Search

Background Thymic stromal lymphopoietin (TSLP) and IL-33 are considered important initiators of type 2 immunity. In asthmatic patients allergic inflammatory responses are associated with increased lung homing of bone marrow–derived CD34 + hematopoietic progenitor cells (HPCs), which include eosinophil lineage–committed progenitor cells. In this study we investigated the role of TSLP and IL-33 in the recruitment of progenitor cells to the airways in asthmatic subjects. Objectives We sought (i) to examine the effect of allergen inhalation challenge on expression levels of receptors for TSLP (thymic stromal lymphopoietin receptor [TSLPR] and CD127) and IL-33 (ST2) and (ii) investigate the functional effects of these cytokines on HPCs. Methods Consenting patients with mild atopic asthma (n = 19) with an FEV 1 of 70% or greater and methacholine PC 20 of 16 mg/mL or less were recruited. Blood- and sputum-extracted progenitors were phenotyped by flow cytometry before and 24 hours after allergen challenge. Functional responses, including cytokine production and migration to TSLP and IL-33, were assessed in vitro . Results Significant increases in mature eosinophil, HPC, and eosinophil lineage–committed progenitor cell counts in sputum were observed 24 hours after allergen and were associated with a significant allergen-induced increase in HPCs expressing TSLPR, CD127, and ST2. Pre-exposure to TSLP and IL-33 primed the migration of HPCs to a potent progenitor cell chemoattractant, stromal cell–derived factor 1α (CXCL12). Incubation with TSLP and IL-33 stimulated significant production of IL-5 and IL-13, but not IL-4, by HPCs. This priming effect was inhibited by blocking antibodies to TSLPR and ST2, respectively, and IL-13 receptor α1 in both scenarios. Conclusions In allergic asthmatic responses increased lung homing of HPCs may be orchestrated by TSLP and IL-33 through an IL-13–dependent axis. [ABSTRACT FROM AUTHOR]

Background: Natural regulatory T (Treg) cells are implicated in the regulation of the inflammatory response in patients with allergic asthma. Objectives: We sought to determine changes in Treg cell numbers in the airways and peripheral blood of isolated early responder (IER) versus dual responder (DR) subjects with mild allergic asthma before and after allergen challenge. Methods: Induced sputum was collected from 22 subjects with allergic asthma (10 IERs and 12 DRs) and peripheral blood collected from 8 DRs with allergic asthma at 0, 7, and 24 hours after allergen challenge. Treg cells were identified by using fluorescently labeled antibodies to CD4 and forkhead box protein 3 and enumerated by using flow cytometry. Results: There was a significant increase in the percentage of sputum CD4+ cells 24 hours after allergen challenge in both IERs and DRs. The percentage of sputum Treg cells significantly decreased 24 hours after challenge in DRs but not IERs. This change was significantly correlated with the magnitude of the late asthmatic response. There was also a significant increase in the absolute number of sputum CD4+ cells and Treg cells at 24 hours in DRs only. The ratio of the number of Treg cells to CD4+ cells at 24 hours was significantly smaller in DRs compared with that in IERs. None of the above changes were observed in peripheral blood. Conclusions: DRs exhibit a diminished percentage of airway Treg cells after allergen challenge that is not observed in IERs and a significantly lower ratio of Treg cells to CD4+ cells, which might contribute to the development of the late asthmatic response. [Copyright &y& Elsevier]

Asthma exacerbations can occur in patients with all degrees of asthma severity. They generally develop over 5 to 7 days and are most often initiated by an upper respiratory tract infection (usually with human rhinovirus) or by environmental allergen exposure in atopic subjects. Inhaled corticosteroids (ICSs) taken on a regular basis are very effective in reducing the risk of asthma exacerbations, and the combination of ICSs and long-acting inhaled β2-agonists further reduces this risk. In addition, use of the combination of the ICS budesonide and the long-acting inhaled β2-agonist formoterol, both as maintenance asthma treatment and also as rescue treatment (instead of a short-acting inhaled β2-agonist), has a significant further beneficial effect on asthma exacerbation risk. Other therapies that have been demonstrated to reduce severe asthma exacerbations are leukotriene receptor antagonists, which have been demonstrated to be effective most consistently in this regard in children, and anti-IgE mAbs, which are effective in subjects with difficult-to-treat allergic asthma. Approximately 50% of severe asthma exacerbations are eosinophilic in nature, whereas many of the remaining are neutrophilic. Several studies have demonstrated that making asthma treatment decisions based on minimizing airway eosinophil numbers (measured in induced sputum) can reduce the risks of severe exacerbations. In addition, treatment of patients with severe asthma with an anti–IL-5 mAb also reduces the number of severe asthma exacerbations, demonstrating a central role of eosinophils in many exacerbations. [ABSTRACT FROM AUTHOR]

Background: Dendritic cells are professional antigen presenting cells that mediate the response to inhaled allergens. In animal models, the induction and maintenance of allergic airway inflammation is primarily a function of myeloid dendritic cells, whereas the tolerization to inhaled allergens is likely a function of plasmacytoid dendritic cells. Objective: To investigate changes in sputum myeloid and plasmacytoid dendritic cells after allergen inhalation in subjects with asthma. Also, the number of myeloid and plasmacytoid dendritic cells expressing both CCR6 and 7 and their chemokine ligands macrophage inflammatory protein (MIP)–3α and 3β were measured in sputum supernatants. Methods: Sputum was induced from 12 dual-responder subjects with allergic asthma before and 7 hours, 24 hours, and 72 hours after inhalation of diluent and allergen. Dendritic cells were enumerated via flow cytometry and the chemokines by using ELISAs. Results: The number of sputum myeloid dendritic cells was significantly higher 24 hours after allergen challenge compared with diluent. Similarly, sputum plasmacytoid dendritic cells increased significantly at 24 hours after allergen challenge. Also, a significant increase in CCR6+ myeloid dendritic cells numbers occurred 72 hours after allergen challenge. In contrast, CCR7+ myeloid dendritic cells, as well as the number of CCR6+ and CCR7+ plasmacytoid dendritic cells, were not different between challenges. Finally, allergen challenge increased sputum levels of MIP-3α, but not MIP-3β, compared with baseline. Conclusions: Both myeloid and plasmacytoid dendritic cells increase in the sputum of subjects with asthma after allergen challenge, suggesting that both subsets are involved in the pathogenesis of allergen responses in asthma. [Copyright &y& Elsevier]

Background: Mobilization of hemopoietic progenitor cells from the bone marrow (BM) is a feature of inflammatory asthmatic responses. Understanding the mechanisms regulating progenitor cell mobilization and trafficking to the peripheral circulation might be important for the development of effective asthma therapies. Objective: We investigated the role of adhesion molecules in the mobilization of hemopoietic progenitor cells from the BM during an allergen-induced asthmatic response. Methods: BM and peripheral blood samples were obtained from dual-responders with mild asthma before and at several time points after allergen challenge. Fluctuations in expression and adhesive properties of β1- and β2-integrins on CD34+CD45+ progenitor cells were assessed by using flow cytometry and adhesion to protein-coated wells, respectively. Results: On BM-derived CD34+CD45+ cells, expression of very late antigen (VLA) 4, but not VLA-5 or Mac-1, decreased significantly 24 hours after allergen challenge and had begun to recover by 48 hours after challenge. In peripheral blood allergen challenge induced a significant decrease in VLA-4 levels after 6 hours, which had not recovered by 96 hours after challenge. Similarly, VLA-5 expression decreased, most prominently at 72 to 96 hours after allergen challenge. In contrast, Mac-1 levels did not change. Chemokine-stimulated adhesion of BM-derived CD34+CD45+ cells to fibronectin was significantly attenuated 24 hours after challenge. Furthermore, adhesion to fibronectin and vascular cell adhesion molecule 1 was greatly reduced by anti-VLA-4 or anti-VLA-5 antibodies. Conclusions: Preferential downregulation of β1-integrin expression on progenitor cells can reduce the tethering forces to BM components, thus facilitating their egress to the peripheral circulation during an allergic inflammatory response. [Copyright &y& Elsevier]

Background: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study enrolled 7241 patients aged 5 to 66 years with recent-onset, mild persistent asthma to assess early intervention with the inhaled corticosteroid budesonide on long-term asthma control. Objective: The open-label phase of the START study was included to determine the effect on lung function and asthma control of adding budesonide to the reference group patients who had not initially received inhaled corticosteroids. Methods: Patients were randomized to double-blind treatment with budesonide, 200 μg (those aged <11 years) or 400 μg once daily, or placebo plus the usual asthma therapy for 3 years, after which all patients received 2 years of open-label treatment with budesonide once daily. Results: During the full 5-year study period, postbronchodilator FEV1 percent predicted decreased, irrespective of randomized treatment during the double-blind phase, by an average of 2.22% (SE, 0.15%). However, patients with inhaled budesonide in the double-blind phase had a significantly lower risk (odds ratio, 0.61; P < .001) of a severe asthma-related event during the full 5-year study period than those in the reference group. Moreover, patients in the reference group used more additional asthma medications during both the open-label and double-blind phases. Conclusions: In mild persistent asthma early intervention with inhaled budesonide was associated with improved asthma control and less additional asthma medication use. [Copyright &y& Elsevier]

In some patients, asthma control is improved by combining inhaled corticosteroids with long-acting β2-agonists. However, fluctuating asthma control and exacerbations can still occur. The STAY study evaluated whether, in patients with moderate to severe asthma, replacing a short-acting β2-agonist reliever with the combination of budesonide/formoterol as reliever would both provide rapid symptom relief and reduce asthma exacerbations. The study evaluated 2760 patients with asthma (4-80 years) randomized to budesonide 400 μg twice daily (bid) and terbutaline as reliever, budesonide/formoterol 100/6 μg bid and terbutaline as reliever, or budesonide/formoterol 100/6 μg bid both as maintenance and reliever. Children (age 4-11 years) used a once-daily maintenance dose. Budesonide/formoterol as maintenance and reliever significantly reduced severe exacerbation risk by 45% to 47% compared with the other 2 treatments and improved symptoms, awakenings, and lung function. The benefit was seen in patients of all ages. Subsequent studies have revealed that this beneficial effect of budesonide/formoterol as maintenance and reliever requires both components of the combination. [Copyright &y& Elsevier]

Background: The use of combination inhaled budesonide and formoterol as maintenance and reliever therapy significantly improves the risk and the time to exacerbations in asthma. Objectives: To explore the mechanisms underlying the effect of the reliever dose on exacerbations by examining the effect of combination therapy on the allergen challenge model when given after allergen exposure. Methods: In a randomized, double-blind crossover study, single doses of budesonide/formoterol (400/12 μg), formoterol (12 μg), budesonide (400 μg), or placebo were administered during the acute bronchoconstriction response (early airway response) immediately after allergen inhalation in 15 patients with mild asthma. Allergen-induced late airway response (LAR), sputum inflammatory markers, airway hyperresponsiveness, and exhaled nitric oxide were measured. Results: All active treatments significantly attenuated the LAR, with budesonide/formoterol significantly better than its monocomponents (maximum FEV1 fall: placebo, [mean ± SEM] 21.2% ± 3.1%; budesonide/formoterol, 4.2% ± 1.4%; formoterol, 7.5% ± 1.7%; budesonide, 10.4% ± 1.6%). Allergen-induced change in methacholine PC20 was significantly attenuated by budesonide/formoterol, but not by its monocomponents. Sputum cell counts and exhaled nitric oxide increased significantly after all allergen challenges, with no significant attenuation by any of the treatments. Therapy with combination and formoterol alone, but not budesonide, significantly reduced the early airway response. Conclusion: A single dose of budesonide/formoterol was superior to its monocomponents in attenuating the allergen-induced LAR and airway hyperresponsiveness. These effects may represent the contribution of the reliever dose to the budesonide/formoterol maintenance and reliever regimen. Clinical implications: The protective effect against allergic airway responses with a single reliever dose of budesonide/formoterol is predominantly related to greater functional antagonism of airway smooth muscles. [Copyright &y& Elsevier]

Background: Inhaled corticosteroid therapy improves exercise symptoms in asthmatic subjects. Objective: We sought to evaluate exercise-induced bronchoconstriction (EIB) as a method of determining the dose and time responses of inhaled corticosteroid therapy. Methods: In this double-blind, randomized, cross-over study with 2 parallel arms, 4 doses of inhaled ciclesonide (40 μg and 160 μg or 80 μg and 320 μg) were compared over 3 weeks of treatment. Twenty-six asthmatic subjects (age range, 14-27 years) with baseline FEV1 values of greater than 70% of predicted value were enrolled. The primary outcome was the maximum percentage decrease in FEV1 after standardized exercise challenge. Results: After 1 week of therapy, the mean ± SEM reduction in maximum decrease in FEV1 in the ciclesonide 40-μg/80-μg dose group was 9% ± 2.6% (95% CI, 3.9% to 14%), with no additional reduction thereafter. In the ciclesonide 160-μg/320-μg dose group, there was an 8.7% ± 2.5% (95% CI, 3.7% to 13.7%) reduction in maximum decrease in FEV1 after week 1, which continued in a linear fashion during subsequent weeks of treatment. No difference was found between the 2 treatment arms in the temporal response of EIB to ciclesonide treatment. The maximum percentage attenuation in EIB achieved was 51.1% ± 7.9%, which was achieved by using the 320-μg dose after 3 weeks of treatment. Conclusions: A significant improvement in EIB was demonstrated for all doses of ciclesonide. Use of 160 μg/320 μg of ciclesonide resulted in a continuing improvement in FEV1 with time, and no plateau was seen in protective effect during 3 weeks of treatment. Clinical implications: Attenuation in exercise-induced decrease can be seen as early as after 1 week of therapy with inhaled ciclesonide at doses greater than 40 μg. However, maximal attenuation in exercise response continues to increase at doses greater than or equal to 200 μg, even after 3 weeks of therapy. [Copyright &y& Elsevier]

Background: Inhalation of allergens by sensitized patients with asthma induces reversible airway obstruction, airway hyperresponsiveness, and eosinophilic airway inflammation. Attenuation of allergen-induced bronchoconstriction and inflammation has been used to examine the efficacy of therapeutic agents such as inhaled corticosteroids in asthma. Ciclesonide, a nonhalogenated inhaled corticosteroid being developed for the treatment of persistent asthma, remains inactive until cleaved by esterases in the lung. Objective: This study examined the effect of low doses of inhaled ciclesonide, 40 μg and 80 μg, on allergen-induced bronchoconstriction, serum eosinophil cationic protein, and eosinophilic airway inflammation. Methods: Twenty-one nonsmokers with mild atopic asthma completed a multicenter, randomized, 3-way crossover study comparing the effects of 7-day treatment of ciclesonide or placebo. Allergen-induced responses, including the early and late fall in FEV1, peripheral blood eosinophils, serum eosinophil cationic protein levels, and eosinophils in induced sputum were measured. Results: Ciclesonide 80 μg attenuated the early and late asthmatic responses, including the change in FEV1, serum eosinophil cationic protein, and sputum eosinophils measured at 24 hours postchallenge (P < .025). Ciclesonide 40 μg attenuated the late asthmatic responses and sputum eosinophils measured at 24 hours postchallenge (P < .025), with no effect on the early allergen-induced bronchoconstriction, 24-hour FEV1, or serum eosinophil cationic protein levels (P < .025). Conclusion: With the exception of 24-hour postchallenge peripheral blood eosinophils, a low dose of ciclesonide, 80 μg, was effective in blocking all allergen-induced responses measured. [Copyright &y& Elsevier]

Background: IFN-γ and IL-12 are anti-inflammatory cytokines released from various cells, including T cells. Allergen inhalation by atopic subjects with asthma results in 2 bronchoconstrictor phenotypes, termed isolated early and dual responders. Persistence of allergen-induced airway response and inflammation is a distinctive feature of dual responders. Objective: To evaluate the roles of IFN-γ and IL-12 in resolving allergen-induced airway inflammation by comparing T lymphocytes (CD4+ and CD8+ cells) producing these cytokines in isolated early and dual responders. Methods: Twenty-four subjects with asthma (12 isolated early and 12 dual responders) were challenged with inhaled allergen. Peripheral blood and induced sputum were taken before and 1 day, 3 days, and 7 days after challenge. Frequency of IFN-γ, IL-12, IL-4, and IL-13 producing CD4+ and CD8+ cells was assessed by using flow cytometry. Results: After allergen, both CD4+ and CD8+ IFN-γ positive cells in peripheral blood significantly decreased in dual responders only, whereas CD4+ and CD8+ IFN-γ positive cells in induced sputum significantly increased in isolated early responders only. By contrast, IL-12 positive cells in peripheral blood significantly increased after allergen challenge only in isolated early responders. The ratio of CD4+ and CD8+ IL-4/IFN-γ positive cells in peripheral blood significantly decreased in isolated early responders by 3 days and had recovered by 7 days. Conclusion: These results suggest that contrasting profiles of IFN-γ and IL-12 production may be responsible for different time courses of allergen-induced airway responses between isolated early and dual responders. [Copyright &y& Elsevier]

Background: Treatment with inhaled steroids is an effective method of reducing bronchoconstriction and airway inflammation after allergen challenge. However, the durationof the protective effects of inhaled steroids after discontinuation of therapy has not been established. Objective: We sought to evaluate the protective effect of 1 week of inhaled steroid therapy against inhaled allergen challenge 12 hours after discontinuation of therapy. Methods: In this randomized, double-blind, placebo-controlled crossover trial, 26 asthmatic subjects (>18 years old) not using inhaled steroids were administered 200 μg of budesonide twice daily, 200 μg of fluticasone twice daily, or placebo twice daily for 1 week. Twelve hours after discontinuation of therapy, subjects were administered an inhaled allergen challenge. Each treatment period was separated by a 3-week washout period. Results: When compared with placebo (26% ± 14%), there was a slight but significant protection against the allergen-induced early response after fluticasone treatment (19% ± 10%, P =.001) but not after budesonide treatment (23% ± 13%, P =.08). However, when the area under the curve for the early airway response was examined, there was no difference between the 2 drugs in the amount of protection (P =.62). Partial protection was demonstrated against the late-response allergen-induced sputum eosinophilia with both treatments (P =.001). By contrast, no protection was observed against allergen-induced airway hyperresponsiveness for either treatment. Conclusions: The protective effects of inhaled steroids against allergen-induced early responses, airway eosinophilia, and allergen-induced airway hyperresponsiveness are partially or completely lost as early as 12 hours after discontinuation of therapy. [ABSTRACT FROM AUTHOR]

Background: CCR3 expression on CD34+ cells mediates migration to eotaxin in vitro. CXCR4 and stromal cell–derived factor (SDF)–1α are important for stem cell homing to hemopoietic compartments. Objective: To study chemokine-mediated progenitor cell traffic in allergic inflammation. Methods: Bone marrow (BM) aspirates were obtained at baseline from normal subjects; atopic subjects without asthma; and subjects with asthma before, 5 hours after, and 24 hours after allergen inhalation (dual and early responders). Changes in chemokine receptor expression and migration were assessed. Results: Expression of CXCR4, but not CCR3, on BM CD34+ cells was greater in normal subjects compared with atopic subjects with asthma. Likewise, SDF-1α, but not eotaxin, stimulated a greater migrational response by BM CD34+ cells from normal subjects compared with subjects with asthma. For all subjects, a positive correlation was found between intensity of CXCR4 expression and magnitude of CD34+ cell response to SDF-1α. Allergen inhalation attenuated both intensity of CXCR4 expression and SDF-1α levels in marrow from dual compared with early responders 24 hours postallergen. In contrast, the intensity of CCR3 expression on BM CD34+ cells increased in dual compared with early responders at 24 hours postallergen. In addition, an increase in migrational responsiveness of BM CD34+ cells to eotaxin and a decrease to SDF-1α 24 hours postallergen was found in dual responder subjects with asthma. Conclusion: After allergen inhalation in subjects with asthma, a downregulation in CXCR4 intensity on BM CD34+ cells and a reduction in BM SDF-1α levels may reduce progenitor retention to marrow stroma promoting peripheral egress, possibly mediated by the CCR3/eotaxin axis. [ABSTRACT FROM AUTHOR]

Cough is a common and troublesome symptom in asthmatic patients, but little is known about the neuronal pathways that trigger cough. The mechanisms by which airway inflammation, airway hyperresponsiveness, and variable airflow obstruction cause cough are unclear. We sought to investigate the effects of allergen exposure on cough reflex sensitivity. We performed a 9-visit, randomized, single-blind, placebo-controlled, 2-way crossover study comparing cough responses to inhaled capsaicin in patients with mild atopic asthma after allergen challenge compared with diluent control. Full-dose capsaicin challenge was performed at screening to determine the capsaicin dose inducing a half-maximal response, which was subsequently administered at 30 minutes and 24 hours after inhaled allergen/diluent challenge. Spontaneous coughing was measured for 24 hours after allergen/diluent. Methacholine challenge and sputum induction were performed before and after allergen/diluent challenge. Twelve steroid-naive subjects completed the study (6 female subjects; mean age, 34.8 years). Allergen inhalation caused both an early (mean ± SD, 38.2% ± 13.0%) and late (mean ± SD, 23.7% ± 13.2%) decrease in FEV 1 and an increase in sputum eosinophil counts 24 hours later (after diluent: median, 1.9% [interquartile range, 0.8% to 5.8%]; after allergen: median, 14.9% [interquartile range, 8.9% to 37.3%]; P =.005). There was also an increase in capsaicin-evoked coughs after allergen exposure compared with diluent at both 30 minutes (geometric mean coughs, 21.9 [95% CI, 16.5-29.20] vs 12.1 [95% CI, 8.3-17.7]; P <.001) and 24 hours (geometric mean coughs, 16.1 [95% CI, 11.3-23.0] vs 9.8 [95% CI, 6.1-15.8]; P =.001). Allergen exposure was also associated with an increase in spontaneous coughs over 24 hours. Allergen-induced bronchoconstriction and airway eosinophilia result in increased cough reflex sensitivity to capsaicin associated with an increase in 24-hour spontaneous coughing. [ABSTRACT FROM AUTHOR]

Background Cough in asthmatic patients is a common and troublesome symptom. It is generally assumed coughing occurs as a consequence of bronchial hyperresponsiveness and inflammation, but the possibility that airway nerves are dysfunctional has not been fully explored. Objectives We sought to investigate capsaicin-evoked cough responses in a group of patients with well-characterized mild-to-moderate asthma compared with healthy volunteers and assess the influences of sex, atopy, lung physiology, inflammation, and asthma control on these responses. Methods Capsaicin inhalational challenge was performed, and cough responses were analyzed by using nonlinear mixed-effects modeling to estimate the maximum cough response evoked by any concentration of capsaicin (E max ) and the capsaicin dose inducing half-maximal response (ED 50 ). Results Ninety-seven patients with stable asthma (median age, 23 years [interquartile range, 21-27 years]; 60% female) and 47 healthy volunteers (median age, 38 years [interquartile range, 29-47 years]; 64% female) were recruited. Asthmatic patients had higher E max and lower ED 50 values than healthy volunteers. E max values were 27% higher in female subjects ( P = .006) and 46% higher in patients with nonatopic asthma ( P = .003) compared with healthy volunteers. Also, patients with atopic asthma had a 21% lower E max value than nonatopic asthmatic patients ( P = .04). The ED 50 value was 65% lower in female patients ( P = .0001) and 71% lower in all asthmatic patients ( P = .0008). ED 50 values were also influenced by asthma control and serum IgE levels, whereas E max values were related to 24-hour cough frequency. Age, body mass index, FEV 1 , PC 20 , fraction of exhaled nitric oxide, blood eosinophil counts, and inhaled steroid treatment did not influence cough parameters. Conclusion Patients with stable asthma exhibited exaggerated capsaicin-evoked cough responses consistent with neuronal dysfunction. Nonatopic asthmatic patients had the highest cough responses, suggesting this mechanism might be most important in type 2–low asthma phenotypes. [ABSTRACT FROM AUTHOR]

Background In patients with severe eosinophilic asthma, local maturation rather than systemic recruitment of mature cells might contribute to persistent airway eosinophilia. Group 2 innate lymphoid cells (ILC2s) are a major source of type 2 cytokines (IL-5 and IL-13) and can facilitate eosinophilic inflammatory responses in mouse models of asthma in the absence of CD4 + lymphocytes. This study investigated the potential role of ILC2s in driving chronic airway eosinophilia in patients with severe asthma, despite regular high-dose oral corticosteroid therapy. Methods In a cross-sectional study we enumerated blood and sputum ILC2s (lin − CD45 + 127 + ST2 + ) and levels of intracellular IL-5 and IL-13 in patients with severe asthma (n = 25), patients with steroid-naive mild atopic asthma (n = 19), and nonatopic control subjects (n = 5). Results were compared with numbers of CD4 + lymphocytes, eosinophil lineage–committed progenitors (eosinophilopoietic progenitor cells [EoPs]), and mature eosinophils. Results Significantly greater numbers of total and type 2 cytokine–producing ILC2s were detected in blood and sputum of patients with severe asthma compared to mild asthmatics. In contrast, intracellular cytokine expression by CD4 cells and EoPs within the airways did not differ between the asthmatic groups. In patients with severe asthma, although sputum CD4 + cells were more abundant than ILC2s and EoPs, proportionally, ILC2s were the predominant source of type 2 cytokines. In addition, there were significantly greater numbers of sputum IL-5 + IL-13 + ILC2s in patients with severe asthma whose airway eosinophilia was greater than 3%, despite normal blood eosinophil numbers (<300/μL). Conclusions Our findings suggest that ILC2s can promote the persistence of airway eosinophilia in patients with severe asthma through uncontrolled localized production of the type 2 cytokines IL-5 and IL-13, despite high-dose oral corticosteroid therapy. [ABSTRACT FROM AUTHOR]

Background Identifying patients at risk of future severe asthma exacerbations, those whose asthma might be less treatment responsive, or both might guide treatment selection. Objective We sought to investigate predictors for failure to achieve Global Initiative for Asthma (GINA)–defined good current asthma control and severe exacerbations on treatment and to develop a simple risk score for exacerbations (RSE) for clinical use. Methods A large data set from 3 studies comparing budesonide/formoterol maintenance and reliever therapy with fixed-dose inhaled corticosteroid/long-acting β 2 -agonist therapy was analyzed. Baseline patient characteristics were investigated to determine dominant predictors for uncontrolled asthma at 3 months and for severe asthma exacerbations within 12 months of commencing treatment. The RSE, right censored at 6 months to include all 3 studies, was based on the dominant predictors for exacerbations in two thirds of the data set and validated in one third. Results Patients (n = 7446) whose symptoms were not controlled on GINA treatment steps 3 and 4 and with 1 or more exacerbations (as judged by a clinician based on patient records, history, or both) in the previous year were included. On multivariate analysis, GINA step, reliever use, postbronchodilator FEV 1 , and 5-item Asthma Control Questionnaire score were dominant (all P < .001) predictors for both the risk of uncontrolled asthma and severe exacerbations. Additional dominant predictors for uncontrolled asthma were smoking status and asthma symptom scores and an additional predictor for severe exacerbation was body mass index. An exponential increase in risk was observed with increments in RSE based on 5 selected predictors for exacerbations. Conclusion Risk of uncontrolled asthma at 3 months and a severe exacerbation within 12 months can be estimated from simple clinical assessments. Prospective validation of these predictive factors and the RSE is required. Use of these models might guide the management of asthmatic patients. [ABSTRACT FROM AUTHOR]

The allergen bronchoprovocation test is a long-standing exacerbation model of allergic asthma that can induce several clinical and pathophysiologic features of asthma in sensitized subjects. Standardized allergen challenge is primarily a research tool, and when properly conducted by qualified and experienced investigators, it is safe and highly reproducible. In combination with validated airway sampling and sensitive detection techniques, allergen challenge allows the study of several features of the physiology of mainly TH2 cell–driven asthma in relation to the kinetics of the underlying airway pathology occurring during the allergen-induced late response. Furthermore, given the small within-subject variability in allergen-induced airway responses, allergen challenge offers an adequate disease model for the evaluation of new (targeted) controller therapies for asthma in a limited number of subjects. In proof-of-efficacy studies thus far, allergen challenge showed a fair positive predicted value and an excellent negative predictive value for the actual clinical efficacy of new antiasthma therapies, underscoring its important role in early drug development. In this review we provide recommendations on challenge methods, response measurements, sample size, safety, and harmonization for future applications. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Exhaled nitric oxide in prednisone-dependent asthma to identify the eosinophilic positive phenotype," by Parameswaran Nair, Paul M. O'Byrne, and Frederick E. Hargreave in the 2010 issue.

Background: Asthma guidelines emphasize both maintaining current control and reducing future risk, but the relationship between these 2 targets is not well understood. Objective: This retrospective analysis of 5 budesonide/formoterol maintenance and reliever therapy (Symbicort SMART Turbuhaler ∗ [∗] Symbicort SMART and Turbuhaler are trademarks owned by AstraZeneca. Neither the Symbicort SMART posology nor the dry powder formulation Turbuhaler are currently approved in the United States. ) studies assessed the relationship between asthma control questionnaire (ACQ-5) and Global Initiative for Asthma-defined clinical asthma control and future risk of instability and exacerbations. Methods: The percentage of patients with Global Initiative for Asthma–defined controlled asthma over time was assessed for budesonide/formoterol maintenance and reliever therapy versus the 3 maintenance therapies; higher dose inhaled corticosteroid (ICS), same dose ICS/long-acting β2-agonist (LABA), and higher dose ICS/LABA plus short-acting β2-agonist. The relationship between baseline ACQ-5 and exacerbations was investigated. A Markov analysis examined the transitional probability of change in control status throughout the studies. Results: The percentage of patients achieving asthma control increased with time, irrespective of treatment; the percentage Controlled/Partly Controlled at study end was at least similar to budesonide/formoterol maintenance and reliever therapy versus the 3 maintenance therapies: higher dose ICS (56% vs 45%), same dose ICS/LABA (56% vs 53%), and higher dose ICS/LABA (54% vs 54%). Baseline ACQ-5 score correlated positively with exacerbation rates. A Controlled or Partly Controlled week predicted at least Partly Controlled asthma the following week (≥80% probability). The better the control, the lower the risk of an Uncontrolled week. The probability of an exacerbation was related to current state and was lower with budesonide/formoterol maintenance and reliever therapy. Conclusions: Current control predicts future risk of instability and exacerbations. Budesonide/formoterol maintenance and reliever therapy reduces exacerbations versus comparators and achieves at least similar control. [Copyright &y& Elsevier]

Background: Combining inhaled corticosteroids with long-acting β2-agonists results in improved asthma symptom control and fewer asthma exacerbations compared with those seen after inhaled corticosteroids alone. However, there are limited data as to whether these beneficial effects are due to enhanced anti-inflammatory actions or whether such combination therapies affect airway remodeling in patients with asthma. Objective: We sought to determine the effects of inhaled budesonide/formoterol combination therapy versus inhaled budesonide alone or inhaled placebo on allergen-induced airway responses, airway inflammation, and airway remodeling. Methods: Fourteen asthmatic subjects with dual responses after allergen inhalation were included in this prospective, randomized, double-blind, 3-period crossover study. Outcomes included early and late asthmatic responses, changes in airway responsiveness, sputum eosinophilia measured before and after allergen challenge, numbers of airway submucosal myofibroblasts, and smooth muscle area measured before and after study treatment. Results: Allergen-induced sputum eosinophilia was significantly reduced by combination treatment to a greater extent than by budesonide alone. Allergen inhalation resulted in a significant increase in submucosal tissue myofibroblast numbers and produced a significant decrease in percentage smooth muscle area. Combination therapy, but not budesonide monotherapy, significantly attenuated these changes in myofibroblast numbers and smooth muscle area. Conclusions: The effects on allergen-induced changes in sputum eosinophils, airway myofibroblast numbers, and smooth muscle seen with combination therapy suggest that the benefits associated with this treatment might relate to effects on airway inflammation and remodeling. The attenuation of early asthmatic responses and airway hyperresponsiveness by combination treatment was likely due to the known functional antagonistic effect of formoterol. [Copyright &y& Elsevier]