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1.  Inhaled corticosteroid effects both eosinophilic and non-eosinophilic inflammation in asthmatic patients. 
Mediators of Inflammation  2004;13(4):285-291.
AIM: To determine induced sputum cell counts and interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-alpha) and leukotriene B4 (LTB4) levels as markers of neutrophilic inflammation in moderate persistent asthma, and to evaluate the response to inhaled steroid therapy. METHODS: Forty-five moderate asthmatic patients and 10 non-smoker controls were included in this study. All patients received inhaled corticosteroid (800 microg of budesonide) for 12 weeks. Before and after treatment pulmonary function tests were performed, and symptom scores were determined. Blood was drawn for analysis of serum inflammatory markers, and sputum was induced. RESULTS: Induced sputum cell counts and inflammatory markers were significantly higher in patients with asthma than in the control group. The induced sputum eosinophil counts of 12 patients (26%) were found to be less than 5%, the non-eosinophilic group, and sputum neutrophil counts, IL-8 and TNF-alpha levels were significantly higher than the eosinophilic group (neutrophil, 50+/-14% versus 19+/-10%, p<0.01). In both groups, there was a significant decrease in sputum total cell counts and serum and sputum IL-8, TNF-alpha and LTB4 levels after the treatment. There was no change in sputum neutrophil counts. Although the sputum eosinophil count decreased only in the eosinophilic subjects, there was no significant difference in inflammatory markers between the groups. The symptom scores were significantly improved after treatment, while the improvement did not reach statistical significance on pulmonary function test parameters. CONCLUSION: Notably, in chronic asthma there is a subgroup of patients whose predominant inflammatory cells are not eosinophils. Sputum neutrophil counts and neutrophilic inflammatory markers are significantly higher in these patients. In the non-eosinophilic group, inhaled steroid caused an important decrease in inflammatory markers; however, there was no change in the sputum eosinophil and neutrophil counts.
doi:10.1080/09629350400003118
PMCID: PMC1781566  PMID: 15545060
2.  Automated quantitation of circulating neutrophil and eosinophil activation in asthmatic patients 
Thorax  2000;55(6):471-477.
BACKGROUND—Asthma has been associated with eosinophil activation, measured in serum, sputum, bronchoalveolar lavage (BAL) fluid, and urine. A whole blood automated method was developed to assess eosinophil and neutrophil activity in terms of peroxidase content and cell morphology using the Bayer haematology analyser. The method was applied to an in vitro stimulation model when fMLP was added to whole blood and the samples were then analysed for changes in granularity and shape. In addition, cells stimulated with interleukin (IL)-8 were examined by electron microscopy.
METHODS—A cross sectional analysis was performed on venous blood from non-atopic, non-asthmatic normal subjects (n = 37), mild (n= 46) and symptomatic (n = 22) asthmatic patients on inhaled β2 agonist only, and more severe asthmatic patients (n = 17) on inhaled and oral corticosteroid therapy. Samples were analysed by the haematology analyser and peroxidase leucograms gated using the WinMDI software program.
RESULTS—There were significant differences in the amount of light scatter by the neutrophil populations in the symptomatic (p = 0.007) and severe asthmatic (p = 0.0001) groups compared with the control group. However, abnormalities in eosinophil populations were not observed. In vitro activation of whole blood with fMLP caused similar changes in neutrophil light scatter, suggesting that neutrophil activation is present in peripheral blood of symptomatic asthmatic patients. IL-8 caused a change in shape of the neutrophils seen using transmission electron microscopy.
CONCLUSIONS—Evidence of neutrophil activation can be seen in whole blood from patients with asthma using a novel automated method. This may potentially be applied to other inflammatory diseases.


doi:10.1136/thorax.55.6.471
PMCID: PMC1745769  PMID: 10817795
3.  Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation 
Background
Phenotyping asthma according to airway inflammation allows identification of responders to targeted therapy. Induced sputum is technically demanding. We aimed to identify predictors of sputum inflammatory phenotypes according to easily available clinical characteristics.
Methods
This retrospective study was conducted in 508 asthmatics with successful sputum induction recruited from the University Asthma Clinic of Liege. Receiver-operating characteristic (ROC) curve and multiple logistic regression analysis were used to assess the relationship between sputum eosinophil or neutrophil count and a set of covariates. Equations predicting sputum eosinophils and neutrophils were then validated in an independent group of asthmatics.
Results
Eosinophilic (≥3%) and neutrophilic (≥76%) airway inflammation were observed in 46% and 18% of patients respectively. Predictors of sputum eosinophilia ≥3% were high blood eosinophils, FENO and IgE level and low FEV1/FVC. The derived equation was validated with a Cohen’s kappa coefficient of 0.59 (p < 0.0001). ROC curves showed a cut-off value of 220/mm3 (AUC = 0.79, p < 0.0001) or 3% (AUC = 0.81, p < 0.0001) for blood eosinophils to identify sputum eosinophilia ≥3%. Independent predictors of sputum neutrophilia were advanced age and high FRC but not blood neutrophil count.
Conclusion
Eosinophilic and paucigranulocytic asthma are the dominant inflammatory phenotypes. Blood eosinophils provide a practical alternative to predict sputum eosinophilia but sputum neutrophil count is poorly related to blood neutrophils.
doi:10.1186/1471-2466-13-11
PMCID: PMC3657295  PMID: 23442497
Asthma; Induced sputum; Eosinophil; Neutrophil
4.  Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma 
Background
Chronic obstructive pulmonary disease (COPD) and asthma may overlap and converge in older people (overlap syndrome). It was hypothesized that patients with overlap syndrome may have different clinical characteristics such as sputum eosinophilia, and better responsiveness to treatment with inhaled corticosteroid (ICS).
Methods
Sixty-three patients with stable COPD (forced expiratory volume in 1 second [FEV1] ≤80%) underwent pulmonary function tests, including reversibility of airflow limitation, arterial blood gas analysis, analysis of inflammatory cells in induced sputum, and chest high-resolution computed tomography. The inclusion criteria for COPD patients with asthmatic symptoms included having asthmatic symptoms such as episodic breathlessness, wheezing, cough, and chest tightness worsening at night or in the early morning (COPD with asthma group). The clinical features of COPD patients with asthmatic symptoms were compared with those of COPD patients without asthmatic symptoms (COPD without asthma group).
Results
The increases in FEV1 in response to treatment with ICS were significantly higher in the COPD with asthma group. The peripheral eosinophil counts and sputum eosinophil counts were significantly higher. The prevalence of patients with bronchial wall thickening on chest high-resolution computed tomography was significantly higher. A significant correlation was observed between the increases in FEV1 in response to treatment with ICS and sputum eosinophil counts, and between the increases in FEV1 in response to treatment with ICS and the grade of bronchial wall thickening. Receiver operating characteristic curve analysis revealed 82.4% sensitivity and 84.8% specificity of sputum eosinophil count for detecting COPD with asthma, using 2.5% as the cutoff value.
Conclusion
COPD patients with asthmatic symptoms had some clinical features. ICS should be considered earlier as a potential treatment in such patients. High sputum eosinophil counts and bronchial wall thickening on chest high-resolution computed tomography might therefore be a good predictor of response to ICS.
doi:10.2147/COPD.S30651
PMCID: PMC3346210  PMID: 22589579
COPD; asthma; HRCT; inhaled corticosteroid; pulmonary function
5.  Association of Eosinophilic Inflammation with FKBP51 Expression in Sputum Cells in Asthma 
PLoS ONE  2013;8(6):e65284.
Background
Airway eosinophilia is a predictor of steroid responsiveness in steroid-naïve asthma. However, the relationship between airway eosinophilia and the expression of FK506-binding protein 51 (FKBP51), a glucocorticoid receptor co-chaperone that plays a role in steroid insensitivity in asthma, remains unknown.
Objective
To evaluate the relationship between eosinophilic inflammation and FKBP51 expression in sputum cells in asthma.
Methods
The FKBP51 mRNA levels in sputum cells from steroid-naïve patients with asthma (n = 31) and stable asthmatic patients on inhaled corticosteroid (ICS) (n = 28) were cross-sectionally examined using real-time PCR. Associations between FKBP51 levels and clinical indices were analyzed.
Results
In steroid-naïve patients, the FKBP51 levels were negatively correlated with eosinophil proportions in blood (r = −0.52) and sputum (r = −0.57), and exhaled nitric oxide levels (r = −0.42) (all p<0.05). No such associations were observed in patients on ICS. In steroid-naïve patients, improvement in forced expiratory volume in one second after ICS initiation was correlated with baseline eosinophil proportions in blood (r = 0.74) and sputum (r = 0.76) and negatively correlated with FKBP51 levels (r = −0.73) (all p<0.0001) (n = 20). Lastly, the FKBP51 levels were the lowest in steroid-naïve asthmatic patients, followed by mild to moderate persistent asthmatic patients on ICS, and the highest in severe persistent asthmatic patients on ICS (p<0.0001).
Conclusions
Lower FKBP51 expression in sputum cells may reflect eosinophilic inflammation and glucocorticoid responsiveness in steroid-naïve asthmatic patients.
doi:10.1371/journal.pone.0065284
PMCID: PMC3675168  PMID: 23762334
6.  Steroid Response in Refractory Asthmatics 
Inhaled glucocorticosteroids are currently the most effective anti-inflammatory controller medications for treating persistent asthma. The efficacies of glucocorticoids include reducing asthma symptoms, reducing exacerbation frequency, improving quality of life, improving lung function, decreasing airway hyperresponsiveness, controlling airway inflammation, and reducing mortality. However, the treatment response to glucocorticosteroids in asthmatics varies, and certain subtypes of asthma, such as refractory asthma, respond poorly to high-dose inhaled glucocorticoid and systemic steroids. The medical costs of treating refractory asthmatics represent about 50% of the total healthcare cost for asthma. A thorough understanding of the mechanisms of glucocorticoid action, patient responses to glucocorticoids, and steroid resistance observed in refractory asthmatics is necessary for the targeted development of therapeutic drugs. This review discusses the characteristics of severe refractory asthmatics and the mechanisms of steroid response and resistance in asthma treatment.
doi:10.3904/kjim.2012.27.2.143
PMCID: PMC3372795  PMID: 22707883
Glucocorticoids; Drug resistance; Asthma
7.  Glucocorticoids: mechanisms of action and anti-inflammatory potential in asthma. 
Mediators of Inflammation  1998;7(4):229-237.
GLUCOCORTICOIDS are potent inhibitors of inflammatory processes and are widely used in the treatment of asthma. The anti-inflammatory effects are mediated either by direct binding of the glucocorticoid/glucocorticoid receptor complex to glucocorticoid responsive elements in the promoter region of genes, or by an interaction of this complex with other transcription factors, in particular activating protein-1 or nuclear factor-kappaB. Glucocorticoids inhibit many inflammation-associated molecules such as cytokines, chemokines, arachidonic acid metabolites, and adhesion molecules. In contrast, anti-inflammatory mediators often are up-regulated by glucocorticoids. In vivo studies have shown that treatment of asthmatic patients with inhaled glucocorticoids inhibits the bronchial inflammation and simultaneously improves their lung function. In this review, our current knowledge of the mechanism of action of glucocorticoids and their anti-inflammatory potential in asthma is described. Since bronchial epithelial cells may be important targets for glucocorticoid therapy in asthma, the effects of glucocorticoids on epithelial expressed inflammatory genes will be emphasized.
PMCID: PMC1781857  PMID: 9792333
8.  Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid non-adherence 
Background
Asthma is an inflammatory condition often punctuated by episodic symptomatic worsening, and accordingly, individuals with asthma may have waxing and waning adherence to controller therapy.
Objective
To measure changes in inhaled corticosteroid (ICS) adherence over time, and to estimate the effect of this changing pattern of use on asthma exacerbations.
Methods
ICS adherence was estimated from electronic prescription and fill information for 298 participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). For each individual we calculated a moving average of ICS adherence for each day of follow-up. Asthma exacerbations were defined as the need for oral corticosteroids, an asthma-related emergency department visit, or an asthma-related hospitalization. Proportional hazard models were used to assess the relationship between ICS medication adherence and asthma exacerbations.
Results
Adherence to ICS medications began to increase prior to the first asthma exacerbation and continued afterward. Adherence was associated with a reduction in exacerbations, but was only statistically significant among individuals whose adherence was >75% of the prescribed dose (hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.41–0.90) when compared with individuals whose adherence was ≤25%. This pattern was largely confined to individuals whose asthma was not well controlled initially. An estimated 24% of asthma exacerbations were attributable to ICS medication non-adherence.
Conclusions
Inhaled corticosteroid adherence varies in the time period leading up to and following an asthma exacerbation, and non-adherence likely contributes to a large number of these exacerbations. High levels of adherence are likely required to prevent these events. [ClinicalTrials.gov number NCT01142947]
doi:10.1016/j.jaci.2011.09.011
PMCID: PMC3229671  PMID: 22019090
medication adherence; inhaled corticosteroids; asthma; patient compliance; asthma exacerbations
9.  Nitric oxide metabolites, eosinophils, and eosinophilic cationic protein in patients with asthma: sputum versus blood. 
Journal of Korean Medical Science  2003;18(4):489-493.
The monitoring of airway inflammation has assessed in bronchial asthma directly by sputum examination, and indirectly by measurements in peripheral blood. To investigate the diagnostic value of these two methods, we compared nitric oxide (NO) metabolites, eosinophils, and eosinophil cationic protein (ECP) in sputum and blood in patients with asthma and control subjects. Sputum and serum were obtained from fifteen patients with asthma, and then were examined before anti-asthma treatment, including steroid preparations. ECP was measured by fluoroimmunoassay. NO metabolites were assayed by using modified Griess reaction. Asthmatic patients, compared with control subjects, had significantly higher level of NO metabolites, higher proportion of eosinophils, and higher levels of ECP in sputum. Asthmatic patients, compared with control subjects, however, had significantly higher number of eosinophils, and were at higher levels of ECP in blood. FEV1, FEV1/FVC was negatively correlated with sputum eosinophils. The area under receiver operating characteristic (ROC) curve showed that eosinophils in sputum are significantly accurate markers than NO metabolites in sputum and blood. These findings suggest that the proportion of eosinophils in sputum have more accurate diagnostic marker of asthmatic airway inflammation than NO metabolites in sputum in differentiating asthmatic patients from control subjects.
PMCID: PMC3055074  PMID: 12923323
10.  Current recommendations for the treatment of mild asthma 
Patients suffering from mild asthma are divided into intermittent or persistent classes based on frequency of symptoms and reliever medication usage. Although these terms are used as descriptors, it is important to recognize the approach of focusing on asthma control in managing asthma patients. Beta-agonists are considered first-line therapy for intermittent asthmatics. If frequent use of beta-agonists occurs more than twice a week, controller therapy should be considered. For persistent asthma, low-dose inhaled corticosteroids are recommended in addition to reliever medication. Compliance to regular therapy can pose problems for disease management, and while intermittent controller therapy regimens have been shown to be effective, it is imperative to stress the value of regular therapy especially if an exacerbation occurs. It is also important when such an approach is adopted that there is regular re-evaluations of asthma control. This is because regular anti-inflammatory therapy may become necessary if symptoms become more persistent. Other therapies are seldom needed. Antileukotrienes can be considered an option for mild asthma; however, studies have shown that they are not as effective as inhaled corticosteroids. Aside from therapy, patient education, which includes a written action plan, should be a component of the patient’s strategy for disease management.
doi:10.2147/JAA.S14420
PMCID: PMC3047902  PMID: 21437051
mild asthma; treatment; inhaled corticosteroids; asthma education
11.  Exacerbations of asthma without sputum eosinophilia. 
Thorax  1995;50(10):1057-1061.
BACKGROUND--Sputum analysis provides a non-invasive method of examining the airway secretions of subjects with asthma in order to better understand the inflammatory process. Increased proportions of eosinophils are generally seen in the sputum of subjects with asthma, especially when there is an exacerbation. An unexpected observation in the sputum of subjects with mild exacerbations of asthma is reported. METHODS--Thirty four consecutive subjects with symptoms consistent with a mild exacerbation of asthma were recruited for a treatment study. Inclusion criteria required persistent symptoms of chest tightness, dyspnoea, or wheezing for two weeks (without spontaneous improvement or alteration in dose of inhaled corticosteroid) and a forced expiratory volume in one second (FEV1) that was reversible to more than 75% predicted or known best to ensure the exacerbation was mild. Sputum (spontaneous or induced with hypertonic saline) from all subjects was examined for differential cell counts. Eosinophilic sputum was defined as > or = 4% eosinophils on two occasions or > 10% eosinophils once. Clinical characteristics, sputum differential counts, and measurements of airways obstruction were compared between the subjects with and without sputum eosinophilia. RESULTS--Almost half of the subjects (16 of 34) considered to have mildly uncontrolled asthma had no sputum eosinophilia. In comparison with the subjects who had sputum eosinophilia the non-eosinophilic group had less airways obstruction (FEV1% predicted 88% v 70%) and less severe airways hyperresponsiveness (PC20 methacholine 0.45 mg/ml v 0.13 mg/ml). There was no difference between the groups in the type or prevalence of symptoms, history of recent infections, smoking, relevant allergen exposure, or use of inhaled corticosteroid. CONCLUSIONS--Symptoms of mildly uncontrolled asthma are not always associated with eosinophilic airways inflammation as measured by sputum analysis. The causes and treatment of the non-eosinophilic condition require further investigation.
PMCID: PMC475018  PMID: 7491553
12.  INDIVIDUALIZED ASTHMA SELF-MANAGEMENT IMPROVES MEDICATION ADHERENCE AND MARKERS OF ASTHMA CONTROL 
Background
Adherence to inhaled anti-inflammatory therapy and self-management skills are essential parts of the asthma treatment plan to improve asthma control and prevent exacerbations. Whether self-management education improves long-term medication adherence is less clear.
Objective
A 24-week prospective, randomized controlled trial was performed to study the impact of self-management education on long-term adherence to inhaled corticosteroid (ICS) therapy and markers of asthma control.
Methods
After stabilization on ICS medication during a run-in phase, 95 adults with moderate to severe asthma were recruited from a large metropolitan community and 84 were randomized to individualized self-management education including self-monitoring of symptoms and peak flow or usual care with self-monitoring alone. The key components of the 30-minute intervention were asthma information, assessment and correction of inhaler technique, an individualized action plan based on self-monitoring data, and environmental control strategies for relevant allergen and irritant exposures. The intervention was personalized based on pulmonary function, allergen skin test reactivity, and inhaler technique and reinforced at 2 week intervals.
Results
Participants randomized to the self-management intervention maintained consistently higher ICS adherence levels and showed a nine-fold greater odds of more than 60% adherence to prescribed dose compared to controls at the end of the intervention (p=.02) and maintained a three-fold greater odds of higher than 60% adherence at the end of the study. Perceived control of asthma improved (p=.006), nighttime awakenings decreased (p=.03), and inhaled beta-agonist use decreased (p=.01) in intervention participants compared to controls.
Conclusion
Our results show that individualized asthma self-management education attenuates the usual decline in medication adherence and improves clinical markers of asthma control.
doi:10.1016/j.jaci.2009.01.053
PMCID: PMC2729175  PMID: 19348923
Asthma; Self-Management; Adherence; Asthma Control
13.  Asthma and Therapeutics: Recombinant Therapies in Asthma 
Numerous recombinant therapies are being investigated for the treatment of asthma. This report reviews the current status of several of these novel agents. Anti-immunoglobulin (Ig)E (omalizumab, Xolair) markedly inhibits all aspects of the allergen challenge in subjects who have reduction of free serum IgE to undetectable levels. Several clinical studies in atopic asthma have demonstrated benefit by improved symptoms and lung function and a reduction in corticosteroid requirements. Early use in atopic asthmatics may be even more effective. Several approaches target interleukin (IL)-4. Soluble IL-4 receptor has been shown to effectively replace inhaled corticosteroid; further studies are under way. Recombinant anti-IL-5 and recombinant IL-12 inhibit blood and sputum eosinophils and allergen-induced eosinophilia without any effect on airway responsiveness, allergen-induced airway responses, or allergen-induced airway hyperresponsiveness. Efalizumab, a recombinant antibody that inhibits lymphocyte trafficking, is effective in psoriasis. A bronchoprovocation study showed a reduction in allergen-induced late asthmatic response and allergen-induced eosinophilia, which suggests that it should be effective in clinical asthma. These exciting novel therapies provide not only promise of new therapies for asthma but also valuable tools for investigation of asthma mechanisms.
doi:10.1186/1710-1492-1-1-34
PMCID: PMC3225821  PMID: 20529233
14.  Adherence to Treatment in Severe Asthma: Predicting Factors in a Program for Asthma Control in Brazil 
Background
In Brazil, like many other low- to middle-income countries, most asthmatic patients cannot afford the medication necessary to prevent exacerbations. The reference clinic of the Programme for Asthma Control in Bahia (ProAR; Salvador-Bahia) offers free medical care, pharmaceutical assistance (inhaled medication) and patient education. The reference clinic is accessible to all the population of Salvador and the Programme is targeted on severe asthma.
Objective
The aim of the present study was to evaluate adherence to inhaled medication in severe asthmatics enrolled in ProAR.
Methods
A sub-group of 160 consecutive severe asthmatics enrolled in ProAR were followed prospectively for 6 months. All patients were assessed by means the Asthma Control Questionnaire, the Beck Depression Inventory and spirometry. The rate of adherence to inhaled corticosteroid was checked monthly. A cut-off point of 80% of the doses prescribed in the period was used to define patients as adherent.
Results
Of the one hundred-sixty patients with severe asthma included, it was possible to objectively assess adherence to the use of the inhaled corticosteroid in 158. Among these, 112 (70.9%) were considered adherent according to the adopted cut-off point. The rate of adherence in the whole sample of subjects was 83.9% of the prescribed doses. There was a significant association between asthma control and adherence to treatment. Predictors of poor adherence were adverse effects, living far from the referral center, limited resources to pay for transportation and dose schedule.
Conclusion
In the present study, adherence to treatment was high. In a sample of patients with severe asthma managed in a public program that provides free medication and multidisciplinary treatment at a referral center, adherence to treatment was found to be associated with favorable clinical outcomes.
doi:10.1097/WOX.0b013e3181d25e8e
PMCID: PMC3651054  PMID: 23282417
adherence; asthma; predictors; severe; treatment
15.  Steroid naive eosinophilic asthma: anti-inflammatory effects of fluticasone and montelukast 
Thorax  2005;60(2):100-105.
Background: Inhaled corticosteroids and leukotriene receptor antagonists reduce airway eosinophilia and have been used as first line anti-inflammatory therapy for mild persistent asthma.
Methods: A multicentre, randomised, placebo controlled, parallel group study was performed to compare the anti-inflammatory effects of fluticasone propionate and montelukast as measured by sputum eosinophils in 50 adults with symptomatic steroid naive asthma and sputum eosinophilia of ⩾3.5%.
Results: Eighteen patients received low dose fluticasone (250 µg/day), 19 received montelukast (10 mg/day), and 13 were given placebo for 8 weeks. Fluticasone treatment resulted in a greater reduction in sputum eosinophils (geometric mean (SD) 11.9 (2.3)% to 1.7 (5.1)%) than montelukast (10.7 (2.3)% to 6.9 (3.8)%; p = 0.04) or placebo (15.4 (2.4)% to 7.8 (4.2)%; p = 0.002), and improvement in FEV1 (mean (SD) 2.6 (0.9) l to 3.0 (0.9) l) than montelukast (2.8 (0.7) l to 2.8 (0.9) l; p = 0.02) or placebo (2.4 (0.8) l to 2.4 (0.9) l; p = 0.01). Treatment with fluticasone suppressed sputum eosinophilia within a week while montelukast only attenuated it. The effect of montelukast was maximal at 1 week and was maintained over 4 weeks. The effect of fluticasone was maintained over 8 weeks while that of montelukast was not.
Conclusions: Montelukast is not as effective as low dose fluticasone in reducing or maintaining an anti-inflammatory effect in steroid naïve eosinophilic asthma.
doi:10.1136/thx.2004.021634
PMCID: PMC1747311  PMID: 15681495
16.  Relationships between repeated instruction on inhalation therapy, medication adherence, and health status in chronic obstructive pulmonary disease 
Purpose
Adherence to inhalation therapy is a critical determinant of the success of chronic obstructive pulmonary disease (COPD) management. However, in practice, nonadherence to inhalation therapy is very common in COPD patients. The effects of adherence to inhalation therapy in COPD have not been fully studied, and less is known about the relationship between medication adherence and quality of life in COPD. Our aim is to assess the factors that contribute to adherence to inhalation therapy and examine their correlation with quality of life.
Patients and methods
A cross-sectional analysis of 88 COPD patients was performed using a self-reported adherence questionnaire with responses on a 5-point Likert scale.
Results
Of the 88 patients who were potential participants, 55 (63%) responded with usable information. The only significant factor associated with the overall mean adherence score was receiving repeated instruction about inhalation techniques (P = 0.032). Of the 55 respondents, 22 (40.0%) were given repeated verbal instruction and/or demonstrations of inhalation technique by a respiratory physician. Significant correlations were found between the overall mean adherence score and the health-related quality of life score (St George’s Respiratory Questionnaire: total, r = −0.35, P = 0.023; symptoms, r = −0.43, P = 0.002; impacts, r = −0.35, P = 0.011). Furthermore, patients with repeated instruction showed better quality of life scores than those who did not receive instruction (total, P = 0.030; symptoms, P = 0.038; impacts, P = 0.019).
Conclusions
Repeated instruction for inhalation techniques may contribute to adherence to therapeutic regimens, which relates to better health status in COPD.
doi:10.2147/COPD.S16173
PMCID: PMC3048085  PMID: 21407822
COPD; adherence; quality of life; repeated instruction
17.  Clinical characteristics and long-term outcomes related to sputum eosinophilia in Korean asthmatics 
Asia Pacific Allergy  2011;1(1):16-24.
Background
Bronchial asthma is usually associated with high sputum eosinophil levels. However, recent reports have suggested the importance of noneosinophilic asthma (NEA) as a distinct phenotype of asthma.
Objective
The aim of this study was to evaluate clinical significance of sputum eosinophilia and long-term treatment outcomes related to sputum eosinophilia in Korean asthmatics.
Methods
A total of 201 steroid-naive asthmatics who had undergone induced sputum analysis at baseline were selected from the Cohort for Reality and Evolution of Adult Asthma study population. Clinical evaluation, spirometry, a skin-prick test, a methacholine bronchial provocation test, and sputum eosinophil analysis were performed initially, and patients received the treatment recommended by the Global Initiative for Asthma. Lung function was evaluated every 6 months, and 53 patients completed 24 months of regular follow-up visits. Sputum eosinophilia was defined as a sputum eosinophil count of >3%.
Results
Of the 201 steroid-naive asthmatics, 97 patients had NEA and 104 had eosinophilic asthma (EA). Only 52% of steroid-naive asthmatic subjects had elevated baseline sputum eosinophil levels. A higher percentage of sputum eosinophils was associated with a lower PC20 (r = -0.193; p = 0.009, Spearman correlation), but not with forced expiratory volume in one second (FEV1) (r = 0.045; p = 0.525). During the 24-month study period, the percentage change of FEV1 was significantly lower in the NEA group than in the EA group at 6, 12, 18, and 24 months (p < 0.05). The NEA group, unlike the EA group, showed no significant improvement in FEV1 at 6, 12, 18, or 24 months (p > 0.05).
Conclusion
A higher sputum eosinophil percentage was correlated with a higher airway hyperresponsiveness. Compared with EA patients, NEA patients had poor treatment outcomes in the 2-year follow-up of a Korean asthma cohort population.
doi:10.5415/apallergy.2011.1.1.16
PMCID: PMC3206232  PMID: 22053292
Asthma; Induced sputum; Eosinophil; Noneosinophilic asthma
18.  Effect of different monotherapies on serum nitric oxide and pulmonary functions in children with mild persistent asthma 
Introduction
Common medications used to treat mild persistent asthma are glucocorticoids, leukotriene receptor antagonists and theophylline. The aim of the study was to evaluate monotherapy with either inhaled steroids, oral leukotriene receptor antagonist or theophylline in Egyptian children with mild persistent asthma by determining their clinical, laboratory and spirometric responses to treatment.
Material and methods
Thirty-nine mild asthmatic children between 8 and 13 years of age were included in the study. Patients were classified according to therapy received into four groups: oral leukotriene receptor antagonist (montelukast), inhaled corticosteroid (fluticasone propionate), sustained-release (SR) theophylline, and no treatment. Pulmonary function testing was performed at the start of therapy and 8 weeks later using spirometry. Eosinophil count and serum nitric oxide were estimated in the blood. Minitab statistical package was used for analysis of data.
Results
Follow-up after 8 weeks revealed significant improvement in FEV1% in groups 1 (p < 0.01) and 3 (p < 0.05), significant improvement in PEFR in groups 1 (p < 0.05) and 2 (p < 0.01), significant decline in serum NO levels in groups 1 (p < 0.05) and 2 (p < 0.05), as well as significant improvement in eosinophil count in groups 1, 2 and 3 (p < 0.01, < 0.001, < 0.01 respectively). There was a statistically significant positive correlation between the decline in serum NO and the decline in blood eosinophil % in group 2 (p < 0.05).
Conclusions
Inhaled corticosteroids and montelukast have a significant role in controlling the pulmonary functions and the inflammatory process in children with mild persistent asthma, although inhaled corticosteroids seem to yield a better response. Children with mild persistent asthma should receive a controller medication, and SR theophylline may be a good cost-benefit alternative for low socio-economic groups of patients.
doi:10.5114/aoms.2010.19302
PMCID: PMC3302705  PMID: 22427767
asthma; inhaled corticosteroids; montelukast; slow-release theophylline
19.  Predictors of Asthma Medication Nonadherence 
Objective
To describe asthma medication adherence behavior and to identify predictors of inhaled corticosteroid (ICS) under use and inhaled beta-agonist (IBA) overuse.
Methods
Self-reported medication adherence, spirometry, various measures of socioeconomic status, and blood for IgE measurement were collected on 158 subjects from a larger cohort of adults with asthma and rhinitis, who were prescribed an ICS, IBA, or both.
Results
There was a positive association between ICS under use and higher forced expiratory volume in one second percent (FEV1%) predicted (p=.01) and a negative association with lower income (p=0.04). IBA overuse was positively associated with greater perceived severity of asthma (p=0.004) and negatively with higher education level (p=0.02).
Conclusions
Nonadherence to prescribed asthma therapy seems to be influenced by socioeconomic factors and by perceived and actual severity of disease; these factors are important to assess when trying to estimate the degree of medication adherence and its relationship to clinical presentation.
doi:10.1016/j.hrtlng.2007.05.014
PMCID: PMC2447544  PMID: 18482633
20.  Medication adherence issues in patients treated for COPD 
Although medical treatment of COPD has advanced, nonadherence to medication regimens poses a significant barrier to optimal management. Underuse, overuse, and improper use continue to be the most common causes of poor adherence to therapy. An average of 40%–60% of patients with COPD adheres to the prescribed regimen and only 1 out of 10 patients with a metered dose inhaler performs all essential steps correctly. Adherence to therapy is multifactorial and involves both the patient and the primary care provider. The effect of patient instruction on inhaler adherence and rescue medication utilization in patients with COPD does not seem to parallel the good results reported in patients with asthma. While use of a combined inhaler may facilitate adherence to medications and improve efficacy, pharmacoeconomic factors may influence patient’s selection of both the device and the regimen. Patient’s health beliefs, experiences, and behaviors play a significant role in adherence to pharmacological therapy. This manuscript reviews important aspects associated with medication adherence in patients with COPD and identifies some predictors of poor adherence.
PMCID: PMC2629978  PMID: 18990964
adherence; chronic obstructive pulmonary disease; compliance; inhalers; inhalation technique; patient preference; quality of life
21.  Adding salmeterol to an inhaled corticosteroid: long term effects on bronchial inflammation in asthma 
Thorax  2006;61(4):306-312.
Background
Addition of the long acting β2 agonist salmeterol to inhaled corticosteroids leads to better symptomatic asthma control than increasing the dose of inhaled corticosteroids. However, little is known about the long term effects of adding salmeterol on the asthmatic inflammatory process, control of which is considered important for the long term outcome of asthma.
Methods
After a 4 week fluticasone run‐in period, 54 patients with allergic asthma were randomised to receive twice daily treatment with fluticasone 250 μg with or without salmeterol 50 μg for 1 year in a double blind, parallel group design (total daily dose of fluticasone 500 μg in both treatment groups). Primary outcomes were sputum eosinophil numbers and eosinophil cationic protein concentrations. Secondary outcomes were neutrophil associated sputum parameters and a respiratory membrane permeability marker. The effects on allergen induced changes were determined before and at the end of the treatment period.
Results
Adding salmeterol to fluticasone resulted in improved peak expiratory flow, symptom scores, rescue medication usage, and bronchial hyperresponsiveness (p<0.05 for all). There was no sustained effect on sputum cell differential counts and cytokine concentrations during the treatment period or on changes induced by allergen challenge at the end of treatment (p>0.05). However, adding salmeterol significantly reduced sputum ratios of α2‐macroglobulin and albumin during the treatment period (p = 0.001).
Conclusions
The addition of salmeterol to fluticasone produces no sustained effect on allergen induced cellular bronchial inflammation but leads to a significant improvement in size selectivity of plasma protein permeation across the respiratory membrane. This may contribute to the improved clinical outcome seen in patients with allergic asthma when a long acting β2 agonist is combined with inhaled corticosteroids.
doi:10.1136/thx.2005.051292
PMCID: PMC2104614  PMID: 16449264
asthma; inflammation; sputum; bronchodilator agents; anti‐inflammatory agents
22.  Update on optimal use of omalizumab in management of asthma 
Omalizumab is a humanized monoclonal anti-IgE antibody recently approved for the treatment of severe allergic asthma. This drug inhibits allergic responses by binding to serum IgE, thus preventing interaction with cellular IgE receptors. Omalizumab is also capable of downregulating the expression of high affinity IgE receptors on inflammatory cells, as well as the numbers of eosinophils in both blood and induced sputum. The clinical effects of omalizumab include improvements in respiratory symptoms and quality of life, paralleled by a reduction of asthma exacerbations, emergency room visits, and use of systemic corticosteroids and rescue bronchodilators. Omalizumab is relatively well-tolerated, and only rarely induces anaphylactic reactions. Therefore, this drug represents a valid option as add-on therapy for patients with severe persistent allergic asthma inadequately controlled by high doses of standard inhaled treatments.
doi:10.2147/JAA.S14520
PMCID: PMC3140296  PMID: 21792319
omalizumab; anti-IgE; severe asthma
23.  Pharmacogenomic Approaches to Asthma Treatment 
Major classes of medication in asthma management include bronchodilating β2-agonists, anti-inflammatory inhaled corticosteroids, leukotriene modifiers and theophyllines. However, all asthmatics do not respond to the same extent to a given medication. Available data suggest that a substantial range of individual variability, as much as 70%, may be due to genetic characteristics of each patient. Pharmacogenomics offers the potential to optimize medications for individual asthmatics by using genetic information to improve efficacy or avoid adverse effects. The best-studied case of the potential contribution of pharmacogenomics to treatment response in asthma comes from studies on human β2 adrenergic receptors. In addition, genetic variation in β2-adrenergic receptor (Arg16Gly) may predict response to anticholinergics for the treatment of asthma. In case of inhaled corticosteroids, a recent investigation using a traditional SNP-based approach identified a gene for corticotropin releasing hormone receptor 1 as a potential marker of response. Another major pathway that has been investigated is the pathway underlying response to cysteinyl leukotriene receptor antagonist. It is likely that in the near future, pharmacogenomic approaches based on individual genetic information will be introduced into an asthma treatment guideline and this guideline will allow us to identify those who have the best chance to respond to a specific medication.
doi:10.4168/aair.2010.2.3.177
PMCID: PMC2892049  PMID: 20592916
Asthma; pharmacogenomics; treatment response
24.  Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma 
Thorax  2002;57(3):226-230.
Background: Although inhaled corticosteroids have an established role in the treatment of asthma, studies have tended to concentrate on non-smokers and little is known about the possible effect of cigarette smoking on the efficacy of treatment with inhaled steroids in asthma. A study was undertaken to investigate the effect of active cigarette smoking on responses to treatment with inhaled corticosteroids in patients with mild asthma.
Methods: The effect of treatment with inhaled fluticasone propionate (1000 µg daily) or placebo for 3 weeks was studied in a double blind, prospective, randomised, placebo controlled study of 38 steroid naïve adult asthmatic patients (21 non-smokers). Efficacy was assessed using morning and evening peak expiratory flow (PEF) readings, spirometric parameters, bronchial hyperreactivity, and sputum eosinophil counts. Comparison was made between responses to treatment in non-smoking and smoking asthmatic patients.
Results: There was a significantly greater increase in mean morning PEF in non-smokers than in smokers following inhaled fluticasone (27 l/min v –5 l/min). Non-smokers had a statistically significant increase in mean morning PEF (27 l/min), mean forced expiratory volume in 1 second (0.17 l), and geometric mean PC20 (2.6 doubling doses), and a significant decrease in the proportion of sputum eosinophils (–1.75%) after fluticasone compared with placebo. No significant changes were observed in the smoking asthmatic patients for any of these parameters.
Conclusions: Active cigarette smoking impairs the efficacy of short term inhaled corticosteroid treatment in mild asthma. This finding has important implications for the management of patients with mild asthma who smoke.
doi:10.1136/thorax.57.3.226
PMCID: PMC1746270  PMID: 11867826
25.  Importin-13 genetic variation is associated with improved airway responsiveness in childhood asthma 
Respiratory Research  2009;10(1):67.
Background
Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20).
Methods
10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC20 were performed using mixed models and confirmed using family-based tests of association.
Results
Among participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC20 (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51–2.17 fold increase in mean PC20 at 8-months post-randomization that persisted over four years of observation (p = 0.01–0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC20 by IPO13 variants among children treated with inhaled corticosteroids.
Conclusion
IPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids.
doi:10.1186/1465-9921-10-67
PMCID: PMC2724419  PMID: 19619331

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