Karel F. Kerrebijn

Effect of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma.

Airway inflammation is assumed to be an important determinant in increased bronchial responsiveness (BR). We tested the hypothesis that treatment with an inhaled anti-inflammatory drug (i.e., budesonide) but not with an inhaled beta-agonist (i.e., terbutaline) would reduce BR in children with asthma and with minimal or no bronchoconstriction. Twelve patients were treated with budesonide and seven with terbutaline for 6 months. BR decreased in 11 patients receiving budesonide and was significant in seven patients. BR decreased in none of the patients receiving terbutaline. FEV1 demonstrated a small increase with budesonide but remained unchanged with terbutaline. Except in one patient who received terbutaline, the clinical effect was good. We conclude that inhaled corticosteroids but not inhaled beta-agonists will decrease persistent BR in most children with asthma.

Effect of a single dose of inhaled salmeterol on baseline airway caliber and methacholine-induced airway obstruction in asthmatic children

BACKGROUND Salmeterol is a new inhaled selective beta 2-adrenergic receptor agonist with a long duration of action. We studied the duration of the bronchodilation and the protective effect against methacholine-induced airway obstruction of a single dose of salmeterol in a double-blind, randomized, placebo-controlled, crossover design. METHODS Seventeen boys and three girls with mild-to-moderate asthma participated in the study. On two separate days either 50 micrograms salmeterol or placebo was inhaled. FEV1 and PD20 methacholine were determined before and 1, 4, 8, 12, and 24 hours after inhalation. RESULTS Salmeterol resulted in a significant bronchodilation compared with placebo, up to 12 hours (p = 0.0001). At 24 hours there was a residual effect that approached significance; mean FEV1 being 8.3% +/- 2.4% above baseline (p = 0.06). Significant protection against airway sensitivity to methacholine after salmeterol inhalation was found at all time points (p < 0.005). Twenty-four hours after administration mean PD20 was still 1.22 +/- 0.29 doubling dose above baseline. No important adverse effects were noted. CONCLUSION We conclude that a single dose of 50 micrograms salmeterol in children with asthma gives a long-lasting bronchodilation, exceeding 12 hours, which is comparable to the results in adult studies. The duration of the protection against airway sensitivity to methacholine exceeds 24 hours.

Does the outcome of the tidal breathing and dosimeter methods of assessing bronchial responsiveness in children with asthma depend on age

As minute volume increases with age, a study was carried out to determine whether the measurement of bronchial responsiveness to pharmacological agents with the tidal breathing technique in children might be influenced by age. Bronchial responsiveness to histamine administered by tidal breathing was therefore compared with that produced with a dosimeter in 25 children with asthma aged 5-18 years. Bronchial responsiveness was defined as the concentration of histamine that caused a 40% rise in pulmonary resistance (PC40) measured by random noise forced oscillation at 6 Hz. Values of PC40 measured by the tidal breathing method were lower than those obtained with the dosimeter method, presumably owing to differences in the dose administered and variations in the pattern of breathing. The difference between the two methods was not related to age, however. It is concluded that the tidal breathing and the dosimeter methods are both suitable for the measurement of bronchial responsiveness in children of various ages and that both can be used in longitudinal studies.

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. (β2‐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.

Measurement of human small airway smooth muscle function in vitro with the bronchiolar strip preparation

The technique by which human bronchiolar strips are prepared is described in detail. The biological viability of the preparations after storage at 4 degrees C overnight and the reproducibility of contractile responses to KCl and methacholine were examined in lung tissue from six patients. Measurements were performed on the first and second day after surgical resection. On both days, most bronchioles showed an increase in contractility. The responses on the first day were not different from those on the second day. No significant changes in time were found for pD2 and slope of the methacholine dose-response curves. The variability of responses between patients was significantly larger than between strips within patients. The pD2 was the best reproducible parameter.

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

The 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.

Effect of hyperosmolarity on human isolated central airways

1 We studied the effect of hyperosmolarity on human isolated airways because a better understanding of the effect of hyperosmolarity on the human airway wall may improve insight into the pathophysiology of hyperosmolarity‐induced bronchoconstriction in asthma. 2 In cartilaginous bronchial rings dissected from fresh human lung tissue, hyperosmolar Krebs‐Henseleit buffer (450 mosm, extra sodium chloride added) evoked a biphasic response: a rapid relaxation phase (peak after 5.0 ± 0.3 min) followed by a slow contraction phase (peak after 25.4 ± 0.8 min). 3 With the histamine (H1) receptor antagonist mepyramine, the contraction phase was reduced to 41.2% of the control value (P < 0.001), with atropine to 50.0% (P < 0.01), with the local anaesthetic lignocaine to 48.7% (P < 0.05) and with mepyramine together with atropine to 19.2% (P < 0.001). 4 With the inhibitor of neutral metalloendopeptidase, phosphoramidon, the contraction phase increased to 128.0% of the control value (P < 0.05) and after removal of the epithelium to 131.8% (P < 0.05). 5 Indomethacin, the leukotriene C4/D4 (LTC4/D4) antagonist FPL 55712 or the blocker of nerve conduction, tetrodotoxin, had no effect on the contractile phase. 6 The relaxation phase was not altered by any of these drugs nor by epithelial denudation. The relaxation phase was also unchanged in the presence of α‐chymotrypsin, which degrades muscle relaxing peptides such as vasoactive intestinal peptide. 7 Hyperosmolar buffer slightly increased the sensitivity and maximal response to methacholine as well as the cholinergic twitch to electric field stimulation. 8 We conclude that hyperosmolarity releases acetylcholine, histamine and neuropeptides in the human airway wall in sufficient quantities to contract airway smooth muscle. This release itself or its effect on airway muscle is modulated by the airway epithelium. The mechanism of the relaxation phase may be an unknown smooth muscle relaxing substance or a direct effect on the airway muscle, related to ion fluxes.

Study on the significance of bronchial hyperreactivity in the bronchus obstruction after inhalation of cat dander allergen

The role of bronchial hyperreactivity in the process that leads to bronchial obstruction after inhalation of an allergen was investigated. In 30 asthmatic children selected because of a positive skin test to cat dander allergen, we measured the histamine threshold, the reaction after allergen inhalation, the allergen-specific IgE concentration in serum, the lowest allergen concentration to which the intracutaneous skin test was positive (skin titer), and the histamine release of leukocytes after challenge with allergen. These variables were correlated with each other. The highest correlation was found between the inhalation reaction and the combination of the histamine threshold and either the allergen-specific IgE or the skin titer. Inhalation was only positive with a decreased histamine threshold (less than or equal to 8 mg/ml). With a low histamine threshold, a positive reaction to inhalation is likely to occur at an allergen-specific IgE concentration of > or = 2 U/ml or at a skin titer of < or = 2.5 x 10(-1) micrograms/ml.

Measurement of human small airway smooth muscle function in vitro. Comparison of bronchiolar strips and segments.

We have compared isotonic responses to methacholine of human bronchiolar segments and spiral strips. Both types of preparations contracted dose-dependently to methacholine and had a stable intrinsic contractile activity, which was significantly higher in segments (p less than 0.001). ANOVA indicated that the total variation in responses of both strips and segments was similar and was mainly due to a significant between-preparations/within-patients variation. There was a small but significant trend towards a decrease of sensitivity (EC50) in time for both segments and strips. Net contraction, i.e. the difference between resting length and the length at maximal contraction, did not change in time. Limited length-active shortening experiments indicated that 250 mg was a suitable load for both strips and segments. We concluded that, although human bronchiolar strips and segments are functionally comparable, bronchiolar segments are preferable because of their practical and theoretical advantages over bronchiolar strips.

Assessment of bronchodilatation after spontaneous recovery from a histamine challenge in asthmatic children.

BACKGROUND: It would be convenient to be able to measure airway responsiveness to histamine and to bronchodilator drugs on the same day, but whether this can be done reliably is unknown. METHODS: The effect of a prior histamine challenge on the bronchodilator response to salbutamol after spontaneous recovery of FEV1 to 95% of the prechallenge level was studied in two groups of asthmatic children. Fourteen children inhaled 400 micrograms salbutamol after spontaneous recovery from a histamine challenge, followed by a further 100 micrograms salbutamol 20 minutes later. In a second group of eight asthmatic children the study was repeated with 800 micrograms salbutamol, followed by a further 200 micrograms 20 minutes later. RESULTS: After histamine challenge FEV1 returned to baseline in 70 minutes or less on all occasions. The FEV1 20 minutes after 400 micrograms salbutamol was significantly lower after the histamine challenge than on the control day. After the further 100 micrograms salbutamol FEV1 values were similar after the histamine challenge and on the control day. FEV1 values after 800 micrograms salbutamol and the further 200 micrograms dose were not influenced by a prior histamine challenge. CONCLUSIONS: In children with stable asthma in whom FEV1 has returned to baseline after a histamine challenge the FEV1 achieved after 800 micrograms salbutamol is not affected by the histamine challenge. Histamine and bronchodilator responsiveness can thus be assessed reliably on the same day in patients with stable asthma. This has clear advantages for patient care.