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>

Budesonide promotes airway epithelial barrier integrity following double-stranded RNA challenge

Airway epithelial barrier dysfunction is increasingly recognized as a key feature of asthma and other lung diseases. Respiratory viruses are responsible for a large fraction of asthma exacerbations, and are particularly potent at disrupting epithelial barrier function through pattern recognition receptor engagement leading to tight junction dysfunction. Although different mechanisms of barrier dysfunction have been described, relatively little is known about whether barrier integrity can be promoted to limit disease. Here, we tested three classes of drugs commonly prescribed to treat asthma for their ability to promote barrier function using a cell culture model of virus-induced airway epithelial barrier disruption. Specifically, we studied the corticosteroid budesonide, the long acting beta-agonist formoterol, and the leukotriene receptor antagonist montelukast for their ability to promote barrier integrity of a monolayer of human bronchial epithelial cells (16HBE) before exposure to the viral mimetic double-stranded RNA. Of the three, only budesonide treatment limited transepithelial electrical resistance and small molecule permeability (4 kDa FITC-dextran flux). Next, we used a mouse model of acute dsRNA challenge that induces transient epithelial barrier disruption in vivo, and studied the effects budesonide when administered prophylactically or therapeutically. We found that budesonide similarly protected against dsRNA-induced airway barrier disruption in the lung, independently of its effects on airway inflammation. Taken together, these data suggest that an under-appreciated effect of inhaled budesonide is to maintain or promote airway epithelial barrier integrity during respiratory viral infections.

Higher exhaled nitric oxide at 6 weeks of age is associated with less bronchiolitis and wheeze in the first 12 months of age

BackgroundNitric oxide in exhaled air (eNO) is used as a marker of type 2 immune response-induced airway inflammation. We aimed to investigate the association between eNO and bronchiolitis incidence and respiratory symptoms in infancy, and its correlation with eosinophil protein X (EPX).MethodsWe followed up infants at 6 weeks of age born to mothers with asthma in pregnancy and measured eNO during natural sleep using a rapid response chemiluminescense analyser (CLD88; EcoMedics), collecting at least 100 breaths, interpolated for an expiratory flow of 50 mL/s. EPX normalised to creatinine was measured in urine samples (uEPX/c). A standardised questionnaire was used to measure symptoms in first year of life. Associations were investigated using multiple linear regression and robust Poisson regression models.ResultseNO levels were obtained in 184 infants, of whom 125/184 (68%) had 12 months questionnaire data available and 51/184 (28%) had uEPX/c measured. Higher eNO was associated with less respiratory symptoms during the first 6 weeks of life (n=184, ß-coefficient: –0.49, 95% CI –0.95 to –0.04, p=0.035). eNO was negatively associated with uEPX/c (ß-coefficient: –0.004, 95% CI –0.008 to –0.001, p=0.021). Risk incidence of bronchiolitis, wheeze, cold or influenza illness and short-acting beta-agonist use significantly decreased by 18%–24% for every unit increase in eNO ppb.ConclusionHigher eNO levels at 6 weeks of age may be a surrogate for an altered immune response that is associated with less respiratory symptoms in the first year of life.

The role of beta-agonist therapy for chronic obstructive airway disease in patients with coexistent atrial fibrillation

Background: New advances have been made in medicine, but the incidence and prevalence of chronic obstructive pulmonary disease (COPD) are evident, and it is established as the fourth cause of death in the United States representing a high cost for the healthcare system. This condition has been related to atrial fibrillation due to the changes in the lungs and vasculature. Based on this history, we seek to evaluate the outcome of AF in the patients with COPD and its relationship with medical therapy utilized to treat this pulmonary condition with the objective of establishing the relationship between the use of beta-agonist therapy for obstructive airway disease in patients with AF. Discussion: Cell receptors participate in multiple reactions and the sympathetic response is received via the alpha- and betareceptors are related to the hemodynamic of the vasculature of the lungs and cardiovascular system. The beta-blockade agents are one of the most common medication classes used for rate control in cardiac arrhythmias, but the side effect could be COPD exacerbation; on the other hand, beta-adrenergic or beta-agonist as a therapy for this pulmonary condition could increase the heart rate leading to AF decompensation. There is a clear dilemma in our patients who have airway disease and AF since the treatment for one might worsen the other. The clear benefit in morbidity and mortality of beta-blocker therapy, especially beta1- selective, outweighs the potential for any pulmonary side-effects related to ex-acerbation of COPD or airway disease. Conclusion: There is clear data showing the evidence of the potential paradoxical side-effect between COPD and AF therapies, given the exacerbation of one due to treatment of the other, benefits versus risks should be discussed and the medical decision should be made based on them. The deteriorated cardiac condition can rapidly predispose to critical complications leading to death, which is why the use of beta-blockade agents will be chosen over possible complications with pulmonary disease. In other words, the benefit should outweigh the risk based on the best outcome for the patient.

The role of beta-agonist therapy for chronic obstructive airway disease in patients with coexistent atrial fibrillation: Literature review

Background: New advances have been made in medicine, but the incidence and prevalence of Chronic Obstructive Pulmonary Disease (COPD) are evident, and it is established as the fourth cause of death in the United States representing a high cost for the healthcare system. This condition has been related to atrial fibrillation due to the changes in the lungs and vasculature. Based on this history, we seek to evaluate the outcome of AF in the patients with COPD and its relationship with medical therapy utilized to treat this pulmonary condition with the objective of establishing the relationship between the use of beta-agonist therapy for obstructive airway disease in patients with AF. Discussion: Cell receptors participate in multiple reactions and the sympathetic response is received via the alpha- and beta-receptors are related to the hemodynamic of the vasculature of the lungs and cardiovascular system. The beta-blockade agents are one of the most common medication classes used for rate control in cardiac arrhythmias, but the side effect could be COPD exacerbation; on the other hand, beta-adrenergic or beta-agonist as a therapy for this pulmonary condition could increase the heart rate leading to AF decompensation. There is a clear dilemma in our patients who have airway disease and AF since the treatment for one might worsen the other. The clear benefit in morbidity and mortality of beta-blocker therapy, especially beta1-selective, outweighs the potential for any pulmonary side-effects related to ex-acerbation of COPD or airway disease. Conclusion: There is clear data showing the evidence of the potential paradoxical side-effect between COPD and AF therapies, given the exacerbation of one due to treatment of the other, benefits versus risks should be discussed and the medical decision should be made based on them. The deteriorated cardiac condition can rapidly predispose to critical complications leading to death, which is why the use of beta-blockade agents will be chosen over possible complications with pulmonary disease. In other words, the benefit should outweigh the risk based on the best outcome for the patient. Keywords: atrial fibrillation; pulmonary disease; obstructive pulmonary disease; chronic obstructive pulmonary disease (COPD); B-Agonist; B-Block (selective; non-selective); digitalis; other antiarrhythmic.

Phenotyping of obstructive airways disease

<p>Background Asthma and Chronic Obstructive Pulmonary Disease (COPD) are heterogeneous disorders which may be made up of different sub-types, or phenotypes, of airflow obstruction with distinct clinical characteristics. To facilitate personalised treatment the different phenotypes and their response to treatment must be clearly defined and sound diagnostic rules developed. In this thesis I explore the evidence supporting candidate phenotypes and report the results of my research, known as the New Zealand Respiratory Health Survey (NZRHS). The NZRHS was designed to determine candidate phenotypes, compare these phenotypes to those previously described, characterize their response to inhaled medication, and develop a method for allocating patients to the most appropriate phenotype. Research Aims -To explore clinical phenotypes of chronic airways disease by cluster analysis. -To examine if phenotypes identified by a previous cluster analysis exist in the independent NZRHS sample. -To compare the response to a short-acting beta-agonist inhaler between phenotype groups. -To compare the response to a short-acting muscarinic antagonist inhaler between phenotype groups. -To compare the response to an inhaled corticosteroid between phenotype groups. -To generate allocation rules and determine their predictive value for the different disorders of airways disease. Conclusions This research has identified phenotypes of airways disease that differ significantly in their clinical and pathophysiological characteristics. Evidence is presented to support the existence of the asthma/COPD overlap and obesity/co-morbid phenotypes and provide data of their responsiveness to inhaled corticosteroid, beta agonist and anti-muscarinic treatments, which may guide future management of patients with these phenotypes of obstructive airways disease.</p>