Mathew Williams

External validity of randomised controlled trials in asthma: to whom do the results of the trials apply?

Background: Asthma is a heterogeneous disease with a wide range of clinical phenotypes, not all of which may be encompassed in the subjects included in randomised controlled trials (RCTs). This makes it difficult for clinicians to know to what extent the evidence derived from RCTs applies to a given patient. Aim: To calculate the proportion of individuals with asthma who would have been eligible for the major asthma RCTs from the data of a random community survey of respiratory health. Methods: A postal survey was sent to 3500 randomly selected individuals aged 25–75 years. Respondents were invited to complete a detailed respiratory questionnaire and pulmonary function testing. Participants with current asthma were assessed against the eligibility criteria of the 17 major asthma RCTs cited in the Global Initiative for Asthma (GINA) guidelines. Findings: A total of 749 participants completed the full survey, of whom 179 had current asthma. A median 4% of participants with current asthma (range 0–36%) met the eligibility criteria for the included RCTs. A median 6% (range 0–43%) of participants with current asthma on treatment met the eligibility criteria. Interpretation: This study shows that the major asthma RCTs on which the GINA guidelines are based may have limited external validity as they have been performed on highly selected patient populations. Most of the participants with current asthma on treatment in the community would not have been eligible for these RCTs.

Distinct clinical phenotypes of airways disease defined by cluster analysis

Airways disease is currently classified using diagnostic labels such as asthma, chronic bronchitis and emphysema. The current definitions of these classifications may not reflect the phenotypes of airways disease in the community, which may have differing disease processes, clinical features or responses to treatment. The aim of the present study was to use cluster analysis to explore clinical phenotypes in a community population with airways disease. A random population sample of 25–75-yr-old adults underwent detailed investigation, including a clinical questionnaire, pulmonary function tests, nitric oxide measurements, blood tests and chest computed tomography. Cluster analysis was performed on the subgroup with current respiratory symptoms or obstructive spirometric results. Subjects with a complete dataset (n = 175) were included in the cluster analysis. Five clusters were identified with the following characteristics: cluster 1: severe and markedly variable airflow obstruction with features of atopic asthma, chronic bronchitis and emphysema; cluster 2: features of emphysema alone; cluster 3: atopic asthma with eosinophilic airways inflammation; cluster 4: mild airflow obstruction without other dominant phenotypic features; and cluster 5: chronic bronchitis in nonsmokers. Five distinct clinical phenotypes of airflow obstruction were identified. If confirmed in other populations, these findings may form the basis of a modified taxonomy for the disorders of airways obstruction.

Effects of cannabis on pulmonary structure, function and symptoms

Background: Cannabis is the most widely used illegal drug worldwide. Long-term use of cannabis is known to cause chronic bronchitis and airflow obstruction, but the prevalence of macroscopic emphysema, the dose-response relationship and the dose equivalence of cannabis with tobacco has not been determined. Methods: A convenience sample of adults from the Greater Wellington region was recruited into four smoking groups: cannabis only, tobacco only, combined cannabis and tobacco and non-smokers of either substance. Their respiratory status was assessed using high-resolution CT (HRCT) scanning, pulmonary function tests and a respiratory and smoking questionnaire. Associations between respiratory status and cannabis use were examined by analysis of covariance and logistic regression. Results: 339 subjects were recruited into the four groups. A dose-response relationship was found between cannabis smoking and reduced forced expiratory volume in 1 s to forced vital capacity ratio and specific airways conductance, and increased total lung capacity. For measures of airflow obstruction, one cannabis joint had a similar effect to 2.5–5 tobacco cigarettes. Cannabis smoking was associated with decreased lung density on HRCT scans. Macroscopic emphysema was detected in 1/75 (1.3%), 15/92 (16.3%), 17/91 (18.9%) and 0/81 subjects in the cannabis only, combined cannabis and tobacco, tobacco alone and non-smoking groups, respectively. Conclusions: Smoking cannabis was associated with a dose-related impairment of large airways function resulting in airflow obstruction and hyperinflation. In contrast, cannabis smoking was seldom associated with macroscopic emphysema. The 1:2.5–5 dose equivalence between cannabis joints and tobacco cigarettes for adverse effects on lung function is of major public health significance.

Proportional classifications of COPD phenotypes

Background: Chronic obstructive pulmonary disease (COPD) encompasses a group of disorders characterised by the presence of incompletely reversible airflow obstruction with overlapping subsets of different phenotypes including chronic bronchitis, emphysema or asthma. The aim of this study was to determine the proportion of adult subjects aged >50 years within each phenotypic subgroup of COPD, defined as a post-bronchodilator ratio of forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.7, in accordance with current international guidelines. Methods: Adults aged >50 years derived from a random population-based survey undertook detailed questionnaires, pulmonary function tests and chest CT scans. The proportion of subjects in each of 16 distinct phenotypes was determined based on combinations of chronic bronchitis, emphysema and asthma, with and without incompletely reversible airflow obstruction defined by a post-bronchodilator FEV1/FVC ratio of 0.7. Results: A total of 469 subjects completed the investigative modules, 96 of whom (20.5%) had COPD. Diagrams were constructed to demonstrate the relative proportions of the phenotypic subgroups in subjects with and without COPD. 18/96 subjects with COPD (19%) had the classical phenotypes of chronic bronchitis and/or emphysema but no asthma; asthma was the predominant COPD phenotype, being present in 53/96 (55%). When COPD was defined as a post-bronchodilator FEV1/FVC less than the lower limit of normal, there were one-third fewer subjects with COPD and a smaller proportion without a defined emphysema, chronic bronchitis or asthma phenotype. Conclusion: This study provides proportional classifications of the phenotypic subgroups of COPD which can be used as the basis for further research into the pathogenesis and treatment of this heterogeneous disorder.

The Effect of Supplemental Oxygen on Hypercapnia in Subjects With Obesity-Associated Hypoventilation: A Randomized, Crossover, Clinical Study

BACKGROUND It is unknown whether oxygen therapy causes worsening hypercapnia in patients with obesity-associated hypoventilation (OAH), similar to the response observed in COPD. The objectives of this study were to investigate whether breathing 100% oxygen results in an increase in hypercapnia in patients with OAH and the mechanisms of any effect. METHODS In this double-blind, randomized, controlled, crossover trial, 24 outpatients with newly diagnosed OAH inhaled 100% oxygen or room air for 20 min on 2 separate days. Transcutaneous CO(2) tension (Ptco(2)), minute ventilation, and volume of dead space to tidal volume ratio were measured at baseline and at 20 min. A mixed linear model was used to determine differences between the two treatments. RESULTS The study was terminated in three subjects breathing 100% oxygen due to a Ptco(2) increase ≥ 10 mm Hg, which occurred after 10:35, 13:20, and 15:51 min. Ptco(2) increased by 5.0 mm Hg (95% CI, 3.1-6.8; P < .001) with oxygen compared with room air. Minute ventilation decreased by 1.4 L/min (95% CI, 0.11-2.6 L/min; P = .03), and volume of dead space to tidal volume ratio increased by 0.067 (95% CI, 0.035-0.10; P < .001) with oxygen compared with room air. CONCLUSIONS Breathing 100% oxygen causes worsening hypercapnia in stable patients with OAH. TRIAL REGISTRY Australia New Zealand Clinical Trials Registry; No.: ACTRN 12608000592347; URL: www.anzctr.org.au.

Original ResearchCritical CareThe Effect of Supplemental Oxygen on Hypercapnia in Subjects With Obesity-Associated Hypoventilation: A Randomized, Crossover, Clinical Study

BACKGROUND It is unknown whether oxygen therapy causes worsening hypercapnia in patients with obesity-associated hypoventilation (OAH), similar to the response observed in COPD. The objectives of this study were to investigate whether breathing 100% oxygen results in an increase in hypercapnia in patients with OAH and the mechanisms of any effect. METHODS In this double-blind, randomized, controlled, crossover trial, 24 outpatients with newly diagnosed OAH inhaled 100% oxygen or room air for 20 min on 2 separate days. Transcutaneous CO(2) tension (Ptco(2)), minute ventilation, and volume of dead space to tidal volume ratio were measured at baseline and at 20 min. A mixed linear model was used to determine differences between the two treatments. RESULTS The study was terminated in three subjects breathing 100% oxygen due to a Ptco(2) increase ≥ 10 mm Hg, which occurred after 10:35, 13:20, and 15:51 min. Ptco(2) increased by 5.0 mm Hg (95% CI, 3.1-6.8; P < .001) with oxygen compared with room air. Minute ventilation decreased by 1.4 L/min (95% CI, 0.11-2.6 L/min; P = .03), and volume of dead space to tidal volume ratio increased by 0.067 (95% CI, 0.035-0.10; P < .001) with oxygen compared with room air. CONCLUSIONS Breathing 100% oxygen causes worsening hypercapnia in stable patients with OAH. TRIAL REGISTRY Australia New Zealand Clinical Trials Registry; No.: ACTRN 12608000592347; URL: www.anzctr.org.au.

Accuracy of patient self-report as a measure of inhaled asthma medication use

Measuring adherence to inhaled asthma treatment is a key priority for asthma care. The aim of this study was to determine the relationship between self‐report and actual medication use as measured by electronic monitoring for single and combination inhaled corticosteroid (ICS) and long‐acting beta‐agonist (LABA) metered‐dose inhaler therapy.

QUALITY OF LIFE MEASURED BY THE ST GEORGE'S RESPIRATORY QUESTIONNAIRE AND SPIROMETRY

The present authors aimed to determine if the criteria for the diagnosis of chronic obstructive pulmonary disease (COPD) and its classification by severity as recommended by the Global Initiative for Chronic Obstructive Lung Disease are supported by measurements of respiratory health-related quality of life. A community-based sample of adults aged 25–75 yrs had pre- and post-bronchodilator spirometry and completed the St Georges Respiratory Questionnaire (SGRQ). Loess scatter plot smoothers of the SGRQ versus post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio and post-bronchodilator FEV1 % predicted together with receiver operating characteristic (ROC) curve analysis were used to determine the relationship between spirometric variables and clinically important differences in the SGRQ score. The scatter plot smoother and ROC curve analyses supported the value of 0.7 for post-bronchodilator FEV1/FVC ratio, which was ∼4 units higher than the nadir of the SGRQ. To represent a distance of 8 units on the SGRQ, the cut-off points for post-bronchodilator FEV1 that delimit COPD severity stages were 80, 60 and 40% pred for mild, moderate and severe COPD, respectively. To diagnose chronic obstructive pulmonary disease the use of post-bronchodilator forced expiratory volume in one second/forced vital capacity ratio of 0.7 is supported by health-related quality of life measurements. There may be advantages in using forced expiratory volume in one second cut-off points of 80, 60 and 40% predicted for the classification of mild, moderate and severe chronic obstructive pulmonary disease, respectively, similar to the approach recommended for asthma.

Randomized controlled trial of adherence with single or combination inhaled corticosteroid/long-acting β-agonist inhaler therapy in asthma

BACKGROUND The inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) combination inhaler has the potential to improve adherence with ICS therapy in asthma. OBJECTIVE To determine whether ICS/LABA combination inhaler therapy improves adherence compared with separate inhaler use. METHODS In a 24-week randomized controlled parallel group study, 111 subjects were prescribed 125 microg fluticasone dipropionate (FP) and 25 microg salmeterol, 2 actuations twice daily through either a combination inhaler or separate inhalers concurrently. Medication use was recorded by covert electronic monitors. The primary outcome variable was adherence during the final 6-week period, defined as the number of doses taken as a percentage of those prescribed. RESULTS Complete adherence data from the final 6-week period were available for 49 and 54 subjects in the separate and combination groups, respectively. The mean (SD) adherence was 73.7% (36.0) for FP, 76.7% (30.5) for salmeterol, and 82.4% (24.5) for FP/salmeterol. There were no significant differences in adherence between FP/salmeterol and FP (-8.7%; 95% CI, -10.6 to 3.3) and salmeterol (-5.6%; 95% CI, -16.4 to 5.1). There was no significant difference in overuse among the FP, salmeterol, or FP/salmeterol groups. In 2 (4%) of 49 subjects, salmeterol was effectively taken as monotherapy during a 6-week period. CONCLUSION In the setting of a randomized controlled trial, use of a combination ICS/LABA inhaler does not markedly increase adherence above that observed with separate inhaler use. LABA monotherapy was observed in a small proportion of patients prescribed ICS and LABA therapy via separate inhalers.

Treatment responsiveness of phenotypes of symptomatic airways obstruction in adults.

BACKGROUND Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous disorders encompassing different phenotypes of airflow obstruction, which might differ in their response to treatment. OBJECTIVE The aim of this study was to determine distinct phenotypes comprising the syndromes of asthma and COPD and the treatment responsiveness of these phenotypes to inhaled β-agonist, antimuscarinic, and corticosteroid therapy. METHODS We undertook a cross-sectional study with 3 phases. In phase 1, 1,264 participants aged 18 to 75 years with self-reported current wheeze and breathlessness were identified from a random population sample of 16,459. In phase 2, 451 participants attended for detailed assessment, including responsiveness to inhaled salbutamol and ipratropium bromide. In phase 3, 168 steroid-naive participants were enrolled in a 12-week trial of inhaled budesonide. Cluster analysis was performed in 389 participants who completed phase 2 with full data. Treatment responsiveness was compared between phenotypes. RESULTS Cluster analysis identified 5 phenotypes: moderate-to-severe childhood-onset atopic asthma, asthma-COPD overlap, obese-comorbid, mild childhood-onset atopic asthma, and mild intermittent. Bronchodilation after salbutamol was equal to or greater than that after ipratropium for all phenotypes. The moderate-to-severe childhood-onset atopic asthma, asthma-COPD overlap, and obese-comorbid phenotypes had greater efficacy with inhaled corticosteroid treatment than the mild intermittent group. CONCLUSION Cluster analysis of adults with symptomatic airflow obstruction identifies 5 disease phenotypes, including asthma-COPD overlap and obese-comorbid phenotypes, and provides evidence that patients with the asthma-COPD overlap syndrome might benefit from inhaled corticosteroid therapy.