the responsiveness to mannitol compared with methacholine in a random population sample is required to elucidate whether mannitol is a more specific test for diagnosing asthma. [ABSTRACT FROM AUTHOR]

Background Atopic traits often co-occur and this can potentially be caused by common aetiological relationships between traits, i.e. a common genetic or a common environmental background. Objective To estimate to what extent the same genetic and environmental factors influence wheeze, rhinitis, airway hyper-responsiveness (AHR), and positive skin prick test (posSPT) in a sample of adult twins. Methods Within a sampling frame of 21 162 twin subjects, 20–49 years of age, from the Danish Twin Registry, a total of 575 subjects (256 intact pairs and 63 single twins), who either themselves and/or their co-twins reported a history of asthma at a nationwide questionnaire survey, were clinically examined. Symptoms of wheeze and rhinitis were obtained by interview; airway responsiveness and skin test reactivity were measured using standard techniques. Correlations in liability between the different traits were estimated and latent factor models of genetic and environmental effects were fitted to the observed data using maximum likelihood methods. Results The various phenotypic correlations between wheeze, rhinitis, AHR and posSPT were all significant and ranged between 0.50 and 0.86. Traits that showed highest genetic correlations were wheeze–rhinitis (ρA=0.95), wheeze–AHR (ρA=0.85) and rhinitis–posSPT (ρA=0.92), whereas lower genetic correlations were observed for rhinitis–AHR (ρA=0.43) and AHR–posSPT (ρA=0.59). Traits with a high degree of environmental sharing were rhinitis–posSPT (ρE=0.92) and wheeze–posSPT (ρE=0.71), whereas a lower environmental correlation was seen for wheeze–rhinitis (ρE=0.25). The estimates were corrected for ascertainment and adjusted for age, sex, inhaled corticosteroids and smoking. Conclusions Different atopic conditions share, to a large extent, a common genetic background. In particular, upper and lower respiratory symptoms seem to be different phenotypic expressions of a common set of genes. These results add new insight into the origins of clinical heterogeneity within atopy and should stimulate the search for pleiotropic genes of importance for these conditions. [ABSTRACT FROM AUTHOR]

Background: The liability to asthma is influenced both by genetic and environmental factors. The objective of this study was to identify risk factors for asthma in young adult twin pairs during an 8-year period. Methods: From the birth cohorts 1953–1982 of the Danish Twin Registry, 6090 twin pairs who were initially unaffected with respect to asthma at a nationwide questionnaire-based study in 1994 participated in a similar follow-up study in 2002. Subjects were regarded incident asthma cases when responding affirmatively to the question ‘Do you have, or have you ever had asthma'? in 2002. Pairs in which only one twin developed asthma – discordant pairs – were identified and conditional logistic regression was applied to detect effects of risk factors. Results: A total of 126 monozygotic (MZ) and 273 dizygotic (DZ) discordant twin pairs were identified. In MZ twins hay fever (OR = 3.16, 95% CI: 1.29–7.73, P = 0.007) and exercise (OR for inactivity = 0.35, 95% CI: 0.13–0.91, P = 0.023) were significantly associated with asthma, whereas in DZ twins, hay fever (OR = 2.44, 95% CI: 1.44–4.13, P = 0.001), eczema (OR = 1.96, 95% CI: 1.02–3.78, P = 0.040), female sex (OR between males and females = 0.54, 95% CI: 0.36–0.80, P = 0.002), and increasing levels of body mass index (BMI; OR per unit = 1.11, 95% CI: 1.02–1.20, P = 0.009) were significant predictors of asthma. Conclusions: Hay fever, eczema, female sex, exercise and increasing levels of BMI were risk factors for asthma in young adults. The different risk profile observed in MZ twins compared with DZ twins may reflect an underlying genetic vulnerability shared between those risk factors and asthma. [ABSTRACT FROM AUTHOR]