Sarah Aldington

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.

COPD prevalence in a random population survey: a matter of definition

A recent American Thoracic Society and European Respiratory Society joint Task Force report recommends using a lower limit of normal (LLN) of forced expiratory volume in one second/forced vital capacity as opposed to a fixed ratio of <0.7 to diagnose airflow obstruction, in order to reduce false positive diagnoses of chronic obstructive pulmonary disease (COPD) as defined by the Global Initiative for Obstructive Lung Disease (GOLD). To date, there is no reliable spirometry-based prevalence data for COPD in New Zealand and the effect of different definitions of airflow obstruction based on post-bronchodilator spirometry is not known. Detailed written questionnaires, full pulmonary function tests (including pre- and post-bronchodilator flow–volume loops) and atopy testing were completed in 749 subjects recruited from a random population sample. The GOLD-defined, age-adjusted prevalence (95% confidence interval) for adults aged ≥40 yrs was 14.2 (11.0–17.0)% compared with an LLN-defined, age-adjusted, post-bronchodilator prevalence in the same group of 9.0 (6.7–11.3)%. The prevalence of chronic obstructive pulmonary disease varied markedly depending on the definition used. Further research using longitudinal rather than cross-sectional data will help decide the preferred approach in chronic obstructive pulmonary disease prevalence surveys.

Cannabis use and cancer of the head and neck: Case-control study

OBJECTIVE: To investigate whether cannabis smoking increases the risk of head and neck cancer. DESIGN: Case-control study. SUBJECTS AND METHODS: Cases of head and neck cancer ≤55 years identified from hospital databases and the Cancer Registry, and controls randomly selected from the electoral roll completed interviewer-administered questionnaires. Logistic regression was used to estimate the relative risk of head and neck cancer. RESULTS: There were 75 cases and 319 controls. An increased risk of cancer was found with increasing tobacco use, alcohol consumption, and decreased income but not increasing cannabis use. The highest tertile of cannabis use (>8.3 joint years) was associated with a nonsignificant increased risk of cancer (relative risk = 1.6, 95% confidence interval, 0.5–5.2) after adjustment for confounding variables. CONCLUSIONS: Cannabis use did not increase the risk of head and neck cancer; however, because of the limited power and duration of use studied, a small or longer-term effect cannot be excluded.

Asthma exacerbations · 5: Assessment and management of severe asthma in adults in hospital

It is difficult to understand why there is such a huge discrepancy between the management of severe asthma recommended by evidence-based guidelines and that observed in clinical practice. The recommendations are relatively straightforward and have been widely promoted both in guidelines and reviews. Specialist physicians need to be more proactive in their implementation of such guidelines through the use of locally derived protocols and assessment sheets, reinforced by audit. The common occurrence of severe asthma and its considerable burden to the community would support such an approach.

Smoking and COPD: what really are the risks?

To the Editors: Chronic obstructive pulmonary disease (COPD) is rapidly becoming a global public health crisis, with around three million people predicted to die from the disease in 2006 1, 2. There is growing awareness of the increasing global burden of COPD not only in terms of mortality, but also its prevalence, morbidity and economic costs 2. In response to these concerns, there has been a renewed research effort to understand the causes of COPD and to develop public health and pharmacological interventions that may reduce the burden. Smoking is recognised as the most important causative factor for COPD, with an individuals susceptibility being a continuous, rather than a categorical characteristic that can interact synergistically with other risk factors. There is now evidence that most smokers develop some respiratory impairment due to COPD 3. One of the most informative recent studies addressing this …

Randomised double-blind, placebo-controlled trial of the effects of the ‘party pills’ BZP/TFMPP alone and in combination with alcohol:

The objective of this study was to determine the clinical effects of party pills containing benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) when taken alone and in combination with alcohol. The study was a randomised, double-blind, placebo-controlled trial conducted in a hospital-based clinic in Wellington, New Zealand. Thirty-five volunteers who had previously used party pills containing BZP were included in this trial. Participants received one of the following four treatments: 300 mg/74 mg BZP/TFMPP and placebo, 300 mg/74 mg BZP/TFMPP and 57.6 g (6 units) alcohol, placebo and 57.6 g (6 units) alcohol and double placebo. The primary outcome variable was a measure of driving performance, the standard deviation of lateral position (SDLP) measured at 6.5 h. Secondary measures included adverse events, cardiovascular effects, psychological function and delayed effects on sleep. The study was stopped early, after 35 of the planned 64 subjects had undertaken testing, because of severe adverse events that occurred in four of 10 BZP/TFMPP-only subjects, three of seven combined BZP/TFMPP and alcohol subjects, none of the 6 placebo subjects, and none of the 12 alcohol-only subjects. The overall rate of severe adverse events (defined as causing considerable interference with usual activity and/or rated by subject as severe) in those receiving BZP/TFMPP was seven of 17 (41.2%, 95% CI 18.4—67.1). The severe events included agitation, anxiety, hallucinations, vomiting, insomnia and migraine. BZP/TFMPP significantly improved the driving performance, decreasing SDLP at −4.2 cm (95% CI −6.8 to −1.6, P = 0.002). The effect of alcohol was to increase SDLP: 2.3 cm (95% CI −0.3 to 4.9, P = 0.08). BZP/TFMPP also resulted in increased heart rate and blood pressure and in difficulty in getting to sleep. BZP/TFMPP alone or with alcohol carries a significant risk of severe adverse events when taken in similar doses to those recommended by manufacturers.

A case–control study of seated immobility at work as a risk factor for venous thromboembolism

Summary Objective To determine the relative risk of prolonged seated immobility at work in patients with a deep vein thrombosis (DVT) or pulmonary embolism (PE). Design A case–control study: cases and controls completed an interviewer-administered questionnaire to obtain information on risk factors for venous thromboembolism (VTE), including prolonged seated immobility at work. Univariate and multivariate logistic regression was used to determine the association between predicted variables and the probability of being a case or control. Participants Cases were patients <65 years old attending the Wellington Hospital Outpatient VTE Clinic following hospital discharge for DVT and/or PE. Controls were patients <65 years old admitted to the Coronary Care Unit at Wellington Hospital. Setting The Wellington Hospital Outpatient VTE Clinic and Coronary Care Unit. Main outcome measures Odds ratio of VTE for prolonged seated immobility. Results There were 97 cases (53 DVT, 29 PE, 15 DVT and PE), and 106 controls. In the multivariate analysis the odds ratio of VTE for prolonged seated immobility at work was 1.8 (95% CI 0.71–4.8). The maximum number of hours seated at work was associated with VTE, with the risk increasing by 10% per hour longer seated (odds ratio 1.1, 95% CI 1.0–1.2). The maximum number of hours seated at work without getting up was associated with VTE, with the risk increasing by 20% per hour longer seated (odds ratio 1.2, 95% CI 0.96–1.6). Conclusions This study provides preliminary evidence that prolonged seated immobility at work may represent a risk factor for VTE.