The Complex Beginnings of Chronic Obstructive Pulmonary Disease.

Over the last decades, an accelerated decline of lung function in response to cigarette smoking was considered the central hallmark of chronic obstructive pulmonary disease (COPD). This conceptual model of the natural history of COPD placed major emphasis on exposures and clinical manifestations that occur in the middle to late adult years, generating the misleading assumption that the trajectories of this disease can be characterized and effective strategies of prevention implemented by simply focusing on adulthood.

More recently, this assumption has been challenged at multiple levels. It has been conclusively shown that in a significant proportion of cases, COPD can develop as a result of lung function deficits that are established by young adult life, with no accelerated decline of lung function thereafter (1). In addition, growing evidence indicates that airway diseases, developmental processes, and exposures that take place in early life (or even in utero) can have long-lasting effects on susceptibility to COPD.

This new evidence has redefined and expanded the scope of COPD research, leading to efforts to characterize risk factors in age spans that traditionally have been left out of COPD studies. In this issue of the Journal, Çolak and colleagues (pp. 671–680) used the rich dataset of the Copenhagen adult cohort to study the prevalence and prognosis of “early” COPD in the general population (2). As previously proposed (3), they defined early COPD as having a FEV1/FVC ratio less than the lower limit of normal in individuals <50 years of age with at least 10 pack-years of tobacco consumption. In this relatively young population of smokers, early COPD had a striking prevalence of 15%, although it should be noted that this estimate was based on pre- (rather than post-) bronchodilator spirometric data. In addition, compared with their smoker peers without COPD, individuals with early COPD had an increased risk for acute obstructive lung disease and pneumonia hospitalizations, and all-cause mortality during follow-up. Interestingly, not only was the risk for hospitalizations largely dependent on the presence of respiratory symptoms among individuals with early COPD, but even among participants without COPD the presence of chronic respiratory symptoms was associated with an increased risk for hospitalizations. These data are in line with previous observations that chronic respiratory symptoms in individuals with normal lung function are an independent risk factor for developing airflow limitation (4) and for having respiratory exacerbations and imaging-assessed airway disease (5). Taken together, the evidence from this and previous studies indicates that airflow limitation among smokers below age 50 is not an uncommon finding, highlights the substantial morbidity and mortality burden of early COPD, and identifies symptomatic individuals as a target population for early interventions.

Although the Copenhagen study provides novel and much needed data regarding the prevalence and morbidity of early COPD in the general population, the actual public health burden of early COPD is likely to be even larger than that suggested by the estimates of this study.

An important issue is the proposed operational definition of early COPD (3), according to which the authors restricted analyses to smokers with ≥10 pack-years. Although using this criterion probably reduced the vast heterogeneity of airflow limitation at this young age, it also removed a substantial proportion of adult individuals below age 50 who, even though they did not have high tobacco consumption (or had no tobacco consumption at all), were still at risk for airflow limitation. In the Copenhagen cohort, by restricting analyses to individuals with ≥10 pack-years, ∼75% of participants below age 50 were excluded from the study, and this proportion is likely to become even larger in future years as smoking rates keep falling in westernized countries. Thus, although airflow limitation is more common among individuals with ≥10 pack-years, because so many young people do not meet this smoking criterion, the absolute number of cases of early COPD contributed by individuals with <10 pack-years is likely not negligible.

Eventually, it will be necessary to characterize airflow limitation among these never and lighter smokers to fully understand the contributions from perinatal and childhood factors that may affect early COPD by either impacting the growth of lung function into adult life or by enhancing the effects of smoking on early decline of lung function (6). With regard to the former, persistent childhood asthma has been extensively investigated. In the Childhood Asthma Management Program, up to 11% of participants with persistent asthma developed postbronchodilator airflow limitation by age 30 years (7), and the significant risk conferred by severe childhood asthma for developing COPD in adult life has been repeatedly confirmed in population-based cohort studies (8). Moreover, it has been argued that any factor that is linked to reduced growth of lung function in childhood (e.g., respiratory infections or air pollution exposure) or lung development in utero (e.g., premature birth or maternal smoking in pregnancy) may in principle have an impact on early COPD risk by placing an individual on a trajectory of low lung function.

Interestingly, the implications of the early-life roots of COPD may go beyond the risk of a trajectory of low lung function, and accumulating evidence suggests that exposures that take place in early life may impact the rate of lung function decline that will occur decades later. In the Tucson Children’s Respiratory Study, for example, exposure to parental smoking in early life was found to enhance susceptibility to active smoking in young adult life, and participants who were exposed to both parental smoking in infancy and active smoking by age 26 years showed an accelerated FEV1 and FEV1/FVC decline (9). These effects were already present at low levels of cumulative cigarette smoking (the mean exposure was just 4 pack-years).

To truly reduce the burden of COPD, we will need to understand the complexities of its natural history, profile of risk factors, and phenotypic manifestations across the entire lifespan. The study by Çolak and colleagues is an important starting point to characterize COPD in the first 50 years of life. Although the importance of smoking cessation cannot be overemphasized, we argue that understanding the interplay among smoking, early life risk factors, and developmental processes in age spans that have been traditionally left out of COPD research will be key to fully advance prevention strategies for stages when the natural history of the disease can still be substantially modified.