C1. Aetiology and natural history

Cigarette smoking is the most important cause of COPD.(Fletcher and Peto, 1977),(Burrows et al., 1977) There is a close relationship between the amount of tobacco smoked and the rate of decline in forced expiratory flow in one second (FEV₁), although individuals vary greatly in susceptibility.(Fletcher and Peto, 1977) Around half of all smokers develop some airflow limitation, and 15%–20% will develop clinically significant disability.(Fletcher and Peto, 1977) Smokers are also at risk of developing lung cancer, and cardiovascular disease such as ischaemic heart disease and peripheral vascular disease.

In susceptible smokers cigarette smoking results in a steady decline in lung function, with a decrease in FEV₁ of 25–100mL/year.(Fletcher and Peto, 1977) While smoking cessation may lead to minimal improvements in lung function, more importantly it will slow the rate of decline in lung function and delay the onset of disablement. At all times smoking cessation is important to preserve remaining lung function.(Fletcher and Peto, 1977)

Impairment increases as the disease progresses, but may not be recognised because of the slow pace of the disease. The time course of development of COPD and disability and the influence of smoking cessation are illustrated in Box 3.

In addition to cigarette smoking, there are a number of other recognised risk factors for COPD(Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2006) (see Figure 3-1 below adapted from GOLD 2006). COPD almost always arises from a gene environment interaction. The best characterised genetic predisposition is alpha₁ antitrypsin deficiency, but multiple other genes each make a small contribution and further investigation is required. The risk of COPD is related to the total burden of inhaled particles(Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2006) and oxidative stress in the lung.  Occupational dust exposure might be responsible for 20 – 30% of COPD. This has long been recognised in coal miners (Santo Tomas, 2011), but recently biological dust has also been identified as a risk factor, particularly in women.(Matheson et al., 2005) Biological dust exposure is also associated with chronic sputum production, dyspnoea and work inactivity in male patients.(Rodriguez et al., 2008) Livestock farmers are also at increased risk of developing chronic bronchitis and COPD (Eduard et al 2009). Dairy farmers have increased wheeze and morning phlegm and increased rate of decline in FEV₁ compared to controls. These effects appear to be associated more with exposure to animal feed than handling hay or straw. (Thaon et al., 2011) Each year of exposure to diesel exhaust increases the risk of dying from COPD by 2.5%.(Hart et al., 2009) A case control study conducted within a large managed care organisation found that self reported exposures to vapours, gas, dust and fumes on the longest held job were responsible for 31% of COPD.(Blanc et al., 2009) Joint exposure both to smoking and occupational factors markedly increased the risk of COPD [evidence level III-2]

Fortunately the air quality in most Australian cities is relatively good and cooking with biomass fuels (coal, wood, dung, crop waste etc) is uncommon. Failure to achieve maximum lung function increases the risk of COPD in later life. The role of gender is uncertain. Beyond the age of 45-50 years, female smokers appear to experience an accelerated decline in FEV₁ compared with male smokers(Gan et al., 2006) [evidence level II]. On the other hand, a family based case control study involving high resolution chest CT scans found that men demonstrated more low attenuation areas consistent with emphysema than did women (Camp et al., 2009) [evidence level III-2] Nor is it known whether the increased risk among lower socioeconomic groups is due to greater exposure to pollution, poorer nutrition, more respiratory infection or other factors.(Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2006) 

Novel risk factors for COPD have recently been reviewed by an assembly of the American Thoracic Society (Eisner et al., 2010a). Exposure to Secondhand (Environmental) Tobacco Smoke was consistently associated with various definitions of COPD; there was a temporal relationship, dose response gradient and biological plausibility. Meta-analysis of 12 studies found a pooled odds ratio of 1.56 (95%CI 1.40 - 1.74). There was sufficient evidence that exposure to smoke from burning biomass fuels was associated with development of COPD in women. Meta-analysis of 15 studies found a pooled odds ratio of 2.23 (95%CI 1.72 - 2.90), but there was significant heterogeneity between studies. [evidence level III-2]. Whilst the risk of biomass smoke in men has only been assessed in three studies, there also appears to be a similarly increased risk of COPD (OR 4.3, 95%CI 1.85-10) (Hu et al., 2010). Pulmonary tuberculosis can lead to scarring and irreversible loss of lung function, however there is currently insufficient evidence that this is clinically similar to COPD caused by cigarette smoking (Eisner et al., 2010a)

Although FEV₁ has long been accepted as the single best predictor of mortality in population studies in COPD (Fletcher and Peto, 1977),(Peto et al., 1983) recent studies have suggested various other indices, which may also predict mortality. In patients with established COPD, degree of hyperinflation as measured by inspiratory capacity/ total lung capacity (IC/TLC) ratio was independently associated with all cause and COPD mortality. (Casanova et al., 2005) The 6 minute walk distance (6MWD), peak VO₂ during a cardiopulmonary exerise test, body mass index and dyspnoea score (measured with the modified Medical Research Council Scale) have all been shown to predict mortality better than FEV₁ in patients with established disease. Several of these latter indices are incorporated together in a single score, the BODE index (BMI, degree of Obstruction as measured by FEV_1, Dyspnoea score and Exercise capacity measured by 6 minute walk distance) strongly predicted mortality.(Celli et al., 2004) Recently a simplified ADO index (Age, Dyspnoea score and Obstruction) has been developed in a Swiss cohort and shown to predict three year mortality in a Spanish cohort (Puhan et al., 2009b) [evidence level III-2]. Further studies are awaited including validation in an Australian cohort of COPD patients.Nonetheless, FEV₁ continues to have utility as a predictor of all-cause mortality in COPD. In one study that followed patients after acute exacerbations, the five-year survival rate was only about 10% for those with an FEV₁ <20% predicted, 30% for those with FEV₁ of 20%–29% predicted and about 50% for those with an FEV₁ of 30%–39% predicted.(Connors et al., 1996) Patients with an FEV₁ <20% predicted and either homogeneous emphysema on HRCT or a D_LCO <20% predicted are at high risk for death after LVRS and unlikely to benefit from the intervention.(National Emphysema Treatment Trial Research, 2001)

Continued smoking and airway hyperresponsiveness are associated with accelerated loss of lung function.(Tashkin et al., 1996) However, even if substantial airflow limitation is present, cessation of smoking may result in some improvement in lung function and will slow progres­sion of disease (Tashkin et al., 1996),(Anthonisen et al., 2002)

The development of hypoxaemic respiratory failure is an independent predictor of mortality, with a three-year sur­vival of about 40%.(Medical Research Council Working Party, 1981) Long term administration of oxygen increases survival to about 50% with nocturnal oxygen(Medical Research Council Working Party, 1981) and to about 60% with oxygen administration for more than 15 hours a day (Nocturnal Oxygen Therapy Trial Group, 1980)(see also section P). There may be a differential in benefit between men and women. A recently reported study (Ekstrom et al.) of Swedish patients receiving long term oxygen therapy demonstrated that overall, women had a lower risk of death than men; nonetheless, when compared with expected death rates for the population, women had a higher relative mortality with a standardised mortality rate (SMR) of 12 (95% CI;11.6-12.5) compared with 7.4 (95%CI 7.1-7.6) [evidence level III-2].

The natural history of COPD is characterised by progressive deterioration with episodes of acute deterioration in symptoms referred to as acute exacerbations.  A large study that included 4951 patients from 28 countries found that health-related quality of life, measured by the SGRQ, deteriorated faster in patients with more severe disease(Jones et al., 2011a). Patients in GOLD stage II who received placebo showed an overall improvement, while those in GOLD stages III and IV deteriorated. When all participants from the different arms were included, the change in SGRQ at three years correlated weakly with change in FEV₁: r = -0.24, p < 0.0001 and there was no difference in this relationship between men and women. However, a significantly faster deterioration in the SGRQ score relative to FEV₁ % predicted was seen in older patients (greater 65 years).

Admission to hospital with an acute exacerbation of COPD complicated by hypercapnic respiratory failure is associated with a poor prognosis. A mortality of 11% during admission and 49% at two years has been reported in patients with a partial pressure of carbon dioxide (Pco₂) >50mmHg. (Connors et al., 1996) For those with chronic carbon dioxide reten­tion (about 25% of those admitted with hypercapnic exacer­bations), the five-year survival was only 11%. (Connors et al., 1996)