Timing of secondhand smoke, pet, dampness or mould exposure and lung function in adolescence.

BACKGROUND: The relevance of timing of exposure in the associations of secondhand tobacco smoke (SHS), pets, and dampness or mould exposure with lung function is unclear. We investigated the relevance of timing of these exposures for lung function in adolescence. METHODS: We used data from participants of the Dutch Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort with spirometric measurements at ages 12 and 16 years (n=552). Data on residential exposure to SHS, pets, and dampness or mould were obtained by repeated parental questionnaires. We characterised timing of exposure through longitudinal patterns using latent class growth modelling and assessed associations of these patterns with FEV1 and FVC at ages 12 and 16 and FEV1 and FVC growth between ages 12 and 16 using linear regression models. RESULTS: Childhood SHS exposure was associated with reduced FEV1 growth/year (95% CI) (-0.34% (-0.64% to -0.04%)). Late childhood and early life pet exposure was associated with increased FEV1 growth (0.41% (0.14% to 0.67%)) and reduced FVC growth (-0.28% (-0.53% to -0.03%)), respectively, compared with very low exposure. Early life dampness or mould exposure was associated with reduced lung function growth. All time windows of SHS exposure tended to be associated with lower attained lung function and pet exposure tended to be associated with higher FEV1. CONCLUSION: SHS exposure during childhood could lead to reduced lung function growth and lower attained lung function in adolescence. While pet exposure in late childhood may not adversely affect lung function, early childhood pet exposure may slow down FVC growth in adolescence.

Effects of Perennial Allergen Immunotherapy in Allergic Rhinitis in Patients with/without Asthma: A-Randomized Controlled Real-Life Study.

BACKGROUND: There have been very few studiesin real-life settingscomparing the treatment effects of allergen immunotherapy (AIT) and pharmacotherapy for perennial allergic rhinitis (AR). OBJECTIVE: This study was performed to compare AIT and pharmacotherapy in terms of their effects on the symptom control and quality of life (QOL) of AR patients with/without asthma. METHODS: A total of 250 patients diagnosed with AR with/without asthma were included and assigned to the immunotherapy (AIT plus pharmacological treatment) or control (pharmacological treatment only) group. Clinical and medication scores, QOL scores, and lung function (forced expiratory volume in one second as a percentage; FEV1%) were measured at baseline and 3 years after the start of treatment. RESULTS: This study showed that there was clinical improvement in AR symptoms in the AIT group, whereas standard pharmacotherapy alone had no significant effect on nasal symptoms. The QOL and satisfaction scores, as evaluated with a visual analogue scale (VAS), were further improved compared to the pharmacotherapy group. There was a significant improvement in medication scores in both AIT groups. According to our results, while total asthma scores and asthma control test scores were significantly improved in the HDM AIT group, they did not change in the Parietaria pollen AIT group. In our study FEV1% was increased compared to the baseline value in the AIT group, but it was not statistically significant. On the other hand, FEV1% remained without any improvement in patients on standard pharmacotherapy. CONCLUSION: Perennial AIT was found to be superior to pharmacotherapy in decreasing symptoms as well as in improving QOL scores in AR patients with/without asthma. HDM AIT was more effective for asthma symptoms than Parietaria pollen AIT.

Airway reversibility and inflammation in stable pre- to late-adolescent asthmatics without long-term control medications.

Objective: Pulmonary function and airway inflammation were investigated in stable pre- to late-adolescent asthmatics without long-term control medications and compared with those in currently medicated asthmatics.Methods: Subjects comprised 34 well-controlled asthmatic children (aged 8.1-18.0 years; group without medication). Flow volume curves before and after inhaling a ß2 agonist, a bronchodilator (BD), were compared and fractional exhaled nitric oxide (FENO) concentrations were measured. All patients were attack-free for at least 12 months prior to testing without the use of asthma medications for at least three months. Fifty-one age-matched stable asthmatics with medications at the time of the present study (group with current medication) underwent the same examinations.Results: The rate of children whose respiratory function after BD improved by 20% or more in both the central and peripheral airways (High responder at total airways subtype: HTA) was significantly higher in the group without medication than in that with current medication (17.6 and 2.0%, respectively; p < 0.01). Furthermore, FEV1.0% pred after BD was significantly lower for HTA than for the low responder subtype in the same group (94.8 ± 3.5 and 104.1 ± 1.5% respectively, p < 0.05). FENO concentrations in the group without medication were high, but not significantly different from those in the group with current medication.Conclusions: Stable asthmatic children without medication include a certain percentage of those with irreversible airflow limitation possibly due to airway remodeling. The control of daily asthma symptoms with long-term control medications may effectively prevent airway remodeling.

Development of a tool predicting severity of allergic reaction during peanut challenge.

BACKGROUND: Reliable prognostic markers for predicting severity of allergic reactions during oral food challenges (OFCs) have not been established. OBJECTIVE: To develop a predictive algorithm of a food challenge severity score (CSS) to identify those at higher risk for severe reactions to a standardized peanut OFC. METHODS: Medical history and allergy test results were obtained for 120 peanut allergic participants who underwent double-blind, placebo-controlled food challenges. Reactions were assigned a CSS between 1 and 6 based on cumulative tolerated dose and a severity clinical indicator. Demographic characteristics, clinical features, peanut component IgE values, and a basophil activation marker were considered in a multistep analysis to derive a flexible decision rule to understand risk during peanut of OFC. RESULTS: A total of 18.3% participants had a severe reaction (CSS >4). The decision rule identified the following 3 variables (in order of importance) as predictors of reaction severity: ratio of percentage of CD63hi stimulation with peanut to percentage of CD63hi anti-IgE (CD63 ratio), history of exercise-induced asthma, and ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio. The CD63 ratio alone was a strong predictor of CSS (P < .001). CONCLUSION: The CSS is a novel tool that combines dose thresholds and allergic reactions to understand risks associated with peanut OFCs. Laboratory values (CD63 ratio), along with clinical variables (exercise-induced asthma and FEV1/FVC ratio) contribute to the predictive ability of the severity of reaction to peanut OFCs. Further testing of this decision rule is needed in a larger external data source before it can be considered outside research settings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02103270.

Respiratory diseases and allergic sensitization in swine breeders: a population-based cross-sectional study.

BACKGROUND: The daily occupation as a swine breeder involves exposure to several bacterial components and organic dusts and inhalation of a large amount of allergens. OBJECTIVE: To investigate the risk of respiratory diseases and atopy in swine breeders compared with the general population living in the same area. METHODS: A population-based cross-sectional study was conducted in an agricultural area of northern Italy that enrolled a random sample of resident male breeders and non-breeders. Demographic features, comorbidities, and presence of allergic respiratory disease were retrieved through interview. Prick tests for common allergens were performed. An evaluation of pollen and mold in air samples taken inside and outside some swine confinement buildings also was performed. RESULTS: One hundred one male breeders (78 native-born, mean age ± SD 43.0 ± 11.1 years) and 82 non-breeders (43.0 ± 11.1 years) were enrolled. When restricting the analysis to native-born subjects, breeders vs non-breeders showed a lower prevalence of respiratory allergy (12.8% vs 31.1%, respectively, P = .002), asthma (6.4% vs 15.8%, P = .059), rhinitis (16.7% vs 51.2%, P < .001), persistent cough (5.1% vs 15.9%, P = .028), and sensitization to grass (7.7% vs 25.6%, P = .002). There was no difference in prick test positivity, polysensitization, nasal cytologic pattern, forced expiratory volume in 1 second, and the ratio of forced expiratory volume in 1 second to forced vital capacity between breeders and non-breeders. Air concentration of molds and pollens was lower inside than outside the swine buildings investigated, particularly when the pigs were inside vs outside the buildings. CONCLUSION: This study suggests that swine breeding does not increase, and might decrease, the risk of pollen sensitization and allergic disease.

Enhanced generation of suppressor T cells in patients with asthma taking oral contraceptives.

Introduction. A dysregulation of regulatory T cells (Tregs) could play a major role in the pathogenesis of bronchial asthma. Sex-dependent differences as well as the impact of hormonal changes in the incidence and severity of asthma are widely recognized. Emerging evidence suggests that asthma symptoms are alleviated in female patients taking hormone oral contraceptives (OCs). The impact of OCs on the generation of induced Tregs (iTregs) was assessed in a cohort of female patients with asthma. Methods. Thirteen patients were included in this pilot study. During three distinct phases of their menstrual cycles, we measured exhaled nitric oxide (eNO) levels, forced expiratory volume at 1 second (FEV1s), asthma control test (ACT) score, sex steroid hormone levels in serum, natural Tregs in peripheral blood, and the ability of CD4(+) T cells to generate iTregs ex vivo. Results. The luteal serum levels of estradiol and progesterone negatively correlated with the proportion of iTregs generated ex vivo in patients not taking OCs. In addition, physiological doses of estradiol and progesterone prevented the acquisition of a suppressor T cell phenotype in vitro. Interestingly, patients taking OCs had reduced serum sex hormone levels associated with higher iTreg induction, a better ACT score, and a tendency toward lower eNO levels. Conclusions. Our results identify an impact of sex hormones on the capacity of T cells to polarize towards a regulatory phenotype and suggest the regulation of peripheral T cell lineage plasticity as a potential mechanism underlying the beneficial effects of OCs in women with asthma.

Respiratory health and endotoxin: associations and modification by CD14/-260 genotype.

Exposure to endotoxin has been associated with increased respiratory symptoms and decrements in lung function in occupational settings but little is known about the health effects of domestic exposure in adults. Here, we describe the association of respiratory disease, immunoglobulin (Ig)E sensitisation, bronchial reactivity and lung function with mattress endotoxin levels in adults, and determine whether these associations are modified by polymorphisms in CD14. Endotoxin levels in mattress dust from a population-based sample of 972 adults were measured. Associations were examined using generalised linear mixed models, adjusting for individual and household confounders. Effect modification of these associations by CD14/-260 (rs2569190) was assessed. Mattress endotoxin levels varied from 0.1 to 402.6 EU · mg(-1). Although there was no overall association of lung function with endotoxin exposure, there was evidence that the association of forced expiratory volume in 1 s and forced vital capacity with endotoxin was modified by CD14/-260 genotype (p-value for interaction 0.005 and 0.013, respectively). There was no evidence that symptoms, IgE sensitisation or bronchial reactivity were associated with mattress endotoxin levels. In this large epidemiological study of adults, there was no evidence that mattress endotoxin level was associated with respiratory symptoms or IgE sensitisation but the association of lung function with endotoxin levels may be modified by CD14 genotype.

Presence in sputum of functional dust mite-specific IgE antibodies in intrinsic asthma.

RATIONALE: Intrinsic asthma was described by Rackemann as asthma without allergy. Local IgE production has been documented in intrinsic asthma, but antigen specificity of this response remains elusive. OBJECTIVES: We investigated (1) the presence of dust mite-specific IgE in sputum of patients with intrinsic asthma, (2) their clinical/immunological relevance, and (3) their functionality. METHODS: Specific IgE to Dermatophagoides pteronyssinus (Der p) and to recombinant major allergens (rDer p1 and rDer p2) were assayed by ELISA in sputum samples from patients with intrinsic versus atopic asthma and control subjects. Whole-lung challenge was performed with Der p for clinical and inflammatory readouts. Functionality of local IgE to trigger effector cells was assessed using basophil activation test (surface expression of CD203c). MEASUREMENTS AND MAIN RESULTS: Both total IgE and Der p-specific IgE levels are increased in patients with intrinsic asthma compared with healthy nonatopic patients. However, no immediate asthmatic responses were observed in patients with intrinsic asthma after Der p exposure. These sputum Der p-specific IgE do, however, recognize major allergens Der p1 and Der p2 and are able to trigger activation of blood basophils from atopic donors. CONCLUSIONS: We confirm that IgE production occurs in intrinsic asthma and show that part of this IgE recognizes Der p antigens. However, this IgE reactivity does not translate into clinical responses to Der p exposure, despite specificity to major allergens and functionality to activate effector cells in vitro. We postulate that a second signal that promotes IgE-mediated asthmatic responses through FcεRI is lacking in intrinsic asthma.

Antinuclear autoantibodies are more prevalent in COPD in association with low body mass index but not with smoking history.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a higher prevalence of antinuclear autoantibodies (ANAs). However, a significant subgroup of patients is ANA negative. It remains to be determined which patient groups carry autoantibodies. METHODS: The association of smoking behaviour, disease status, gender, age and body mass index (BMI) with the presence of autoantibodies in the serum was determined in 124 patients with COPD and 108 non-COPD control subjects. In addition, the role of B cells in autoantibody generation in COPD was investigated by sequencing the antibody repertoire of B cells in the lungs of patients with COPD and of ex-smoking and never-smoking control subjects. RESULTS: Patients with COPD had a significantly higher risk of being serum positive for ANAs (OR 3.12, 95% CI 1.68 to 5.76, p<0.001). ANAs were not significantly associated with age, smoking status, gender or pack-years of smoking. Within the COPD population, subjects with BMI <22 kg/m2 had a significantly higher risk of ANAs (OR 4.93, 95% CI 1.50 to 16.50, p=0.009) than those with normal or high BMI. The antibody repertoire of B cells in the lungs of patients with COPD had a high frequency of positively charged CDR3 residues, a feature which is associated with self-reactive antibodies. CONCLUSION: The results show that COPD is a heterogeneous disease with respect to the prevalence of ANAs. ANAs are primarily associated with the presence of COPD and with low BMI, but not with smoking and forced expiratory volume in 1 s.

Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects.

BACKGROUND: Phosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge. METHODS: 25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15. RESULTS: Roflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen. CONCLUSIONS: This study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01365533.

Prospective evaluation of current asthma control using ACQ and ACT compared with GINA criteria.

BACKGROUND: The goal of asthma treatment is to achieve and maintain current best control and reduce future risk of exacerbations and long-term morbidity. OBJECTIVE: To prospectively compare current asthma control as defined by ACQ (asthma control questionnaire) and ACT (asthma control test) criteria with the GINA (Global Initiative for Asthma) classification in treated patients in a real-life setting. METHODS: In 150 adult patients (48% male, age 46.3 ± 14.4 years., forced expiratory volume in 1 second [FEV(1)], 2.3 ± 0.9 L or 78.5 ± 21.8% pred.), asthma control was evaluated using the GINA classification as the "true" and ACQ-7, ACQ-5, and ACT as "predictor" criteria. The relationship between GINA-defined uncontrolled vs controlled/partly controlled asthma and ACQ and ACT scores was assessed with the ACQ cutpoint of ≥ 1.50 and the ACT cut-point of ≤ 19 for uncontrolled asthma. RESULTS: The ACQ-7 and ACT correctly predicted GINA-defined uncontrolled asthma in 71.3% and 80.7% of patients, respectively. Sensitivity was high, with 88% for ACQ-7 and 94% for ACT, specificity was 57% and 70%, positive predictive value was 63% and 72%, and negative predictive value was 86% and 93%. Similar results were obtained using ACQ-5. ACQ-7 and ACT classified significantly more patients as having uncontrolled asthma compared with the GINA criteria (P < .001). CONCLUSIONS: ACQ scores ≥ 1.50 and ACT scores ≤ 19 are suitable to indicate uncontrolled asthma. To identify GINA-defined uncontrolled asthma, cutoff points for ACQ-5 should be ≥ 1.9 and for ACT ≤ 16, at least in real-life adult patients with mostly moderate and severe asthma.

IL-13 and IL-17A gene polymorphisms in Japanese patients with aspirin-exacerbated respiratory disease.

BACKGROUND: The role of interleukin (IL) 13 and IL-17A in aspirin-exacerbated respiratory disease (AERD) remains unknown. OBJECTIVE: To analyze the IL-13 and IL-17A gene polymorphisms in Japanese patients with AERD. METHODS: The single-nucleotide polymorphisms in each gene were examined in patients with AERD, patients with aspirin-tolerant asthma (ATA), and healthy controls. RESULTS: Frequencies of the TT/CT genotype of the IL-13 -1111C>T gene were higher than frequencies of the CC genotype in AERD patients compared with ATA patients (P < .001). In female patients with AERD, frequencies of the TT/CT genotype were higher than those of the CC genotype compared with female patients with ATA (P < .001). However, genotype frequencies of IL-13 Arg110Gln did not differ between AERD and ATA patients. Frequencies of the CC genotype of the IL-17A -737C>T gene were higher than those of the TT/CT genotype in AERD patients compared with ATA patients (P = .02). In female patients with AERD, frequencies of the CC genotype were higher than those of the TT/CT genotype compared with female patients with ATA (P = .03). Forced expiratory volume in 1 second (percentage predicted) in AERD patients with the CC genotype of the IL-13 -1111C>T gene was lower than that in the patients with the TT/CT genotype. AERD patients with the TT/CT genotype of the IL-17A -737C>T gene had a higher peripheral total eosinophil count compared with the patients with the CC genotype. The comparison of the clinical characteristics according to the IL-13 Arg110Gln gene polymorphism showed no difference. CONCLUSIONS: These findings suggest that the IL-13 -1111C>T and IL-17A -737C>T gene sequence variations might have a role in the development of AERD.

IgE sensitization to Aspergillus fumigatus is associated with reduced lung function in asthma.

RATIONALE: The importance of Aspergillus fumigatus sensitization and colonization of the airways in patients with asthma is unclear. OBJECTIVES: To define the relationship between the clinical and laboratory features of A. fumigatus-associated asthma. METHODS: We studied 79 patients with asthma (89% classed as GINA 4 or 5) classified into 3 groups according to A. fumigatus sensitization: (1) IgE-sensitized (immediate cutaneous reactivity > 3 mm and/or IgE > 0.35 kU/L); (2) IgG-only-sensitized (IgG > 40 mg/L); and (3) nonsensitized. These were compared with 14 healthy control subjects. Sputum culture was focused toward detection of A. fumigatus and compared with clinical assessment data. MEASUREMENTS AND MAIN RESULTS: A. fumigatus was cultured from 63% of IgE-sensitized patients with asthma (n = 40), 39% of IgG-only-sensitized patients with asthma (n = 13), 31% of nonsensitized patients with asthma (n = 26) and 7% of healthy control subjects (n = 14). Patients sensitized to A. fumigatus compared with nonsensitized patients with asthma had lower lung function (postbronchodilator FEV1 % predicted, mean [SEM]: 68 [±5]% versus 88 [±5]%; P < 0.05), more bronchiectasis (68% versus 35%; P < 0.05), and more sputum neutrophils (median [interquartile range]: 80.9 [50.1-94.1]% versus 49.5 [21.2-71.4]%; P < 0.01). In a multilinear regression model, A. fumigatus-IgE sensitization and sputum neutrophil differential cell count were important predictors of lung function (P = 0.016), supported by culture of A. fumigatus (P = 0.046) and eosinophil differential cell count (P = 0.024). CONCLUSIONS: A. fumigatus detection in sputum is associated with A. fumigatus-IgE sensitization, neutrophilic airway inflammation, and reduced lung function. This supports the concept that development of fixed airflow obstruction in asthma is consequent upon the damaging effects of airway colonization with A. fumigatus.

Utility of nitric oxide for the diagnosis of asthma in an allergy clinic population.

Fractionated exhaled nitric oxide (FeNO) expression is increased in airway inflammation and several studies have suggested that FeNO measurement can be useful in patients with asthma. Atopic individuals have increased FeNO levels, indicating that atopy may be a codeterminant in FeNO production. The aim of this study was to determine the discriminative value of FeNO for asthma and other atopic conditions in the general allergy clinic. Patients referred to the outpatient allergy clinic were screened. A standardized questionnaire was taken and atopic status was assessed (skin-prick test or specific plasma IgE). FeNO level and spirometry were measured. If the patient's history was suspect for asthma, a provocative concentration causing a 20% decrease in forced expiratory volume in 1 second (PC(20)) histamine challenge followed. One hundred fourteen steroid-naive patients were included. Forty-two subjects were diagnosed as asthmatic patients and 72 were diagnosed as nonasthmatic patients, comprising patients with allergic rhinitis (n = 32), nonallergic rhinitis (n = 11), urticaria (n = 11), eczema (n = 7), and other (n = 11). Asthmatic patients had a higher FeNO level than nonasthmatic patients (44 ppb versus 17 ppb; p < 0.001). Receiver operating characteristic curve analysis revealed the optimal FeNO level to distinguish asthma from nonasthma at 27 ppb, with a sensitivity of 78%, specificity of 92%, a positive predictive value of 86%, and a negative predictive value of 87%. Increased FeNO was positively correlated with the presence of respiratory symptoms (p < 0.01), airflow reversibility (p < 0.001), total IgE (p < 0.001), and negatively correlated with PC(20) histamine (p = 0.019). Multivariate analysis revealed that atopy was not a significant predictor of FeNO in asthmatic patients. Measuring FeNO is a simple and useful test to differentiate new asthma patients from those with other atopic conditions in a general allergy clinic.

After 6 years with Xolair; a 3-year withdrawal follow-up.

BACKGROUND: This study reports the clinical and immunological state of patients 3 years after a 6-year period of Xolair treatment for severe allergic asthma. METHODS: The patient's cat allergen sensitivity, measured as CD-sens, IgE and IgE- and IgG4 antibodies, was analysed and compared with asthma severity evaluated from FEV(1) and a questionnaire. RESULTS: Three years after treatment with Xolair was stopped, 12/18 patients reported improved or unchanged asthma compared with ongoing Xolair treatment. Most of the patients were in a stable clinical condition, 16/18 had not increased nightly asthma attacks and 14/18 little or no increase in medication. The CD-sens to cat was still significantly lower (P < 0.02) than untreated patients with allergic asthma and lower than expected from their serum IgE antibody levels. CONCLUSION: Most of the patients in this study had, still 3 years after closing of 6 years Xolair treatment, a surprisingly mild and stable asthma. Interestingly, the observed, considerable, downregulation of basophil allergen sensitivity, CD-sens, most likely representing mast cell allergen sensitivity, contributed to the clinical results.

Effect of natural seasonal pollen exposure and repeated nasal allergen provocations on elevation of exhaled nitric oxide.

BACKGROUND: Exhaled nitric oxide (FENO) is a marker for allergic airway inflammation. We wondered whether in patients with intermittent allergic rhinitis only (i) natural pollen exposure and (ii) artificial pollen exposure by repeated nasal allergen provocations may lead to an elevation of FENO. METHODS: In two prospective studies, we compared the FENO of nonatopic controls with the FENO of nonasthmatic individuals with mild intermittent rhinitis to tree and/or grass pollen. Study I: 13 atopic individuals and seven controls had measurements of FENO, blood eosinophils and eosinophilic cationic protein (ECP) before, during and after pollen season. Study II: 16 atopic individuals and 12 controls had nasal allergen provocations on four following days out of pollen season, with daily measurements of FENO before, 2 and 6 h after provocation, and determination of blood eosinophils, ECP and FEV1 at baseline, on days 5 and 10-12. RESULTS: Natural pollen exposure (study I) caused a significant elevation of FENO in allergic individuals. Nasal allergen provocations (study II) did not elicit a statistically significant rise neither of FENO nor of blood eosinophils between baseline and day 5. However, a subgroup of four individuals with a rise of blood eosinophils during nasal allergen provocations showed also a rise of FENO. CONCLUSIONS: We suppose that in allergic rhinitis a concomitant reaction of the bronchial system is dependent on a strong local inflammation leading to a generalized immune stimulation.

A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications.

BACKGROUND: The specific genetic contributions to childhood asthma have been difficult to elucidate. A recent whole-genome association study suggested that single nucleotide polymorphisms at loci controlling the expression of the ORMDL3 gene and others in the neighborhood of the NRG1 and ERO1LB genes might be important. OBJECTIVE: We sought to replicate the associations of these genetic markers with asthma in a large population of asthmatic patients from Scotland and to assess the effect of these variants on asthma outcomes. METHODS: Using mouthwash-derived DNA and clinical interviews and measurements, we investigated the association of 3 single nucleotide polymorphisms in the candidate genes with susceptibility to asthma in a case-control study and also exacerbations in a group of 1054 patients aged 3 to 22 years. RESULTS: A common C/T polymorphism at a locus controlling ORMDL3 gene expression (rs7216389) was significantly associated with the risk of childhood asthma (P = 1.73 x 10(-12)), with a single copy of the T allele conferring an odds ratio of 1.50 (95% CI, 1.24-1.81) and 2 copies of the T allele conferring an odds ratio of 2.11 (95% CI, 1.71-2.61), respectively. In asthmatic patients the T allele was associated with exacerbations of the condition (P = .008). Polymorphisms at the loci of nearby genes for NRG1 (rs4512342) and ERO1LB (rs10924993) were associated with neither the occurrence of nor exacerbations of asthma. CONCLUSION: A common genetic variation at a locus controlling the expression of the ORMDL3 locus increases the susceptibility to asthma and is associated with poor control of the condition in children and young adults.

Clinical and microbiological characteristics of cystic fibrosis adults never colonized by Pseudomonas aeruginosa: Analysis of the French CF registry.

Pseudomonas aeruginosa is the main cause of chronic airway infection in cystic fibrosis (CF). However, for unclear reasons some patients are never colonized by P. aeruginosa. The objectives of this study were to better define the clinical, genetic, and microbiological characteristics of such a subpopulation and to identify predictive factors of non-colonization with P. aeruginosa. The French CF patient registry 2013-2014 was used to identify CF patients aged ≥ 20 years. The clinical outcomes, CF Transmembrane conductance Regulator (CFTR) genotypes, and microbiological data of patients reported positive at least once for P. aeruginosa ("Pyo" group, n = 1,827) were compared to those of patients with no history of P. aeruginosa isolation ("Never" group, n = 303). Predictive factors of non-colonization by P. aeruginosa were identified by multivariate logistic regression model with backward selection. Absence of aspergillosis (odds ratio (OR) [95% CI] = 1.64 [1.01-2.66]), absence of diabetes (2.25 [1.21-4.18]), pancreatic sufficiency (1.81 [1.30-2.52]), forced expiratory volume 1 (FEV1) ≥ 80% (3.03 [2.28-4.03]), older age at CF diagnosis (1.03 [1.02-1.04]), and absence of F508del/F508del genotype (2.17 [1.48-3.19]) were predictive clinical factors associated with absence of infection ("Never" group). Microbiologically, this same group was associated with more frequent detection of Haemophilus influenzae and lower rates of Stenotrophomonas maltophilia, Achromobacter xylosoxidans and Aspergillus spp. (all p<0.01) in sputum. This study strongly suggests that the absence of pulmonary colonization by P. aeruginosa in a minority of CF adults (14.2%) is associated with a milder form of the disease. Recent progress in the development of drugs to correct CFTR deficiency thus may be decisive in the control of P. aeruginosa lung infection.

Eosinophils in COPD: just another biomarker?

Eosinophils are innate immune cells that, under certain conditions, can be recruited to the lungs, where they have an incompletely understood role in health and disease. Eosinophils have been found in the airways, tissues, and circulation of patients with COPD, during both stable disease and exacerbations. Epidemiological studies and post-hoc analyses of clinical trials of corticosteroid treatment for COPD have shown that the blood eosinophil count is associated with the risk of COPD exacerbations, mortality, decline in FEV1, and response to both inhaled and systemic corticosteroids. Further studies are urgently needed to explore the contribution of eosinophils to the mechanism of disease in COPD and to identify their association with levels of clinical risk. In this review, we explore the role of the eosinophil as a biomarker and mediator of disease in COPD.

Association of interleukin-25 levels with development of aspirin induced respiratory diseases.

BACKGROUND: Aspirin-exacerbated respiratory diseases (AERD) are caused by ingestion of non-steroidal anti-inflammatory drugs and are characterized by acute bronchospasms and marked infiltration of eosinophils, the latter being attributable to altered synthesis of cysteinyl leukotrienes (LT) and prostaglandins (PG). Recently, the innate Th2 response is revealed to induce eosinophil infiltration in allergic inflammation, however the role of the innate Th2 response has not been studies in AERD. Thus, we evaluated the relationship between the innate Th2 cytokines including IL-25, thymic stromal lymphopoietin (TSLP) and IL-33 and the development of AERD. METHODS AND MATERIALS: Plasma IL-25, IL-33, and TSLP levels were measured before and after aspirin challenge in subjects with AERD (n = 25) and aspirin-tolerant asthma (ATA, n = 25) by enzyme-linked immunosorbent assay (ELISA). Pre and post-aspirin challenge levels of LTC4 and PGD2 were measured using ELISA. RESULTS: Basal plasma IL-25 levels were significantly higher in AERD group than in normal controls and in ATA group (p = 0.025 and 0.031, respectively). IL-33 and TSLP levels were comparable in the AERD and ATA groups. After the aspirin challenge, the IL-25 levels were markedly decreased in the ATA group (p = 0.024), while not changed in the AERD group. The post-challenge IL-25 levels of all asthmatic subjects were significantly correlated with aspirin challenge - induced declines in FEV1 (r = 0.357, p = 0.011), but not with basal and post challenge LTC4 and PGD2 levels. CONCLUSIONS: IL-25 is associated with bronchospasm after aspirin challenge, possibly via mechanisms other than altered LTC4 and PGD2 production.