Sputum proteomic signature of gastro-oesophageal reflux in patients with severe asthma.

Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship. 610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MSE. Univariate and multiple logistic regression analyses (MLR) were conducted to identify proteins associated with GORD in this cohort. When compared to mild/moderate asthmatics and healthy individuals, respectively, GORD was three- and ten-fold more prevalent in severe asthmatics and was associated with increased asthma symptoms and oral corticosteroid use, poorer quality of life, depression/anxiety, obesity and symptoms of sino-nasal disease. Comparison of sputum proteomes in severe asthmatics with and without active GORD showed five differentially abundant proteins with described roles in anti-microbial defences, systemic inflammation and epithelial integrity. Three of these were associated with active GORD by multiple linear regression analysis: Ig lambda variable 1-47 (p = 0·017) and plasma protease C1 inhibitor (p = 0·043), both in lower concentrations, and lipocalin-1 (p = 0·034) in higher concentrations in active GORD. This study provides evidence which suggests that reflux can cause subtle perturbation of proteins detectable in the airways lining fluid and that severe asthmatics with GORD may represent a distinct phenotype of asthma.

Serum periostin relates to type-2 inflammation and lung function in asthma: Data from the large population-based cohort Swedish GA(2)LEN.

BACKGROUND: Periostin has been suggested as a novel, phenotype-specific biomarker for asthma driven by type 2 inflammation. However, large studies examining relationships between circulating periostin and patient characteristics are lacking and the suitability of periostin as a biomarker in asthma remains unclear. AIM: To examine circulating periostin in healthy controls and subjects with asthma from the general population with different severity and treatment profiles, both with and without chronic rhinosinusitis (CRS), in relation to other biomarkers and clinical characteristics. METHODS: Serum periostin was examined by ELISA in 1100 subjects aged 17-76 from the Swedish Global Allergy and Asthma European Network (GA(2)LEN) study, which included 463 asthmatics with/without chronic rhinosinusitis (CRS), 98 individuals with CRS only, and 206 healthy controls. Clinical tests included measurement of lung function, Fraction of exhaled NO (FeNO), IgE, urinary eosinophil-derived neurotoxin (U-EDN), and serum eosinophil cationic protein (S-ECP), as well as completion of questionnaires regarding respiratory symptoms, medication, and quality of life. RESULTS: Although median periostin values showed no differences when comparing disease groups with healthy controls, multiple regression analyses revealed that periostin was positively associated with higher FeNO, U-EDN, and total IgE. In patients with asthma, an inverse relationship with lung function was also observed. Current smoking was associated with decreased periostin levels, whereas increased age and lower body mass index (BMI) related to higher periostin levels in subjects both with and without asthma. CONCLUSION: We confirm associations between periostin and markers of type 2 inflammation, as well as lung function, and identify novel constitutional factors of importance to the use of periostin as a phenotype-specific biomarker in asthma.

Assessment of in vivo mast cell reactivity in patients with systemic mastocytosis.

BACKGROUND: Patients with systemic mastocytosis (SM) have clinical signs of mast cell (MC) activation and increased levels of MC mediators. It is unclear whether the increased mediator levels are caused by increased numbers of tissue MCs, or whether these cells in affected individuals have a hyperactive phenotype. OBJECTIVE: To determine reactivity of the skin and the airways to directly acting mediators and indirectly acting mast cell secretagogues in subjects with SM. METHODS: Skin reactivity to morphine and histamine, and airway responsiveness to mannitol and methacholine, was assessed in 15 patients with SM, 11 patients with allergic asthma (A) and 13 healthy controls (HC). Serum tryptase and urinary metabolites of the MC mediators histamine and prostaglandin D2 were measured, as well as ex vivo basophil histamine release. RESULTS: Mast cell mediators in the blood and urine were significantly higher in patients with SM than in HC and A controls. Responsiveness to local activation of skin MCs (by morphine) and airway MCs (by mannitol) was similar in SM and HC groups. Likewise, end-organ responsiveness in the skin to histamine, and in the airways to methacholine, was similar in all three subject groups. There was no evidence of increased basophil reactivity in SM patients. CONCLUSIONS AND CLINICAL RELEVANCE: Mast cells in the skin and airways of subjects with SM do not exhibit hyper-reactivity towards the MC-activating stimuli morphine and mannitol, respectively. Therefore, the highly elevated baseline levels of MC mediators in SM are most likely due to increased MC numbers, rather than altered MC responsiveness. The underlying mechanisms could involve leakage of MC mediators, or dysfunctions in mediator synthesis, storage and release. One clinical implication of our study is that there is no contraindication to perform skin tests using morphine in subjects with mastocytosis.

Respiratory hypersensitivity reactions to NSAIDs in Europe: the global allergy and asthma network (GA2 LEN) survey.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prevalent drugs inducing hypersensitivity reactions. The aim of this analysis was to estimate the prevalence of NSAID-induced respiratory symptoms in population across Europe and to assess its association with upper and lower respiratory tract disorders. METHODS: The GA2 LEN survey was conducted in 22 centers in 15 European countries. Each of 19 centers selected random samples of 5000 adults aged 15-74 from their general population, and in three centers (Athens, Munich, Oslo), a younger population was sampled. Questionnaires including questions about age, gender, presence of symptoms of asthma, allergic rhinitis, chronic rhinosinusitis, smoking status, and history of NSAID-induced hypersensitivity reactions were sent to participants by mail. Totally, 62 737 participants completed the questionnaires. RESULTS: The mean prevalence of NSAID-induced dyspnea was 1.9% and was highest in the three Polish centers [Katowice (4.9%), Krakow (4.8%), and Lodz (4.4%)] and lowest in Skopje, (0.9%), Amsterdam (1.1%), and Umea (1.2%). In multivariate analysis, the prevalence of respiratory reactions to NSAIDs was higher in participants with chronic rhinosinusitis symptoms (Odds Ratio 2.12; 95%CI 1.78-2.74), asthma symptoms in last 12 months (2.7; 2.18-3.35), hospitalization due to asthma (1.53; 1.22-1.99), and adults vs children (1.53; 1.24-1.89), but was not associated with allergic rhinitis. CONCLUSION: Our study documented significant variation between European countries in the prevalence of NSAID-induced respiratory hypersensitivity reactions, and association with chronic airway diseases, but also with environmental factors.

A standard, single dose of inhaled terbutaline attenuates hyperpnea-induced bronchoconstriction and mast cell activation in athletes.

Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled ß2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11ß-prostaglandin F2α (11ß-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12-20)% (median and interquartile range) following placebo was attenuated to 7 (5-9)% with the administration of terbutaline (P < 0.001). EVH caused a significant increase in 11ß-PGF2α from 41 (27-57) ng/mmol creatinine at baseline to 58 (43-72) ng/mmol creatinine at its peak post-EVH following placebo (P = 0.002). The rise in 11ß-PGF2α was inhibited with administration of terbutaline: 39 (28-44) ng/mmol creatinine at baseline vs. 40 (33-58) ng/mmol creatinine at its peak post-EVH (P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB.

Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease.

Mastocytosis is a complex disorder characterized by the accumulation of abnormal mast cells (MC) in the skin, bone marrow and/or other visceral organs. The clinical manifestations result from MC-derived mediators and, less frequently, from destructive infiltration of MCs. Patients suffer from a variety of symptoms including pruritus, flushing and life-threatening anaphylaxis. Whilst mastocytosis is likely to be suspected in a patient with typical skin lesions [i.e. urticaria pigmentosa (UP)], the absence of cutaneous signs does not rule out the diagnosis of this disease. Mastocytosis should be suspected in cases of recurrent, unexplained or severe insect-induced anaphylaxis or symptoms of MC degranulation without true allergy. In rare cases, unexplained osteoporosis or unexplained haematological abnormalities can be underlying feature of mastocytosis, particularly when these conditions are associated with elevated baseline serum tryptase levels. The diagnosis is based on the World Health Organization criteria, in which the tryptase level, histopathological and immunophenotypic evaluation of MCs and molecular analysis are crucial. A somatic KIT mutation, the most common of which is D816V, is usually detectable in MCs and their progenitors. Once a diagnosis of systemic mastocytosis (SM) is made, it is mandatory to assess the burden of the disease, its activity, subtype and prognosis, and the appropriate therapy. Mastocytosis comprises seven different categories that range from indolent forms, such as cutaneous and indolent SM, to progressive forms, such as aggressive SM and MC leukaemia. Although prognosis is good in patients with indolent forms of the disease, patients with advanced categories have a poor prognosis.

Stability of phenotypes defined by physiological variables and biomarkers in adults with asthma.

BACKGROUND: Although asthma is characterized by variable airways obstruction, most studies of asthma phenotypes are cross-sectional. The stability of phenotypes defined either by biomarkers or by physiological variables was assessed by repeated measures over 1 year in the Pan-European BIOAIR cohort of adult asthmatics. METHODS: A total of 169 patients, 93 with severe asthma (SA) and 76 with mild-to-moderate asthma (MA), were examined at six or more visits during 1 year. Asthma phenotype clusters were defined by physiological variables (lung function, reversibility and age of onset of the disease) or by biomarkers (eosinophils and neutrophils in induced sputum). RESULTS: After 1 year of follow-up, the allocation to clusters was changed in 23.6% of all asthma patients when defined by physiological phenotypes and, remarkably, in 42.3% of the patients when stratified according to sputum cellularity (P = 0.034). In the SA cohort, 30% and 48.6% of the patients changed allocation according to physiological and biomarker clustering, respectively. Variability of phenotypes was not influenced by change in oral or inhaled corticosteroid dose, nor by the number of exacerbations. Lower stability of single and repeated measure was found for all evaluated biomarkers (eosinophils, neutrophils and FeNO) in contrast to good stability of physiological variables (FEV1 ), quality of life and asthma control. CONCLUSION: Phenotypes determined by biomarkers are less stable than those defined by physiological variables, especially in severe asthmatics. The data also imply that definition of asthma phenotypes is improved by repeated measures to account for fluctuations in lung function, biomarkers and asthma control.

The presence of mast cell clonality in patients with unexplained anaphylaxis.

BACKGROUND: The mechanisms by which mast cells in patients with unexplained anaphylaxis (UEA) are triggered remain elusive. Onset of episodes is unpredictable and often recurrent. The substantial overlap between the clinical manifestations of UEA and clonal mast cell disorders (CMD) suggests an association between these rare disorders. The two forms of CMD characterized to date are systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS). OBJECTIVE: To examine the hypothesis that the pathogenesis of UEA reflects the presence of aberrant subpopulations of mast cells. METHODS: Thirty (14 men, 16 women) patients (≥ 18 years) suffering from UEA and with no signs of cutaneous mastocytosis were recruited. Patients underwent an initial complete allergy work-up to confirm the diagnosis of UEA. Level of baseline serum tryptase (sBT) and total IgE were determined. In addition, a bone marrow examination was performed on all 30 patients to investigate possible underlying CMD. RESULTS: Fourteen (47%) of our cases (nine men, five women) were diagnosed with CMD: 10 with SM and four with MMAS. Four of the 10 patients with SM had mast cell aggregates in their bone marrow. All patients with SM exhibited a sBT level > 11.4 ng/mL, whereas this level was elevated in only two of those with MMAS and four with UAE but not diagnosed with CMD. Total IgE levels were lower in the group of patients with CMD (P < 0.03). CONCLUSION AND CLINICAL RELEVANCE: The pathogenic mechanism underlying UEA could be explained by the presence of immunophenotypically aberrant mast cells with clonal markers in 47% of our subjects, indicating that clonal mast cell disorders are present in a substantial subset of these patients. Thus, the presence of CMD should be considered in patients with UEA if they have an elevated level of sBT (≥ 11.4 ng/mL) and cardiovascular symptoms such as syncope.

Frequent exacerbators--a distinct phenotype of severe asthma.

BACKGROUND: Exacerbations represent a major source of morbidity and mortality in asthma and are a prominent feature of poorly controlled, difficult-to-treat disease. OBJECTIVE: The goal of our study was to provide a detailed characterization of the frequent exacerbator phenotype and to identify risk factors associated with frequent and seasonal exacerbations. METHODS: Ninety-three severe asthmatics (SA) and 76 mild-to-moderate patients (MA) were screened and prospectively followed up for 1 year (NCT00555607). Medical history, baseline clinical data and biomarkers were used to assess risk factors for frequent exacerbations. RESULTS: During the study, 104 exacerbations were recorded in the SA group and 18 in the MA. Frequent exacerbators were characterized by use of higher doses of inhaled (1700 vs. 800 µg) and oral (6.7 vs. 1.7 mg) glucocorticosteroids, worse asthma control (ACQ score 2.3 vs. 1.4), lower quality of life (SGRQ score 48.5 vs. 33.3), higher sputum eosinophils (25.7% vs. 8.2%) and a more rapid decline in FEV1 /FVC ratio (-0.07 vs. -0.01 ΔFEV1 /FVC, frequent vs. non-frequent, respectively, P < 0.05). Exhaled NO > 45 p.p.b. and a history of smoking were associated with an increased risk of frequent exacerbations (odds ratios: 4.32 and 2.90 respectively). CONCLUSION AND CLINICAL RELEVANCE: We were able to distinguish and characterize a subphenotype of asthma subjects--frequent exacerbators--who are significantly more prone to exacerbations. Patients with FeNO > 45 p.p.b. and a history of smoking are at increased risk of frequent exacerbations and require careful monitoring in clinical practice.

High prevalence of anaphylaxis in patients with systemic mastocytosis - a single-centre experience.

BACKGROUND: Systemic mastocytosis (SM) is a clonal mast cells disorder characterized by the proliferation, accumulation and activation of mast cells in extracutaneous tissues. The clinical picture is heterogeneous and may range from asymptomatic to potentially fatal anaphylactic reactions due to excessive mast cell mediator release. OBJECTIVE: The aim of this study was to investigate the prevalence and trigger factors of anaphylactic reactions among adult SM patients. We also explored the clinical spectrum of mast cell mediator-related symptoms in patients with SM. METHODS: This descriptive study was performed among 84 consecutive adult (≥ 18 years) patients those were diagnosed with SM according to WHO criteria. Sixty-six of the patients also underwent a comprehensive allergy work-up. RESULTS: Sixty of 84 patients with SM (71%) had bone marrow mast cell aggregates and fulfilled the major criteria for SM and 76 patients (91%) had indolent disease. Simultaneous occurrence of cutaneous mastocytosis was observed in 59 patients (70%). Thirty-six patients (43%) had had at least one episode of an anaphylactic reaction. The clinical courses of the reactions were usually severe and patients often presented with syncope attacks (72%). Most patients reacted after hymenoptera venom stings (19/36; 53%). In 39% (14/36), a clear aetiology could not be determined. While males and females were equally frequent among the patients with SM, anaphylaxis patients showed a male predominance (61%). Anaphylactic reactions occurred more frequently in patients without cutaneous engagement. The rate of allergy sensitization was significantly higher in SM patients with anaphylaxis as compared with non-anaphylaxis SM patients, 70% vs. 23%, respectively (P = 0.0002). CONCLUSIONS AND CLINICAL RELEVANCE: Anaphylaxis is more prevalent in patients with SM, predominantly in patients with atopic SM. Hymenoptera venom-induced and idiopathic anaphylaxis were the most frequent elicitors. Our findings implicate that all mastocytosis patients with anaphylaxis should undergo detailed allergological assessment before considering treatment and preventive measures.

The antimicrobial peptide LL-37 induces synthesis and release of cysteinyl leukotrienes from human eosinophils--implications for asthma.

BACKGROUND: Eosinophils and their products, including leukotrienes and eosinophil cationic protein (ECP), are well-known mediators of inflammation and tissue damage in asthma. The antimicrobial peptide LL-37 exhibits a variety of immunomodulatory activities. However, the role of LL-37 in asthma has not been fully addressed. Here, we aim to investigate the effect of LL-37 on inducing inflammatory mediators in human eosinophils, probe the underlying mechanisms, and search for a clinical correlate. METHODS: Primary eosinophils were isolated from peripheral blood. Leukotriene and ECP levels were measured using EIAs or ELISAs. Activation of leukotriene-synthesizing enzymes and signaling kinases was analyzed by Western blot or immunofluorescent imaging. LL-37/its proform hCAP18 expression was analyzed by Western blot. RESULTS: LL-37, via formyl peptide receptor-2 (FPR-2), triggered the release of cysteinyl leukotrienes (cys-LTs) from eosinophils. The release was more prominent in cells primed with the eosinophilopoietic cytokine GM-CSF or IL-5 or cells from asthmatic patients. LL-37 stimulates lipid body formation and activates cys-LT-synthesizing enzymes by multiple mechanisms: enhancing cPLA(2) activity by pERK1/2-mediated phosphorylation and inducing intracellular translocation and assembly of 5-LO and LTC(4) S at perinuclear locations and lipid bodies. In addition to cys-LTs, LL-37 enhances ECP release from eosinophils via pERK1/2. The expression of hCAP18 and its release following leukotriene stimulation are significantly higher in eosinophils from asthmatics. CONCLUSIONS: This study identifies LL-37 as an eosinophil-activating peptide that triggers release of inflammatory mediators. The clinical correlation suggests that LL-37/hCAP18 and its signaling pathway represent potential therapeutic targets for this disease.

Corticosteroid treatment selectively decreases mast cells in the smooth muscle and epithelium of asthmatic bronchi.

BACKGROUND: Mast cells are important in the pathophysiology of airway inflammation and evidence suggests their sub-localisation within the airway is altered in asthma. Little is known about the effect of corticosteroids on mast cell localisation within the bronchi. METHODS: We therefore performed an immunohistochemical analysis of mast cell numbers within the smooth muscle, epithelium and submucosa of healthy subjects (n = 10) and well-characterised asthmatic patients, using either ß(2)-agonists alone (n = 10) or ß(2)-agonists and inhaled corticosteroids (n = 10). RESULTS: Patients using inhaled corticosteroids displayed significantly lower numbers of mast cells within their epithelium and smooth muscle compared to those not treated with inhaled corticosteroids. Submucosal mast cells were not affected by corticosteroid treatment. Numbers of smooth muscle mast cells correlated with bronchial responsiveness and epithelial mast cells with exhaled NO. CONCLUSION: We demonstrate that glucocorticosteroids differentially affect mast cell numbers within specific airway sub-locations highlighting the importance of mast cell and smooth muscle/epithelial interactions in asthma pathogenesis.

Basophil allergen threshold sensitivity, CD-sens, is a measure of allergen sensitivity in asthma.

BACKGROUND: Allergic asthma is IgE-mediated and the IgE-sensitisation is usually demonstrated by skin prick tests (SPT) and IgE antibody determinations in serum. The SPT and IgE-antibody values do not directly predict if the allergy clinically contributes to the asthma. There is therefore a need for new objective tests that may indicate the clinical importance of an IgE-sensitisation. OBJECTIVE: To evaluate basophil allergen threshold sensitivity (CD-sens) as a measure of allergen sensitivity in allergic asthma. METHODS: Twenty-six subjects with stable, intermittent allergic asthma were tested with SPT and spirometry, and methacholine and allergen inhalation challenges to determine methacholine PD(20) (provocative dose causing a 20% drop in forced expiratory volume in 1 s) and allergen PD(20) . The results were compared with CD-sens and serological parameters, i.e. IgE- and IgG4 antibodies to the relevant allergens. RESULTS: A significant correlation was found between CD-sens and allergen PD(20) (P = 0.01; r = 0.49; n = 26) as well as between CD-sens and the ratio of allergen PD(20) to methacholine PD(20) (P = 0.007; r = 0.52; n = 26). In patients with a moderate to low degree of bronchial hyperresponsiveness there was an excellent correlation (P = 0.0001; r = 0.88, n = 13) between CD-sens and allergen sensitivity. No relation to either allergen PD(20) or the ratio was found for basophil allergen reactivity measured as CD63 up-regulation at high concentrations of the respective allergen. CONCLUSIONS AND CLINICAL RELEVANCE: CD-sens was found to be an objective marker of airway allergen sensitivity in stable allergic asthmatics, that may be used to predict airway responsiveness when bronchial challenge tests cannot be performed.

Effects of celecoxib on major prostaglandins in asthma.

BACKGROUND: Prostaglandin (PG) D(2) is a pro-inflammatory and bronchoconstrictive mediator released from mast cells, and is currently evaluated as a new target for treatment of asthma and rhinitis. It is not known which cyclooxygenase (COX) isoenzyme catalyses its biosynthesis in subjects with asthma. OBJECTIVES: Primarily, to assess whether treatment with the COX-2 selective inhibitor celecoxib inhibited biosynthesis of PGD(2) , monitored as urinary excretion of its major tetranor metabolite (PGDM). Secondarily, to determine the effects of the treatment on biosynthesis of PGE(2) , thromboxane A(2) and PGI(2) , also measured as major urinary metabolites. METHODS: Eighteen subjects with asthma participated in a cross-over study where celecoxib 200mg or placebo were given b.i.d. on 3 consecutive days following 2 untreated baseline days. Six healthy controls received active treatment with the same protocol. Urinary excretion of the eicosanoid metabolites was determined by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Lung function was followed as FEV(1) and airway inflammation as fraction of exhaled nitric oxide (F(E) NO). RESULTS: Celecoxib treatment inhibited urinary excretion of PGEM by 50% or more in subjects with asthma and healthy controls, whereas there was no significant change in the excretion of PGDM. In comparison with the healthy controls, the subjects with asthma had higher baseline levels of urinary PGDM but not of PGEM. The 3-day treatment did not cause significant changes in FEV(1) or F(E) NO. CONCLUSION AND CLINICAL RELEVANCE: Biosynthesis of PGD(2) was increased in subjects with asthma and its formation is catalysed predominantly by COX-1. By contrast, COX-2 contributes substantially to the biosynthesis of PGE(2) . The asymmetric impact of celecoxib on prostanoid formation raises the possibility of long-term adverse consequences of COX-2 inhibition on airway homeostasis by the decreased formation of bronchodilator PGs and maintained production of increased levels of bronchoconstrictor PGs in asthmatics.

Evaluation of nasal mucosal swelling and microcirculation throughout nasal and bronchial provocation tests with lysine-aspirin in asthmatics with nasal polyposis.

According to the GA2LEN recommendations, nasal challenge test with lysine-aspirin should be performed only in patients with severe asthma, because the sensitivity of this test has been lower than in bronchial and oral challenge tests. The AIA patient group often have severe asthma with impaired lung function, and therefore improvement of the nasal challenge is warranted. The outcomes of this study clearly indicate that a prolonged detection time from two to three hours might improve the sensitivity of the nasal challenge as a method for diagnosing aspirin intolerance. Moreover, we found a different vascular response in the nasal mucosa in the subjects with AIA after local challenge with lysine-aspirin as compared to an ATA patient group. This puts RSM-LDF as a possible new method in addition to those previously recommended for this particular test.

Clinical effects of purified air administered to the breathing zone in allergic asthma: A double-blind randomized cross-over trial.

BACKGROUND: Exposure to inhaled allergens is a pathogenetic factor in allergic asthma. However, most studies that previously looked at air cleaning devices have shown little or no effect on patients with perennial allergic asthma. AIMS AND OBJECTIVES: We examined a novel treatment using temperature regulated laminar airflow with a very low particle concentration directed to the breathing zone of teenagers and young adults with mild to moderate allergic asthma during night sleep. We hypothesised that the decreased allergen exposure during the night would have an effect on bronchial inflammation and quality of life. METHOD: Twenty-two patients (mean 18.8 years) were randomized to start with active or placebo treatment for 10 weeks. All patients received both active and placebo treatment with unfiltered air, with a 2-week wash-out period in between treatments. Maintenance treatment with inhaled corticosteroids was unaltered during the trial period. Health related quality of life (miniAQLQ) was the primary effectiveness measure. Exhaled nitric oxide (FeNO) and spirometry were also investigated. RESULTS: Active treatment resulted in an improved miniAQLQ compared to placebo (mean score 0.54, p<0.05, n=20). An effect on bronchial inflammation was also detected with significantly lower FeNO values during the active treatment period (mean -6.95 ppb, p<0.05, n=22). Both effects were evident after 5 weeks. The change in lung function was not statistically significant. CONCLUSION: Clean air, administered directly to the breathing zone during sleep, can have a positive effect on bronchial inflammation and quality of life in patients with perennial allergic asthma.

Functional endoscopic sinus surgery improved asthma symptoms as well as PEFR and olfaction in patients with nasal polyposis.

BACKGROUND: Nasal polyposis is a disease known to be associated with asthma. The management is anti-inflammatory, with topical and oral corticosteroids as the first-line treatment. The effect of surgical treatment on lower airway inflammation has not been sufficiently studied. AIM: The aim of this study is to investigate the effects of functional endoscopic sinus surgery (FESS) as well as fluticasone proprionate nasal drops (FPND) 400 microg b.i.d. on nasal and lower airway parameters in asthmatics with nasal polyposis. METHODS: This was a prospective 21-week study of 68 patients with asthma and nasal polyposis, on the benefits of FESS on nasal '(butanol test, subjective olfaction, peak nasal inspiratory flow, congestion, rhinorrhoea, and polyp score)', and on the lower airway parameters (dyspnea, cough, mean daily peak expiratory flow rate (PEFR), and lung function tests). It also included a randomized, double-blind, placebo-controlled 14 weeks phase on FPND. RESULTS: Functional endoscopic sinus surgery significantly improved mean asthma symptom scores and daily PEFR and all nasal parameters including subjective and objective olfaction tests. This is the first study that shows the benefits of FESS on butanol tests in patients with nasal polyposis. We found no significant difference between topical treatment with FPND or placebo in the nasal or lower airway variables. CONCLUSION: Functional endoscopic sinus surgery improved nasal and asthma symptoms in patients with nasal polyposis. Functional endoscopic sinus surgery could be considered early in the natural course of nasal polyposis with concomitant asthma, as well as a second-line treatment in nasal polyposis patients with a reduced sense of smell. The potential benefits of FPND 400 microg b.i.d. were probably overshadowed by FESS.

Effect of formoterol with or without budesonide in repeated low-dose allergen challenge.

The use of combination therapy in mild asthma is debated. The current authors evaluated the effects of formoterol alone and a formoterol/budesonide combination inhaler on asthma deterioration induced by repeated low-dose allergen exposure. In total, 15 subjects with intermittent allergic asthma inhaled low doses of allergen on seven consecutive weekdays in a three-period, crossover, double-blind, double-dummy comparison between formoterol 4.5 microg Turbuhaler, budesonide 160 microg/formoterol 4.5 microg Turbuhaler and placebo, each taken as two puffs 30 min after allergen dosing. The outcome variables were: provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD(20)), exhaled nitric oxide fraction (F(eNO)), sputum eosinophils and prostaglandin D(2), and diary card recordings of symptoms (on a scale of 0-10), short-acting beta(2)-agonist use and evening forced expiratory volume in one second (FEV(1)). With placebo treatment, allergen exposure caused significant increases in airway hyperresponsiveness (geometric mean (coefficient of variation) PD(20): 397 (98) microg before versus 168 (82) microg after), F(eNO) (mean+/-sd 46+/-31 ppb before versus 73+/-46 ppb after) and asthma symptom score (mean+/-sd 0.39+/-0.55 before versus 0.68+/-0.67 after). Budesonide/formoterol abolished these changes and significantly improved baseline FEV(1). Formoterol alone, while providing symptom relief, was no better than placebo in protecting against the allergen-induced increase in airway inflammation. Signs of deteriorating asthma, provoked by low-dose allergen, are prevented by short-term use of budesonide/formoterol but not by temporary use of formoterol alone.

Pharmacovigilance of drug allergy and hypersensitivity using the ENDA-DAHD database and the GALEN platform. The Galenda project.

Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA(2)LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD((R))) has been established under FileMaker((R)) Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA(2)LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA(2)LEN-ENDA-DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments.

The protective effect of farm animal exposure on childhood allergy is modified by NPSR1 polymorphisms.

BACKGROUND: Little is known about the asthma candidate gene neuropeptide S receptor 1 (NPSR1) in relation to environmental exposures, but recent evidences suggest its role as an effect modifier. OBJECTIVES: To explore the interaction between NPSR1 polymorphisms and environmental exposures related to farming lifestyle and to study the in vitro effects of lipopolysaccharide (LPS) stimulation on NPSR1 expression levels. METHODS: We studied 3113 children from PARSIFAL, a European cross-sectional study on environmental/lifestyle factors and childhood allergy, partly focused on children brought up on a farm. Information on exposures and outcomes was primarily obtained from parental questionnaires. Seven tagging polymorphisms were analysed in a conserved haplotype block of NPSR1. Multivariate logistic regression was used to evaluate a multiplicative model of interaction. NPSR1 protein and messenger RNA (mRNA) levels in monocytes were measured after LPS stimulation by fluorescence activated cell sorting (FACS) and quantitative real-time polymerase chain reaction (PCR). RESULTS: A strong interaction was seen between current regular contact to farm animals and several NPSR1 polymorphisms, particularly rs323922 and rs324377 (p<0.005), with respect to allergic symptoms. Considering the timing of initiation of such current regular farm animal contact, significant interactions with these and two additional polymorphisms (SNP546333, rs740347) were revealed. In response to LPS, NPSR1-A protein levels in monocytes were upregulated (p = 0.002), as were NPSR1-A mRNA levels (p = 0.02). CONCLUSIONS: The effect of farm animal contact on the development of allergic symptoms in children is modified by NPSR1 genetic background.