The studies discussed above show that death from COPD is most commonly the result of smoking — but what of the processes that lead to these deaths? It is clear that a healthy individual has to pass through mild, then moderate and then severe stages of COPD to reach the stage at which COPD may cause death. But the processes by which this happens and the rate at which it develops require a different sort of study.
It is unclear what distinguishes individuals who develop clinically significant COPD from those who do not, despite a similar smoking history. In 1970, Thurlbeck showed that almost all smokers of more than 20 pack-years will have some emphysema detectable at post-mortem, although only about 15-20% had had any loss of lung function in life . However, while an autopsy-based study can suggest likely causal factors and can add detail to information from longitudinal death certificate studies, it cannot detemine how the disease developed.
Cross-sectional studies of large populations can examine the manifestation of disease at stages of development in large numbers of people. The National Health and Nutrition Examination Survey (NHANES 3)  in the US questioned 34 000 people between 1988 and 1994. It reported that up to 24% of current smokers reported chronic cough. Airflow limitation (defined as FEV1/FVC < 70%) among white males was present in 14.2% of current smokers, 6.9% of ex-smokers and 3.3% of those who had never smoked. Similar proportions were found in white females, while the incidence of airflow obstruction was lower in the black population. Other studies have also suggested ethnic variations in COPD incidence, with 15% of active white cigarette smokers and 5% of active Asian cigarette smokers developing clinically significant COPD . Because the disease develops over many years, it is inevitable that the majority of the most severe disease cases are seen in the elderly, but the statistics from North America indicate that 50% are below age 65 and 22% are below 55, with a mean age at diagnosis of 53 years.
The heterogeneity of the disease is illustrated by the fact than even 'light' smokers can develop severe emphysema. Thus, deaths before the age of 50 in individuals claiming to only have smoked five cigarettes daily (equating to approximately nine pack-years) do occur, although such cases are unusual. Clearly, factors other than cigarette smoke alone must be involved (see below), whether acting through a separate mechanism or in synergy with cigarette smoke. More than 40 years ago, the 'Dutch hypothesis'  suggested that the risks of developing COPD were related to environmental exposures in combination with the genetic make-up of the individual. This concept may still be true today.
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