Inhaled corticosteroids and growth of airway function in asthmatic children

Airway inflammation and remodelling play an important role in the pathophysiology of asthma. Remodelling may affect childhood lung function, and this process may be reversed by anti-inflammatory treatment. The current study assessed longitudinally whether asthma affects growth of airway function relative to airspaces, and if so whether this is redressed by inhaled corticosteroids (ICS). Every 4 months for up to 3 yrs, lung function was assessed in 54 asthmatic children (initial age 7-16 yrs), who inhaled 0.2 mg salbutamol t.i.d. and 0.2 mg budesonide t.i.d. (beta2-agonist (BA)+ICS), or placebo (PL) t.i.d. (BA+PL) in a randomised, double-blind design. Measurements were carried out before and after maximal bronchodilation. Airway growth was assessed from the change of forced expiratory volume in one second and of maximal expiratory flows (at 60% and 40% of total lung capacity (TLC) remaining in the lung) relative to TLC, as measures of more central, intermediate and more peripheral airways. Growth patterns were compared with the longitudinal findings in 376 healthy children. Airway patency after maximal bronchodilation in patients on BA+PL remained reduced compared to healthy subjects, whereas in patients on BA+ICS a marked improvement was observed to subnormal. No differences between patients and controls could be demonstrated for growth patterns of central and intermediate airway function. Compliance with BA+ICS was 75% of the prescribed dose, resulting in significant, sustained improvement of symptoms and postbronchodilator calibre of central and intermediate airways to subnormal within 2 months, but postbronchodilator small airway patency remained reduced, though improved compared to patients on BA+PL. Anti-inflammatory treatment of asthmatic children is associated with normal functional development of central and intermediate airways. The persistently reduced postbronchodilator patency of peripheral airways may reflect remodelling, or insufficient anti-inflammatory treatment

Airway responsiveness after a single dose of salmeterol and during four months of treatment in children with asthma

Background: Inhalation of a single dose of the long-acting β2- adrenoceptor agonist salmeterol protects against methacholine-induced airway obstruction and other bronchoconstricting stimuli for at least 12 hours. Hypothetically, twice daily dosing of salmeterol may result in continuous protection. Objective: this study was designed to investigate the protective effect of a single dose of salmeterol and of continuous twice daily treatment on airway responsiveness to methacholine. Methods: In a double-blind, parallel study, salmeterol 50 μg twice daily was compared with salbutamol 200 μg twice daily. Thirty children with mild asthma, who had little or no bronchial obstruction and were hyperresponsive to methacholine (PD20 ≤ 150 μg) were allocated to receive either salmeterol or salbutamol. Airway responsiveness was measured before study entry, 12 hours after a single dose of drug was given, and monthly during 4 months of daily treatment. Measurements were always performed at the same time of the day, 12 hours after the last dose of medication was administered. Results: No significant differences in FEV1 were found between treatments at any time point. PD20 significantly increased after the first dose of salmeterol was given (geometric mean, 100 μg). Geometric mean PD20 values were significantly better during salmeterol treatment than during salbutamol treatment, 52 and 25 μg, respectively (p = 0.005). Conclusion: The protection provided by salmeterol during maintenance treatment was less than that provided after the first dose (p < 0.001). However, protection did not diminish during the 4- month treatment period and remained significant compared with baseline (p = 0.003)

The correlation between increased reactivity of the bronchi and of mediator releasing cells in asthma

textabstractThe hypothesis that increased reactivity in asthma is not always limited to the bronchi but also exists in the mediator releasing system was investigated in forty‐five asthmatic children, approximately half of whom had exercise‐induced bronchoconstriction (EIB). The bronchial threshold to histamine was measured as an indicator of the reactivity of the bronchi and the histamine release from leucocytes without adding allergen (spontaneous histamine release) was considered as an indicator of the reactivity of the basophil leucocytes. There was a significant correlation between the histamine threshold and spontaneous histamine release and between these and EIB. These findings support the hypothesis. Copyrigh

Release of histamine from leucocytes and its determinants in vitro in rotation to bronchial responsiveness to inhaled histamine and exercise in vivo

textabstractThe hypothesis studied is that increased responsiveness in asthma is not limited to the airways. Forty asthmatic children were analysed for their bronchial responsiveness (BR) to exercise. Twenty patients revealed bronchial obstruction after exercise while the remainder did not. These observations were compared with the responsiveness of leucocytes, which was determined by their histamine ‘releasability’. Twenty healthy children served as controls. Release of histamine induced by calcium ionophore‐aided calcium influx was significantly higher in both groups of asthmatics than in the healthy children (P < 0.005). Similar findings were obtained by induction of microtubule aggregation due to deuterium oxide (D2O). The S‐shaped dose‐response relationship with D2O was shifted to the left in the patients with BR to exercise compared to patients without (P < 0.025). The slope was increased in both patient groups compared with the healthy children (P < 0.01). It is concluded that the mean ‘releasability’ of histamine release due to both stimulants correlated well (P < 0.01). This suggests that the ‘releasability’ is determined by the responsiveness of the microtubules. This may also apply to allergen‐induced histamine release, as was revealed from studies with anti‐IgE. The differences in histamine release found in relation to BR due to exercise were also present if the patients were divided according to BR due to histamine. A significant relationship existed between the degree of BR to histamine and the responsiveness of the microtubules (P < 0.02). Copyrigh

Addition of salmeterol versus doubling the dose of beclomethasone in children with asthma. The Dutch Asthma Study Group

Studies in adults revealed that addition of salmeterol to a moderate dose of inhaled corticosteroid resulted in better symptom control and higher PEF compared with doubling the dose of inhaled corticosteroid. The aim of this three group study was to compare the effects of a moderate dose of beclomethasone, the same dose of beclomethasone with salmeterol, and a doubling dose of beclomethasone on lung function and symptoms in children with moderate asthma. A total of 177 children already treated with inhaled corticosteroids, were randomized in a double-blind parallel study either to salmeterol 50 microg twice daily (BDP400+salm), beclomethasone 200 microg twice daily (BDP800), or placebo (BDP400) in addition to beclomethasone 200 microg twice daily. No significant differences between groups were found in FEV1, PD20 methacholine, symptom scores, and exacerbation rates after 1 yr. Salmeterol resulted in slightly better PEF in the first months of treatment. FEV1, and PD20 methacholine significantly improved in all groups. After 1 yr mean changes in FEV1, percent predicted were 4.3% (95% CI 1.3; 7.2), 5.8% (95% CI 2.9; 8.7), and 4.3% (95% CI 2.1; 6.5) for BDP400+salm, BDP800, and BDP400, respectively. Changes in airway responsiveness were 0.60 (95% CI 0.05; 1.14), 1.30 (95% CI 0.73; 1. 87), and 0.80 (95% CI 0.33; 1.27) doubling doses. Growth was significantly slower in the BDP800 group. We conclude that no additional benefit was found of adding either salmeterol or more beclomethasone to a daily dose of 400 microg beclomethasone in this group of children with excellent compliance of medication

One year treatment with salmeterol compared with beclomethasone in children with asthma. The Dutch Paediatric Asthma Study Group

The aim of this study was to compare the effects of salmeterol and beclomethasone on lung function and symptoms in children with mild to moderate asthma. Sixty-seven children not treated with inhaled corticosteroids were randomized in a double-blind parallel study either to salmeterol 50 micrograms b.i.d. or beclomethasone 200 micrograms b.i.d. After one year, FEV1 significantly increased in the beclomethasone group, whereas in the salmeterol group there was a small reduction. Differences between groups were 14.2% predicted (p < 0.0001) and 7.0% predicted (p = 0.007) for pre- and postbronchodilator FEV1 values, respectively. PD20 methacholine decreased by 0.73 DD (p = 0.05) in the salmeterol group and increased by 2.02 DD (p < 0.0001) in the beclomethasone group. Morning and evening PEF and symptom scores improved in both groups, although more in the beclomethasone group. Asthma exacerbations, for which prednisolone was needed, were more frequent in the salmeterol group (17 versus two), as were the number of withdrawals due to exacerbations (six versus one). However, growth was significantly slower in the beclomethasone group (-0.28 SDS) compared with that in the salmeterol group (-0.03 SDS) (p = 0.001). We conclude that treatment with a moderate dose of beclomethasone is superior to salmeterol in children with mild to moderate asthma and recommend that salmeterol should not be used as monotherapy