Exhaled matrix metalloproteinase-9 (MMP-9) in different biological phenotypes of asthma

Background and objectivesAirway remodeling is a main feature of asthma. Different biological phenotypes of severe asthma have been recently recognized by the ENFUMOSA study group and among these one is characterized by neutrophilic airway inflammation. Concentrations of MMP-9 in airways have been suggested as a marker to monitor airway remodeling in asthma.ObjectiveThe aim of the present study was to explore airway remodeling in different biological phenotypes of asthma by measuring MMP-9 in EBC and correlating these with other variables.MethodsSixty consecutive subjects with asthma and 20 healthy controls were enrolled in the study. Exhaled MMP-9, pH and NO levels and inflammatory cells in sputum were measured in all subjects enrolled.ResultsWe observed an increase of exhaled MMP-9 in asthmatic subjects compared to controls. Higher exhaled MMP-9 concentrations were described in severe asthmatics compared to mild to moderate especially in those with neutrophilic airway inflammation. We further found a correlation between exhaled MMP-9 and percentage of neutrophils in sputum, FEV_1, exhaled NO and pH.ConclusionOur results seem to substantiate the feasibility of measuring exhaled MMP-9 in the breath of asthmatic patients. MMP-9 may be considered a proxy of the amount of the ongoing airway remodeling in asthma. MMP-9 has been shown to be differentially released in different phenotypes of asthma. The measure of exhaled MMP-9 could help to monitor the ongoing airway remodeling, recognize severe stages of asthma, and possibly help determine the appropriate choice of therapy.     

Serum Levels of Interleukins (IL)-4, IL-5, IL-13, and Interferon-γ in Acute Asthma

T-cell activation and alteration of cytokine levels are involved in the pathogenesis of bronchial asthma. However, the profile of circulating T-lymphocyte subsets and related cytokines during acute asthmatic attacks is still unclear. We hypothesized that serum levels of interleukin (IL)-4, IL-5, and IL-13 would be increased, whereas IFN-γ would be decreased in acute asthma. The subjects enrolled in this study included 58 acute asthmatics, 22 asymptomatic asthmatics, and 10 healthy controls. Serum levels of IL-4, IL-5, IL-13, and IFN-γ were measured using a sandwich enzyme-linked immunosorbent assay. We correlated serum levels of IL-4, IL-5, IL-13, and IFN-γ with initial forced expiratory volume in 1 sec (FEV₁). Compared with control subjects, acute asthmatics had significantly increased levels of circulating IL-4 (p < 0.001), IL-5 (p < 0.001), and IL-13 (p < 0.001), although the differences were of borderline significance in serum IFN-γ (p = 0.069). There were also significant differences in the circulating levels of IL-4, IL-5, and IL-13 between acute asthmatics and asymptomatic asthmatics. There was no significant association between initial FEV₁ and serum levels of IL-4 or IL-13, however, among acute asthmatics, a lower initial FEV₁ was associated with higher IL-5 and/or lower IFN-γ levels. Our results suggest that serum levels of IL-4, IL-5, and IL-13 may be elevated in acute asthma, and that higher levels of IL-5 and/or lower levels of IFN-γ are associated with severe airway obstruction.     

Relationship of circulating chemerin and omentin levels with Th17 and Th9 cell immune responses in patients with asthma

Objective: Adipokines are correlated with immune responses in asthma, but data on the roles of chemerin and omentin in asthma are limited. This study explored the relationship of chemerin and omentin levels with Th17 and Th9 cells in asthma. Methods: Seventy-six asthmatics were divided into intermittent-to-mild persistent (n = 28), moderate persistent (n = 26) and severe persistent (n = 22) and were enrolled in the study. Additionally, 20 healthy subjects were enrolled as controls. Clinical characteristics of the subjects, the Asthma Control Test, lung function, fractional exhaled nitric oxide score, and plasma chemerin and omentin levels were evaluated, and the percentages of Th17 and Th9 cells were determined by flow cytometry. Results: The percentages of Th17 and Th9 cells were higher in the moderate-to-severe persistent asthmatics than in the intermittent-to-mild persistent asthmatics or healthy controls (p < 0.05). The severe persistent asthma group had a higher chemerin level but lower omentin levels than the control group (p < 0.05). Chemerin levels were positively correlated with Th17 and Th9 cell percentages, while omentin levels were negatively correlated with Th17 and Th9 cell percentages (p < 0.01). Conclusions: The regulatory functions of adipokines on immune responses may be associated with pathogenesis and processes of asthma.     

Comparison between montelukast and tiotropium as add-on therapy to inhaled corticosteroids plus a long-acting β2-agonist in for patients with asthma

Objective: Asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS) alone or with ICS plus a long-acting β₂-agonist (LABA). The recommended alternative is the addition of either montelukast or tiotropium. The aim of this study was to compare the effects of montelukast and tiotropium on airway inflammation and remodeling in persistent asthma. Methods: Eighty-seven patients with asthma were treated with budesonide and formoterol (640/18?μg); then, the patients were randomly allocated to three groups to receive oral montelukast (10?mg/day), inhaled tiotropium (5?μg/day), or no add-on to the maintenance therapy for 48 weeks. Fractional exhaled nitric oxide (FeNO) and pulmonary function were measured, and quantitative computed tomography was performed. Results: Compared to the maintenance therapy, add-on montelukast significantly decreased FeNO (p?<?0.05) and improved airflow obstruction (p?<?0.05), whereas airway dimensions remained unchanged. Changes in FeNO were significantly correlated with changes in FEV₁ (r?=??0.71, p?<?0.001). In contrast, the addition of tiotropium significantly decreased airway wall area corrected for body surface area (WA/BSA) (p?<?0.05), decreased wall thickness (T/√BSA) (p?<?0.05) and improved airflow obstruction (p?<?0.05) with no change in FeNO. Changes in WA/BSA and T/√BSA were significantly correlated with the change in percentage predicted FEV₁ (r?=??0.84, p?<?0.001 and r?=??0.59, p?<?0.01, respectively). Conclusions:Adding either montelukast or tiotropium to ICS/LABA may provide additive benefits with respect to the pulmonary function and airway inflammation or remodeling in patients with asthma.     

Treatment of Persistent Asthma With Symbicort® (Budesonide/Formoterol Inhalation Aerosol): An Inhaled Corticosteroid and Long-Acting β2-Adrenergic Agonist in One Pressurized Metered-Dose Inhaler

Objective. Budesonide/formoterol inhalation aerosol (Symbicort® AstraZeneca, Wilmington, Delaware) is an inhaled corticosteroid (ICS) and long-acting β₂-adrenergic agonist (LABA) combination administered twice daily via one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) approved in the United States for the long-term maintenance treatment of persistent asthma in patients ≥12 years of age whose asthma cannot be controlled by an ICS alone. The objective was to review efficacy, safety, and pharmacogenetic data on budesonide/formoterol pMDI in the treatment of persistent asthma. Methods. The authors searched PubMed and respiratory meeting databases to identify asthma studies of budesonide/formoterol pMDI. Studies involving traditional and patient-reported outcomes, safety, tolerability, or pharmacogenetics were included. Results. In two 12-week pivotal trials in adolescents and adults, treatment with budesonide/formoterol pMDI 160/4.5 μg × 2 inhalations (320/9 μg) twice daily for moderate to severe persistent asthma or 80/4.5 μg × 2 inhalations (160/9 μg) twice daily for mild to moderate persistent asthma, demonstrated greater efficacy and similar tolerability compared with placebo and the same nominal dose of its monocomponents. Comparisons with formoterol dry powder inhaler (DPI) for predose forced expiratory volume in one second (FEV₁) and with budesonide pMDI for 12-hour mean postdose FEV₁ demonstrated the anti-inflammatory and bronchodilatory contributions of budesonide and formoterol, respectively. Evaluations of patient-reported outcomes, including asthma-specific quality of life and treatment satisfaction, further supported the clinical benefits of budesonide/formoterol pMDI. In a 52-week tolerability study of patients aged ≥12 years, budesonide/formoterol pMDI was delivered at up to double the maximum dose (640/18 μg twice daily) and demonstrated a safety profile similar to that of budesonide (640 μg twice daily), with no unexpected pattern of abnormalities. Additional studies reported that budesonide/formoterol pMDI 320/9 μg twice daily and fluticasone propionate/salmeterol DPI 250/50 μg twice daily have similar efficacy and tolerability, with significantly more patients achieving ≥15% improvement in FEV₁ within 15 minutes with budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI. Moreover, inheritance of the Gly16Arg polymorphism of the β₂-adrenergic receptor does not appear to affect clinical outcomes with budesonide/formoterol pMDI. Conclusion. Budesonide/formoterol pMDI administered twice daily is effective and generally well tolerated in patients whose asthma is not well controlled on ICS alone.     

BAL eotaxin and IL-5 in asthma, and the effects of inhaled corticosteroid and beta2 agonist

Objective:   In a longitudinal ex vivo placebo-controlled study, asthmatics already treated with inhaled corticosteroid received supplemental long-acting β-agonist (LABA) or increased doses of their inhaled corticosteroid (ICS). Previously reports have shown significant reductions in biopsy eosinophil numbers after treatment with LABA. Following these findings, eosinophil chemokines eotaxin and IL-5 in the BAL fluid at baseline and after 3 months of study medication have now been measured, and these data with that from new cross-sectional controls have also been compared. It is hypothesised that changes in airway eosinophils would be related to eosinophil cytokines.
Methodology:   BAL cytokines were measured by chemiluminescent enzyme-linked immunosorbent assay, while eosinophils were measured by immunohistochemistry or differential cell counting. For all measures, longitudinal data were compared to that from ICS-free asthmatics ( n  = 42) and non-asthmatic controls ( n  = 28).
Results:   BAL eotaxin in asthmatics was elevated above non-asthmatic levels regardless of ICS levels. BAL IL-5 was elevated in ICS-free asthmatics, but not in asthmatics on low-dose ICS treatment. Longitudinally, BAL eotaxin was unchanged after 3 months. Unexpectedly, IL-5 increased after 3 months of additional LABA treatment but was not further affected by increasing the dose of ICS. Airway eotaxin seemed to be constitutively raised in asthmatics, whereas, IL-5 levels were more steroid-responsive. No relationship was observed between eosinophils and eosinophilic cytokines in the BAL.
Conclusions:   While the elevation of luminal IL-5 with LABA treatment cannot be accounted for, it may have contributed to luminal clearance of airway wall eosinophils. The lack of correlation between airways eosinophils and eosinophilic cytokines in the BAL is particularly important.     

儿童中度持续性哮喘临床治疗的疗效观察

目的在对中度持续性哮喘的治疗中比较各治疗方案间的疗效差异。方法将105名中度持续性哮喘患儿随机分为三组,分别给予吸入激素（ICS）＋抗白三烯（LTRA）、ICS＋长效β-2受体激动剂（LABA）、ICS＋LABA＋LTRA治疗。经过在3个月的治疗比较各治疗方案控制等级、有症状人数及肺功能（第一秒呼气容积占预计值百分比-FEV1％、呼气峰流速占预计值百分比-PEF、FEF25、FEF50、FEF75）改善情况。结果经过3个月的治疗,ICS＋LABA＋LTRA和ICS＋LABA组各观察指标均较1CS＋LTRA组好（P〈0.05）,其中前者对于改善小气道功能效果最好。结论对于中度持续性哮喘ICS联合LABA治疗优于ICS联合LTRA治疗,其中三者联合疗效最好,提示对于中度持续性哮喘ICS＋LABA疗效欠佳时可加用LTRA治疗。     

Serum levels of IL-10, IL-17F and IL-33 in patients with asthma: a case–control study

Objectives: The development of inflammation in asthma involves an intricate network of cytokines that recruit and activate numerous immune cells. This study was aimed to compare serum levels of IL-10, IL-17F, and IL-33 in asthmatic patients and non-asthmatic controls and correlate cytokine levels to asthma severity and various clinical, spirometric, and laboratory variables. Methods: Using ELISA, serum levels of IL-10, IL-17F, and IL-33 were evaluated in 44 asthmatics (14 mild persistent, 15 moderate persistent, and 15 severe persistent) and 44 controls. Results: This is one of the first reports showing a significant difference in serum levels of asthma-associated cytokines, anti-inflammatory IL-10, and pro-inflammatory IL-17F and IL-33, in the same subset of asthmatic patients. Our results showed diminished level of IL-10 and elevated levels of IL-17F and IL-33 in asthmatics than in controls (p?p?=?0.001). Conclusions: Negative correlation between IL-10 and IL-33 levels may reflect a converse relationship between anti-inflammatory and pro-inflammatory cytokines in an individually balanced pattern. The association between IL-17F level and asthmatic phenotypes such as reduced FVC and FEV1, higher degree of sensitization, and post-bronchodilator reversibility needs further assessments.     

哮喘患者诱导痰中IL-17A、IL-8及MMP-9水平变化及糖皮质激素对其的影响

目的探讨哮喘患者气道炎症特点及糖皮质激素的作用机制。方法将33例哮喘患者（哮喘组）按病情程度分为轻、中度19例及重度14例,予规范吸入糖皮质激素治疗4周,行诱导痰炎性细胞分类并计数,采用ELISA法检测痰上清液炎性介质白细胞介素-17A（IL-17A）、IL-8、基质金属蛋白酶-9（MMP-9）水平,并与15例查体健康者（对照组）进行比较。对诱导痰细胞分类、1秒钟用力呼气量占预计值百分比（FEVl％）及炎性介质水平进行相关分析。结果重度哮喘者诱导痰中性粒细胞、嗜酸性粒细胞比值及上清液IL-17A、IL-8、MMP-9水平显著高于对照组及轻、中度者;轻-中度者除MMP-9无显著升高外,余各指标均显著高于对照组（P均〈0．01）。诱导痰中性粒细胞及嗜酸性粒细胞比值与FEV1％呈显著负相关;中性粒细胞比值与IL-8、MMP-9呈正相关;IL-17A水平与中性粒细胞比值、IL-8呈正相关。糖皮质激素治疗后重度者中性粒细胞、嗜酸性粒细胞比值及MMP-9水平仍显著高于轻-中度者。结论中性粒细胞浸润性气道炎症是重度持续性哮喘的重要特征;IL-17A、IL-8与MMP-9可能在其中发挥重要作用。吸入糖皮质激素能抑制炎症细胞的趋化效应,阻止炎症释放,稳定细胞溶酶体膜,减轻组织损伤。     

Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics

Objective: Periostin, a matricellular protein, is produced from airway epithelial cells and lung fibroblasts by IL-13. It has been suggested that periostin is involved in allergic inflammation and fibrosis. However, the usefulness of serum periostin measurement in the assessment of airway inflammation and remodeling and management of asthmatic patients is still debated. We aimed to determine whether serum periostin levels reflect eosinophilic airway inflammation and airway remodeling in asthma. Methods: We examined the relationship of serum periostin levels with clinical features, biomarkers for eosinophilic airway inflammation, fraction of exhaled nitric oxide (FeNO) levels and blood eosinophil counts, and pulmonary functions in 235 well-controlled asthmatic patients on inhaled corticosteroids (ICS) treatment. Results: Serum periostin levels were positively correlated with blood eosinophil counts (%) and age (r = 0.36 and 0.23, respectively), and were negatively correlated with body weight and FEV₁/FVC (%) (r = ?0.24 and ? 0.23, respectively) in well-controlled asthmatic patients on ICS treatment (daily dose of 453 µg equivalent to fluticasone propionate). Blood eosinophil counts and serum periostin levels were similarly associated with increased FeNO levels (≥40 ppb) in the asthmatics. Serum periostin levels were better associated with fixed airflow limitation (FEV₁/FVC ratio <70%) than FeNO levels, blood eosinophil counts or total IgE levels in the asthmatics. Multivariate analysis showed that fixed airflow limitation was significantly associated with high serum periostin levels (≥97 ng/ml) (Odds ratio 3.2). Conclusions: Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics on ICS treatment.     

Evaluation of Th17-related cytokines and IFNγ production from blood mononuclear cells of moderate and severe asthmatic children reveals methylprednisolone does not decrease IL-22 levels

Objective: The aim of this study was to correlate IL-6, IL-17A, IFNγ, and IL-22 production with asthma disease severity and to evaluate if methylprednisolone downregulated cytokine production in peripheral blood mononuclear cells (PBMCs). Methods: Forty-two children with chronic persistent asthma and 34 non-asthmatic children were selected. Cytokines were quantified by ELISA from serum or PBMCs supernatants, after the PMA and Ionomycin stimulation, with or without methylprednisolone at 100?µM. Results: Our data showed undetectable levels of serum cytokines in most patients and controls. In the PBMCs, we have observed a higher production of IL-17A than IL-22 among asthmatics and controls, although it is not statistically significant. IL-6, IFNγ, and IL-17A levels were significantly reduced after methylprednisolone treatment (p?=?0.02, 0.03, and 0.03, respectively) in Severe Persistent Asthma (SPA) and in Moderate Persistent Asthma (MPA), (p?=?0.007, 0.01, and 0.007, respectively). However, IL-22 levels were unaffected (SPA, p?=?0.12 and MPA, p?=?0.93). Conclusion: Methylprednisolone downregulated IL-6, IL17A, and IFNγ, but not IL-22, in stimulated PBMCs from asthmatic children indicating that methylprednisolone has no effect on IL-22 production by PBMCs.     

A subgroup analysis of the MONICA study: A 12-month,open-label study of add-on montelukast treatment in asthma patients

Objective. We evaluated montelukast, a leukotriene receptor antagonist (LTRA), added to inhaled corticosteroids (ICS) or ICS+long-acting β₂ agonist (LABA) regimens over a period of 1 year to explore the therapeutic effects on asthma patients in patient subgroups. Methods. The majority of patients enrolled in this 12-month, open-label study were ≥18 years of age (n = 1681) with mild to moderate asthma insufficiently controlled by ICS or ICS+LABA. Patients received montelukast 10 mg qd as add-on therapy and were evaluated at Months 3, 6, 9, and 12. Asthma Control Test (ACT) score in the overall population was the primary endpoint; ACT score categories range from <16 (uncontrolled) to 25 (completely controlled). A post hoc secondary analysis of the following subgroups was conducted. age (< 30 years, 30–50 years, >50 years), gender, presence of allergic rhinitis, duration of asthma (< 5 years, ≥5 years), and the use of ICS or ICS+LABA. Results. Over 12 months of therapy, mean ACT scores improved by 5.7 units (p < .0001); at baseline, the mean (SD) ACT score for all patients was 14.6 (4.6) and at Month 12, the mean (SD) ACT score was 20.3 (4.2). The subgroups of patients who had allergic rhinitis and those who were <30 years of age demonstrated numerically better ACT scores compared with those who did not have allergic rhinitis or who were >30 years of age. Additional evaluation of the ACT score categories also demonstrated better control among patients who had duration of asthma <5 years and were treated with ICS without LABA. Conclusion. Add-on montelukast demonstrated significant improvement in asthma symptoms over 12 months in all patients in the study. Asthma control was improved in all patient subgroups, but comorbid allergic rhinitis, younger age, shorter duration of asthma, and treatment with only ICS and not ICS+LABA were indicators of better control with add-on montelukast. These observations may likely be shared with other antiasthmatic medications and should be further explored.     

Reduced clot retraction rate and altered platelet energy production in patients with asthma

Objective: Asthma enhances the risk of pulmonary embolism. The mechanism of this phenomenon is unclear. Methods: We evaluated the kinetics of clot formation, clot retraction rate (CRR), clot volume at 40 min, the rate of lactate production (a marker of aerobic glycolysis in platelets in contracting clots), blood eosinophil count (EOS), nitric oxide in exhaled breath (FE_NO), and spirometry (FEV₁) in 50 healthy controls and in 81 allergic asthmatics (41 subjects with steroid-naïve asthma and 40 with steroid-treated asthma). Results: Thromboelastometry revealed that only steroid-treated asthmatics had slightly activated coagulation. Compared with healthy controls, whole asthmatics demonstrated (p < 0.05) reduced CRR, higher clot volume at 40 minutes, higher FE_NO, decreased FEV₁, elevated EOS, and augmented lactate production in retracting clots. Reduced CRR was observed also in the absence of native plasma. In whole study population (asthmatics and healthy controls), CRR positively correlated with spirometry (r_S = 0.668, p = <0.001) and negatively with FE_NO (r_S = ?0.543; p < 0.001), EOS (r_S = ?0.367, p < 0.002), and lactate production (r_S = ?0.791; p < 0.001). However, in steroid-treated asthmatics, the CRR did not correlate with FE_NO and EOS. In all study patients lactate production negatively correlated with FEV₁ and positively with FE_NO. Conclusion: Collectively, this data is consistent with the hypothesis that, in asthmatics, reactive nitrogen species produced in the lungs may reduce platelet contractility (and CRR) through the diminution of platelet energy production. CRR inhibition would predispose asthmatics to pulmonary embolism.     

Fibroblast growth factor-2 is a sputum remodeling biomarker of severe asthma

Objective: Given the large phenotypic diversity of asthma, our aim was to characterize molecular profiles related to asthma severity using selected remodeling biomarkers in induced sputum. Methods: Induced sputum from healthy controls, patients with mild to moderate asthma and severe asthma were collected. Twelve selected biomarkers previously associated to airway remodeling such as connective tissue growth factor (CTGF), fibroblast growth factor (FGF)-2, matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, procollagen type 1 and tissue inhibitor of metalloproteinase (TIMP)-1 were measured in sputum samples using ELISA or Luminex technology. FGF-2 level was also evaluated in bronchial biopsies using immunohistochemistry. Results: Sputum of severe asthma was characterized by reduced percentage of macrophages and increased percentage of neutrophils and eosinophils. FGF-2, MMP-1 and TIMP-1 levels increased with asthma severity. Interestingly, only FGF-2 level inversely correlated with FEV₁/FVC ratio. Although percentage of eosinophils correlated with asthma severity, it did not correlate with FGF-2 levels. Increased levels of FGF-2 with asthma severity were confirmed in bronchial biopsies by immunohistochemistry. Conclusions: Level of FGF-2 in induced sputum represents a relevant remodeling biomarker of asthma severity and significantly correlates with pulmonary function. FGF-2 sputum biomarker is proposed to reveal the phenotype of asthma characterized by fixed airflow obstruction.     

Effect of Aging on the Relationship between Asthma Severity and Bronchial Hyperresponsiveness in Children with Asthma

An association between asthma and bronchial hyperresponsiveness (BHR) has been demonstrated. It is possible that the relationship between asthma severity and BHR in children with asthma is different in infants and in adolescents. The aim of this study is therefore to evaluate the effect of aging on the relationship between the severity of asthma and BHR in children with asthma.

We measured BHR in 386 subjects ranging from 2 to 20 years of age. The subjects consisted of 323 children with asthma (boys : girls = 193 : 130, mean age 9.7 years) and 63 age-matched controls (boys : girls = 25 : 38, mean age 8.2 years). BHR was measured using the methacholine inhalation challenge by measuring the transcutaneous oxygen pressure (tcPO₂) in children less than 6 years of age (Dmin-PO₂) and by measuring the respiratory resistance (Rrs) in children 6 years of age and older (Dmin-Rrs). Throughout the whole age range, both the Dmin-PO₂ and Dmin-Rrs in each asthma severity group were higher than those in the controls. In the asthmatics aged 2–5 years, the Dmin-PO₂ levels in the mild asthma group were higher than those in the moderate and severe asthma groups (p < 0.001, p < 0.001, respectively), and the Dmin-PO₂ levels in the moderate asthma group were also higher than those in the severe asthma group. This tendency was also found in the age ranges of 6–9 years and 10–13 years. In the asthmatics aged 14–20 years, the Dmin-Rrs levels were not significantly different among the three groups.

Taken together, these data show that aging has an effect on the relationship between the severity of asthma and BHR during childhood and that BHR may not be the sole determinant for the severity of asthma in adolescence.     

Asthmatics able to step down from inhaled corticosteroid treatment without loss of asthma control have low serum eotaxin/CCL11

Introduction: The addition of a long‐acting β2 agonist (LABA) to inhaled corticosteroid (ICS) may control asthma better than ICS alone. Eosinophil markers may predict symptom severity in asthma. Objectives: The effect of combination treatment on moderate to severe asthmatics not selected to respond rapidly to steroid deprivation was compared with monotherapy. The ability of serum markers to predict symptom severity was assessed. Methods: Asthmatics treated adequately with ICS (750–1000 mcg ICS daily) were randomised to receive ICS (fluticasone propionate) + LABA (salmeterol) (500 mcg/50 mcg bd) or ICS alone (500 mcg bd). If asthma was controlled at clinic visits every 6 weeks, ICS dose was tapered until asthma exacerbated (hospitalisation, ICS above study medication, peak flow variation, decline in forced expiratory volume in 1 s and/or use of rescue medication), or placebo was maintained for 6 weeks. Efficacy of the treatments was compared. Serum cytokines and chemokines were compared among the groups reporting severe, mild or no symptoms. Results: There was no difference between the treatment arms in the clinical analysis. Nine patients could be maintained on placebo for 6 weeks, 36 developed mild symptoms and 16 developed severe symptoms. Patients on placebo for 6 weeks had significantly lower serum eotaxin at baseline than patients with symptoms. Patients with mild symptoms had intermediate serum eotaxin concentrations. Conclusion: Patients with asthma controlled on ICS respond heterogeneously to ICS tapering. Serum eotaxin/CCL11 may be useful in predicting the severity of symptoms patients develop during steroid tapering and should be evaluated in guiding asthma treatment. Please cite this paper as: Hoffmann HJ, Nielsen LP, Harving H, Heinig JH and Dahl R. Asthmatics able to step down from inhaled corticosteroid treatment without loss of asthma control have low serum eotaxin/CCL11. The Clinical Respiratory Journal 2008; 2: 149–157.     

Association of Asthma Education with Asthma Control Evaluated by Asthma Control Test,FEV1, and Fractional Exhaled Nitric Oxide

Background. Asthma education is an important adjunct for asthma control although the way asthma education affects asthma outcomes is poorly understood. The asthma control test (ACT), forced expiratory volume in 1 s (FEV₁), and fractional exhaled nitric oxide (FeNO) have all been used as markers of asthma control. However, the use of FeNO as a surrogate marker remains controversial. Objectives. (i) To examine whether asthma education is associated with asthma control; (ii) to compare absolute levels and changes of ACT, FEV₁, and FeNO over a year; and (iii) to evaluate whether FeNO can be used as an additional marker of asthma control. Methods. Fifty asthmatics with poor adherence (12 mild, 21 moderate, and 17 severe) received asthma education at study entry. Medications were unchanged for the first 3 months, and ACT, FEV₁, and FeNO measurements were recorded at entry, 3, 6, and 12 months. Asthma control was assessed at each visit and patients were categorized as either “stable” or “unstable” asthmatics according to the global initiative for asthma (GINA) guidelines. Results. A significant decrease in FeNO and increase in ACT score were noted in the stable asthmatic group at 3 months (p < .001), and this persisted over 12 months. Significant correlations were seen between changes (Δ) in FeNO, ACT, and FEV₁ over time. However, significant correlations between the absolute levels were not maintained over 12 months. A decrease of ≥18.6% in FeNO and a ≥3-point increase in ACT score (sensitivity: 80% and 73.3% and specificity: 83.3% and 87.5%, respectively) were associated with stable asthma control although the absolute levels were not. Conclusions. Asthma education may be useful to achieve stable control. In addition, changes rather than absolute levels of FeNO and ACT may be better markers of asthma control.     

Asthma outcomes are poor among older adults with low health literacy

Objective: To examine the association of health literacy (HL) with asthma outcomes among older asthmatics. Methods: The study included adults ages ≥60 with moderate to severe asthma in New York City and Chicago. We assessed asthma control with the Asthma Control Questionnaire (ACQ) and the percent predicted forced expiratory volume at 1?s (FEV₁) by spirometry, hospitalizations and emergency department (ED) visits in the past 6 months, and quality of life. HL was assessed with the Short Test of Functional Health Literacy in Adults (S-TOFHLA). Multivariate logistic regression models controlled for age, sex, race, income, general health and years with asthma. Results: Among 433 individuals, 36% had low HL, 55% were over age 65, 38% were Hispanic and 22% were black. Poor asthma control was reported by 40% and 32% had FEV₁ <70% of predicted; 9% had a hospital stay, 23% had an ED and 38% had poor quality of life. In multivariable analysis, individuals with low HL were more likely to have FEV₁ <70% predicted (odds ratio [OR] 2.34, 95% confidence interval [CI] 1.39–3.94, p?=?0.001), hospitalizations (OR 2.53, 95% CI 1.17–5.49, p?=?0.02) and ED visits for asthma (OR 1.81, 95% CI 1.05–3.10, p?=?0.03). There were no differences in self-reported asthma control and quality of life. Conclusions: Low HL is associated with poor asthma control by objective measure, and greater likelihood of ED visits and hospitalization. HL is a modifiable target for interventions to improve asthma outcomes in the elderly.     

Relationship of Mannitol Challenge to Methacholine Challenge and Inflammatory Markers in Persistent Asthmatics Receiving Inhaled Corticosteroids

Background

Mannitol is a novel osmotic indirect bronchial challenge agent used to aid asthma diagnosis and management and is thought to reflect underlying inflammatory processes in asthma. Our objective was to evaluate relationships between mannitol airway hyperresponsiveness (AHR) and other measures of airway inflammation as well as direct-acting methacholine challenge in persistent asthmatics receiving inhaled corticosteroids.

Methods

We analysed screening data of mild to moderate persistent asthmatics, all receiving inhaled corticosteroids (ICS), who had mannitol and/or methacholine challenges, fractional exhaled nitric oxide (FeNO), and salivary eosinophilic cationic protein (ECP) performed as part of the same screen. Mannitol AHR was grouped by PD₁₀ (cumulative provocative dose required to produce a 10?% fall in FEV₁): mild (315–635?mg), moderate (75–315?mg), and severe (0–75?mg). FeNO groups were low (<25?ppb), medium (25–50?ppb), and high (>?50?ppb) and methacholine PC₂₀ (provocative concentration of methacholine required to cause a 20?% fall in FEV₁) groups were mild (2–8?mg/ml), moderate (0.5–2?mg/ml), and severe (0–0.5?mg/ml).

Results

Mannitol PD₁₀ groups were significantly different overall for FeNO (p?=?0.023): 43?% higher in the severe vs. the mild group. There was a significant overall difference for methacholine PC₂₀ (p?=?0.006): a 2.1 doubling dilution difference between severe vs. mild mannitol groups. FeNO groups were significantly different overall for mannitol PD₁₀ (p?=?0.01) and methacholine PC₂₀ (p?=?0.029). Methacholine PC₂₀ groups were significantly different overall for mannitol PD₁₀ (p?p?=?0.005). No significant differences were found across any groups for salivary ECP, FEV₁ % predicted, or ICS dose. Mannitol PD₁₀, methacholine PC₂₀, and FeNO as continuous variables all correlated with each other.

Conclusions

Mannitol challenge reflects underlying inflammation using FeNO and direct AHR using methacholine. Thus, mannitol may be a useful screening tool for the assessment of asthmatic patients receiving inhaled corticosteroids.