Guy B. Marks

International variation in the prevalence of COPD (The BOLD Study): a population-based prevalence study

BACKGROUND Chronic obstructive pulmonary disease (COPD) is a growing cause of morbidity and mortality worldwide, and accurate estimates of the prevalence of this disease are needed to anticipate the future burden of COPD, target key risk factors, and plan for providing COPD-related health services. We aimed to measure the prevalence of COPD and its risk factors and investigate variation across countries by age, sex, and smoking status. METHODS Participants from 12 sites (n=9425) completed postbronchodilator spirometry testing plus questionnaires about respiratory symptoms, health status, and exposure to COPD risk factors. COPD prevalence estimates based on the Global Initiative for Chronic Obstructive Lung Disease staging criteria were adjusted for the target population. Logistic regression was used to estimate adjusted odds ratios (ORs) for COPD associated with 10-year age increments and 10-pack-year (defined as the number of cigarettes smoked per day divided by 20 and multiplied by the number of years that the participant smoked) increments. Meta-analyses provided pooled estimates for these risk factors. FINDINGS The prevalence of stage II or higher COPD was 10.1% (SE 4.8) overall, 11.8% (7.9) for men, and 8.5% (5.8) for women. The ORs for 10-year age increments were much the same across sites and for women and men. The overall pooled estimate was 1.94 (95% CI 1.80-2.10) per 10-year increment. Site-specific pack-year ORs varied significantly in women (pooled OR=1.28, 95% CI 1.15-1.42, p=0.012), but not in men (1.16, 1.12-1.21, p=0.743). INTERPRETATION This worldwide study showed higher levels and more advanced staging of spirometrically confirmed COPD than have typically been reported. However, although age and smoking are strong contributors to COPD, they do not fully explain variations in disease prevalence-other factors also seem to be important. Although smoking cessation is becoming an increasingly urgent objective for an ageing worldwide population, a better understanding of other factors that contribute to COPD is crucial to assist local public-health officials in developing the best possible primary and secondary prevention policies for their regions.

A scale for the measurement of quality of life in adults with asthma

A 20-item self-administered questionnaire with Likert scale responses was developed to measure quality of life in adult subjects with asthma. A total scale score together with subscale scores for breathlessness, mood disturbance, social disruption and concerns for health were calculated by addition of item scores. Items for the scale were selected by principal components analysis of the responses of 283 subjects to a preliminary pool of 69 items. In 58 subjects with stable asthma, good short term test-retest reliability was demonstrated with the intraclass correlation coefficient for the total scale being 0.80. The questionnaire was internally consistent in a sample of outpatients (Cronbachs alpha 0.92 in 77 subjects) and in a community sample with asthma (Cronbachs alpha 0.94 in 87 subjects). Weak correlations in the expected direction were seen with three medical markers of asthma severity. This supports the construct validity of the questionnaire and emphasizes that quality of life represents a separate dimension of asthma.

Asthma in older adults

Asthma in older people is common and is characterised by underdiagnosis and undertreatment. Ageing is associated with unique issues that modify expression, recognition, and treatment of the disease. In particular, asthma and chronic obstructive pulmonary disease (COPD) both overlap and converge in older people. This concurrence, together with absence of precise diagnostic methods, makes diagnosis complex. A multidimensional assessment that addresses airway problems, comorbidities, risk factors, and management skills will draw attention to key needs for intervention. Increased attention to the complications of asthma and obstructive airway disease in older people is needed, specifically to develop effective systems of care, appropriate clinical practice guidelines, and a research agenda that delivers improved health outcomes.

Identification of IL6R and chromosome 11q13.5 as risk loci for asthma

BACKGROUND We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. METHODS We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. FINDINGS Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR 1·09, combined p=2·4×10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10(-8)) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10(-4)), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. INTERPRETATION The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. FUNDING National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.

Health Outcomes of Continuous Positive Airway Pressure versus Oral Appliance Treatment for Obstructive Sleep Apnea A Randomized Controlled Trial

RATIONALE Continuous positive airway pressure (CPAP) and mandibular advancement device (MAD) therapy are commonly used to treat obstructive sleep apnea (OSA). Differences in efficacy and compliance of these treatments are likely to influence improvements in health outcomes. OBJECTIVES To compare health effects after 1 month of optimal CPAP and MAD therapy in OSA. METHODS In this randomized crossover trial, we compared the effects of 1 month each of CPAP and MAD treatment on cardiovascular and neurobehavioral outcomes. MEASUREMENTS AND MAIN RESULTS Cardiovascular (24-h blood pressure, arterial stiffness), neurobehavioral (subjective sleepiness, driving simulator performance), and quality of life (Functional Outcomes of Sleep Questionnaire, Short Form-36) were compared between treatments. Our primary outcome was 24-hour mean arterial pressure. A total of 126 patients with moderate-severe OSA (apnea hypopnea index [AHI], 25.6 [SD 12.3]) were randomly assigned to a treatment order and 108 completed the trial with both devices. CPAP was more efficacious than MAD in reducing AHI (CPAP AHI, 4.5 ± 6.6/h; MAD AHI, 11.1 ± 12.1/h; P < 0.01) but reported compliance was higher on MAD (MAD, 6.50 ± 1.3 h per night vs. CPAP, 5.20 ± 2 h per night; P < 0.00001). The 24-hour mean arterial pressure was not inferior on treatment with MAD compared with CPAP (CPAP-MAD difference, 0.2 mm Hg [95% confidence interval, -0.7 to 1.1]); however, overall, neither treatment improved blood pressure. In contrast, sleepiness, driving simulator performance, and disease-specific quality of life improved on both treatments by similar amounts, although MAD was superior to CPAP for improving four general quality-of-life domains. CONCLUSIONS Important health outcomes were similar after 1 month of optimal MAD and CPAP treatment in patients with moderate-severe OSA. The results may be explained by greater efficacy of CPAP being offset by inferior compliance relative to MAD, resulting in similar effectiveness. Clinical trial registered with https://www.anzctr.org.au (ACTRN 12607000289415).

Contact investigation for tuberculosis: a systematic review and meta-analysis

Investigation of contacts of patients with tuberculosis (TB) is a priority for TB control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines. We performed a systematic review and meta-analysis of all studies reporting the prevalence of TB and latent TB infection, and the annual incidence of TB among contacts of patients with TB. After screening 9,555 titles, we included 203 published studies. In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1% (95% CI 2.2–4.4%, I2=99.4%), microbiologically proven TB was 1.2% (95% CI 0.9–1.8%, I2=95.9%), and latent TB infection was 51.5% (95% CI 47.1–55.8%, I2=98.9%). The prevalence of TB among household contacts was 3.1% (95% CI 2.1–4.5%, I2=98.8%) and among contacts of patients with multidrug-resistant or extensively drug-resistant TB was 3.4% (95% CI 0.8–12.6%, I2=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1–1.8%, I2=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2–32.4%, I2=99.5%). There was substantial heterogeneity among published studies. Contacts of TB patients are a high-risk group for developing TB, particularly within the first year. Children <5 yrs of age and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.

Differences between asthma exacerbations and poor asthma control

BACKGROUND Increased variation in peak expiratory flow (PEF) is characteristic of poorly controlled asthma, and measurement of diurnal variability of PEF has been recommended for assessment of asthma severity, including during exacerbations. We aimed to test whether asthma exacerbations had the same PEF characteristics as poor asthma control. METHODS Electronic PEF records from 43 patients with initially poorly controlled asthma were examined for all exacerbations that occurred after PEF reached a plateau with inhaled corticosteroid treatment. Diurnal variability of PEF was compared during exacerbations, run-in (poor asthma control), and the period of stable asthma before each exacerbation. FINDINGS Diurnal variability was 21.3% during poor asthma control and improved to 5.3% (stable asthma) with inhaled corticosteroid treatment. 40 exacerbations occurred in 26 patients over 2-16 months; 38 (95%) of exacerbations were associated with symptoms of clinical respiratory infection. During exacerbations, consecutive PEF values fell linearly over several days then improved linearly. However, diurnal variability during exacerbations (7.7%) was not significantly higher than during stable asthma (5.4%, p=0.1). PEF data were consistent with impaired response to inhaled beta2-agonist during exacerbations but not during poorly controlled asthma. INTERPRETATION Asthmatics remain vulnerable to exacerbations during clinical respiratory infections, even after asthma is brought under control. Calculation of diurnal variability may fail to detect important changes in lung function. PEF variation is strikingly different during exacerbations compared with poor asthma control, suggesting differences in beta2-adrenoceptor function between these conditions.

Asthma in preschool children: prevalence and risk factors

BACKGROUND The prevalence of asthma in children has increased in many countries over recent years. To plan effective interventions to reverse this trend we need a better understanding of the risk factors for asthma in early life. This study was undertaken to measure the prevalence of, and risk factors for, asthma in preschool children. METHODS Parents of children aged 3–5 years living in two cities (Lismore, n=383; Wagga Wagga, n=591) in New South Wales, Australia were surveyed by questionnaire to ascertain the presence of asthma and various proposed risk factors for asthma in their children. Recent asthma was defined as ever having been diagnosed with asthma andhaving cough or wheeze in the last 12 monthsand having used an asthma medication in the last 12 months. Atopy was measured by skin prick tests to six common allergens. RESULTS The prevalence of recent asthma was 22% in Lismore and 18% in Wagga Wagga. Factors which increased the risk of recent asthma were: atopy (odds ratio (OR) 2.35, 95% CI 1.49 to 3.72), having a parent with a history of asthma (OR 2.05, 95% CI 1.34 to 3.16), having had a serious respiratory infection in the first 2 years of life (OR 1.93, 95% CI 1.25 to 2.99), and a high dietary intake of polyunsaturated fats (OR 2.03, 95% CI 1.15 to 3.60). Breast feeding (OR 0.41, 95% CI 0.22 to 0.74) and having three or more older siblings (OR 0.16, 95% CI 0.04 to 0.71) decreased the risk of recent asthma. CONCLUSIONS Of the factors tested, those that have the greatest potential to be modified to reduce the risk of asthma are breast feeding and consumption of polyunsaturated fats.

Sahaja yoga in the management of moderate to severe asthma: a randomised controlled trial

Background: Sahaja Yoga is a traditional system of meditation based on yogic principles which may be used for therapeutic purposes. A study was undertaken to assess the effectiveness of this therapy as an adjunctive tool in the management of asthma in adult patients who remained symptomatic on moderate to high doses of inhaled steroids. Methods: A parallel group, double blind, randomised controlled trial was conducted. Subjects were randomly allocated to Sahaja yoga and control intervention groups. Both the yoga and the control interventions required the subjects to attend a 2 hour session once a week for 4 months. Asthma related quality of life (AQLQ, range 0–4), Profile of Mood States (POMS), level of airway hyperresponsiveness to methacholine (AHR), and a diary card based combined asthma score (CAS, range 0–12) reflecting symptoms, bronchodilator usage, and peak expiratory flow rates were measured at the end of the treatment period and again 2 months later. Results: Twenty one of 30 subjects randomised to the yoga intervention and 26 of 29 subjects randomised to the control group were available for assessment at the end of treatment. The improvement in AHR at the end of treatment was 1.5 doubling doses (95% confidence interval (CI) 0.0 to 2.9, p=0.047) greater in the yoga intervention group than in the control group. Differences in AQLQ score (0.41, 95% CI –0.04 to 0.86) and CAS (0.9, 95% CI –0.9 to 2.7) were not significant (p>0.05). The AQLQ mood subscale did improve more in the yoga group than in the control group (difference 0.63, 95% CI 0.06 to 1.20), as did the summary POMS score (difference 18.4, 95% CI 0.2 to 36.5, p=0.05). There were no significant differences between the two groups at the 2 month follow up assessment. Conclusions: This randomised controlled trial has shown that the practice of Sahaja yoga does have limited beneficial effects on some objective and subjective measures of the impact of asthma. Further work is required to understand the mechanism underlying the observed effects and to establish whether elements of this intervention may be clinically valuable in patients with severe asthma.

An evaluation of an asthma quality of life questionnaire as a measure of change in adults with asthma

In assessing the effectiveness of management strategies for patients with asthma, it is important to measure outcomes which are relevant to the concerns of patients. Quality of life is one such outcome which may not be adequately reflected in lung function measurements. We have developed an asthma quality of life questionnaire (the AQLQ) for this purpose. The aim of this study was to test the validity and responsiveness of the AQLQ as a measure of change. Forty four adults with asthma were assessed on two occasions 4 months apart. On each occasion subjects completed the AQLQ and the Sickness Impact Profile (SIP). Lung function and the degree of bronchial hyperresponsiveness (BHR) were measured and diary cards were used to derive a symptom score and mean daily peak flow variability. The relation of change in AQLQ scores to change in the other outcomes was assessed. Questionnaire responsiveness was assessed by comparing the change in AQLQ scores between 19 improved and 20 stable subjects. Improvement was assessed on lung function and BHR criteria. As expected, change in AQLQ score was correlated with change in symptom score (r = 0.37, 95% CI -0.04 to 0.64) and change in BHR (r = 0.38, 95% CI 0.06 to 0.64). The associations with change in peak flow variability (r = 0.12, 95% CI -0.26 to 0.47) and change in SIP score (r = 0.18, 95% CI -0.12 to 0.45) were in the expected direction but weaker than expected. The AQLQ was capable of detecting differences between improved and stable subjects (p = 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)