Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death in the USA.1 Its defining feature is limitation of expiratory airflow, which is usually relentlessly progressive. Current therapies have meaningful, but limited benefits. For those who have resting hypoxaemia, supplemental oxygen improves survival. Rehabilitation can improve health status and exercise performance. However, neither of these treatments alters lung function or the rate at which it declines. Volume reduction surgery, by removing the most dysfunctional parts of the lung, can reduce exacerbations2 and improve lung function, performance, symptoms and survival, but only in a subset of patients, and the effects are limited, both in magnitude and in duration.3 4 Currently available pharmacotherapy, including bronchodilators and combinations of bronchodilators and inhaled corticosteroids, modestly improve airflow and symptoms and reduce exacerbations.5 6 Statistically significant effects in slowing the rate at which lung function is lost have been reported with pharmacotherapy,7 but the clinical importance of the benefits achieved remain uncertain.

With this background, a major goal for novel therapy in COPD is to alter the natural history of the disease.

The classic study of Fletcher and colleagues8 provided the basis for current understanding of the natural history of COPD and has guided attempts at altering its course. The ‘British Postal Worker's Study’ included 792 men who were evaluated for a period of eight years. Based on this study, Fletcher and colleagues suggested that normal individuals lost lung function at an accelerating rate with age. Individuals who were exposed, for example, to cigarette smoke, and who were susceptible, experienced an accelerated rate of decline in lung function. A portion of these would eventually be diagnosed with COPD. To their credit, Fletcher and colleagues recognised that their ‘model’ was an extrapolation based on a limited data …