Clinical and immunologic factors associated with the presence or absence of airways hyper-responsiveness in childhood asthma

BACKGROUND: During the baseline period of a clinical trial comparing different dosage schedules of inhaled steroids, asthmatic children (aged 6-10 years) were expected to meet the inclusion criterion of airways hyper-responsiveness (PD(20) methacholine < 80 micro g) after withdrawal of inhaled corticosteroids for 2-8 weeks. However, many children failed to do so. OBJECTIVE: It has been shown that young wheezing children may outgrow their symptoms. We investigated if differences between children with and without airways hyper-responsiveness after withdrawal of inhaled corticosteroids were compatible with differences between transient and persistent wheezers found in other studies. METHODS: Seventy-eight children entered the study, of which 41 developed airways hyper- responsiveness after withdrawal of inhaled corticosteroids, and 37 did not. These two groups of children were compared with respect to differences in demographic, clinical, and immunological features (IL-4, IL-5, IL-10, and IFN-gamma produced by Con A stimulated peripheral mononuclear cells (PBMCs) and serum IL-4, IL-5 and soluble intercellular adhesion molecule-1 (sICAM-1)). RESULTS: Hyper-responsive children had more atopic features (positive RAST, high IgE, eczema), lower levels of FEV1 and lower concentrations of sICAM-1 than non-hyper-responsive children. Apart from a borderline significantly higher IL-4 production in the hyper-responsive group, other immunologic parameters were comparable. Multivariate logistic regression analysis showed that high serum IgE, low FEV1, and low sICAM-1 levels were independently associated with the presence of airways hyper-responsiveness after stopping inhaled corticosteroids. Atopy was associated with higher concentrations of IL-4 in the hyper-responsive group. CONCLUSION: After withdrawal of inhaled corticosteroids many children previously diagnosed with asthma did not develop airways hyper-responsiveness. We conclude that hyper-responsive children share features with persistent wheezers as found in previous studies, whereas the non-hyper- responsive children may represent transient wheezers.     

Diagnosis and management of early asthma in preschool-aged children

Asthma is a common disease in young children and is associated with significant morbidity and an increasing prevalence over time. Early childhood wheezing and asthma are heterogeneous disorders; thus identifying phenotypes of asthma remains a goal to identify high-risk children who might benefit from specific therapies or secondary prevention interventions. The typical pattern of illness in preschool-aged children consists of short but recurrent exacerbations of cough and wheeze usually triggered by viral respiratory tract infections. Documenting reversible airflow obstruction on lung function, allergen sensitization, increased IgE levels, or blood eosinophilia is helpful in establishing a diagnosis of asthma in preschool-aged children, if present; however, the diagnosis is most often based on symptom patterns, presence of risk factors, and therapeutic responses. The preschool-aged asthmatic population tends to be characterized as exacerbation prone with relatively limited impairment, unlike older children and adolescents who have more impairment-dominant disease. However, management of persistent disease is based largely on expert opinion and extrapolation from studies in older children given the relative lack of data in this age group. Strategies used to manage intermittent disease include daily and intermittent controller therapy. Management strategies for persistent asthma include daily inhaled corticosteroids, daily leukotriene receptor antagonists, and combination therapies. Finally, regular monitoring of symptom control and medication side effects is important along with titrating controllers to the minimally effective dose.     

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.     

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。     

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.     

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.     

High fractional concentration of nitric oxide in exhaled air despite steroid treatment in asthmatic children

BACKGROUND: The fractional concentration of nitric oxide in exhaled air (FENO) is elevated in atopic asthma and typically responds to treatment with inhaled corticosteroids (ICS). However, some patients have persistently high FENO levels despite treatment. OBJECTIVE: We studied how optimizing the inhalation technique and increasing ICS doses would affect FENO in stable atopic asthmatic children who had elevated FENO while using ICS. METHODS: In 41 stable asthmatic children who were treated with ICS (median daily dose 800 microg budesonide equivalent, range 100-1600 microg) and maintained FENO> or =20 p.p.b., we optimized the inhalation technique by thorough instruction and measured FENO 2 weeks later. Then, if FENO remained > or =20 p.p.b., we increased the ICS dose and reassessed FENO 2 weeks later. RESULTS: Improving the inhalation technique did not reduce FENO. Increasing ICS from a daily median dose of 800 to 1200 microg budesonide had no significant effect on FENO. FENO correlated positively with symptom scores in the following 2 and 4 weeks (P=0.001, 0.002) and beta2-agonist use the 2 and 4 weeks following FENO measurement (P=0.02, 0.004). CONCLUSION: We conclude that common steps in asthma treatment, i.e. inhalation instruction and increasing ICS dose, were both ineffective in reducing FENO in atopic asthmatic children with elevated FENO values despite treatment with ICS. This implies that FENO cannot simply be incorporated in current treatment guidelines.     

Antibiotic use in early childhood and the development of asthma

BACKGROUND AND OBJECTIVE: Recent investigations have focused on the role of infections in infancy in promoting or protecting against the subsequent development of asthma. A related hypothesis concerns the possible role of medical responses to infections, including the widespread use of antibiotics. We chose children at Rudolf Steiner schools to test this latter hypothesis because a significant proportion of parents rejects the use of conventional treatments, including antibiotics. METHODS: Seventy-five per cent (n = 456) of parents of children aged 5-10 years attending Rudolf Steiner schools throughout New Zealand completed questionnaires which included questions on the use of antibiotics and a history of asthma and wheeze in their children. RESULTS: After controlling for potential confounders, antibiotic use was significantly associated with having a history of asthma (OR = 2.74, 95% CI: 1.10-6.85) or wheeze (OR = 1. 86, 95% CI: 1.06-3.26) but not with current wheeze (OR = 1.08, 95% CI: 0.54-2-16). The adjusted odds ratio for asthma was 4.05 (95% CI: 1.55-10.59) if antibiotics were used in the first year of life and 1. 64 (95% CI: 0.60-4.46) if antibiotics had been used only after the first year of life when compared with children who had never used antibiotics. The number of courses of antibiotics during the first year of life was also associated with increased odds ratios for asthma: 2.27 (95% CI: 1.14-4.51) for one to two courses and 4.02 (95% CI: 1.57-10.31) for three or more courses when compared with no antibiotic use in the first year of life. Although not significant, the association of antibiotics and hay fever (OR = 1.99 [95% CI: 0. 93-4.26]) was of a similar strength to the association of antibiotics with a history of wheeze. Antibiotics were not significantly associated with eczema (OR = 1.23 [95% CI: 0.71-2.13]). CONCLUSION: Antibiotic use in infancy may be associated with an increased risk of developing asthma. Further study is required to determine the reasons for this association.     

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.     

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.     

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.     

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.     

Effect of montelukast on lung function in asthma patients with allergic rhinitis: analysis from the COMPACT trial

BACKGROUND: The Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) trial demonstrated that montelukast added to budesonide (MNT + BD) was as efficacious as double the dose of budesonide (dBD) in improving morning peak expiratory flow (AM PEF) in adult asthmatics. Recent studies have demonstrated that montelukast is also effective in treating daytime and nighttime allergic rhinitis (AR) symptoms in asthmatic patients. This analysis was designed to examine whether asthmatic patients with comorbid AR respond differently than patients without comorbid AR in terms of asthma control (lung function). METHODS: There were 216 asthmatic patients in the MNT+BD group and 184 patients in the dBD group with AR. Treatment differences in the change from baseline in AM PEF were compared. Least square (LS) mean and 95% confidence interval (CI) were derived from an anova model adjusting for baseline and study site. RESULTS: There was a 9.2% increase in AM PEF from baseline in the MNT+BD group compared with a 6% increase in the dBD group. The LS mean difference [(MNT+BD)-dBD] was 14.2 l/min (P=0.028). Other secondary endpoints were similar between groups. CONCLUSION: In the subgroup of asthmatic patients with AR, a combined treatment approach that included montelukast and budesonide provided significantly greater efficacy in reducing airflow obstruction compared with doubling the dose of budesonide. These results support recommendations by the Allergic Rhinitis and its Impact on Asthma initiative that suggest a unified approach aimed at treating the airway inflammation common to both diseases is beneficial for the large proportion of asthmatics who also suffer from AR.