Moderate dose inhaled corticosteroids plus salmeterol versus higher doses of inhaled corticosteroids in symptomatic asthma

BACKGROUND: There is uncertainty as to the dose of inhaled corticosteroids (ICS) at which to start concomitant long acting beta agonist (LABA) treatment in patients with asthma not adequately controlled by ICS alone. METHODS: A meta-analysis was carried out of randomised, double blind clinical trials that compared the efficacy of adding salmeterol to moderate doses of ICS (fluticasone propionate 200 mug/day or equivalent) with increasing the ICS dose by at least twofold in symptomatic adult patients with asthma. The main outcome measures were the number of subjects withdrawn from the study due to asthma and the number of subjects with at least one moderate or severe exacerbation. RESULTS: Twelve studies with a total of 4576 subjects met the inclusion criteria for the analyses. The number of subjects withdrawn due to asthma and with at least one moderate or severe exacerbation was higher in the high dose ICS group (odds ratios 1.58, 95% CI 1.12 to 2.24 and 1.35, 95% CI 1.10 to 1.66, respectively). For the secondary outcome variables (forced expiratory volume in 1 second, morning and evening peak expiratory flow, and daytime beta agonist use) there was significantly greater benefit in the salmeterol group. CONCLUSIONS: This meta-analysis shows that the addition of salmeterol to moderate doses of ICS (fluticasone 200 mug/day or equivalent) in patients with asthma symptomatic at that dose results in significantly greater clinical benefit than increasing the dose of ICS by twofold or more.     

Use of inhaled corticosteroids in patients with mild asthma.

A double blind, parallel group study was carried out to investigate the effect of inhaled budesonide in a moderate (200 micrograms) and a low (100 micrograms) twice daily dosage compared with the effect of placebo in 103 adults with mild symptomatic asthma. Subjects recorded peak expiratory flow (PEF), asthma symptoms, and beta 2 agonist consumption at home for a period of seven weeks (a one week run in and six weeks' treatment). Morning baseline PEF (around 80% of predicted normal) increased non-significantly to 88% with 200 micrograms budesonide daily and to 90% (p less than 0.05) with 400 micrograms, compared with 81% with placebo. Evening PEF (around 94% of predicted normal) did not change significantly with active or placebo treatment. By comparison with placebo, there was a significant decrease in nocturnal asthma symptoms and beta 2 agonist consumption. The changes during the day were less pronounced and significant only for 400 micrograms budesonide daily. No significant differences between the two active treatments were detected. It is concluded that low doses of inhaled budesonide are effective in patients with mild symptomatic asthma, particularly for night time symptoms and early morning lung function. The early introduction of inhaled corticosteroids for patients with mild asthma and night time symptoms may improve their quality of life during the night and early morning.     

Initial starting dose of inhaled corticosteroids in adults with asthma: a systematic review

BACKGROUND: Asthma guidelines vary in their recommendations for the initial dose of inhaled corticosteroid (ICS) in asthma. A systematic review of the literature was conducted to establish the optimal starting dose of ICS for asthma in adults. METHODS: Randomised controlled trials comparing two doses of the same ICS in adults with asthma and no concomitant inhaled or oral corticosteroid were assessed. Included trials were analysed according to the following ICS dose comparisons: high (> or =800 microg/day beclomethasone (BDP)) versus moderate (400<800 microg/day BDP) (n = 7); moderate versus low (<400 microg/day BDP) (n = 6); step down versus constant dose (n = 4). RESULTS: Fourteen publications describing 13 trials were included in the review. Studies (n = 4) that compared a step down approach with a constant moderate/low dose of ICS found no difference in lung function, symptoms, or rescue medications between the two treatment approaches (p>0.05). There was no difference in the change in morning peak flow after treatment with high compared with moderate dose ICS. When compared with low dose ICS, moderate dose ICS significantly improved morning peak flow (change from baseline WMD 11.14 l/min, 95% CI 1.34 to 20.93) and nocturnal symptoms (SMD -0.29, 95% CI -0.53 to -0.06). CONCLUSIONS: For patients with asthma who require ICS, starting with a moderate dose is equivalent to starting with a high dose and stepping down. The small non-significant benefits of starting with a high ICS dose are not of sufficient clinical benefit to warrant its use. Initial moderate ICS doses appear to be more effective than an initial low ICS dose.     

Use of inhaled corticosteroids and risk of fractures.

Treatment with systemic corticosteroids is known to increase the risk of fractures but little is known of the fracture risks associated with inhaled corticosteroids. A retrospective cohort study was conducted using a large UK primary care database (the General Practice Research Database [GPRD]). Inhaled corticosteroid users aged 18 years or older were compared with matched control patients and to a group of noncorticosteroid bronchodilator users. Patients with concomitant use of systemic corticosteroids were excluded. The study comprised 170,818 inhaled corticosteroid users, 108,786 bronchodilator users, and 170,818 control patients. The average age was 45.1 years in the inhaled corticosteroid, 49.3 years in the bronchodilator, and 45.2 years in the control groups. In the inhaled corticosteroid cohort, 54.5% were female. The relative rates (RRs) of nonvertebral, hip, and vertebral fractures during inhaled corticosteroid treatment compared with control were 1.15 (95% CI, 1.10-1.20), 1.22 (95% CI, 1.04-1.43), and 1.51 (95% CI, 1.22-1.85), respectively. No differences were found between the inhaled corticosteroid and bronchodilator groups (nonvertebral fracture RR = 1.00; 95% CI, 0.94-1.06). The rates of nonvertebral fractures among users of budesonide (RR = 0.95; 95% CI, 0.85-1.07) and fluticasone propionate (RR = 1.03; 95% CI, 0.71-1.49) were similar to the rate determined for users of beclomethasone dipropionate. We conclude that users of inhaled corticosteroids have an increased risk of fracture, particularly at the hip and spine. However, this excess risk may be related more to the underlying respiratory disease than to inhaled corticosteroid.     

Relative effects of inhaled corticosteroids on immunopathology and physiology in asthma: a controlled study.

BACKGROUND: Although corticosteroids are recognised as the most efficacious treatment for bronchial asthma, their mode of action remains unclear. A placebo controlled trial was undertaken of the effect of inhaled corticosteroids on physiological and immmunopathological parameters in asthmatic patients in whom the correlations between these indices were tested after treatment. METHODS: Sixteen patients (two women) with asthma entered a double blind, placebo controlled, parallel study during which they inhaled either budesonide 800 micrograms twice daily or matching placebo for six weeks. Spirometric parameters and bronchial reactivity to histamine and terbutaline were measured and endobronchial biopsy samples were taken before and after treatment. Patients recorded morning and evening flow rates during the treatment period. The biopsy samples were subjected to immunohistological analysis to determine the disposition of inflammatory cells within the bronchial wall. RESULTS: Treatment with budesonide resulted in a significant improvement in the 25-75% forced expiratory flow (FEF25-75) from a mean of 133 l/min before treatment to 169 l/min after treatment, and in the morning peak expiratory flow rate (PEFR) from a mean of 384 l/min before treatment to 415 l/min after treatment. No changes were seen in the placebo group. Comparison between the changes in the immunopathological indices after six weeks of treatment with placebo or budesonide showed a significant reduction in the numbers of mast cells (0.5/unit area to 0.2/ unit area), activated eosinophils, and the expression of HLA-DR antigens (relative density -1.9 before to 1.02 after treatment) on inflammatory cells in response to treatment with budesonide. Although reductions in the numbers of other inflammatory cells within the bronchial wall were recorded using immunohistological analysis, these changes were not statistically significant. Significant correlations were found between changing immunological indices and lung physiology. CONCLUSIONS: This controlled study shows that inhaled corticosteroids cause improvement in physiological and immunopathological parameters in patients with stable asthma that are not seen with placebo, and that cause and effect relationships may exist between these two measures of disease status.     

Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice

BACKGROUND: Theophylline is widely used in the treatment of asthma, and there is evidence that theophylline has anti-inflammatory or immunomodulatory effects. A study was undertaken to determine whether theophylline added to low dose inhaled steroids would be as efficacious as high dose inhaled steroids in asthma. METHODS: In a study in general practice of 155 recruited asthmatic patients with continuing symptomatic asthma while on 400 microgram beclomethasone dipropionate (BDP) daily and inhaled beta(2) agonist as required, the effect of (1) continuing low dose inhaled steroids alone (LDS, 200 microgram BDP twice daily), (2) low dose inhaled steroids plus low dose theophylline (LDT, 400 mg daily), or (3) high dose inhaled steroids (HDS, 500 microgram BDP) over a six month period was examined. RESULTS: One hundred and thirty patients completed the study. Between group comparison using analysis of variance showed no overall differences in peak flow measurements, diurnal variation, and symptom scores. Changes in evening peak flows approached significance at the 5% level (p=0.077). The mean improvement in evening peak flow in the LDT compared with the LDS group was 20.6 l/min (95% confidence interval (CI) -2.5 to 38.8). In the LDT group there was an increase in evening peak flows at the end of the study compared with entry values (22.5 l/min), while in the LDS and HDS groups evening peak flows increased by 1.9 and 8.3 l/min, respectively. There was no significant difference in exacerbations or in side effects. CONCLUSION: There were no overall significant differences between the low dose steroid, low dose steroid with theophylline, and the high dose steroid groups. The greatest within-group improvement in evening peak flows was found after theophylline. A larger study may be necessary to show significant effects.     

First treatment with inhaled corticosteroids and the prevention of admissions to hospital for asthma

BACKGROUND: Early treatment with inhaled corticosteroids appears to improve clinical symptoms in asthma. Whether a first treatment initiated in the year following the recognition of asthma can prevent major outcomes such as admission to hospital has yet to be studied. METHODS: A case-control study nested within a cohort of 13,563 newly treated asthmatic subjects selected from the databases of Saskatchewan Health (1977-1993) was undertaken to investigate the effectiveness of a first treatment with inhaled corticosteroids in preventing admissions to hospital for asthma. Study subjects were aged between five and 44 years at cohort entry. First time users of inhaled corticosteroids were compared with first time users of theophylline for a maximum of 12 months of treatment. The two treatments under study were further classified into initial and subsequent therapy to minimize selection bias and confounding by indication. Odds ratios associated with hospital admissions for asthma were estimated using conditional logistic regression. Markers of asthma severity, as well as age and sex, were considered as potential confounders. RESULTS: Three hundred and three patients admitted to hospital with asthma were identified and 2636 matched controls were selected. subjects initially treated with regular inhaled corticosteroids were 40% less likely to be admitted to hospital for asthma than regular users of theophylline (odds ratio 0.6; 95% CI 0.4 to 1.0). The odds ratio decreased to 0.2 (95% CI 0.1 to 0.5) when inhaled corticosteroids and theophylline were given subsequently. CONCLUSION: The first regular treatment with inhaled corticosteroids initiated in the year following the recognition of asthma can reduce the risk of admission to hospital for asthma by up to 80% compared with regular treatment with theophylline. This is probably due, at least in part, to reducing the likelihood of a worsening in the severity of asthma.     

Perception of airway narrowing during reduction of inhaled corticosteroids and asthma exacerbation

BACKGROUND: The perception of airway narrowing is reduced in subjects with severe asthma and may be related to the severity of airway inflammation. A study was undertaken to determine if the perception of airway narrowing changes during the reduction of inhaled corticosteroid (ICS) dose or during an asthma exacerbation. METHODS: Forty two asthmatic subjects with well controlled asthma had their daily ICS dose halved every 2 months until they were weaned off ICS or they developed an exacerbation. Perception was measured at baseline and at monthly intervals during bronchial challenge with mannitol as the slope and intercept of the regression of the Borg score and percentage fall in forced expiratory volume in 1 second (FEV(1)), and as the Borg score at 20% fall in FEV(1) (PS(20)FEV(1)). Sputum was collected for measurement of inflammatory cell numbers. RESULTS: In 33 subjects who successfully halved their ICS dose without exacerbation there were significant reductions in slope (p = 0.01), intercept (p = 0.01), and PS(20)FEV(1) (p = 0.003). Sputum eosinophils and airway hyperresponsiveness increased significantly but, in 14 subjects from whom sputum was obtained, changes in eosinophils were not correlated with changes in perception. Change in airway hyperresponsiveness correlated with change in PS(20)FEV(1) (r = -0.40, p = 0.025). In 27 subjects who developed an exacerbation, slope decreased (p = 0.02) and intercept increased (p = 0.01) compared with the visit before the exacerbation. Changes in intercept correlated with changes in resting FEV(1) (r = -0.57, p = 0.002). CONCLUSIONS: Perception of airway narrowing decreases during ICS dose reduction and decreases further during a mild asthma exacerbation. These changes are related to concurrent changes in airway hyperresponsiveness and resting lung function. The effect of changes in airway inflammation on perception is unclear.     

Cross-sectional study on bone density-related sonographic parameters in children with asthma: correlation to therapy with inhaled corticosteroids and disease severity

The aim of this study was to screen asthmatic children for bone density-related sonographic parameters on the calcaneal bone. Findings were correlated to therapy with inhaled corticosteroids (ICS) as well as with asthma severity (AS), concomitance and severity of atopic dermatitis (AD), and rhinitis (AR). We enrolled 173 children with AS1-3 consecutively; 44% (AS1) had not received any ICS medication; 56% (AS2 and -3) received ICS therapy for > or =6 months (medium daily dose, 286 microg fluticasone-proprionate-equivalent/maximum 500 microg); and in addition 38% (n = 65) presented with AD and 66% (n = 115) with AR. Broadband ultrasound attenuation (BUA) and speed of sound (SOS) results were compared to regional normative values of 3299 children obtained with the identical system. ICS-treated children showed a tendency toward reduced age-, weight-, and height-adjusted standard deviation scores (SDS) for SOS compared to children without ICS treatment, which tendency did not reach statistical significance and was not as consistent for BUA (mean of ICS-treated children compared to our controls: SOS-SDS, -0.29/-0.31/-0.30; BUA-SDS, -0.23/-0.17/-0.05). For ICS-treated children, the proportion of patients with BUA and SOS values below -1 SDS was statistically significant higher for age-adjusted BUA and SOS than for children without ICS medication (BUA 15.00% vs. 5.41%; SOS 32.98% vs. 17.56%). However, we cannot differentiate possible negative effects of ICS from influences of the underlying inflammatory disease because higher asthma severity was associated with greater use of ICS medication. Additionally, the higher physical activity of children with less severe asthma can have influenced quantitative ultrasound (QUS) parameters positively, compared to patients with a higher degree of exercise-induced symptoms. For differentiation of possible negative effect of ICS on ultrasonic bone quality and for evaluation of the potentials of the method, further longitudinal QUS assessment of asthmatics receiving a new ICS treatment is needed.     

Use of inhaled corticosteroids during the first trimester of pregnancy and the risk of congenital malformations among women with asthma

AIM: To investigate whether the maternal use of different doses of inhaled corticosteroids (ICSs) during the first trimester of pregnancy for the treatment of asthma increases the risk of congenital malformations in the offspring. METHODS: From the linkage of three administrative Canadian databases, a cohort of 4561 pregnancies from women with asthma who delivered between 1990 and 2000 was reconstructed. A two-stage sampling cohort design was used to acquire additional data from the woman's medical chart. Cases of congenital malformation were identified from the medical services database or the hospital database. Using refill patterns of medications, the average daily dose of ICSs used during the first trimester was calculated and categorised as follows: 0, 1-500, 500-1000 and >1000 microg/day in beclomethasone-chlorofluorocarbon equivalent. A Generalized Estimation Equation model was used to estimate the adjusted odds ratio of congenital malformation as a function of ICS daily dose. All analyses were performed for all malformations and major malformations separately. RESULTS: Within the cohort 418 babies were identified with a congenital malformation (9.2%), 278 of which had a major malformation. About 40% of women used ICSs during the first trimester, but only 5.3% of women used >500 microg/day. The adjusted odds ratio (95% CI) for all malformations associated with the use of ICSs during the first trimester was: 0.77 (0.53 to 1.13) for 1-500, 0.41 (0.19 to 0.92) for 501-1000 and 1.00 (0.42 to 2.36) for >1000 microg/day. The corresponding figures for major malformations were 0.90 (0.64 to 1.24), 0.56 (0.22 to 1.43) and 1.67 (0.56 to 5.03). CONCLUSION: This study adds evidence to the safety of ICSs for the treatment of asthma during pregnancy, with regard to the likelihood of congenital malformation.     

Laryngeal aspergillosis following high dose inhaled fluticasone therapy for asthma

The case history is presented of a 75 year old man with chronic asthma who was treated with inhaled fluticasone propionate in a daily dose of 2 mg using a Diskhaler. After three years of treatment he developed progressive hoarseness. Both vocal cords were colonised by Aspergillus fumigatus which formed a white slough on the surface. Biopsy specimens showed changes suggestive of laryngeal aspergillosis with an ulcerated epithelium, fibrinopurulent debris, and colonies of fungal hyphae. A slow recovery occurred after three months of treatment with topical amphotericin and with cessation of inhaled corticosteroids. Laryngoscopy is recommended if hoarseness occurs during treatment with fluticasone.     

Lung function decline in asthma: association with inhaled corticosteroids, smoking and sex

BACKGROUND: Inhaled corticosteroids (ICS) provide short term benefits in asthma but the long term effects are still unknown. METHODS: 281 patients diagnosed with moderate to severe asthma in 1963-75 were re-examined in 1991-9. Information was collected on forced expiratory volume in 1 second (FEV(1)), bronchial hyperresponsiveness, atopy, smoking, use and dosage of oral and ICS. Patients were included in the analyses if they had at least three FEV(1) measurements during two consecutive years after the age of 30 and used ICS during follow up. RESULTS: Analyses were performed on 122 patients. During a median follow up period of 23 years, 71 men and 51 women had on average 37 and 40 individual FEV(1) measurements, respectively. Linear mixed effect models showed that men had a mean annual decline in FEV(1) of 20.6 ml/year less after ICS initiation than before (p = 0.011), and in women the decline in FEV(1) was 3.2 ml/year less (p = 0.73). In individuals with <5 pack years of smoking the decline in FEV(1) was 36.8 ml/year less after ICS institution in men (p = 0.0097) and 0.8 ml/year less in women (p = 0.94), the difference between the sexes being significant (p = 0.045). These effects were not observed in those with > or =5 pack years smoking. A higher daily dose of ICS was associated with a smaller decline in FEV(1) in men (p = 0.006), an effect not observed in women. CONCLUSION: Treatment with ICS in adult patients with moderate to severe asthma was associated with a reduction in the decline in FEV(1) over a 23 year follow up period in men who had smoked <5 pack years. This effect was dose dependent and was not present in women or in men with > or =5 pack years of smoking at follow up. The lack of effect of ICS on the decline in FEV(1) in women needs further study.     

Nedocromil sodium in adults with asthma dependent on inhaled corticosteroids: a double blind, placebo controlled study.

Eighty nine adults with asthma who were receiving inhaled corticosteroid and bronchodilator treatment took part in a double blind, randomised, placebo controlled trial of nedocromil sodium, 4 mg four times daily by inhalation. During a run in period of two to four weeks corticosteroid treatment was reduced when possible to produce a comparable level of symptoms across the trial population. The test treatment was then taken for four weeks, with the severity of asthma recorded daily by patients and assessed at two weekly hospital visits. There was an improvement in symptoms in the patients taking nedocromil sodium by comparison with those having the placebo, the differences being significant for diary card PEF readings, asthma symptom scores, and bronchodilator usage at night. The mean difference between the two groups was 18 l/min for PEF, 0.42 for daytime asthma score, and 1.73 puffs in 24 hours for bronchodilator usage. These results suggest that asthmatic patients who require inhaled steroids show better control of their asthma with the addition of nedocromil sodium than of placebo over a four week period after reduction of the dosage of their inhaled steroids.     

Regular use of inhaled corticosteroids and the long term prevention of hospitalisation for asthma

BACKGROUND: Inhaled corticosteroids are effective at preventing asthma morbidity and mortality. Most studies, however, have focused on short term effects, raising uncertainty about their effectiveness in the long term. METHODS: The Saskatchewan Health databases were used to form two population based cohorts of asthma patients aged 5-44 between 1975 and 1991. The first cohort included all subjects from the start of asthma treatment, while the second included subjects hospitalised for asthma from the date of discharge. Subjects were followed up, starting 1 year after cohort entry and continuing until 1997, 54 years of age, or death. The outcome was the first asthma hospital admission and readmission, respectively, to occur during follow up. A nested case-control design was used by which all cases were matched on calendar time and several markers of asthma severity to all available controls within the cohort. RESULTS: The full cohort included 30 569 asthmatic subjects of which 3894 were admitted to hospital for asthma and 1886 were readmitted. The overall rate of asthma hospitalisation was 42.4 per 1000 asthma patients per year. Regular use of inhaled corticosteroids was associated with reductions of 31% in the rate of hospital admissions for asthma (95% confidence interval (CI) 17 to 43) and 39% in the rate of readmission (95% CI 25 to 50). The rate reduction found during the first 4 years of follow up was sustained over the longer term. Regular use of inhaled corticosteroids can potentially prevent between five hospital admissions and 27 readmissions per 1000 asthma patients per year. CONCLUSION: Regular use of low dose inhaled corticosteroids prevents a large proportion of hospital admissions with asthma, both early and later on in the course of the disease.