Other aetiological factors in the pathogenesis of COPD

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A proportion of asthma patients develop an irreversible component that is usually attributed to airway remodelling. It is not known why some asthmatics progress to fixed airflow obstruction — but once they have, it is very difficult to differentiate them from patients with COPD on clinical or physiological grounds. Approximately 2% of asthmatics have a forced expiratory volume in 1s (FEVj) below 60% predicted. As asthma is so common, even this small percentage may explain many of those who are labelled as having COPD despite not having any history of exposure to cigarette smoke. In comparison, 10% of moderate smokers (21-40 pack-years) and over 22% of heavy smokers (> 60 pack-years) will develop this severity of airway obstruction [8].


An alternative mislabelling can occur with bronchiolitis. Bronchiolitis and bronchiolitis obliterans are general terms used to describe a non-specific inflammatory injury that primarily affects the small airways, often sparing the interstitium. This disorder is currently poorly understood. It is likely that a small proportion of patients with a diagnosis of COPD have a progressive, constrictive bronchiolitis that has not been recognized—hardly surprising, as there is no test other than histology with which to differentiate the cause of the airflow limitation.


The precise role of occupation in the pathogenesis of COPD remains unclear. Epidemiological studies assessing the role of occupation in the development of COPD are difficult both to conduct and interpret [9]. Most of the evidence is derived from cross-sectional studies, in which it has been difficult to record dust exposure, or indeed cigarette exposure, reliably. There is no doubt that exposure to heavy dust loads leads to a productive cough, but this can be a normal physiological response to the particular burden that has to be cleared. There are cross-sectional studies of populations [10,11] that have described more COPD amongst those working in dusty jobs. But while cross-sectional studies can indicate associations, they cannot differentiate causality between the dust and other factors. Those in dustier jobs tend to be of lower social class and have a higher smoking prevalence, poorer nutrition and worse general health. Most data are available on coal miners, but even here the data are not conclusive. A UK legal ruling concluded that on the balance of probabilities, coal dust could cause emphysema and airway obstruction and thus miners are to receive compensation even with a smoking history [12]. There remains no mechanism to explain how coal dust (generally a remarkably inert substance) should compare with cigarette smoke (containing 1017 free radicals per puff), but legal cases are not science and conclude on a 'balance of probabilities'. Other studies have claimed similar effects from gold mining and for underground tunnel workers [13], although in the legal case which considered coal dust, the other rock dusts were excluded as likely causes.

Atmospheric pollution

If occupational dust can cause airway obstruction, then it is logical to examine the effects of pollution. A small additional contribution to COPD severity has been reported in patients who live in cities. However, these effects are small and remain contentious. High exposures to very small particles of less than 10 pm (PM10) have also been associated with an increase in both cardiac and respiratory deaths in cross-sectional population studies [14]. These exposures are many times less than the occupational exposures experienced by miners, and thus the question arises as to whether other components of pollution may be additive in causing these apparent effects. Ozone and diesel have also been associated with the development of COPD, but the latter claim must be balanced by the studies of miners in diesel pits (i.e. pits in which the underground trains that transported men and coal along the shafts were diesel-powered). Despite heavy exposures in quite enclosed environments, no adverse effects have been observed in these coal mines [15]. Indoor exposure to wood smoke and fumes from biomass fuels has also been implicated [16,17]. Paradoxically, while concerns in the popular press about the effect of outdoor pollutants on the lung have escalated in recent times, the levels of sulphur dioxide and black smoke have been dramatically reduced in most developed countries over the last 30years. The situation regarding environmental pollution and COPD can best be described as confused — and of an order of magnitude less than any effect of smoking cigarettes.

Socio-economic status

Low socio-economic status correlates strongly with the development of

COPD. Men of social classes IV and V aged between 20 and 64 in the UK are 14 times more likely to die of COPD than men with professional occupations [18]. This seems to occur even when different smoking rates are taken into account. It is unclear whether this is due to nutrition, different patterns of respiratory infection exposure in early life, or environmental exposures.

Premature birth is more common amongst mothers of lower socioeconomic group and in mothers who smoke. Smoking mothers produce smaller babies [19]. Prematurity is associated with early-life infections [20], and early-life infections are associated with COPD deaths 50years later [21]. Precise mechanisms, or even a clear sequence of events that might cause this, are unknown, but it does seem increasingly likely that some of the later lung morbidity is due to failure to grow and develop properly both in utero and shortly thereafter.

In the Copenhagen City Heart Study, men in the lowest income/least education group had a forced vital capacity (FVC) that was 400 mL less than those in the highest group [22]. Even after control for smoking duration and quantity, the difference was still 363 mL. In females, the differences were smaller, at 259 mL (220 mL adjusted), but of similar pattern. The lowest socioeconomic groups were more likely to have had an admission for COPD even after adjustment for smoking, so these differences would seem to be of clinical importance to patients.

Some of these changes may be due to effects of poor nutrition either precipitating or accelerating the development of COPD. Harik-Khan et al. [23] studied 458 men without COPD and followed them for a mean of 10.2years. An inverse relationship between body mass index (BMI) and the risk of developing COPD was demonstrated. The relative risk of developing COPD was 2.76 times greater (95% confidence interval 1.15-6.59) in the lowest BMI tertile compared to the highest tertile. In rats, starvation has been shown to induce emphysematous changes within the lungs [24]. While this association has not been proven in humans, poor nutrition has been associated with pneumothorax [25] and pneumomediastinum [26].


Latent infection with viruses has been cited as a factor that may predispose to COPD. Double-stranded DNA viruses have the ability to persist in airway epithelial cells long after the acute infection has cleared. Expression of adenoviral genes produces a trans-activating protein that has been demonstrated to amplify the inflammatory response to cigarette smoke [27]. Thus far this remains speculation only.

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