C1.1 Natural History

Although FEV₁ has long been accepted as the single best predictor of mortality in population studies in COPD (Fletcher 1977, Peto 1983) 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 2005). Exercise capacity (as measured by the 6-minute walk distance (6MWD), incremental shuttle walk distance (ISWD), or 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 COPD mortality better than FEV₁ in patients with established disease. Several of these latter indices are incorporated together in a single score, the BODE index (Body mass index, degree of Obstruction as measured by FEV_1, Dyspnoea score and Exercise capacity measured by 6MWD) or the i-BODE index, in which the ISWD replaces the 6MWD strongly predictsmortality (Celli 2004, Williams 2012). 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 2009b) [evidence level III-2]. Further studies are awaited including validation in an Australian  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 an exacerbation, the five-year survival rate was only about 10% for those with an FEV₁ <20% predicted, 30% for those with FEV₁ of 20% to 29% predicted and about 50% for those with an FEV₁ of 30% to 39% predicted (Connors 1996). Patients with an FEV₁ <20% predicted and either homogeneous emphysema on high resolution computed tomography (HRCT) or a diffusing capacity of lung for carbon monoxide (D_LCO) test <20% predicted are at high risk for death after LVRS and unlikely to benefit from the intervention (National Emphysema Treatment Trial Research 2001). A review of 15 COPD prognostic indices found that although the prognostic information of some has been validated, they lack evidence for implementation. Impact studies will be required in the future to determine whether such indices improve COPD management and patient outcomes (Dijk 2011).

Continued smoking and airway hyperresponsiveness are associated with accelerated loss of lung function (Tashkin 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 1996, Anthonisen 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 study (Ekstrom 2010) 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 exacerbation.  A large study that included 4951 patients from 28 countries found that health-related quality of life (HRQoL), measured by the St George’s Respiratory Questionnaire (SGRQ), deteriorated faster in patients with more severe disease (Jones 2011a). Patients then classified as 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 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 1996). For those with chronic carbon dioxide reten­tion (about 25% of those admitted with hypercapnic exacer­bations), the five-year survival was only 11% (Connors 1996).

The Tasmanian Longitudinal Health Study investigated spirometry patterns in a cohort of 2422 subjects at ages 7, 13, 18, 45, 50, and 53 years (n=2422) (Dharmage 2023) [evidence level III-2]. The finding of obstructive and mixed pattern phenotypes may contribute to early detection of individuals who are at risk of developing COPD, while a restrictive phenotype predicted a high prevalence of comorbidities (obesity, diabetes, cardiovascular conditions, hypertension, and obstructive sleep apnoea). These findings could assist with targeted early management (Dharmage 2023). Five asthma phenotypes have also been identified in this study, four of which were strongly associated with developing COPD by age 53 years old (Tan 2023) [evidence level III-2].

A report from the multicentre, observational, prospective COPDGene study indicated that the presence of mucous plugs on CT chest was associated with higher all-cause mortality in the 4363 subjects who had smoked >10 pack years and in whom mucous plug scores had been measured (Diaz 2023) [evidence level III-2]. However, the CT methods used submillimetric slice thickness, which might not be routinely acquired in clinical practice. Also, as this was an observational study it cannot be concluded that mucous plugs cause death.