The protective effect of salbutamol inhaled using different devices on methacholine bronchoconstriction

STUDY OBJECTIVE: To determine the protective effect of salbutamol, 100 microg, inhaled by different devices (pressurized metered-dose inhaler [pMDI; Ventolin; GlaxoWellcome; Greenford, UK], pMDI + spacer [Volumatic; GlaxoWellcome], or breath-activated pMDI [Autohaler; 3M Pharmaceuticals; St. Paul, MN]) on bronchoconstriction induced by methacholine. DESIGN: Randomized, double-blind, cross-over, placebo-controlled study. PATIENTS: Eighteen subjects with stable, moderate asthma, asymptomatic, receiving regular treatment with salmeterol, 50 microg bid, and inhaled beclomethasone dipropionate, 250 microg bid, in the last 6 months, with high hyperreactivity to methacholine (baseline provocative dose of methacholine causing a 20% fall in FEV(1) [PD(20)] geometric mean [GM], 0.071 mg). Subjects were classified into two groups: subjects with incorrect (n = 5) pMDI inhalation technique, and subjects with correct (n = 13) inhalation technique. METHODS AND MEASUREMENTS: After cessation of therapy for 3 days, all subjects underwent four methacholine challenge tests, each test 1 week apart, each time 15 min after inhalation of salbutamol, 100 microg (via pMDI, pMDI + spacer, or Autohaler), or placebo. The protective effect on methacholine challenge test was evaluated as the change in the PD(20), and expressed in terms of doubling doses of methacholine in comparison with placebo treatment. RESULTS: The PD(20) was significantly higher after salbutamol inhalation than after placebo inhalation, but no significant difference was observed among the three different inhalation techniques. Only when salbutamol was inhaled via pMDI + spacer, PD(20) was slightly but not significantly higher (pMDI GM, 0.454 mg; pMDI + spacer GM, 0.559 mg; and Autohaler GM, 0.372 mg; not significant [NS]) than other inhalation techniques. Similar results (mean +/-SEM) were obtained with doubling doses of methacholine (pMDI, 2 +/- 0.47; pMDI + spacer, 3 +/- 0.35; and Autohaler, 2.4 +/- 0.40; NS). No significant difference was found among techniques when subjects with correct or incorrect inhalation technique were separately considered. CONCLUSIONS: Our data show that the protective effect of salbutamol, 100 microg, on methacholine-induced bronchoconstriction is not affected by the different inhalation techniques, although inhalation via pMDI + spacer tends to improve the bronchoprotective ability of salbutamol. These data confirm the clinical efficacy of salbutamol, whatever the device, and the patient's inhalation technique.     

One week treatment with salmeterol does not prevent early and late asthmatic responses and sputum eosinophilia induced by allergen challenge in asthmatics

Salmeterol is an effective long-acting beta(2)-agonist bronchodilator, able to inhibit, as a single dose, asthmatic responses induced by several stimuli including allergen, and the subsequent increase in sputum eosinophilia. Aim of the present study was to investigate whether these effects of salmeterol persisted after 1 week of continuous treatment, or whether a loss of the bronchoprotective effects of salmeterol can occur over time. We investigated in a cross-over double blind placebo-controlled study, the protective effect of 1 week treatment with salmeterol on allergen-induced early and late responses and the associated airway inflammation in 15 atopic asthmatic subjects. Eosinophil percentage and Eosinophil Cationic Protein (ECP) concentration in peripheral blood and in hypertonic saline induced sputum were measured at baseline and 24 h after allergen inhalation. Salmeterol partially inhibited early asthmatic response, but it did not inhibit late asthmatic response in comparison with placebo. Salmeterol did not inhibit also the increase in sputum eosinophils percentage 24 h after allergen inhalation (E%, median: 22.7 and 15%, after placebo and after salmeterol respectively, p=n.s. between two post-allergen sputum samples). Also, the increase in blood eosinophils and both sputum and serum ECP at 24 h after allergen challenge was not affected by salmeterol pre-treatment. In conclusion, 1 week treatment with salmeterol causes a loss of its protective effect on allergen-induced airway bronchoconstriction, and does not prevent the subsequent increase in sputum and serum eosinophilic markers.     

Predictors of symptom recurrence after low-dose inhaled corticosteroid cessation in mild persistent asthma

In order to identify predictors of recurrence of asthma symptoms after withdrawal of therapy in mild persistent asthmatics, asymptomatic on low-dose inhaled corticosteroids (ICS), we studied 87 asthmatic patients regularly treated with ICS for at least 6 months. At the enrollment visit (T1), 71 on ICS were asymptomatic over the past 3 months and discontinued asthma treatment. Symptoms and PEF were then monitored for up to 3 months or until symptoms recurred (T2). At T1 and T2, all subjects underwent methacholine challenge and sputum induction. Thirty nine out of 71 patients experienced symptom recurrence. At T1, clinical and functional data and sputum eosinophilia between patients with or without recurrence of symptoms were similar. Age > 40 yr, and disease duration > 5 yr were significantly associated with recurrence of asthma symptoms, while the presence of allergic rhinitis, low baseline FEV(1) and untreated time span > 60 months showed a trend to be associated with symptoms recurrence. At T2, symptoms, pulmonary function, bronchial hyperresponsiveness and sputum eosinophilia deteriorated in patients with symptom recurrence but not in patients without symptom recurrence. In conclusion, age and asthma duration were the best predictors of symptom recurrence in mild persistent asthmatics who withdrew pharmacological therapy, as recommended in the step-down of international guidelines.     

Inhaled beclomethasone dipropionate reverts tolerance to the protective effect of salmeterol on allergen challenge

STUDY OBJECTIVE: One week of regular treatment with salmeterol can induce tolerance to the protective effect of a beta2-agonist on early airway response to allergen (EAR). The objective was to assess whether inhaled corticosteroids revert tolerance to salmeterol. STUDY DESIGN: The study had a randomized, double-blind, placebo-controlled design. PATIENTS AND METHODS: Twelve subjects with mild allergic asthma and positive result of specific bronchial provocation test (sBPT) to allergen underwent three sBPTs, separated by 1 week. sBPT was done in all subjects after a single dose (T1) and after 1 week of regular treatment with inhaled salmeterol (50 microg bid) (T2) in order to induce tolerance. Subjects were then randomized to receive either the same dose of salmeterol + beclomethasone dipropionate (BDP, 500 microg bid) (group 1, n = 6) or placebo + BDP (group 2, n = 6) for 1 week before sBPT (T3). RESULTS: After a single dose of salmeterol (T1), all subjects were protected against EAR, whereas after 1 week of regular treatment, the protective effect of salmeterol was totally or partially lost (T2). Maximum FEV1 percent fall (MaxdeltaFEV1%) after allergen inhalation was significantly higher at T2 than at T1. All subjects except one of group 1 were protected against EAR after salmeterol + BDP (T3), and MaxdeltaFEV1% at T3 (median, 12%; range, 4 to 6%) was significantly lower than T2 (median, 22%; range, 12 to 43%; p < 0.05 by Wilcoxon test). Subjects of group 2 did not show any significant protection against EAR after placebo + BDP treatment (T3) MaxdeltaFEV1% at T2 (median, 31%; range, 9 to 40%) and T3 (median, 31%; range, 3 to 42%; not significant). CONCLUSIONS: In conclusion, the addition of inhaled BDP partially restored the bronchoprotective effect of salmeterol on allergen challenge that was lost after 1 week of regular treatment with salmeterol alone. This ability of BDP in reverting tolerance cannot be ascribed to a direct effect of corticosteroids per se on allergen challenge in this group of asthmatics.     

Ozone exposure increases eosinophilic airway response induced by previous allergen challenge

We investigated whether exposure to ozone (O(3)) 24 hours after an allergen challenge test would increase airway eosinophilia induced by allergen in subjects with mild asthma with late airway response. Twelve subjects with mild atopic asthma participated in a randomized, single-blind study. Subjects underwent allergen challenge 24 hours before a 2 hour exposure to O(3) (0.27 ppm) or filtered air. Pulmonary function was monitored during the allergen challenge and after the exposure to O(3) or air. Six hours later, induced sputum was collected. After 4 weeks, the experiment was repeated with the same subjects. Allergen induced a comparable late airway response in both challenges. O(3) exposure induced a significant decrease in FVC, FEV(1), and vital capacity, and was associated with a significant increase in total symptom score compared with air exposure. The percentage of eosinophils, but not the percentage of neutrophils, in induced sputum was significantly higher after exposure to O(3) than after exposure to air (p = 0.04). These results indicate that O(3) exposure after a late airway response elicited by allergen challenge can potentiate the eosinophilic inflammatory response induced by the allergen challenge itself in subjects with mild atopic asthma. This observation may help explain the synergistic effect of air pollution and allergen exposure in the exacerbation of asthma.     

Salbutamol plus beclomethasone dipropionate, but not salbutamol alone, completely prevent early and late asthmatic responses to allergen.

The effect of a week treatment with inhaled salbutamol plus placebo (S+P) vs. salbutamol combined with beclomethasone dipropionate (S+BDP) on early and late asthmatic responses to inhaled allergen was studied in ten atopic patients in a randomized, double-blind, cross-over study. All patients had previously shown a dual type response to the specific bronchial provocative test (sBPT). Each patient performed two periods of treatment for a week, with a 15 day interval between them: (a) salbutamol 0.3 mg, tid + placebo; (b) salbutamol 0.3 mg+BDP 0.2 mg, tid; at the end of each treatment period, sBPT was performed and the last treatments were given 1.5-2 h before and 3-4 h after allergen challenge. S + BDP completely prevented both early and late responses to allergen, while S + P reduced but did not completely inhibit early and late responses. The difference between the two treatments was significant for early and late asthmatic responses. Non-specific bronchial hyperresponsiveness to methacholine was performed before each treatment period, after 6 days of treatment before sBPT and the day after sBPT at the end of the treatment period; there was only a mild increase in PD15FEV1 methacholine after 6 days of treatment with S + BDP in comparison with S + P treatment. These results suggest that salbutamol plus beclomethasone may be used effectively in the prophylaxis of early and late asthmatic reactions induced by allergen in sensitized subjects.     

Low sputum eosinophils predict the lack of response to beclomethasone in symptomatic asthmatic patients

BACKGROUND: The prognostic role of low sputum eosinophils in steroid-na?ve, symptomatic asthmatic patients is controversial. AIM: To verify whether low sputum eosinophils predict poor response to treatment with inhaled corticosteroids. METHODS: Sixty-seven symptomatic asthmatic patients with moderate asthma were examined before and after 2 weeks and 4 weeks of treatment with beclomethasone dipropionate, 500 microg bid. None received corticosteroids in the 3 months preceding the study. At each visit, all patients underwent spirometry, methacholine challenge, and sputum induction. The patients recorded symptom scores and peak expiratory flow (PEF) throughout the study. RESULTS: Seventeen patients had low sputum eosinophils despite being symptomatic. Patients with high (> 3%) sputum eosinophils at baseline showed significant improvement in symptoms, pulmonary function, and bronchial hyperresponsiveness after treatment, whereas patients with low sputum eosinophils showed no significant improvement in most clinical and functional outcomes. Among the baseline indexes examined, sputum eosinophils had the highest negative predictive value but low positive predictive value for the response to treatment. Multiple stepwise regression showed that only baseline FEV(1) and sputum eosinophil percentages significantly correlated with changes in FEV(1) after treatment. CONCLUSIONS: We suggest that, among the indexes examined, low sputum eosinophils are the best predictor for poor corticosteroid effects in asthma.     

NK and NKT-like cells in granulomatous and fibrotic lung diseases

Clinical and Experimental Medicine - Background The pathogenetic and regulatory roles of natural killer (NK) and natural killer T-like cells in interstitial lung diseases (ILDs), fibrotic and...     

Analysis of induced sputum before and after withdrawal of treatment with inhaled corticosteroids in asthmatic patients

To assess whether sputum eosinophilia predicts the recurrence of asthma symptoms after withdrawal of therapy in moderate stable asthmatics on low-dose inhaled corticosteroids. Randomized, double-blind, placebo-controlled study involving 30 subjects with stable asthma, asymptomatic, with low PEF variability measured over two run-in weeks, on treatment with low-dose inhaled beclomethasone dipropionate (BDP, 250 microgram b.i.d. in the last 3 months). At the end of the run-in, all patients underwent a methacholine challenge test and sputum induction (T1). They then stopped therapy and received either placebo (20 subjects, study group) or BDP at the same dose as in the previous 3 months (10 subjects, control group). They continued to monitor PEF and symptom score for 3 months, or until asthma symptoms recurred (diurnal and nocturnal symptom score >/=2 on two consecutive days). At the end of the study (T2), i.e., either within 5 days from the beginning of asthma symptoms or after 3 months in subjects without recurrence of asthma symptoms, all subjects repeated the methacholine challenge test and sputum induction. In the placebo-treated group, sputum eosinophils at T1 were significantly higher in subjects who subsequently developed recurrence of asthma symptoms (n = 7) after cessation of treatment than in subjects who remained asymptomatic for 3 months (8.2% [0-56.6] vs 0.9% [0-11], P < 0.05). At the time of recurrence of asthma symptoms, sputum eosinophil percentages significantly increased (from 8.2% [0-56.6] to 16.6% [5.8-73.6], P < 0.05). The positive predictive value of sputum eosinophils for the recurrence of asthma symptoms was 71%, while the negative predicting value was 84%. In the BDP-treated control group, none of the subjects experienced recurrence of asthma symptoms, and sputum eosinophil percentages measured at the beginning (T1) and at the end (T2) of the study were similar. Sputum eosinophil percentages may vary over a wide range in asthmatic subjects, although regularly treated and apparently well controlled. However, high sputum eosinophil percentages are related to early recurrence of asthma symptoms after cessation of inhaled corticosteroids.