Predictors of excessive short-acting ß2-agonist use and asthma exacerbations: a retrospective analysis of a Polish prescription database.

Introduction: Despite being linked to unfavourable outcomes, short-acting ß2-agonists (SABAs) are still overused by a substantial proportion of patients with asthma. Aim: To analyse the prevalence and predictors of SABA overuse and exacerbations in patients with asthma in a nationwide database of prescription purchase records. Material and methods: The prevalence of excessive SABA use (≥ 12 canisters) and overuse (≥ 3 canisters) was analysed among patients aged 18-64 years who purchased asthma medications in 2018. Predictors of excessive SABA use and SABA overuse were examined by quasi-Poisson regression. Negative binomial regression was used to study the association of excessive SABA use or overuse to the risk of asthma exacerbation defined as a prescription for oral corticosteroids. Results: Of 91,763 patients with asthma, 42,189 (46%) were SABA users (mean age, 47 years; 58% female). Among them, 34% purchased ≥ 3 SABA canisters, and 6% purchased ≥ 12 canisters. The risk (risk ratio, 95% CI) of excessive SABA use was lower in patients with concomitant prescriptions for inhaled corticosteroids (0.41, 0.34-0.48) or inhaled corticosteroids and long-acting ß2-agonists (0.52, 0.47-0.56), women (0.63, 0.58-0.68), and those in secondary care (0.60, 0.44-0.66); older age was associated with a higher risk of excessive SABA use (1.06, 1.03-1.10). Excessive SABA use was the strongest predictor of asthma exacerbations among all patients (3.24, 2.84-3.70) and in those with ≥ 1 exacerbation (1.60, 1.50-1.71). Conclusions: Excessive SABA use is highly prevalent in asthma management, is associated with lack of prescriptions for inhaled corticosteroids, and substantially increases the exacerbation risk.

Results of a Phase 2b Trial With GB001, a Prostaglandin D2 Receptor 2 Antagonist, in Moderate to Severe Eosinophilic Asthma.

BACKGROUND: Prostaglandin D2 receptor 2 (DP2) antagonists inhibit prostaglandin D2-induced effects, including recruitment and activation of cells driving asthma pathogenesis. However, challenges identifying target population and end points persist. RESEARCH QUESTION: What is the effect of the DP2 antagonist GB001 on asthma worsening in patients with moderate to severe eosinophilic asthma? STUDY DESIGN AND METHODS: In this phase IIb, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multicenter study, GB001 or placebo was added to standard-of-care treatment in patients with moderate to severe asthma with a blood eosinophil count ≥ 250 cells/µL. Patients aged ≥ 18 years to < 75 years received one of four once-daily treatments (GB001 20 mg, 40 mg, or 60 mg or placebo). The primary end point was the proportion of patients who experienced asthma worsening by 24 weeks. Efficacy analyses were performed for the intention-to-treat population and safety analyses for patients who received at least one dose of study treatment. RESULTS: A total of 480 patients were treated. The ORs for asthma worsening for GB001 20 mg, 40 mg, and 60 mg vs placebo were 0.674 (95% CI, 0.398-1.142), 0.677 (95% CI, 0.399-1.149), and 0.651 (95% CI, 0.385-1.100), respectively. Analysis according to baseline blood eosinophil levels and/or fractional exhaled nitric oxide did not show greater treatment effects with higher values. Elevated liver aminotransferase levels and adverse events leading to discontinuation were more frequent for GB001 60 mg than with placebo, GB001 20 mg, and GB001 40 mg. INTERPRETATION: Although GB001 did not significantly reduce the odds of asthma worsening, reductions favoring GB001 were observed. Treatment effects were consistent regardless of high/low type 2 phenotype. The overall safety profile was acceptable, although GB001 60 mg was associated with risk of liver injury. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03683576; URL: www. CLINICALTRIALS: gov.

A new formulation of fluticasone propionate/salmeterol in a metered-dose inhaler (MDI HFA) allows for the reduction of a daily dose of corticosteroid and provides optimal asthma control - A randomized, multi-center, non-inferiority, phase IV clinical study.

BACKGROUND: Improvement of the delivery method of inhaled corticosteroids and subsequent dose reduction can minimize the risk of unfavorable outcomes while providing optimal asthma control. OBJECTIVE: This randomized, multi-center, non-inferiority, phase IV clinical study compared the efficacy and safety of a new formulation of fluticasone propionate/salmeterol (250 µg/50 µg, twice daily) administered in a metered-dose inhaler hydrofluoroalkane (MDI HFA) with a dry-powder inhaler (DPI) containing fluticasone propionate/salmeterol (500 µg/50 µg, twice daily). METHODS: Adults with asthma (n = 231) were randomly assigned to either the study group (treated for 12 weeks with fluticasone propionate/salmeterol MDI HFA) or a control group (treated for 12 weeks with fluticasone propionate/salmeterol DPI). Asthma symptoms, exacerbations, short-acting ß2-agonist (SABA) use, physical activity, lung function, and general health status were assessed during four study visits. RESULTS: Compared with the reference drug, the study drug decreased the incidence of daytime and night-time asthma symptoms, asthma exacerbations, self-administration of SABA, and the limitation of physical activity. Comparable improvement in peak expiratory flow ([MDI HFA] from 6.2 ± 0.2 to 6.6 ± 0.2 l/s vs. [DPI] from 6.0 ± 0.2 to 6.9 ± 0.2 l/s; p > 0.05), forced expiratory volume in one second, and forced vital capacity were obtained in both groups. Significantly lower incidence of hoarseness was observed in the study group ([MDI HFA] 0.0% vs. [DPI] 2.8%; p = 0.0267); no major differences were found for other adverse events. CONCLUSIONS: Fluticasone propionate/salmeterol (250 µg/50 µg, twice daily) MDI HFA provides optimal asthma control and is non-inferior to fluticasone propionate/salmeterol (500 µg/50 µg, twice daily) DPI.

Impact of Birth Weight and Smoking on Lung Function in Patients with Asthma, COPD, and Healthy Volunteers.

BACKGROUND: Birth weight (BW) is an important factor for determining the development of the respiratory system. The majority of research analyzed the impact of BW on lung function in youth. BW influence and smoking on lung function in adults with asthma and COPD is an interesting issue. OBJECTIVES: The aim of the study was to investigate relationships between BW, smoking, and lung function in adult healthy individuals and diagnosed with asthma or COPD. MATERIAL AND METHODS: Four hundred seventy-nine subjects were divided into 5 groups: 123 healthy non-smokers, 180 healthy smokers, 72 non-smoking asthmatics, 57 smoking asthmatics, and 47 COPD patients. Relationships between 4 BW quartiles and lung function was analyzed with respect to smoking. RESULTS: Impact analyzes of BW, smoking, and asthma on FVC% revealed that asthma is the only significant differentiating factor in this spirometric parameter (p < 0.01). FEV1% was significantly influenced by asthma and BW, and FEV1/ FVC% was exclusively influenced by asthma. Spirometric parameters increased proportionally to particular BW quartiles in healthy non-smokers group; however optimal BW quartile predicting increase of parameters was 2751-3250 g. In asthma, BW quartile predicting the increase of spirometric parameters was 3251-3750 g, but BW quartile predicting decrease of FEV1/FVC% was 2751-3250 g. The comparison of results between COPD group and results from other 4 groups showed that values of all parameters in patients with COPD did not change proportionally to all quartiles of BW. In terms of FEV1/FVC%, the proportional increase of parameter in BW quartile 2751-3250 g was observed. CONCLUSIONS: BW, as independent factor influences on spirometric parameters of healthy individuals, patients with asthma, COPD in a differentiated manner depending on quartile of BW rather than on simple linear increase of BW, regardless of smoking.

The Prevalence of Allergic Diseases in Poland - the Results of the PMSEAD Study in Relation to Gender Differences.

BACKGROUND: Males and females exhibit different susceptibility to allergic diseases. OBJECTIVES: The aim of the study was to evaluate gender-related differences in the prevalence of allergic diseases in Poland. MATERIAL AND METHODS: To evaluate this problem, data from the Polish Multicenter Study of the Epidemiology of Allergic Diseases (PMSEAD) was analyzed. There were assessed 16,238 individuals, aged 3 to 80 years, among them 12,970 adults and 3,268 children. RESULTS: In adults the prevalence of asthma was 5.4%, seasonal allergic rhinitis 8.5%, persistent allergic rhinitis 3.0%, atopic dermatitis 1.6%, contact dermatitis 2.0%, and drug allergy 8.6%. In children asthma was diagnosed in 8.6% of the individuals assessed, seasonal allergic rhinitis in 8.6%, persistent allergic rhinitis in 2.1%, atopic dermatitis in 4.7%, contact dermatitis in 1.1% and drug allergy in 8.9%. Among the children in the sample, significantly higher prevalence rates were found in boys than in girls for asthma (10.9% vs. 6.3%; OR = 1.81; p < 0.001), seasonal allergic rhinitis (9.8% vs 7.4%; OR = 1.37, p = 0.018) and persistent allergic rhinitis (2.6% vs. 1.5%; OR = 1.74, p = 0.029). When comparing the differences by gender among adults, there was a lower proportion of male than female subjects suffering from asthma (4.9% vs. 5.8%; OR = 0.83, p = 0.018), seasonal allergic rhinitis (7.6% vs. 9.3%; OR = 0.81, p = 0.001), atopic dermatitis (1.1% vs. 2.0%; OR = 0.53, p < 0.001), contact dermatitis (1.1% vs. 2.8%; OR = 0.39; p < 0.001) and drug allergy (5.1% vs. 11.6%; OR = 0.41, p < 0.001). CONCLUSIONS: The opposite susceptibility to allergic diseases among children and adults may indicate that sex hormones play an important role in this phenomenon.

The G/G genotype of transforming growth factor beta 1 (TGF-beta1) single nucleotide (+915G/C) polymorphism coincident with other host and environmental factors is associated with irreversible bronchoconstriction in asthmatics.

Irreversible airflow obstruction may develop in some cases of asthma even in absence of known risk factors such as smoking and environmental insults and despite implementing apparently appropriate therapy. This implies that genetic factors may significantly contribute to determining the severity in the course of the disease. The published reports on genetic predisposition to irreversible bronchoconstriction in asthma, however, are relatively scarce, and disregard its potential association with transforming growth factor (TGF)-beta1 gene polymorphism despite established role that TGF-beta1 plays in airway remodelling. We tested TGF-beta1 single-nucleotide polymorphisms (SNPs) at position +869 of codon 10 (leucine or proline) and position +915 of codon 25 (arginine or proline) for association with irreversible bronchoconstriction in a case-control study involving 110 patients with asthma and 109 controls. Multivariate logistic regression analysis revealed that genotype G/G at codon 25 was significantly associated with irreversible bronchoconstriction in asthmatics (odds ratio = 4.44; 95% confidence interval: 1.00-19.61; P = 0.05), but only after adjustment for gender, disease duration and smoking index. The influence of SNPs at codon 10 on irreversible airway obstruction was not significant. Our results suggest that presence of SNP (+915G/G) at codon 25 in TGF-beta1 gene may predispose to the development of irreversible bronchoconstriction in asthmatic patients, but only when coincident with the male gender, habitual smoking and relevant duration of the disease.

The overproduction of nitric oxide associated with neutrophilic predominance is relevant to airway mycotic infections in asthmatics undergoing prolonged glucocorticoid treatment.

The complex relationship between the local inflammatory response and the spread of airway mycosis during prolonged glucocorticoid therapy in bronchial asthma patients remains unclear. We assessed the ability of airway leukocytes to produce nitric oxide (NO) in relation to differential inflammatory cell counts, levels of asthma severity, and coexisting airway mycotic infections. The study was carried out on leukocytes from the induced sputa (IS) of 14 patients with asthma complicated by mycotic airway infections undergoing prolonged glucocorticoid therapy (group FcA). Three groups of subjects without airway fungal infections were also studied: 18 glucocorticoid-treated asthmatics (group cA), 11 steroid-free asthmatics (group A), and 13 healthy control subjects (group H). In group FcA, both the level of spontaneous production of NO and the percentages of neutrophils in the IS were significantly higher than in all the remaining groups. Additionally, a significant positive correlation was noticed between the NO levels and both the percentages of neutrophils in the IS and the symptom intensity scores. The results suggest a possible predominant role of neutrophils in the overproduction of NO related to asthma severity and coexisting fungal infections in glucocorticoid-treated patients.

[TGF-beta1 gene polymorphism in chronic obstructive pulmonary disease]. / Polimorfizm genu TGF-beta1 w przewleklej obturacyjnej chorobie pluc.

Gene polymorphism is often responsible for occurrence of some chronic diseases. It has not been clarified, why only 15-20% of smokers suffer from chronic obstructive pulmonary disease (COPD). TGF-beta1 gene polymorphism has been postulated as one of possible genetic risk factors. The aim of our study was to evaluate TGF-beta1 gene polymorphism in codons 10 and 25 in COPD patients in comparison to healthy controls. Thirty six COPD patients and 60 healthy persons entered the study. The distribution of TGF-beta1 genotypes in codon 10 was as follows in COPD group: T/C--50%, T/T--25% and C/C--25% in control group: 45%, 42% and 13% respectively. The distribution of genotypes in codon 25 in COPD patients was: G/G 86% and G/C 14%, in control group 83% and 17% respectively. There were not statistically significant differences between evaluated groups with regard to both polymorphisms. Moreover, in group of 27 smokers without COPD the distribution of the analysed TGF-beta1 gene polymorphism was similar to that in COPD group. After adjustment to sex, age and smoking index, in the logistic regression model, we can not confirm the hypothesis that TGF-beta1 gene polymorphisms in codons 10 and 25 might be significant risk factors of COPD.

Prevalence of Hymenoptera venom allergy and its immunological markers current in adults in Poland.

BACKGROUND: The prevalence of insect venom allergy is still being assessed. The aim of our study was to estimate, on the basis of an interviewer-administered questionnaire survey, the frequency of post-sting allergic reactions and venom sensitization. MATERIAL/METHODS: The study was performed within the framework of the ECRHS. A random sampling of 3000 persons was selected from among 68,000 persons living in the area of Wroclaw, Poland. Of the 2050 persons responding to a mailed screening questionnaire, 169 were randomly selected to complete a questionnaire designed only for insect allergy detection. Venom skin test and sIgE assessment were performed on 146 and 132 patients, respectively. RESULTS: Allergic post-sting symptoms were found in 20.7% of surveyed patients. Large local reactions (LLs) occurred in 11.8% and systemic reactions (SYSs) in 8.9% of the study population. SYS was most often manifested by urticaria (4.7%). The frequencies of SYS II, III and IV were 1.8%, 1.8%, and 0.6%, respectively. Only LLs were more frequent in subjects with other allergic diseases (p=0.03). The presence of positive skin tests and/or sIgE in serum were 42.8% of subjects with LL, 53.3% with SYS, and 17.1% of "asymptomatic" patients. No significant differences were found between these groups regarding venom skin test results and sIgE serum concentrations. Occurrence of sIgE to bee venom was frequently associated with the presence of sIgE to timothy grass. CONCLUSIONS: Insect venom allergy and asymptomatic venom sensitization in adults are common in Poland. Only some venom allergy cases are IgE dependent.

[Inhaled glucocorticosteroids in the treatment of asthma and chronic obstructive pulmonary disease]. / Glikokortykosteroidy wziewne w leczeniu astmy oskrzelowej i przewleklej obturacyjnej choroby pluc.

Molecular mechanisms of actions, pharmacokinetics and anti-inflammatory potency of inhaled glucocorticosteroids (ICS) are described. Differences in clinical effectiveness of ICS in asthma and chronic obstructive pulmonary disease (COPD) therapy and up-to-date recommendations for treatment with ICS in asthma and COPD patients are discussed. Finally there are presented data on safety of long-term treatment with ICS, specially in asthmatic children.

Comparison of leukocyte populations from bronchoalveolar lavage and induced sputum in the evaluation of cellular composition and nitric oxide production in patients with bronchial asthma.

Bronchoalveolar lavage (BAL) or induced sputum (IS) techniques may provide leukocytes for the evaluation of airway inflammatory response in bronchial asthma. The aim of the present study was to compare features of leukocyte populations obtained by the two different methods regarding the cell types and their activity in patients with bronchial asthma. The nitric oxide (NO) level released from the cells was measured as a marker of their activity. Pulmonary leukocytes were obtained from the BAL and IS of 11 asthmatic patients in stable condition at the time of the study. The BAL and IS leukocyte populations varied in cell count and NO production. Macrophages were the predominant leukocyte population in BAL (median (Me) = 83.0%, range 67.9-88.4%), whereas sputum sediments were found to consist mainly of neutrophils (Me = 55.7%, range 29.0-64.9%). The IS leukocytes released much more NO (p = 0.0022) than the BAL leukocytes. In spite of these quantitative differences, a similar pattern of NO production was observed in BAL and in IS cells. Both BAL and IS leukocyte populations produced almost the same amounts of NO before and after lipopolysaccharide stimulation (p = 0.9063, p = 0.4801, respectively). Furthermore, a slight positive correlation Spearman's rank (RS) = 0.5578, p = 0.0594) was noticed between the neutrophil percentages and NO levels produced by BAL cells, whereas in IS a statistically significant correlation between the percentage of neutrophils and the levels of NO (RS = 0.6643, p = 0.0184) was observed. In conclusion, the BAL and IS leukocyte populations are different in cell type, their size and activity. Depending on the asthma severity and the type of cells needed in a study, either BAL or IS specimens may be chosen as a source of pulmonary leukocytes. The use of IS as a noninvasive technique is supposed to be potential value particularly in the study of the airway inflammatory response mediated mainly by neutrophils, i.e. during and/or after exacerbation of the disease. Based on our results, a possible contribution of neutrophils in the production of NO in the airways of asthmatic patients can be proposed apart from other cells such as macrophages.