Wan C. Tan

Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial *

BACKGROUND Although inhaled glucocorticosteroids are recommended for persistent asthma, their long-term effect on recent onset, mild, persistent asthma has yet to be established. METHODS We did a randomised, double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids. Patients aged 5-66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications. The daily budesonide dose was 400 microg, or 200 microg for children younger than 11 years. The primary outcome was time to first severe asthma-related event, and analysis was by intention to treat. FINDINGS 198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation; hazard ratio 0.56 (95% CI 0.45-0.71, p<0.0001). Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo. Compared with placebo, budesonide increased postbronchodilator forced expiratory volume in 1 s (FEV1) from baseline by 1.48% (p<0.0001) after 1 year and by 0.88% (p=0.0005) after 3 years (expressed as percent of the predicted value). The corresponding increase in prebronchodilator FEV1 was 2.24% after 1 year and 1.71% after 3 years (p<0.0001 at both timepoints). The effect of treatment on all outcome variables was independent of the baseline lung function (prebronchodilator or postbronchodilator) or baseline medication. In children younger than 11 years, 3-year growth was reduced in the budesonide group by 1.34 cm. The reduction was greatest in the first year of treatment (0.58 cm) than years 2 and 3 (0.43 cm and 0.33 cm, respectively). INTERPRETATION Long-term, once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset.

Severe exacerbations and decline in lung function in asthma.

RATIONALE To evaluate the association between asthma exacerbations and the decline in lung function, as well as the potential effects of an inhaled corticosteroid, budesonide, on exacerbation-related decline in patients with asthma. OBJECTIVES To determine whether severe asthma exacerbations are associated with a persistent decline in lung function. METHODS The START (inhaled steroid treatment as regular therapy in early asthma) study was a 3-year, randomized, double-blind study of 7,165 patients (5-66 yr) with persistent asthma for less than 2 years, to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events (exacerbations requiring hospitalization or emergency treatment) and decline in lung function. MEASUREMENTS AND MAIN RESULTS There were 315 patients who experienced at least one severe asthma exacerbation, of which 305 were analyzable, 190 in the placebo group and 115 in the budesonide group. In the placebo group, the change in post-bronchodilator FEV(1) % predicted from baseline to the end of the study, in patients who did or did not experience a severe exacerbation was -6.44% and -2.43%, respectively (P < 0.001). A significant difference was seen in both children and in adults, but not in adolescents. In the budesonide group, the change in the post-bronchodilator FEV(1) % predicted in patients who did or did not experience a severe exacerbation was -2.48% and -1.72%, respectively (P = 0.57). The difference in magnitude of reduction afforded by budesonide, in patients who experienced at least one severe asthma-related event compared with those who did not, was statistically significant (P = 0.042). CONCLUSIONS Severe asthma exacerbations are associated with a more rapid decline in lung function. Treatment with low doses of inhaled corticosteroid is associated with an attenuation of the decline.

Prevalence and underdiagnosis of chronic obstructive pulmonary disease among patients at risk in primary care

Background: People with known risk factors for chronic obstructive pulmonary disease (COPD) are important targets for screening and early intervention. We sought to measure the prevalence of COPD among such individuals visiting a primary care practitioner for any reason. We also evaluated the accuracy of prior diagnosis or nondiagnosis of COPD and identified associated clinical characteristics. Methods: We recruited patients from three primary care sites who were 40 years or older and had a smoking history of at least 20 pack-years. Participants were asked about respiratory symptoms and underwent postbronchodilator spirometry. COPD was defined as a ratio of forced expiratory volume in the first second of expiration to forced vital capacity (FEV1/FVC) of less than 0.7 and an FEV1 of less than 80% predicted. Results: Of the 1459 patients who met the study criteria, 1003 (68.7%) completed spirometry testing. Of these, 208 were found to have COPD, for a prevalence of 20.7% (95% confidence interval 18.3%–23.4%). Of the 205 participants with COPD who completed the interview about respiratory symptoms before spirometry, only 67 (32.7%) were aware of their diagnosis before the study. Compared with patients in whom COPD had been correctly diagnosed before the study, those in whom COPD had been over-diagnosed or undiagnosed were similar in terms of age, sex, current smoking status and number of visits to a primary care practitioner because of a respiratory problem. Interpretation: Among adult patients visiting a primary care practitioner, as many as one in five with known risk factors met spirometric criteria for COPD. Underdiagnosis of COPD was frequent, which suggests a need for greater screening of at-risk individuals. Knowledge of the prevalence of COPD will help plan strategies for disease management.

Global burden of COPD

It is estimated that the world population will reach a record 7.3 billion in 2015, and the high burden of chronic conditions associated with ageing and smoking will increase further. Respiratory diseases in general receive little attention and funding in comparison with other major causes of global morbidity and mortality. In particular, chronic obstructive pulmonary disease (COPD) has been a major public health problem and will remain a challenge for clinicians within the 21st century. Worldwide, COPD is in the spotlight, since its high prevalence, morbidity and mortality create formidable challenges for health‐care systems. This review emphasizes the magnitude of the COPD problem from a clinicians standpoint by drawing extensively from the new findings of the Global Burden of Disease study. Updated, distilled information on the population distribution of COPD is useful for the clinician to help provide an appreciation of the relative impact of COPD in daily practice compared with other chronic conditions, and to allocate minimum resources in anticipation of future needs in care. Despite recent trends in reduction of COPD standardized mortality rates and some recent successes in anti‐smoking efforts in a number of Western countries, the overarching demographic impact of ageing in an ever‐expanding world population, joined with other factors such as high rates of smoking and air pollution in Asia, will ensure that COPD will continue to pose an ever‐increasing problem well into the 21st century.

Marijuana and chronic obstructive lung disease: a population-based study

Background: Our aim was to determine the combined and independent effects of tobacco and marijuana smoking on respiratory symptoms and chronic obstructive pulmonary disease (COPD) in the general population. Method: We surveyed a random sample of 878 people aged 40 years or older living in Vancouver, Canada, about their respiratory history and their history of tobacco and marijuana smoking. We performed spirometric testing before and after administration of 200 μg of salbutamol. We examined the association between tobacco and marijuana smoking and COPD. Results: The prevalence of a history of smoking in this sample was 45.5% (95% confidence interval [CI] 42.2%–48.8%) for marijuana use and 53.1% (95% CI 49.8%–56.4%) for tobacco use. The prevalence of current smoking (in the past 12 months) was 14% for marijuana use and 14% for tobacco use. Compared with nonsmokers, participants who reported smoking only tobacco, but not those who reported smoking only marijuana, experienced more frequent respiratory symptoms (odds ratio [OR] 1.50, 95% CI 1.05–2.14) and were more likely to have COPD (OR 2.74, 95% CI 1.66–4.52). Concurrent use of marijuana and tobacco was associated with increased risk (adjusted for age, asthma and comorbidities) of respiratory symptoms (OR 2.39, 95% CI 1.58–3.62) and COPD (OR 2.90, 95% CI 1.53–5.51) if the lifetime dose of marijuana exceeded 50 marijuana cigarettes. The risks of respiratory symptoms and of COPD were related to a synergistic interaction between marijuana and tobacco. Interpretation: Smoking both tobacco and marijuana synergistically increased the risk of respiratory symptoms and COPD. Smoking only marijuana was not associated with an increased risk of respiratory symptoms or COPD.

The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: Effectiveness of early intervention with budesonide in mild persistent asthma

BACKGROUND The Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study enrolled 7241 patients aged 5 to 66 years with recent-onset, mild persistent asthma to assess early intervention with the inhaled corticosteroid budesonide on long-term asthma control. OBJECTIVE The open-label phase of the START study was included to determine the effect on lung function and asthma control of adding budesonide to the reference group patients who had not initially received inhaled corticosteroids. METHODS Patients were randomized to double-blind treatment with budesonide, 200 mug (those aged < 11 years) or 400 mug once daily, or placebo plus the usual asthma therapy for 3 years, after which all patients received 2 years of open-label treatment with budesonide once daily. RESULTS During the full 5-year study period, postbronchodilator FEV(1) percent predicted decreased, irrespective of randomized treatment during the double-blind phase, by an average of 2.22% (SE, 0.15%). However, patients with inhaled budesonide in the double-blind phase had a significantly lower risk (odds ratio, 0.61; P < .001) of a severe asthma-related event during the full 5-year study period than those in the reference group. Moreover, patients in the reference group used more additional asthma medications during both the open-label and double-blind phases. CONCLUSIONS In mild persistent asthma early intervention with inhaled budesonide was associated with improved asthma control and less additional asthma medication use.

Chronic obstructive pulmonary disease mortality and prevalence: the associations with smoking and poverty—a BOLD analysis

Background Chronic obstructive pulmonary disease (COPD) is a commonly reported cause of death and associated with smoking. However, COPD mortality is high in poor countries with low smoking rates. Spirometric restriction predicts mortality better than airflow obstruction, suggesting that the prevalence of restriction could explain mortality rates attributed to COPD. We have studied associations between mortality from COPD and low lung function, and between both lung function and death rates and cigarette consumption and gross national income per capita (GNI). Methods National COPD mortality rates were regressed against the prevalence of airflow obstruction and spirometric restriction in 22 Burden of Obstructive Lung Disease (BOLD) study sites and against GNI, and national smoking prevalence. The prevalence of airflow obstruction and spirometric restriction in the BOLD sites were regressed against GNI and mean pack years smoked. Results National COPD mortality rates were more strongly associated with spirometric restriction in the BOLD sites (<60 years: men rs=0.73, p=0.0001; women rs=0.90, p<0.0001; 60+ years: men rs=0.63, p=0.0022; women rs=0.37, p=0.1) than obstruction (<60 years: men rs=0.28, p=0.20; women rs=0.17, p<0.46; 60+ years: men rs=0.28, p=0.23; women rs=0.22, p=0.33). Obstruction increased with mean pack years smoked, but COPD mortality fell with increased cigarette consumption and rose rapidly as GNI fell below US

Characteristics of COPD in never-smokers and ever-smokers in the general population: results from the CanCOLD study

15 000. Prevalence of restriction was not associated with smoking but also increased rapidly as GNI fell below US

COPD in Asia: Where East Meets West

15 000. Conclusions Smoking remains the single most important cause of obstruction but a high prevalence of restriction associated with poverty could explain the high ‘COPD’ mortality in poor countries.

Risk factors for COPD spirometrically defined from the lower limit of normal in the BOLD project

Background There is limited data on the risk factors and phenotypical characteristics associated with spirometrically confirmed COPD in never-smokers in the general population. Aims To compare the characteristics associated with COPD by gender and by severity of airway obstruction in never-smokers and in ever-smokers. Method We analysed the data from 5176 adults aged 40 years and older who participated in the initial cross-sectional phase of the population-based, prospective, multisite Canadian Cohort of Obstructive Lung Disease study. Never-smokers were defined as those with a lifetime exposure of <1/20 pack year. Logistic regressions were constructed to evaluate associations for ‘mild’ and ‘moderate-severe’ COPD defined by FEV1/FVC <5th centile (lower limits of normal). Analyses were performed using SAS V.9.1 (SAS Institute, Cary, North Carolina, USA). Results The prevalence of COPD (FEV1/FVC<lower limits of normal) in never-smokers was 6.4%, constituting 27% of all COPD subjects. The common independent predictors of COPD in never-smokers and ever-smokers were older age, self reported asthma and lower education. In never-smokers a history of hospitalisation in childhood for respiratory illness was discriminative, while exposure to passive smoke and biomass fuel for heating were discriminative for women. COPD in never-smokers and ever-smokers was characterised by increased respiratory symptoms, ‘respiratory exacerbation’ events and increased residual volume/total lung capacity, but only smokers had reduced DLCO/Va and emphysema on chest CT scans. Conclusions The study confirmed the substantial burden of COPD among never-smokers, defined the common and gender-specific risk factors for COPD in never-smokers and provided early insight into potential phenotypical differences in COPD between lifelong never-smokers and ever-smokers. Trial registration number NCT00920348 (ClinicalTrials.gov); study ID number: IRO-93326.