Access to inhaled corticosteroids is key to improving quality of care for asthma in developing countries

Asthma is a worldwide public health problem affecting about 300 million people. The majority of persons living with asthma are in the developing world where there is limited access to essential drugs. The financial burden for persons living with asthma and their families, as well as for healthcare systems and governments, is very high. Inadequate treatment and the high cost of medications leads to disability, absenteeism and poverty. Despite the existence of effective asthma medications and international guidelines, and progress made in the implementation of such guidelines over the last decade, the high cost of essential asthma medications remains a major obstacle for patient access to treatment in developing countries. The International Union Against Tuberculosis and Lung Disease has evaluated this problem and created an Asthma Drug Facility (ADF) so that countries can purchase affordable, good quality essential drugs for asthma. The ADF uses pooled procurement along with other purchasing and supply strategies to obtain the lowest possible prices. Accompanied by the implementation of standardized asthma management, the increased affordability of drugs provided by the ADF should bring rapid and significant health and cost benefits for patients, their communities and governments.     

Adherence rate to inhaled corticosteroids and their impact on asthma control

Background:  Poor asthma control is associated to high morbidity. The objective of this study was to assess the association between adherence rates to beclomethasone dipropionate (BDP) and the degree of asthma control.
Methods:  A cohort concurrent study was carried out for 12 months with 122 asthmatic patients, aged 3–12 years, randomly selected in a pediatric pulmonology outpatient clinic, who received BDP free of charge. Adherence rates were verified by pharmacy records. Clinical control was assessed through a scoring system comprised four variables (nocturnal and morning symptoms, limitation of physical activities and exacerbations). Total score was 16 points. Patients whose score was below or equal to two were considered controlled (group 1), and patients whose score was above or equal to three were considered uncontrolled (group 2). For patients able to perform spirometry, we considered as controlled the patients with forced expiratory volume in 1 s (FEV₁) equal to or above 80% of the predicted value, and as uncontrolled the patients with FEV₁ below 80%.
Results:  Fewer than half (40.3% maximum) of the 122 patients maintained asthma control. Median adherence rate of groups 1 and 2 were 85.5% and 33.8%, ( P  < 0.001) in the 4th month, 90.0% and 48.0% ( P  < 0.001) in the 8th month and 84.4% and 47.0% in the 12th month ( P  < 0.001), respectively.
Conclusion:  In all periods, there were statistically significant differences in adherence rates for maintaining or not maintaining the asthma control. Optimal asthma control entailed adherence rate higher than 80%. Strategies for reducing asthma morbidity should include a regular monitoring of adherence to inhaled steroids.     

Poor adherence with inhaled corticosteroids for asthma: can using a single inhaler containing budesonide and formoterol help?

BACKGROUND: Poor adherence with inhaled corticosteroids is an important problem in asthma management. Previous approaches to improving adherence have had limited success. AIM: To determine whether treatment with a single inhaler containing a long-acting beta(2)-agonist and a corticosteroid for maintenance treatment and symptom relief can overcome the problem of poor adherence with inhaled corticosteroids. DESIGN OF STUDY: Randomised, parallel group, open-label trial. SETTING: Forty-four general practices in Nottinghamshire. METHOD: Participants who used less than 70% of their prescribed dose of inhaled corticosteroid and had poorly controlled asthma were randomised to budesonide 200 microg one puff twice daily plus their own short-acting beta(2)-agonist as required (control group), or budesonide/formoterol 200/6 microg one puff once daily and as required (active group) for 6 months. The primary outcome was inhaled corticosteroid dose. RESULTS: Seventy-one participants (35 control, 36 active group) were randomised. Adherence with budesonide in the control group was approximately 60% of the prescribed dose. Participants in the active group used approximately 80% more budesonide than participants in the control group (448 versus 252 microg/day, mean difference 196 mug, 95% confidence interval 113 to 279; P<0.001) and were less likely to withdraw from the study (3 versus 13; P<0.01). No safety issues were identified. CONCLUSION: Using a single inhaler for both maintenance treatment and symptom relief approximately doubled the dose of inhaled corticosteroid taken, suggesting this could be a useful strategy to overcome the problems related to poor adherence with inhaled corticosteroids.     

Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma

BACKGROUND: Regular use of inhaled corticosteroids (ICSs) can improve asthma symptoms and prevent exacerbations. However, overall adherence is poor among patients with asthma. Objective To estimate the proportion of poor asthma-related outcomes attributable to ICS nonadherence. METHODS: We retrospectively identified 405 adults age 18 to 50 years who had asthma and were members of a large health maintenance organization in southeast Michigan between January 1, 1999, and December 31, 2001. Adherence indices were calculated by using medical records and pharmacy claims. The main outcomes were the number of asthma-related outpatient visits, emergency department visits, and hospitalizations, as well as the frequency of oral steroid use. RESULTS: Overall adherence to ICS was approximately 50%. Adherence to ICS was significantly and negatively correlated with the number of emergency department visits (correlation coefficient [ R ] = -0.159), the number of fills of an oral steroid ( R = -0.179), and the total days' supply of oral steroid ( R = -0.154). After adjusting for potential confounders, including the prescribed amount of ICS, each 25% increase in the proportion of time without ICS medication resulted in a doubling of the rate of asthma-related hospitalization (relative rate, 2.01; 95% CI, 1.06-3.79). During the study period, there were 80 asthma-related hospitalizations; an estimated 32 hospitalizations would have occurred were there no gaps in medication use (60% reduction). CONCLUSIONS: Adherence to ICS is poor among adult patients with asthma and is correlated with several poor asthma-related outcomes. Less than perfect adherence to ICS appears to account for the majority of asthma-related hospitalizations.     

Maintenance of asthma control by once-daily inhaled ciclesonide in adults with persistent asthma

BACKGROUND: Inhaled corticosteroids (ICS) are recommended therapy for persistent asthma, although side effects can limit appropriate use. Ciclesonide, a novel ICS, is activated in the lung, thereby reducing systemic activity and side effects. This 12-week, double-blind, randomized, parallel-group, placebo-controlled study evaluated the efficacy and safety of ciclesonide in adults with persistent asthma. METHODS: After a 2-week baseline period in which current ICS treatment was continued, 329 patients were randomized to receive ciclesonide 160 microg (n = 107) or 640 microg (n = 112) (ex-actuator doses, equivalent to 200 and 800 microg ex-valve, respectively), or placebo (n = 110) once daily in the morning. Efficacy was monitored by asthma symptom scores, rescue medication use, morning and evening peak expiratory flow (PEF) measurements, spirometry, and probability of study completion without experiencing lack of efficacy. RESULTS: Morning PEF remained stable with either ciclesonide dose but decreased with placebo; the differences were significant (P < 0.0001) for both ciclesonide doses vs placebo. The forced expiratory volume in 1 s and forced vital capacity decreased significantly with placebo (P < 0.005), but were unchanged with ciclesonide. Lack of efficacy was significantly greater for patients switched to placebo (63%) than it was for those treated with ciclesonide 160 microg (30%) (P < 0.0001 vs placebo) or ciclesonide 640 microg (31%) (P < 0.0001 vs placebo). There were no significant differences between the two tested doses of ciclesonide with respect to efficacy and safety. Serum and 24-h urine cortisol were unaffected by ciclesonide treatment. Both doses of ciclesonide were well tolerated with no cases of oral candidiasis. CONCLUSION: Ciclesonide (160 or 640 microg) once daily in the morning effectively maintains asthma control, does not affect cortisol levels, and has an adverse event profile comparable with placebo in adults with primarily mild to moderate asthma.     

Increased numbers of dendritic cells in the bronchial mucosa of atopic asthmatic patients: downregulation by inhaled corticosteroids

Background Dendritic cells (DC) are the most potent antigen-presenting cells (APC) and stimulators of T cells. Dendritic cells are also likely to be essential for the initiation of allergic immune responses in the lung. However, there are not many data on the presence of dendritic cells in the airways of patients with atopic asthma and on the effects of corticosteroid-treatment on such dendritic cells. Objective We investigated the distribution of dendritic cells in the bronchial epithelium and mucosa of 16 non-smoking atopic asthmatic patients and eight healthy control subjects using detailed immunohistochemistry (CD l a, HLA-DR, L25 as markers for dendritic cells). Methods Eleven asthmatics were treated for 2.5 years with bronchodilators only and five with bronchodilators and inhaled beclomethasone dipropionate (BDP), 800 μg daily. The patients were randomly sampled from a double-blind multicentre study. Results There were higher numbers of CD la⁺ DC (P = 0.003), L25⁺ DC (P = 0.002) and HLA-DR expression (P = 0.042) in the bronchial mucosa of asthmatic patients compared with healthy controls. After 2.5 years of treatment, we found a significant increase in fiow expiratory volume in I second (FEV₁) (P = 0.009) and a significant decrease in hyperresponsiveness (PC₂₀ histamine) (P= 0.013) in the corticosteroid group (n = 5) compared with the bronchodilator group (n= 11). This dinical improvement in the corticosteroid-treated group was accompanied by significantly lower numbers of CDla⁺ DC (P = 0.008), and HLA-DR expression (P- 0.028) in the bronchial mucosa than in the bronchodilator-treated group. Conclusion Our data suggest that dendritic cells are involved in asthmatic inflammation and that corticosteroids may downregulute the number of dendritic.     

Assessment of asthma control and its impact on optimal treatment strategy

Achieving and maintaining optimal asthma control is a major asthma management goal advocated by the Global Initiative for Asthma (GINA). Recent evidence suggests that while asthma control is clearly achievable in most asthmatics, not all asthmatics attain optimal asthma control. The difficulty is compounded further because patients, physicians and regulatory bodies have different perceptions of what is meant by asthma control. The challenge therefore remains as to how best to assess asthma control and define management strategies to ensure that this control is achieved and maintained. Despite the availability of several patient-based tools for assessing asthma control, these are mostly employed in a research setting or in selected specialist clinics. A symptom-based treatment approach also may have its limitations because patients can be poor judges of disease symptoms and severity and under-estimation may lead to inadequate treatment of airway inflammation and airway hyperresponsiveness (AHR) when treatment is administered as on-demand reliever therapy, since the effect of treatment on these underlying features occurs over a longer time course. The clinical benefits of sustained maintenance treatment for at least 3 months has been documented in recent studies of salmeterol/fluticasone propionate combination, which have demonstrated correlations between reduction in airway inflammation/AHR and reduction in exacerbation rates. In view of the putative limitations of a purely symptom-based asthma management plan, we suggest that treatment should be focussed on management of all aspects of the disease rather than management of symptoms alone, with a practical approach being treatment for a minimum of 3 months with an optimal dose to ensure maximal effects are seen on asthma control, airway inflammation, lung function, and remodelling.     

Sodium cromoglycate as a replacement for inhaled corticosteroids in mild-to-moderate childhood asthma

We investigated whether sodium cromoglycate 10 mg three times daily, delivered as an aerosol via Nebuhaler (in addition to terbutaline 0.5 mg three times daily), could replace inhaled steroid in children with mild-to-moderate asthma. Children (mean age 10.3 years) were randomly allocated to 12-week treatment with sodium cromoglycate 10 mg plus terbutaline 0.5 mg (group A; n =30) or placebo plus terbutaline 0.5 mg (group B; n =32), both taken three times a day. The daily steroid dose was reduced by 50 μg/ week for 4 weeks from a starting dose of 200 μg. Fewer patients withdrew owing to worsening asthma from group A ( n =1) than group B ( n =11). Symptom scores, morning and evening peak flows, and additional β₂-agonist usage, recorded on diary cards, were better in group A than group B. Lung function measured at clinic visits was unchanged in either group. Overall opinions of efficacy favoured Group A. Adverse events were similar in the groups. Sodium cromoglycate plus terbutaline substituted effectively for inhaled steroid therapy.     

Butterbur, a herbal remedy, confers complementary anti-inflammatory activity in asthmatic patients receiving inhaled corticosteroids

BACKGROUND: The effects of butterbur (BB), a herbal remedy, as add-on therapy to inhaled corticosteroids in patients with atopic asthma is currently unknown. OBJECTIVE: We evaluated the effects of BB, given as add-on therapy to asthmatic patients maintained on inhaled corticosteroids, assessing adenosine monophosphate (AMP) bronchoprovocation (primary outcome variable) along with other surrogate inflammatory markers such as exhaled nitric oxide, serum eosinophil cationic protein and peripheral blood eosinophil count. METHODS: Sixteen atopic asthmatic patients with mean (standard error of mean) forced expiratory volume in 1 s (FEV1) of 78 (4)% predicted, maintained on their constant dose of inhaled corticosteroids throughout the study, received twice daily for 1 week either BB 25 mg or placebo (PL), in a double-blind, cross-over fashion, with a 1-week washout period prior to each randomized treatment. Measurements were made at baselines prior to each randomized treatment and following the randomized treatment period. RESULTS: Baseline values for the primary and secondary outcomes were not significantly different prior to BB and PL. AMP provocative concentration causing a 20% reduction from baseline FEV1 (PC20) as doubling dilution change from baseline, significantly improved (P<0.05) with BB, 0.6 (0.2), compared with PL, -0.1 (0.3); a 0.7 doubling dilution difference. Exhaled nitric oxide as change from baseline was significantly reduced (P<0.05) with BB, -1.2 (0.8) p.p.b., compared with PL, 0.5 (0.4) p.p.b. Both serum eosinophil cationic protein and peripheral blood eosinophil count as change from baseline were also significantly suppressed (P<0.05) with BB, -3.9 (3.3) microg/L, -31 (28)x106/L compared with PL, 3.3 (2.5) microg/L, 38 (16)x106/L, respectively. CONCLUSION: Chronic dosing with BB conferred complementary anti-inflammatory activity in atopic asthmatic patients maintained on inhaled corticosteroids. Further studies are now required to assess the potential role for BB as either monotherapy in milder patients or add-on therapy in more severe asthmatics.     

Inhaled corticosteroids decrease vascularity of the bronchial mucosa in patients with asthma

BACKGROUND: Increased vascularity in airway mucosa is a distinctive feature of airway remodelling in asthma. While corticosteroids have proved most effective in modifying airway inflammation, the effect of inhaled corticosteroids on increased airway mucosal vascularity in asthmatics has been little studied. OBJECTIVE: We examined the effect of inhaled corticosteroid on airway vascularity in bronchial biopsy specimens taken from asthmatic patients. SUBJECTS AND METHODS: We studied bronchial biopsies from 28 asthmatic patients before and after treatment with inhaled beclomethasone dipropionate (BDP) 800 microg/daily, or placebo, for 6 months in a double-blind manner. Biopsy specimens were evaluated for number of vessels and percentage of area occupied by vessels, using computerized image analysis after staining for type IV collagen in vessel walls. Specimens were also examined for extent of collagen III in the subepithelial basement membrane. In addition, we compared asthmatic specimens with biopsy specimens taken from non-asthmatic control subjects. RESULTS: There was a significant increase in number of vessels (P < 0.01) and percent vascularity (P < 0.001) in the submucosa of asthmatic patients compared with control subjects. After 6 months of treatment, we observed significant improvements in forced expiratory volume in 1 s (FEV1), FEV1% and airway responsiveness (P < 0.05, each) in the BDP treatment group compared with the placebo group. This was accompanied by significant decreases in both vessel number and percent vascularity in the airways of BDP-treated patients (P < 0.05, each). We also observed a significant correlation between change in percent vascularity and change in collagen III thickness in the BDP-treated patients (rs = 0.90, P < 0.001). Furthermore, the change in percent vascularity was inversely correlated with both FEV1 (rs = -0.49, P < 0.05) and airway responsiveness (rs = -0.36, P < 0.05). CONCLUSION: These findings suggest that inhaled corticosteroid treatment of asthma reduced airway wall vascularity during airway remodelling.     

Predicting episodes of poor asthma control in treated patients with asthma

BACKGROUND: Asthma exacerbations are dangerous, expensive, and difficult to anticipate. OBJECTIVE: To characterize patients with asthma who had asthma episodes and exacerbations during 4 weeks of observation. METHODS: A total of 2032 volunteers with asthma (age, 3-64 years; 62% female subjects) were studied over two 2-week intervals after flu vaccine and placebo. Baseline data, including several asthma questionnaires, were analyzed for prediction of subsequent asthma events as recorded on diaries detailing peak flow, medication use, and health care use. RESULTS: During 28 days of diary collection, 43.2% of participants had at least 1 episode of poor asthma control. Most episodes were characterized by increased use of rescue medications or reductions in peak flow, but nearly 15% of participants had exacerbations characterized by use of systemic corticosteroids, unscheduled health care visits, or both. Episode frequency was highest in children <10 years of age. Additional risk factors were smoking, African American ethnicity, low lung function, and past history of severe asthma. The best predictors were symptom questionnaires, and a simple questionnaire concerning the preceding 2 weeks worked as well as more complex questionnaires or those reflecting longer periods. In regression analyses, questionnaire results, smoking, lung function, ethnicity, and asthma history all were associated with asthma episodes in people older than 10 years, whereas only asthma history was predictive in those <10 years. CONCLUSION: Symptom questionnaires are predictive of subsequent asthma episodes in people older than age 10 years, but not in younger people. CLINICAL IMPLICATIONS: Simple assessments may be helpful in identifying patients most at risk for future asthma episodes.     

Low-dose inhaled budesonide once or twice daily for 27 months in children with mild asthma

This study is an extended follow-up for 24 months of a 12-week trial to study the long-term clinical efficacy of low-dose inhaled budesonide (BUD) once or twice daily in children with mild asthma. A total of 122 children (mean age 9.7 years, girls/boys; 42/80) with mild asthma (FEV1 103.7% of predicted, reversibility in FEV1 3.5%, and fall in FEV1 after exercise 12.2%), not previously treated with inhaled steroids, were included in a double-blind, randomized, parallel-group study. The children were treated with inhaled BUD 100 or 200 microg administered via Turbuhaler once daily in the morning, 100 microg twice daily, or placebo for 27 months. Exercise and methacholine challenges were performed at 3-month intervals the first year and at 6-month intervals the second year, in a total of seven visits. A significant dose-response effect favoring BUD 200 microg daily (vs 100 microg daily) was found when comparing changes in FEV1, FEF25%, and FEV50%; the fall in FEV1 after an exercise test; and the effect on blood eosinophils. Bronchial hyperreactivity to methacholine decreased significantly on three visits in patients treated with BUD 200 microg daily compared to placebo. Growth rate was not significantly affected except in children aged 7-11 years at baseline after 12 months of treatment. In conclusion, 100 or 200 microg daily of inhaled BUD for 27 months is safe and effective in protecting against exercise-induced asthma and achieving nearly normal lung function. Baseline lung function was not significantly affected in this group of children with mild asthma.