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Background Respiratory infections with rhinoviruses (RV) are strongly associated with development and exacerbations of asthma, and they pose an additional health risk for subjects with allergy. Objective How RV infections and chronic allergic diseases are linked and what role RV plays in the breaking of tolerance in regulatory T (Treg) cells is unknown. Therefore, this study aims to investigate the effects of RV on Treg cells. Methods Treg cells were isolated from subjects with asthma and controls after experimental infection with the RV-A16 (RV16) and analyzed with next-generation sequencing. Additionally, suppression assays, quantitative PCR assays, and protein quantifications were performed with Treg cells after in vitro RV16 infection. Results RV16 induced a strong antiviral response in Treg cells from subjects with asthma and controls, including the upregulation of IFI44L, MX1, ISG15, IRF7, and STAT1. In subjects with asthma, the inflammatory response was exaggerated and showed a dysregulated immune response compared with that in the controls. Furthermore, subjects with asthma failed to upregulate several immunosuppressive molecules such as CTLA4 and CD69, and they upregulated the inflammasome-related genes PYCARD and AIM2. Additionally, RV16 reduced the suppressive capacity of Treg cells from healthy subjects and subjects with asthma in vitro and increased TH2 cell–type cytokine production. Conclusions Treg cells from healthy subjects and subjects with asthma displayed an antiviral response after RV infection and showed reduced suppressive capacity. These data suggest that Treg cell function might be altered or impaired during RV infections, which might play an important role in the association between RV and the development of asthma and asthma exacerbations.

Introduction: Omalizumab is a monoclonal anti-immunoglobulin E antibody developed for the treatment of severe allergic asthma. The number of exacerbations used as a parameter of omalizumab therapy efficacy may be insuf- ficient in many cases due to a relatively short time to first evaluation (16 weeks). Therefore, it is advisable to look for parameters of more prognostic value while continuing omalizumab therapy. Aim: To evaluate usefulness of analysis of changes of blood eosinophilia after 16 weeks of omalizumab therapy as a predictor of asthma exacerbations. Material and methods: The study was conducted on a group of 13 patients with severe persistent allergic asthma treated with omalizumab. Blood eosinophil counts were measured before and after 16 weeks of anti-IgE therapy. On the basis of percentage of eosinophilia decrease (> 50% or < 50% of the initial value), patients were divided into two groups. Analysis of the asthma exacerbation rate during 12 months and time to first exacerbation was performed. Results: In the group with a high decrease in blood eosinophil counts (group 1) we showed a statistically significantly lower asthma exacerbation rate in 12 months compared with the group with a low decrease in blood eosinophil counts (group 2) (p = 0.02). We also observed the tendency to longer time to first asthma exacerbation in group 1 compared to group 2 (p = 0.06). Conclusions: Our results showed that a decrease in blood eosinophilia during omalizumab therapy can be a predic- tor of asthma exacerbation. Evaluation of changes in blood eosinophil count should be taken into the consideration while estimating response to anti-IgE therapy in patients with severe allergic asthma.

Asthma is a heterogeneous disease with variable characteristics such as lung function, symptoms and control, body weight, pattern of inflammation, and response to treatment. Brittle asthma is one of clinical phenotypes of asthma with unclear pathogenic mechanisms and appropriate treatment. Analysis of 2 described cases suggests that omalizumab could be useful in the treatment of brittle allergic asthma.

Background: Omalizumab is a humanized monoclonal anti-IgE antibody developed for the treatment of IgE-mediated diseases, including asthma. The aim of the study was to determine the effect of omalizumab treatment on changes in RANTES in exhaled breath condensate and other inflammatory markers in patients with persistent severe asthma. Methods: The study was conducted on a group of 19 patients with severe persistent allergic asthma treated with conventional therapy (according to GINA 2006) and with or without omalizumab (9 vs. 10 patients). Changes in inflammatory parameters [RANTES in exhaled breath condensate, exhaled nitric oxide, blood eosinophil count and serum eosinophil cationic protein (ECP)] were measured before and after 16 weeks of therapy. Results: Omalizumab-treated patients showed a statistically significant decrease in the concentrations of RANTES in exhaled breath condensate, exhaled nitric oxide (FENO), serum ECP, and blood eosinophil count compared with patients with conventional therapy after 16 weeks of treatment. In this group of patients, statistically significant correlations were revealed between the decrease in RANTES and a decrease in FENO and between the decrease in FENO and a decrease in ECP or blood eosinophil count after omalizumab therapy. Conclusions: Our results confirmed that during anti-immunoglobulin E therapy with omalizumab in patients with severe persistent allergic asthma, RANTES expression is decreased. This process in turn could lead to a limitation of airway inflammation and could be essential for the beneficial effect of anti-IgE therapy with omalizumab.

Background: Exercise-induced bronchoconstriction (EIB) is a highly prevalent condition, whose pathophysiology is not well understood. Endothelins are proinflammatory, profibrotic, bronchoand vasoconstrictive peptides which play an important role in the development of airway inflammation and remodeling in asthma. The aim of the study was to evaluate the changes in endothelin-1 levels in exhaled breath condensate following intensive exercise in asthmatic patients. Methods: The study was conducted in a group of 19 asthmatic patients (11 with EIB, 8 without EIB) and 7 healthy volunteers. Changes induced by intensive exercise in the concentrations of endothelin-1 (ET-1) in exhaled breath condensate (EBC) during 24 hours after an exercise challenge test were determined. Moreover, the possible correlations of these measurements with the results of other tests commonly associated with asthma and with the changes of airway inflammation after exercise were observed. Results: In asthmatic patients with EIB a statistically significant increase in the concentration of ET1 in EBC collected between 10 minutes and 6 hours after an exercise test was observed. The concentration of ET-1 had returned to its initial level 24 hours after exercise. No effects of the exercise test on changes in the concentrations of ET-1 in EBC in either asthmatic patients without EIB or healthy volunteers were observed. A statistically significant correlation between the maximum increase in ET-1 concentrations in EBC after exercise and either baseline FENO and the increase in FENO or BHR to histamine 24 hours after exercise in the groups of asthmatics with EIB was revealed. Conclusion: The release of ET-1 from bronchial epithelium through the influence of many inflammatory cells essential in asthma and interactions with other cytokines, may play an important role in increase of airway inflammation which was observed after postexercise bronchoconstriction in asthmatic patients.

Summary Background Asthma is a chronic airway inflammatory disease. Measurement of serum high- sensitivity C-reactive protein (hs-CRP) levels has suggested the involvement of low-grade systemic inflammation in several disorders, such as cardiovascular disease and diabetes mellitus. In recent years, there have been some reports concerning hs-CRP assessment as a useful tool for detecting systemic inflammation in asthma. The study was undertaken to evaluate hs-CRP levels in the exhaled breath condensate (EBC) of asthmatics with different degrees of asthma severity and their relationship to hs-CRP levels in serum, clinical characteristics, and the intensification of airway inflammation. Methods The study group was 62 patients with allergic asthma (20 with steroid-naive mild asthma, 19 with ICS-treated, stable mild-to-moderate asthma, 23 with ICS-treated unstable, severe asthma) and 15 healthy volunteers. Results In the three groups of asthmatics hs-CRP concentrations in EBC and serum were significantly higher than in healthy volunteers. hs-CRP levels both in EBC and serum were significantly higher in patients with unstable asthma than in the two groups with stable disease. hs-CRP concentrations in EBC strongly correlated with those measured in serum. There was a significant correlation between hs-CRP levels both in EBC and serum and exhaled nitric oxide (F ENO ) in the three groups of asthmatics or serum ECP in the group of patients with steroid-naive mild asthma and unstable, severe asthma. Conclusion The levels of hs-CRP in EBC are correlated with those measured in serum and may provide another useful diagnostic tool for detecting and monitoring low-grade inflammation in patients with asthma.

SummaryRANTES has been implicated in the allergic inflammation of asthma by promoting the migration and activation of the inflammatory cells, including eosinophils. The study was undertaken to evaluate RANTES levels in the exhaled breath condensate (EBC) of asthmatics with different degrees of asthma severity.EBC was collected from 33 patients with allergic asthma (11 with steroid-naïve mild asthma, 10 with ICS-treated, stable mild-to-moderate asthma, 12 with ICS-treated unstable, severe asthma) and seven healthy volunteers.In the three groups of asthmatics, RANTES concentrations in EBC were significantly higher compared with healthy volunteers. RANTES levels were significantly higher in patients with unstable asthma than in the two groups with stable disease. We observed statistically significant correlations between the concentrations of RANTES in EBC and FENO in the three studied groups of asthmatics; notably, the correlation between the parameters described above was strong positive in the group of unstable and steroid-naïve stable asthmatics. We also discovered a significantly positive correlation between RANTES in EBC and the serum ECP or blood eosinophil count in the groups of asthmatics with severe, unstable asthma and between RANTES and serum ECP in the group of steroid-naïve stable asthmatics.Measurements of RANTES in EBC may provide another useful diagnostic tool for detecting and monitoring inflammation in patients with asthma.

Background: Airway eosinophilia is considered a central event in the pathogenesis of asthma. Eotaxin plays a key role in selective eosinophil accumulation in the airways and, subsequently, their activation and degranulation. The study was undertaken to evaluate eotaxin-1 levels in the exhaled breath condensate (EBC) of asthmatics with different degrees of asthma severity and to establish the possible correlation of these measurements with other recognized parameters of airway inflammation. Methods: EBC was collected from 46 patients with allergic asthma (14 with steroid-naive asthma, 16 with ICStreated, stable asthma, 16 with ICS-treated unstable asthma) and 12 healthy volunteers. Concentrations of eotaxin-1 were measured by ELISA. Results: In the three groups of asthmatics, eotaxin-1 concentrations in EBC were significantly higher compared with healthy volunteers (steroid-naive asthma: 9.70 pg/ml ± 1.70, stable ICS-treated asthma: 10.45 ± 2.00, unstable ICS-treated asthma: 17.97 ± 3.60, healthy volunteers: 6.24 ± 0.70). Eotaxin-1 levels were significantly higher in patients with unstable asthma than in the two groups with stable disease. We observed statistically significant correlations between the concentrations of eotaxin-1 in EBC and exhaled nitric oxide (FENO) or serum eosinophil cationic protein (ECP) in the three studied groups of asthmatics. We also discovered a significantly positive correlation between eotaxin-1 in EBC and blood eosinophil count in the groups of patients with unstable asthma and steroid-naive asthma. Conclusions: Measurements of eotaxin-1 in the EBC of asthma patients may provide another useful diagnostic tool for detecting and monitoring airway inflammation and disease severity.

Background: N-acetyl-β-hexosaminidase (β-hex) is a lysosomal hydrolase, which is selectively secreted into the extracellular space by inflammatory cells. The aim of our study was to assess the activity of β-hex in the plasma of asthmatic patients, and to establish whether it correlates with asthma severity and airway inflammation. Methods: The study was conducted in a group of 46 asthmatic patients and 13 healthy volunteers. All study participants underwent analysis of exhaled nitric oxide and flow-volume spirometry. β-hex activity, peripheral blood eosinophils, total serum IgE and eosinophil cationic protein were analyzed in blood samples from all asthmatic patients and healthy volunteers. Results: β-hex activity was significantly higher in patients with severe or moderate asthma compared with healthy volunteers and was positively correlated with exhaled nitric oxide levels and serum eosinophil cationic protein in these groups of patients. There was no correlation between β-hex activity and forced expiratory volume in 1 s, blood eosinophil count or total serum IgE in these groups of asthmatics. Conclusions: Our results suggest that β-hex could take part in airway inflammation and remodeling in asthma. Our study is the first report in which the elevated activity of β-hex in subjects with asthma has been observed. However, more studies are needed to establish the precise role of this enzyme in asthma in humans.

Background: Exercise-induced bronchoconstriction (EIB) is a highly prevalent condition whose pathogenesis and effect on airways remain unclear. The aim of the study was to evaluate the changes in endothelial-derived mediators following intensive exercise in asthmatic patients. Methods: The study was conducted in a group of 25 asthmatic patients (15 with EIB, 10 without EIB) and 8 healthy volunteers. Changes induced by intensive exercise in the plasma concentrations of endothelin-1 (ET-1), thrombomodulin and soluble E-selectin were determined. Moreover, the possible correlations of these measurements with the results of baseline lung function, bronchial hyperreactivity (BHR), exhaled nitric oxide (FENO), baseline eosinophil cationic protein, peripheral blood eosinophilia and total IgE were investigated. Results: In the group of asthmatics with EIB, statistically significantly higher baseline concentrations of ET-1 and soluble E-selectin compared with asthmatics with negative exercise test results were revealed. In this group of patients, ET-1, thrombomodulin and soluble E-selectin concentrations significantly increased after exercise. Baseline concentrations of ET-1 as well as an increase in soluble E-selectin concentrations 60 min after exercise showed a statistically significant correlation with baseline eosinophil cationic protein, FENO and BHR. The increase in plasma concentrations of ET-1 15 min after exercise and soluble E-selectin 60 min after exercise showed a statistically significant correlation with the increase in FENO and BHR to histamine 24 h after exercise. Conclusions: We suggest that during EIB changes in the function of pulmonary endothelium occur and these changes may influence inflammation of the airway and remodeling in asthmatic patients.

Purpose The central role of IgE in allergic inflammation in asthma has provided a rationale for the development of omalizumab, the humanized monoclonal anti-IgE antibody. The aim of the study was to determine the effect of omalizumab treatment on changes in airway inflammatory process and eotaxin in exhaled breath condensate in patients with persistent severe allergic asthma. Material and Methods The study was performed on a group of 19 patients with severe persistent allergic asthma treated with conventional therapy (according to GINA 2006) and with or without omalizumab (9 vs 10 patients). Eotaxin in exhaled breath condensate, exhaled nitric oxide, blood eosinophil count and serum ECP were measured before and after 16 weeks of therapy. Results In the group treated with omalizumab, a statistically significant decrease in the concentrations of eotaxin in EBC, FENO, serum ECP, and blood eosinophil count after 16 weeks of treatment was observed. Statistically significant correlations were revealed between the decrease in eotaxin and the decrease in FENO, serum ECP and blood eosinophil count after omalizumab therapy. Conclusions Downregulation of eotaxin expression in the airways through limitation of eosinophilic inflammation could be essential in the beneficial effect of anti-IgE therapy with omalizumab in asthma patients.

Background: Omalizumab is a humanized monoclonal anti-IgE antibody, especially useful for the treatment of severe persistent allergic asthma, inadequately controlled despite regular therapy. Objectives: The aim of the study was to determine the effect of omalizumab treatment on changes in endothelin-1 (ET-1), which plays an important role in the development of airway inflammation and remodeling in exhaled breath condensate (EBC) in patients with severe asthma. Methods: The study was conducted in a group of 19 patients with severe persistent allergic asthma treated with conventional therapy (according to the Global Initiative for Asthma, 2006) and with or without omalizumab (9 vs. 10 patients). Changes in ET-1 in EBC compared with other inflammatory parameters [exhaled nitric oxide – (FENO), blood eosinophil count, and serum eosinophil cationic protein (ECP)] were measured after 16 and 52 weeks of therapy. Results: Omalizumab-treated patients demonstrated a statistically significant decrease in the concentrations of ET-1 in EBC, FENO, serum ECP, and blood eosinophil count and an increase in spirometry parameters compared to patients with conventional therapy. In the group of omalizumab-treated patients, statistically significant correlations between the decrease in ET-1 in EBC and a decrease in FENO, ECP, and blood eosinophil count as well as the increase in forced expiratory volume in 1 s after omalizumab therapy were revealed. Conclusions: Our results confirmed that anti-IgE therapy with omalizumab in patients with severe persistent allergic asthma results in decreased expression of ET-1 in the airways. This could be very important in limiting airway inflammation and bronchial structural changes caused by such treatment in asthmatic patients.

Background: Exercise-induced bronchoconstriction (EIB) in asthmatics depends on the presence of allergic inflammation. This study was performed to assess the possible association of EIB with low-grade systemic inflammation, whose presence was revealed in asthmatic patients. Methods: The study was conducted in a group of 24 asthmatics (14 with EIB, 10 without EIB) and 8 healthy volunteers. Changes in serum and exhaled breath condensate (EBC) high-sensitivity C-reactive protein (hs-CRP) levels induced by intensive exercise were determined. Moreover, the possible correlation of these measurements with the results of other tests used in the diagnosis of asthma as well as laboratory tests commonly associated with asthma were investigated. Results: In asthmatic patients with EIB, a statistically significant increase in hs-CRP levels both in serum and EBC after an exercise test was observed. Twenty-four hours after the exercise test in the group of asthmatics with EIB, a statistically significant increase in exhaled nitric oxide (FENO), serum eosinophil cationic protein (ECP) concentrations and bronchial hyperreactivity to histamine was revealed. A statistically significant correlation between the maximum increase in hs-CRP levels both in serum and EBC after exercise and either baseline FENO and an increase in serum ECP or FENO 24 h after exercise in the group of asthmatics with EIB was revealed. Conclusions: We show that, as a result of intensive exercise leading to bronchoconstriction, an increase in serum and EBC hs-CRP occurs. Our observations could suggest that in asthmatic patients, as a consequence of exercise-induced bronchoconstriction, an intensification of low-grade systemic inflammation can be observed.

Background: There is increasing evidence that exercise-induced bronchoconstriction (EIB) is associated with eosinophilic airway inflammation. In the pathogenesis of EIB the role of chemokines – responsible for promoting the migration and activation of inflammatory cells – as well as blood platelets, a potential source of those chemokines, remains unclear. Methods: The study was conducted in a group of 19 asthmatics (11 with EIB, 8 without EIB) and 8 healthy volunteers. Changes in the plasma concentrations of RANTES and β-thromboglobulin (β-TG) induced by intensive exercise were determined. Moreover, the possible correlation of these measurements with the results of other tests used in the diagnosis of asthma as well as laboratory tests commonly associated with asthma were investigated. Results: A comparison of the concentrations of β-TG in all groups studied at rest did not reveal any significant differences. In all groups studied, 30 min after exercise elevated β-TG concentrations were observed; the most significant increase was revealed in asthmatics with EIB. The baseline concentrations of RANTES before exercise in both groups of asthmatics were significantly higher in comparison to the group of healthy volunteers. After exercise, in the group of patients with EIB, a significant increase in RANTES concentrations was observed. These changes correlated with an increase in other markers of airway inflammation 24 h after exercise. Conclusions: We suggest that platelet activation, resulting in elevated RANTES release, could be one of the factors responsible for the increase of airway inflammation observed in consequence of EIB in asthmatics.

Background Exercise-induced bronchoconstriction (EIB) is a highly prevalent condition, whose pathophysiology is not well understood. Endothelins are proinflammatory, profibrotic, broncho- and vasoconstrictive peptides which play an important role in the development of airway inflammation and remodeling in asthma. The aim of the study was to evaluate the changes in endothelin-1 levels in exhaled breath condensate following intensive exercise in asthmatic patients. Methods The study was conducted in a group of 19 asthmatic patients (11 with EIB, 8 without EIB) and 7 healthy volunteers. Changes induced by intensive exercise in the concentrations of endothelin-1 (ET-1) in exhaled breath condensate (EBC) during 24 hours after an exercise challenge test were determined. Moreover, the possible correlations of these measurements with the results of other tests commonly associated with asthma and with the changes of airway inflammation after exercise were observed. Results In asthmatic patients with EIB a statistically significant increase in the concentration of ET-1 in EBC collected between 10 minutes and 6 hours after an exercise test was observed. The concentration of ET-1 had returned to its initial level 24 hours after exercise. No effects of the exercise test on changes in the concentrations of ET-1 in EBC in either asthmatic patients without EIB or healthy volunteers were observed. A statistically significant correlation between the maximum increase in ET-1 concentrations in EBC after exercise and either baseline FENO and the increase in FENO or BHR to histamine 24 hours after exercise in the groups of asthmatics with EIB was revealed. Conclusion The release of ET-1 from bronchial epithelium through the influence of many inflammatory cells essential in asthma and interactions with other cytokines, may play an important role in increase of airway inflammation which was observed after postexercise bronchoconstriction in asthmatic patients.

Summary Ciclesonide is a novel, lung-activated, inhaled corticosteroid with once-daily efficacy and potent anti-inflammatory activity. The aim of the study was to compare the effect of ciclesonide and fluticasone propionate on exhaled nitric oxide (F ENO ), pulmonary function, and other parameters used in clinical evaluation of patients with mild allergic asthma. The study indicates that ciclesonide (in a daily dose of either 80 or 160μg) induces both a faster and stronger decrease of F ENO in comparison with fluticasone (100μg twice daily). In both groups of patients treated with ciclesonide, the highest decrease in F ENO levels was observed after 2 weeks of treatment. In the group of patients treated with fluticasone, this maximum effect was not observed till 8 weeks. An improvement in spirometric indices was observed in all groups studied. Statistical differences between the groups were not found; however, there was a trend toward higher increase in the group receiving 160μg of ciclesonide. In all groups studied we observed clinical improvement (asthmatic symptoms and consumption of rescue medication were reduced), but there were no significant differences between these groups. Our results indicate that ciclesonide, compared with fluticasone, has stronger anti-inflammatory activity in patients with mild allergic asthma.

Background: Nitrosative and acid stress play an important role in the pathogenesis of asthma. The aim of this study was to evaluate whether, in asthmatics, a link exists between the concentrations of nitrite/nitrate, ammonia and pH values in exhaled breath condensate (EBC) and asthma severity, lung function, exhaled nitric oxide (FENO), total IgE, eosinophil cationic protein (ECP) and blood eosinophilia. Methods: The above-mentioned parameters were measured in 19 healthy volunteers and 91 allergic asthmatics divided into three groups, i.e. 22 subjects with steroid-naïve stable asthma, 35 with inhaled corticosteroid (ICS)-treated stable asthma and 34 with ICS-treated unstable asthma. Results: Compared with healthy subjects, EBC from asthmatics had significantly lower pH values and ammonia concentrations and significantly higher levels of nitrite/nitrate. The extent of these changes was higher in patients with unstable than in patients with steroid-naïve and stable ICS-treated asthma. The EBC pH was positively correlated with ammonia and negatively correlated with nitrite/nitrate, FENO or blood eosinophilia in all three groups of asthmatics. Significant positive correlations between EBC nitrite/nitrate and blood eosinophilia, ECP levels or FENO were observed in all groups of asthmatics. Significant negative correlations between EBC ammonia and nitrite/nitrate, FENO, ECP concentrations or blood eosinophilia were demonstrated in the groups of ICS-naïve and ICS-treated stable asthmatics. Conclusions: In asthmatic patients there is a relationship between EBC pH, ammonia and nitrite/nitrate concentrations and other recognized markers of airway inflammation. EBC pH values, ammonia and nitrite/nitrate levels measured together may help to assess airway inflammatory status and asthma severity.