Assessment of the relation between short and intermediate term growth in children with asthma treated with inhaled glucocorticoids

OBJECTIVE: To assess the relation between short-term growth and intermediate term growth in children with asthma treated with inhaled glucocorticoids. DESIGN: An open 12 months parallel group trial with visits to the clinic on day 1, after 2, 4, 8, 12, 20, 28, 36, 44 and 52 weeks. SETTING: Outpatient clinic in a secondary referral centre. SUBJECTS: Sixteen children with asthma aged 9 (6-13) years; 16 matched healthy subjects. METHODS: Knemometry and stadiometry. INTERVENTIONS: Dry-powder inhaled budesonide 200 microg twice daily. Primary outcome measures: Intra-group comparisons of mean lower leg growth rates. Secondary outcome measures: Inter-group comparisons of mean lower leg growth rates and intra-group comparisons of mean height-standard deviation scores. RESULTS: One year mean lower leg growth rate (0.36 mm/week) did not differ from the rates during the 2 (0.27 mm/week; P = 0.23), 4 (0.33 mm/week; P = 0.54), 8 (0.36 mm/week; P = 0.79) or 12 (0.33 mm/week; P = 0.49) weeks intervals in the asthma group. Similarly, in the healthy children 2 (0.56 mm/week; P = 0.63), 4 (0.46 mm/week; P = 0.36), 8 (0.43 mm/week; P = 0.49) and 12 (0.43 mm/week; P = 0.66) weeks mean growth rates did not vary statistically significantly from the 1 year growth rate (0.42 mm/week). Mean lower leg growth rates, however, were consistently lower during all periods in the children with asthma (P = 0.02-0.03). At completion of the study mean height-standard deviation score in the asthma group (-0.19) was significantly suppressed as compared with the score at study entry (-0.03) (P = 0.02), whereas no statistically significant variation was detected in the control group. CONCLUSIONS: Short-term lower leg growth rates are consistent with intermediate term growth rates in group studies in children with asthma treated with inhaled dry powder budesonide 400 microg/day. Short-term group knemometry should be an integral part of growth evaluations of new inhaled glucocorticoids, doses and inhalation devices in children with asthma.     

Addition of theophylline or increasing the dose of inhaled corticosteroid in symptomatic asthma: a meta-analysis of randomized controlled trials

Purpose

Low-dose theophylline has anti-inflammatory effects. The aim of this study was to evaluate the effects of adding theophylline compared with increasing the dose of inhaled corticosteroid (ICS) on symptomatic asthma.

Materials and Methods

The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications. The extracted data were further analyzed by a meta-analysis

Results

Four randomized, controlled, parallel studies were selected. Addition of theophylline produced a greater increase of forced expiratory volume in one second as %predicted (FEV₁pred) by 2.49% [95% confidence interval (CI) 1.99-3.00; z = 9.70; p < 0.001], compared with increasing the dose of ICS. There was no difference between the two treatments in terms of peak expiratory flow (PEF).

Conclusion

Addition of theophylline to ICS has similar therapeutic effects on improving lung function as increasing the dose of ICS in the treatment of symptomatic asthma.     

Comparison of dose-response effects of inhaled beclomethasone dipropionate and budesonide in the management of asthma

The dose-response effects of inhaled beclomethasone dipropionate (BDP) and budesonide (BUD) administered b.i.d. with the aid of metered dose aerosols were studied in 128 patients (67 men and 61 women, mean age 53 years) suffering from asthma bronchiale. The study was designed as a multi-centre, double-blind, four-period cross-over study, followed by a single-blind double placebo period. BDP was administered in doses of 400 and 1000 micrograms, and BUD in doses of 400 and 800 micrograms. The results in terms of peak expiratory flow (PEF) in the morning and evening, daily symptoms score and use of inhaled beta 2-agonists did not reveal any clinically significant differences between the drugs or between high (800 micrograms BUD, 1000 micrograms BDP) and low (400 micrograms BUD/BDP) doses. However, statistically significant differences were recorded for the corresponding parameters when comparing the placebo with preceding steroid periods. Adverse effects consisting mainly of oropharyngeal candidiasis, hoarseness and cough occurred in 54 of 468 treatment months (12%). The carry-over effects of inhaled steroids are longer lasting than was previously assumed.     

Direct and indirect bronchoprovocation tests in dose-response studies of inhaled corticosteroids: Past,present, and future directions

Inhaled corticosteroids (ICS) are a mainstay of treatment in eosinophilic asthma. Many studies have explored the dose-response effect of different formulations of ICS through direct or indirect bronchoprovocation testing. Such studies are important for investigating efficacy and identifying the relative potency between formulations. However, lack of consistency in methods and designs has hindered the comparability of study findings. This review discusses current knowledge of the dose-response, or lack thereof, of different formulations of ICS through direct and indirect bronchoprovocation testing. The strengths and weaknesses of past studies inform recommendations for future methodological considerations in this field, such as utilizing a randomized double-blind crossover design, enrolling participants likely to respond to ICS therapy, and carefully selecting treatment durations and washout periods to assess incremental improvement in airway hyperresponsiveness while reducing the likelihood of a carryover effect.     

The effect of oral steroids with and without vitamin D3 on early efficacy of immunotherapy in asthmatic children

Background The possibility of additional strategies to enhance the effectiveness of specific immunotherapy (SIT) is highly attractive. Aim The aim of our study was to assess the influence of oral corticosteroids and oral corticosteroids combined with vitamin D₃ on the early clinical and immunological effects of SIT. Methods It was a randomized, double‐blind, placebo‐controlled trial conducted in 54 asthmatic children allergic to house dust mites. Intervention was based on receiving a single dose of oral steroid, with or without vitamin D₃, or placebo only on the day of the build‐up phase of SIT. Results After 12 months of SIT, the median daily inhaled corticosteroid (ICS) dose, which controls the symptoms of asthma, was reduced by 25% in the steroid group. However, a 50% reduction of the median daily ICS dose was observed in the control group. The clinical effects of SIT were not affected in the steroid+D₃ group. Concomitantly, we found that intervention with prednisone significantly impaired the induction of T regulatory lymphocytes. Importantly, the clinical and immunological effects of SIT were not affected by intervention with steroids administered with vitamin D₃. Conclusions Our study failed to show a beneficial effect of oral corticosteroids on allergen‐specific immunotherapy. We observed that the combined administration of a corticosteroid drug and allergen extract suppressed the early clinical and immunological effects of SIT and that vitamin D₃ prevented this ‘adverse’ influence of steroids.     

激素治疗对运动诱发性哮喘患者痰嗜酸性粒细胞计数的影响

目的探讨气道嗜酸性粒细胞性炎症和运动诱发的支气管痉挛（EIB）之间的关系,及其对吸入糖皮质激素（ICS）治疗的反应。方法本研究为随机、双盲、二阶段交叉试验,将26例有运动诱发性支气管痉挛发作史且从未接受过激素治疗的哮喘患者随机分为两组,每组分别给予两个剂量水平的布地奈德吸入：①100μg/d与400μg/d对比;②200μg/d与800μg/d对比。每一阶段为3周,洗脱期3～8周。治疗前及开始治疗后每隔1周进行1次运动激发试验并留取痰液标本行嗜酸性粒细胞计数。结果高剂量ICS治疗（400μg/d和800μg/d）可显著减少痰嗜酸性粒细胞比例。痰嗜酸性粒细胞百分比与运动诱发性支气管痉挛严重程度相关,且对EIB的严重程度有预测作用;高剂量ICS治疗时,尚可预测EIB对激素治疗有效,而对低剂量ICS组（100μg/d和200μg/d）则无预测作用。低剂量ICS治疗,不管基线痰嗜酸性粒细胞计数是否增多,EIB在第1周末发作显著减轻,尔后几无改善。而高剂量ICS治疗对EIB的改善作用在痰嗜酸性粒细胞增多的患者中显著优于嗜酸性粒细胞计数小于5%者,这种明显的差异在开始治疗1周后即显现,且随时间的推移而继续加大。结论气道嗜酸性粒细胞性炎症可能在EIB的发生及其对ICS治疗有效的调节机制中起重要的作用。测定痰嗜酸性粒细胞计数在预测EIB的严重程度及其对不同剂量ICS治疗的反应具有一定的临床应用价值。     

Cost-effectiveness of inhaled steroids in asthma: impact of effect on bone mineral density

BACKGROUND: The effects of inhaled corticosteroid (ICS) preparations on bone health have been debated. Multiple analyses have been published examining the question, with mixed results. OBJECTIVES: We examined how assumptions about the effect of ICS on bone mineral density (BMD) influence the cost-effectiveness of ICS in asthma. METHODS: We developed a mathematical simulation model to estimate clinical outcomes and costs for a cohort with mild/moderate asthma. The analysis conformed to reference case recommendations of the US Panel on Cost-Effectiveness in Health and Medicine. Sensitivity analysis evaluated the stability of our results to uncertainty in treatment duration, age at treatment, and ICS dose. RESULTS: Assuming a dose of 200 microg twice per day of ICS, a literature-based average effect of ICS on BMD and a 10-year time horizon, we observed a minimal increase in the costs attributed to hip fracture and incremental cost effectiveness ratio of $26,000 per quality-adjusted life-year and $14.00 per symptom-free day gained. Over an extended the time horizon (lifetime), the incremental cost effectiveness ratio increased to $42,000/quality-adjusted life-year. Only under a scenario of high-dose ICS, a lifetime horizon, and a large effect of ICS on BMD did the potential impact of ICS on BMD dramatically affect the economic attractiveness of therapy. CONCLUSION: To minimize any potential impact, use of the lowest effective dose of ICS and measures to target and intervene in high-risk individuals are warranted. However, ICS therapy in mild/moderate asthma compares favorably with commonly accepted interventions over a wide range of assumptions regarding this treatment and its effects on BMD.     

Influence of different dosage schedules of inhaled fluticasone propionate on peripheral blood cytokine concentrations in childhood asthma

BACKGROUND: Asthma is characterized by eosinophilic airways inflammation with elevated levels of IL-4, IL-5 and sICAM-1, and reduced levels of IL-10 and IFN-gamma. Inhaled corticosteroids powerfully reduce airways inflammation. OBJECTIVE: To investigate if eosinophil counts, serum eosinophilic cationic protein (ECP) and sICAM-1 levels, as well as serum and production of cytokines (IL-4, IL-5, IL-10, IFN-gamma) by peripheral blood monocytes (PBMCs) are useful markers to monitor therapy with inhaled fluticasone propionate (FP) in asthmatic children. METHODS: In a double-blind, 1-year study, 55 asthmatic children (aged 6-10 years) stopped inhaled corticosteroids for a mean period of 24 days and were randomized to receive either FP 200 microg/day (constant dose group), or a starting dose of FP 1000 microg/day with two monthly reductions to 500, 200 and 100 microg/day (stepdown group). Hyper-responsiveness, symptom scores and blood sampling were performed at 2-month intervals. RESULTS: Symptoms and hyper-responsiveness improved significantly in both treatment groups after reintroduction of FP. Eosinophil counts decreased significantly more during the first 2 months of FP in the stepdown group than in the constant dose group (P = 0.03). We found a trend towards a dose-dependent response in changes of eosinophil counts and serum ECP levels during treatment. Serum IL-4 and IL-5 levels were undetectable in the majority of children. No significant effect of the dose of FP on the release of IL-4, IL-5, IL-10 or IFN-gamma by Con A stimulated PBMCs was found. sICAM-1 levels did not significantly differ at any time point between the two groups. CONCLUSION: Serum ECP as well as peripheral blood eosinophils, cytokine production by PBMCs and sICAM-1 levels are insensitive markers in titrating and monitoring therapy with inhaled corticosteroids over a wide dose range in childhood asthma.     

Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant

BACKGROUND: This study tested the hypothesis that there would be improved asthma control with increasing doses of beclomethasone dipropionate (BDP) formulated in hydrofluoroalkane-134a (HFA-BDP) and the standard chlorofluorocarbon propellants (CFC-BDP). Because HFA-BDP has improved lung deposition compared with CFC-BDP, this study also tested the hypothesis that HFA-BDP would provide more effective control of asthma than CFC-BDP. METHODS: In this multicenter, randomized, parallel-group blinded study, asthmatic subjects who had deterioration in asthma control after discontinuation of inhaled corticosteroids were randomized to receive one of 6 possible treatments: 100 microg/d, 400 microg/d, or 800 microg/d of HFA-BDP or 100 microg/d, 400 microg/d, or 800 microg/d of CFC-BDP for 6 weeks. Changes in spirometry, daytime asthma symptom and nighttime asthma-related sleep disturbance scores, morning and evening peak expiratory flows, and daily use of inhaled beta-agonist for symptom control on diary cards were assessed over 6 weeks of treatment. RESULTS: Three hundred twenty-three patients were randomized to the 6 treatment groups, which had similar demographics and baseline lung function. There were significantly larger changes from baseline at week 6 in FEV(1) percent predicted with increasing doses of both HFA-BDP and CFC-BDP. The FEV(1) percent predicted dose-response curve for HFA-BDP was shifted to the left compared with the dose-response curve for CFC-BDP. By using the Finney bioassay method, it was calculated that 2.6 times as much CFC-BDP would be required to achieve the same improvement in FEV(1) percent predicted as HFA-BDP (95% confidence interval, 1.1-11.6). All treatment groups except the 100 microg/d CFC-BDP group tolerated study drug well. Ten (17%) of 59 patients in this group reported an acute asthma episode, increased asthma symptoms (6 of the 8 reports of increased asthma symptoms were classified as severe), or both, and 8 patients withdrew from the study (3 for adverse events related to asthma). CONCLUSIONS: Increasing doses of inhaled corticosteroids lead to improved lung function and asthma control. Moreover, the reformulation of BDP in HFA enables effective asthma control at much lower doses than CFC-BDP.     

Effect of ciclesonide on allergen challenge in subjects with bronchial asthma

BACKGROUND: The aim of this clinical trial was to investigate whether repeated inhalation of the new inhaled steroid ciclesonide reduces the early-phase (EAR) and late-phase (LAR) reactions after allergen challenge in patients with mild allergic asthma. Also, this study provides further data on safety and tolerance of ciclesonide. METHODS: The study was designed as a double-blind placebo-controlled randomized crossover trial. Following a baseline period, patients were randomized to either of two treatment sequences (ciclesonide/placebo, placebo/ciclesonide) each of which lasted for one week and were separated by 3-5 weeks from the alternate treatment sequence. Patients received 800 micro g ciclesonide twice daily by means of a Cyclohaler. At the end of each treatment patients were subjected to an allergen challenge. RESULTS: Thirteen asthmatic patients (mean FEV1 of 91% predicted) who experienced an EAR and LAR after allergen challenge participated in the study. The time-average FEV1 decreases 0-2 h (2-12 h) after allergen challenge as measure of the EAR (LAR) were significantly reduced (P < 0.05, one-sided) from 0.426 L to 0.233 L (EAR) and from 0.443 L to 0.213 L (LAR), respectively. Thus, the study results suggest that ciclesonide significantly lowered the extent of EAR and LAR compared to placebo. Ciclesonide was well tolerated and no drug-related adverse events were reported. Cortisol excretion in 24-h urine showed no significant difference between ciclesonide and placebo. CONCLUSIONS: The study supports the efficacy and safety of ciclesonide.     

Effect of high dose inhaled glucocorticoids on quality of life in patients with moderate to severe asthma

Asthma is a chronic disorder that can place considerable restrictions on the physical, emotional, and social aspects of the lives of patients. Inhaled glucocorticoids (GCs) are the most effective controller therapy. The purpose of this study was to evaluate the effect of inhaled GCs on quality of life in patients with moderate to severe asthma. Patients completed the asthma quality of life questionnaire (AQLQ) and pulmonary function test at baseline and after 4 wks treatment of GCs. We enrolled 60 patients who had reversibility in FEV1 after 200 microgram of albuterol of 15% or more and/or positive methacholine provocation test, and initial FEV1% predicted less than 80%. All patients received inhaled GCs (fluticasone propionate 1,000 microgram/day) for 4 wks. The score of AQLQ was significantly improved following inhaled GCs (overall 51.9+/-14.3 vs. 67.5+/-12.1, p<0.05). The change from day 1 to day 28 in FEV1 following inhaled GCs was diversely ranged from -21.0% to 126.8%. The improvement of score of AQLQ was not different between at baseline and after treatment of GCs according to asthma severity and GCs responsiveness. Quality of life was improved after inhaled GCs regardless of asthma severity and GCs responsiveness in patients with moderate to severe asthma.     

The beneficial role of FeNO in association with GINA guidelines for titration of inhaled corticosteroids in adult asthma: A randomized study

PurposeThis study aimed to demonstrate the role of fractional concentration of exhaled nitric oxide (FeNO) in association with Global Initiative for Asthma (GINA) guidelines for treatment of adult patients with asthma.MethodsIt was a prospective and randomized study. The symptomatic asthmatic patients were randomly divided into two groups: GINA group (followed GINA guidelines; N = 86) or GINA + FeNO group (followed GINA guidelines + FeNO for titration of inhaled corticosteroids - ICS; N = 90). They were followed-up for 9 months.ResultsIn GINA group, 37.2% patients had no treatment and 62.8% patients discontinued treatment vs. 40.0% and 60.0% in GINA + FeNO, respectively. After 3, 6 and 9 months of treatment, the percentage of mild, moderate and severe asthma showed no significant difference between the two groups. At 9th month, Δ moderate asthma (reduction) in GINA + FeNO group was significantly higher than in the GINA group (−22.0% vs. −11.6%; P = 0.018). The improvement of asthma control test (ACT) score was not different between the groups at 9th month (12 ± 6 vs. 10 ± 5; P > 0.05); the level of FeNO reduction in GINA + FeNO group was significantly higher than that in GINA group (−42 ± 11 vs. −35 ± 9; P = 0.022). The daily dose of ICS in GINA + FeNO group was significantly lower than that in GINA group (397 ± 171 vs. 482 ± 240 mcg and 375 ± 203 vs. 424 ± 221 mcg; respectively) at the end of 6 and 9 months.ConclusionThe use of FeNO in association with GINA guidelines has a beneficial role for accurate daily dose of ICS in adult patients with asthma.     

甘利欣对大鼠哮喘模型及哮喘患者血清IgE水平的影响

目的：探讨甘利欣对哮喘模型及患者血清中IgE水平的影响。方法：将大鼠随机分为正常对照组、哮喘模型组、甘利欣(GL)用药组及地塞米松(DS)阳性对照组。哮喘模型制备用卵白蛋白(OVA)致敏大鼠并雾化吸入刺激。模型建立成功指标采用描记呼吸曲线、肺组织病理切片及血清IgE水平的变化。除动物模型外并观察了哮喘息者血清IgE的水平。结果：哮喘模型组呼吸曲线的呼吸幅度变深，节律变快，肺组织病理切片HE染色显示有较多炎症细胞浸润，杯状细胞增生明显，平滑肌增厚。血清IgE较正常组明显增高，两组比较差异显著(P＜0．005)。甘利欣用药组呼吸曲线的呼吸幅值变小，肺组织病理切片HE染色支气管壁炎症细胞浸润减轻，无大量杯状细胞增生，血清IgE检测较模型组减低，两组比较差异显著(P＜0．01)，但与地塞米松(DS)阳性对照治疗组比较无差异。哮喘患者血清IgE治疗前明显高于正常水平(P＜0．01)，甘利欣用药后明显降低。结论：甘利欣能降低大鼠哮喘模型及哮喘息者的血清IgE水平。     

雷公藤多甙片治疗小儿哮喘疗效及其免疫作用机理的研究

作者对37例小儿哮喘病患者经用雷公藤多甙片(Tabellon Multiglycosidorum Triptergii)治疗12周后,随访8个月,其中有效者33例,总有效率为89.18%,各类型病者间有效率无显著差异(P>0.05);对其中27例病儿服药前后外周血T细胞亚群及抑制性细胞活性进行检测,结果显示:病儿CD_?~+亚群从25.36±5.16%上升为28.96±3.03,(P<0.05),CD_3~+、CD_4~+亚群改变不大(P>0.05),而抑制率(SR)从-20.86±39.10上升为11.93±30.83(P<0.001),同时发现,抑制率的恢复与临床疗效间有一定关系。由此,作者认为,该药对小儿哮喘的治疗机理可能与机体免疫抑制功能恢复有关。     

哮喘患儿激素治疗后TH1/TH2的变化

目的观察哮喘患儿血清中白细胞介素IL12、IL13和IgE水平的变化及糖皮质激素对其的影响。方法采用ELISA法分别检测哮喘患儿急性期及口服强的松5～7天后、健康对照组血清中IL12、IL13和IgE的水平。结果哮喘组患儿IL12水平急性发作期较治疗后和健康对照组低,差异均有显著性（P〈0.01）。IL13水平急性发作期较治疗后和健康对照组高,差异均有显著性（P〈0.01）,IgE水平急性发作期较治疗后和健康对照组高,差异均有显著性（P〈0.01）。直线相关分析表明,血清中IL12与IL13负相关,与IgE呈负相关,IL13与IgE呈正相关。结论哮喘患者血清中IL13、IgE水平升高,IL12水平下降,3者的变化相关,糖皮质激素可使IL13水平下降,IL12水平升高。     

The effect of aerosol distribution on airway responsiveness to inhaled methacholine in patients with asthma.

It has been demonstrated that airway deposition of inhaled aerosols is more heterogeneous in patients with asthma than in normal subjects. Nevertheless, the influence of abnormal airway deposition on responses to bronchoactive aerosols is poorly understood. We altered bronchopulmonary deposition heterogeneity of methacholine aerosol in nine asymptomatic patients with asthma by controlling inspiratory flow at high (approximately 60 L/min) versus low (approximately 12 L/min) rates on 2 study days and determined the effect on the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) (often used as a measure of airway responsiveness). Deposition uniformity was quantified from gamma-camera scans of the lungs in terms of the distribution of a technetium-labeled aerosol that was inhaled rapidly or slowly before the inhalation of methacholine. Increased deposition in an inner (large, central airways) versus an outer (peripheral airways and alveoli) zone of the right lung (inner/outer ratio, greater than 1) and higher values of skew (an index of deposition asymmetry) and kurtosis (an index of deposition range) indicated enhanced heterogeneity of deposition. Mean (+/- SD) inner/outer ratio was significantly higher during rapid inspiration compared to slow inspiration with 2.91 +/- 0.51 and 1.84 +/- 0.30, respectively (p less than 0.01). Mean skew and kurtosis were also significantly higher after rapid inspiration, with 1.12 +/- 0.35 and 3.86 +/- 1.25, respectively, compared to 0.74 +/- 0.36 and 2.64 +/- 0.77 after slow inhalation (p less than 0.01). Geometric mean PD20 methacholine was significantly reduced when the aerosol was inhaled rapidly, with 5.9 cumulative methacholine units compared to 15.7 units after slow inhalation (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of immunotherapy on symptoms, PEFR, spirometry, and airway responsiveness in patients with allergic asthma to house-dust mites (D. pteronyssinus) on inhaled steroid therapy

The present study was designed to investigate the effects of immunotherapy (IT) with an extract of Dermatophagoides pteronyssinus (Alergo-Merck Depot®) during a 27-month period in patients with allergic asthma to house-dust mites. We included 11 patients (mean age 18 years) treated with a combination of IT and inhaled beclomethasone dipropionate (BDP) in comparison to another 11 (mean age 22 years) treated with BDP alone. We evaluated symptom scores, salbutamol use, peak expiratory flow rates (PEFR), spirometry, and bronchial hyperresponsiveness (BHR) during 18 months of therapy with BDP and in the 9 months after BDP interruption. The two kinds of treatment were efficient and comparable in relation to symptom score, salbutamol use, morning PEFR, FVC, and FEV_l but patients treated with IT and BDP had a faster improvement of BHR and PEFR variability. The interruption of BDP after 18 months of therapy was linked to an impairment of all end points, which were more pronounced in patients previously treated only with BDP. These findings suggest that in selected asthmatic patients allergic to house-dust mites, the association of IT and BDP is more effective than therapy with this inhaled steroid alone due to a faster and more striking improvement during the first months of treatment and to a lower rate of relapse after the interruption of therapy with BDP.