Zenon Siergiejko

Beclometasone–formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial

BACKGROUND According to international treatment guidelines, inhaled rapid-acting β2 agonists should be used for the control of symptoms in patients with asthma. We compared the efficacy and safety of an extrafine combination inhaler containing a corticosteroid (beclometasone) plus a rapid-onset, long-acting β2 agonist (formoterol) with a short-acting β2 agonist (salbutamol) as reliever strategies in patients taking beclometasone-formoterol combination as maintenance treatment. METHODS In a double-blind trial undertaken in 183 centres in 14 European countries over 48 weeks, patients (aged ≥18 years) with asthma that was not fully controlled, with a forced expiratory volume in 1 s (FEV1) of at least 60% predicted, had a 2-week run in. During this period, patients were treated with a combination of beclometasone 100 μg and formoterol 6 μg per one inhalation twice daily plus salbutamol 100 μg as required delivered by use of a pressurised metered-dose inhaler. They were then randomly assigned in a 1:1 ratio with a computer-generated randomisation list to receive beclometasone 100 μg plus formoterol 6 μg or salbutamol 100 μg as reliever in addition to maintenance with beclometasone 100 μg plus formoterol 6 μg twice daily. Primary outcome was the time to first severe exacerbation (admission to hospital or visit to emergency department, or use of systemic steroids for ≥3 consecutive days). Secondary outcomes were number of severe exacerbations (events per 100 patients per year), time to and number of mild exacerbations, additional exacerbation variables, lung function, symptom scores, and asthma control. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00861926. FINDINGS 1714 patients were randomly assigned to the as-needed beclometasone-formoterol (n=857) and as-needed salbutamol groups (n=857), and 1701 were analysed (852 and 849, respectively). 326 severe exacerbations were reported by 251 patients during the study, and 99 versus 152 patients had at least one exacerbation during the 48 weeks, respectively. Compared with beclometasone-formoterol plus salbutamol as needed, beclometasone-formoterol for both maintenance and reliever treatment significantly increased the time to first exacerbation (209 days vs 134 days) by 75 days, with a 36% reduction in risk (hazard ratio 0·64 [95% CI 0·49 to 0·82]; p=0·0005), and the estimated probability was 12% and 18%, respectively (p=0·0003). The number of days with mild asthma exacerbations was also lower with as-needed beclometasone-formoterol than with as-needed salbutamol (56·04 days per patient per year vs 65·11 days per patient per year; 0·86 [0·76 to 0·98]; p=0·021). From the run-in period to week 48, both treatments improved symptoms (mean change -1·59 [-1·94 to -1·25] in the as-needed beclometasone-formoterol group vs -1·44 [-1·78 to -1·10] in the as-needed salbutamol group, difference -0·15 [-0·60 to 0·30]; p=0·507), percentage of asthma control days (9·5% [7·3 to 11·8] vs 10·9% [8·7 to 13·1], respectively, -1·4 [-4·3 to 1·6]; p=0·359), use of reliever (-0·29 [-0·38 to -0·20] vs -0·27 [-0·36 to -0·19], respectively, -0·02 [-0·13 to 0·10]; p=0·794), and lung function (FEV1, 0·090 [0·060 to 0·120] vs 0·090 [0·060-0·120], respectively, 0·001 [-0·040 to 0·040]; p=0·969), and were well tolerated (patients with serious adverse events, 32 [4%] and 41 [5%], respectively). INTERPRETATION Our results lend support to the use of the combination of a single inhaled corticosteroid plus a rapid-onset, long-acting β2 agonist for maintenance and relief in patients with moderate to severe asthma and provide encouraging data for the formulation of beclometasone-formoterol for this use. FUNDING Chiesi Farmaceutici.

Oral corticosteroid sparing with omalizumab in severe allergic (IgE-mediated) asthma patients

Abstract Background: Long-term oral corticosteroid (OCS) therapy and related adverse events are associated with a significant burden on patients and healthcare resources. Methods: This subgroup analysis of a randomized, open-label, parallel-group study evaluated the OCS-sparing effect of omalizumab (OMA) added to optimized asthma therapy (OAT), compared with OAT alone. Patients (12–75 years) with severe allergic asthma, uncontrolled despite GINA 2004 Step 4 therapy, received OMA or OAT for 32 weeks. The change from baseline in OCS use by Week 32 in patients requiring maintenance OCS at baseline was assessed in terms of percent OCS dose change and numbers of patients with reduced/stopped or maintained/increased OCS. Results: Eighty-two patients were receiving maintenance OCS at baseline (OMA/OAT n = 59, OAT n = 23). Change from baseline in mean maintenance OCS dose at Week 32 was significantly greater in the OMA/OAT group compared with the OAT group (−45% vs. + 18.3%, p = 0.002). In the OMA/OAT group, 37 patients (62.7%) reduced/stopped OCS use at Week 32, compared with seven patients (30.4%) receiving OAT (p = 0.013). Improvements in other efficacy outcomes were seen at Week 32 in the OMA/OAT group, irrespective of OCS use. An investigator global evaluation of treatment effectiveness at Week 16 was an effective predictor of persistent treatment response at 32 weeks for the majority of OMA/OAT patients (93%), also irrespective of OCS use. Conclusion: In this open-label study of patients with severe allergic asthma, OMA/OAT therapy reduced maintenance OCS use, compared with OAT alone. Improvements in efficacy measures were observed in the OMA/OAT group, irrespective of OCS change. Clinicaltrials.gov identifier: NCT00264849.

Bronchial Allergen Challenge in Allergic Children: Continuous Increase of Nitric Oxide in Exhaled Air 72 Hours After Allergen Inhalation Independent of Bronchial Obstruction

BACKGROUND Changes in fractional exhaled nitric oxide (FeNO) occurring after bronchial allergen challenges (BAC) are still not understood, neither are any possible associations between FeNO and forced expiratory volume in 1 sec (FEV(1)). The aim of the study was to compare the fluctuations of FeNO and FEV(1), which occur within 72 h of BAC in children sensitive to grass pollen. METHODS Seventy-four children were divided into two groups based on their medical histories and the results of skin prick tests with 10 common allergens. Individuals in whom the test yielded a positive result to at least grass pollen (Group A, n = 57), and those with negative test results against all of the allergens applied (Group B, n = 17) were subjected to BAC. FeNO was measured at a baseline and at 1, 8, 21, and 72 h after the last dose of the allergen inhalation, whereas FEV(1) was measured at a baseline, hourly for 8 h after the challenge and at 21 and 72 h thereafter. RESULTS Baseline FeNO in sensitive subjects (Group A) was significantly higher than in controls of Group B. In all grass pollen-sensitive subjects, even those that were free of a bronchial response, FeNO was markedly elevated compared to its baseline values, starting from the eighth hour onward, and still increased 72 h post-BAC, whereas FEV(1) returned to a baseline at the 72nd h post-BAC. The highest increase in FeNO was registered in individuals with a dual asthmatic response. CONCLUSIONS An increase in FeNO in sensitive subjects starts a few hours later than the decrease in FEV(1). Consequently, measurements of FeNO seem to be useful in long-term monitoring of the allergic reaction triggered by a specific allergen.

Long-term intense exposure to grass pollen can mask positive effects of allergenic immunotherapy on non-specific bronchial hyperresponsiveness

Introduction There are many potential factors that can modulate bronchial reactivity, including exposure to allergens, viral infections, and medications. The aim of this study was to analyze the effect of grass pollination intensity on the bronchial reactivity in seasonal allergic rhinitis (SAR) patients subjected to subcutaneous allergenic immunotherapy (SCIT). Material and methods This study, performed between 2005 and 2008, included 41 patients with confirmed sensitivity to grass pollens and predominating symptoms of SAR, randomly assigned to desensitization by pre-seasonal or maintenance SCIT. Bronchial provocation challenge with histamine was performed before the onset of immunotherapy, and repeated three times after each pollen season covered by this study. Bronchial reactivity was analyzed with regard to grass pollination intensity in 2005–2008 (air concentration of grass pollen grains, seasonal number of days when air concentration of grass pollen reached at least 20 or 50 grains per 1 m3). Results After 3 years of SCIT, a significant decrease in bronchial responsiveness was observed in the analyzed group as confirmed by an increase in PC20 FEV1 histamine values (p = 0.001). An inverse tendency was observed after 2 years of SCIT, however. This second year of SCIT corresponded to the 2007 season, when a significantly higher number of days with at least 50 grains of pollen per 1 m3 of air was recorded. Conclusions Fluctuations in pollination intensity observed during consecutive years of immunotherapy can influence bronchial reactivity in patients subjected to SCIT (ISRCTN Register: ISRCTN 86562422).

Mannitol Challenge Does Not Confirm Bronchial Hyperreactivity in Some Histamine-Responsive Asthmatic Children

Objective. The aim of this study was to compare the usefulness of mannitol provocation test to that of classical histamine challenge in children with PC20FEV1 histamine lower than 4 mg/ml. Methods. Twenty-two adolescent patients (mean age of 15.4 ± 4.1 years) with established asthma (PC20FEV1 histamine below 4 mg/ml) were included in this study. Bronchial challenge with mannitol was performed 1–2 days after the test with histamine. Results. The fraction of positive results of mannitol test was markedly lower when compared with the histamine challenge (72.7% vs. 100%, p = .015). The test was discontinued in one case due to severe coughing after inhalation of 315 mg of mannitol. Coughing during inhalation of dry mannitol powder occurred in most patients, although drinking water after subsequent doses alleviated this symptom in nearly all of them. Of note, triboelectrification of the inhaler and capsules was observed during the administration of consecutive mannitol doses, markedly hindering the delivery of this provoking agent. The relative decrease in FEV1 resulting from bronchial provocation was significantly lower following mannitol delivery when compared with the histamine test (70.3% vs. 81.6% of resting value, p < .001). Significant correlation was not observed between the values of PC20FEV1 histamine and PD15FEV1 mannitol levels. Conclusions. Bronchial challenge with mannitol can be used as a screening test in everyday practice, but one cannot exclude bronchial hyperresponsiveness based on its negative results. Moreover, its usefulness is limited by the influence of static on the delivery of sequential mannitol doses and coughing which can be often associated with mannitol inhalation.

Allergenic Immunotherapy and Seasonal Changes in Nitric Oxide Concentration in Exhaled Air in Seasonal Rhinitis Patients

BACKGROUND Concentration of nitric oxide in exhaled air (FeNO) was revealed to decrease as a result of immunotherapy. However, individuals who are exposed to environmental allergens are characterized by elevated values of FeNO. The aim of this study was to analyze the effects of subcutaneous immunotherapy (SCIT) on the dynamics of FeNO determined during consecutive pollination seasons. METHODS This study, performed between 2005 and 2008, included 41 patients with confirmed sensitivity to grass pollens and predominating symptoms of seasonal allergic rhinitis, randomly assigned to desensitization by preseasonal or maintenance SCIT. FeNO was measured prior to and during each pollen season (November-January and May-July, respectively). The results were conferred to data on grass pollination intensity in 2006-2008 (air concentration of grass pollen grains, seasonal number of days when air concentration of grass pollen reached at least 50 grains per 1 m(3)). RESULTS Median content of FeNO in exhaled air was significantly higher in 2007 compared to 2006 and 2008 pollen seasons. During 2007 and 2008 pollen seasons, significant increase in FeNO was observed compared to the respective preseasonal values. Median number of days with air concentration of grass pollen ≥ 50 grains per 1 m(3) of air during 4 weeks preceding seasonal FeNO measurement was significantly higher in 2007, corresponding to higher FeNO value recorded during this pollen season. However, no significant correlation was observed between seasonal number of days with ≥ 50 grass pollen grains per 1 m(3) of air and FeNO in exhaled air (r=0.09, p=0.362). CONCLUSIONS Most seasonal allergic rhinitis patients show physiological levels of FeNO prior to the pollen seasons and a marked increase in this parameter, probably proportional to pollination intensity, is observed within the seasons. ISRCTN Registry: ISRCTN86562422.

Antiasthmatic versus Surgical Treatment—How Important Is the Precise Analysis of Spirometry?

Objective. Carcinoids are low-grade, slow growing malignant tumors in the bronchi usually producing symptoms secondary to bronchial obstruction. We describe a case of 25-year-old woman who was initially diagnosed with asthma. Method. Case report. Results. Because of exacerbation and unresponsiveness to proper asthma treatment she was referred to spirometry, which showed low values of forced expiratory volume in 1 second. The shape of inspiratory limb of flow volume curve suggested an obstruction in the main bronchus or in the trachea. Further bronchoscopy revealed a tumor of the right main bronchus with characteristic histological features for carcinoid. Conclusions. Both the inspiratory curve and the expiratory part of the flow-volume loop should be evaluated in patients being evaluated for asthma. If there are changes in the shape of the inspiratory limb suggesting an obstruction, CT and/or bronchoscopy should be considered.