Pretreatment Alveolar Nitric Oxide Levels Predict Improvement of Pulmonary Function 1 Year Following Anti-Asthma Treatments in Patients with Inhaled Corticosteroid-Naïve Asthma

<b><i>Introduction:</i></b> Inhaled corticosteroids (ICS) are fundamental agents to subside airway inflammation and improve forced expiratory volume in 1 s (FEV₁) among asthmatics. Alveolar concentrations of nitric oxide (CANO), as well as the classical fraction of exhaled nitric oxide (FeNO50), are associated with the pathophysiology of asthma. However, the association between pretreatment CANO levels and response to anti-asthma treatments, including ICS, remains unknown. <b><i>Methods:</i></b> We retrospectively analyzed 107 patients newly diagnosed with asthma. ICS in combination with long-acting β₂-agonists (ICS/LABA) was initiated. FEV₁ and FeNO levels were evaluated at diagnosis and were followed up at 6 and 12 months after the treatment intervention. CANO levels were estimated using various expiratory flows of FeNO measurements. Factors associated with annual changes in FEV₁ (ΔFEV₁) were analyzed. Patients with a ΔFEV₁ &#x3c;–20 mL were defined as “poor-responders.” <b><i>Results:</i></b> FEV₁, FeNO50, and CANO levels significantly improved by anti-asthma treatments. The average ΔFEV₁ was 85 (176) mL. Eighty-two patients continuously took ICS/LABA treatment. Higher pretreatment CANO levels and continuous use of LABA were independent predictive factors for the improvement of FEV₁ on multivariate analysis. The decline in FeNO50 and CANO levels by the anti-asthma treatments was significantly greater in 81 responders than in 26 poor-responders. CANO, but not FeNO50, levels at 12 months were significantly higher in poor-responders than in responders (<i>p</i> = 0.009). <b><i>Conclusion:</i></b> Levels of CANO, but not FeNO50, predict changes in pulmonary function in ICS-naïve asthmatics. Meanwhile, persistently high levels of CANO may be related to poor responsiveness to treatments assessed by ΔFEV₁.

Beclometasone but not fluticasone modulates PDGFD expression in the H295R adrenal cell line.

BackgroundAdrenal suppression is a clinically concerning side effect of inhaled corticosteroid (ICS) treatment in patients with asthma. Increased susceptibility to ICS-induced adrenal suppression has previously been identified in those with the rs591118 polymorphism in Platelet Derived Growth Factor D (PDGFD). The mechanism underpinning this relationship is not known.MethodsH295R cells were genotyped for rs591118 using a validated Taqman PCR allelic discrimination assay. H295R cell viability was determined after treatment with beclometasone and fluticasone (range 0-330 μM). Cortisol was measured in cell culture medium using competitive enzyme immunoassay.ResultsPDGFD protein expression in H295R cells was confirmed using Western blotting. When ACTH and forskolin were added to H295R cells, a reduction in PDGFD expression was seen which was then restored by incubation with prochloraz, a known inhibitor of steroidogenesis.A dose-dependent, decrease in PDGFD expression was observed with beclometasone (over a 24 h incubation period) but not with beclometasone incubations beyond 24 hour nor with fluticasone (at 24 or 48 hours).ConclusionsH295R cells express PDGFD protein which can be modulated by incubation with steroidogenesis agonists and antagonists and additionally with exogenous beclometasone.

Efficacy and safety of a budesonide/formoterol reliever therapy regimen in mild-moderate asthma: A randomised controlled trial

<p>Background Inhaled corticosteroids taken regularly reduce exacerbation risk in patients with mild asthma. In clinical practice however, adherence to inhaled corticosteroids is poor and the burden of disease from exacerbations is substantive. In this thesis I explore an alternative approach, that of an inhaled corticosteroid/formoterol combination used as sole reliever therapy, that potentially overcomes the problem of poor adherence. I report the results of my research, known as the PeRsonalised Asthma Combination Therapy: with Inhaled Corticosteroid And fast-onset Long acting beta agonist (PRACTICAL) study. Research aims To investigate the efficacy and safety of as-needed budesonide/formoterol, an inhaled corticosteroid (ICS)/fast-onset long-acting beta agonist (LABA) combination, as compared with maintenance budesonide (ICS) plus as-needed terbutaline, a short-acting beta-agonist (SABA), in adult patients with mild-moderate asthma. Methods This research was performed as a 52-week, open-label, parallel-group, multicentre, phase III randomised controlled trial of adults aged 18-75 with mild to moderate asthma using SABA for symptom relief, with or without low to moderate doses of maintenance ICS in the previous 12 weeks. Participants were randomly assigned (1:1) to either: (i) budesonide/formoterol Turbuhaler, an ICS/fast-onset LABA, 200/6 micrograms (μg), one inhalation as needed for relief of symptoms, or (ii) budesonide Turbuhaler, an ICS, 200µg, one inhalation twice daily, plus terbutaline Turbuhaler, a SABA, 250µg, two inhalations as needed. Participants and investigators were not masked to group assignment. Participants were seen for six study visits: randomisation, and at weeks 4, 16, 28, 40 and 52. The primary outcome was rate of severe exacerbations per patient per year, with severe exacerbations defined as the use of systemic glucocorticoids for at least three days because of asthma, or a hospitalisation or emergency department visit because of asthma requiring systemic glucocorticoids. Findings Between May 4, 2016 and Dec 22, 2017, 890 participants were assigned to treatment. The analysis included 885 of 890 randomised participants; 437 assigned to budesonide/formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. 70% of participants were using ICS at entry. The annualised severe exacerbation rate was lower with as-needed budesonide/formoterol than with maintenance budesonide (absolute rate 0.119 vs 0.172; relative rate, 0.69 [95% confidence interval [CI], 0.48 to 1.00]; p=0.049). The Asthma Control Questionnaire-5 score with budesonide/formoterol was not significantly different from budesonide maintenance (mean difference, 0.06; 95% CI -0.005 to 0.12). Conclusion This research has demonstrated that in adults with mild to moderate asthma in the real-world setting, budesonide/formoterol reliever therapy was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline without a clinically important worsening in asthma control. The evidence presented in this thesis supports the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid/formoterol reliever therapy is an alternative regimen to maintenance low-dose inhaled corticosteroid and SABA reliever for the prevention of severe exacerbations for patients with mild to moderate asthma.</p>

Efficacy and safety of a budesonide/formoterol reliever therapy regimen in mild-moderate asthma: A randomised controlled trial

<p>Background Inhaled corticosteroids taken regularly reduce exacerbation risk in patients with mild asthma. In clinical practice however, adherence to inhaled corticosteroids is poor and the burden of disease from exacerbations is substantive. In this thesis I explore an alternative approach, that of an inhaled corticosteroid/formoterol combination used as sole reliever therapy, that potentially overcomes the problem of poor adherence. I report the results of my research, known as the PeRsonalised Asthma Combination Therapy: with Inhaled Corticosteroid And fast-onset Long acting beta agonist (PRACTICAL) study. Research aims To investigate the efficacy and safety of as-needed budesonide/formoterol, an inhaled corticosteroid (ICS)/fast-onset long-acting beta agonist (LABA) combination, as compared with maintenance budesonide (ICS) plus as-needed terbutaline, a short-acting beta-agonist (SABA), in adult patients with mild-moderate asthma. Methods This research was performed as a 52-week, open-label, parallel-group, multicentre, phase III randomised controlled trial of adults aged 18-75 with mild to moderate asthma using SABA for symptom relief, with or without low to moderate doses of maintenance ICS in the previous 12 weeks. Participants were randomly assigned (1:1) to either: (i) budesonide/formoterol Turbuhaler, an ICS/fast-onset LABA, 200/6 micrograms (μg), one inhalation as needed for relief of symptoms, or (ii) budesonide Turbuhaler, an ICS, 200µg, one inhalation twice daily, plus terbutaline Turbuhaler, a SABA, 250µg, two inhalations as needed. Participants and investigators were not masked to group assignment. Participants were seen for six study visits: randomisation, and at weeks 4, 16, 28, 40 and 52. The primary outcome was rate of severe exacerbations per patient per year, with severe exacerbations defined as the use of systemic glucocorticoids for at least three days because of asthma, or a hospitalisation or emergency department visit because of asthma requiring systemic glucocorticoids. Findings Between May 4, 2016 and Dec 22, 2017, 890 participants were assigned to treatment. The analysis included 885 of 890 randomised participants; 437 assigned to budesonide/formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. 70% of participants were using ICS at entry. The annualised severe exacerbation rate was lower with as-needed budesonide/formoterol than with maintenance budesonide (absolute rate 0.119 vs 0.172; relative rate, 0.69 [95% confidence interval [CI], 0.48 to 1.00]; p=0.049). The Asthma Control Questionnaire-5 score with budesonide/formoterol was not significantly different from budesonide maintenance (mean difference, 0.06; 95% CI -0.005 to 0.12). Conclusion This research has demonstrated that in adults with mild to moderate asthma in the real-world setting, budesonide/formoterol reliever therapy was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline without a clinically important worsening in asthma control. The evidence presented in this thesis supports the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid/formoterol reliever therapy is an alternative regimen to maintenance low-dose inhaled corticosteroid and SABA reliever for the prevention of severe exacerbations for patients with mild to moderate asthma.</p>