American Journal of Respiratory and Critical Care Medicine

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation that is not fully reversible (1). Like many other major chronic diseases the burden of disease—for the individual patient as well as for society—is substantial; in fact, COPD is expected to be the third leading cause of mortality and number five on the list of most important diseases when it comes to morbidity measured as disability-adjusted life years (2).

The current “measure” of COPD is the FEV1. It is both the defining feature of the disease and its measure of severity (1). As a biomarker of disease severity, FEV1 does not correlate exceptionally well with symptoms. However, numerous surveys have shown that FEV1 is a strong predictor of mortality as well as morbidity. Because of its widespread use, and in contrast to many other surrogate markers in medicine, we have a wealth of studies of change in FEV1 (3, 4). This measure has been so reliable and used for so long that our understanding of the natural history of COPD, and how important factors such as smoking impact the disease, come from relating these factors to FEV1 decline. This decline has become synonymous with disease progression—or disease activity—in COPD. It has generally been assumed that individuals with the lowest FEV1, (i.e., the most severe disease) were also progressing the fastest as they had “clearly” lost more function than individuals with more normal lung function. However, evidence is accumulating that this assumption is in error, making it essential to distinguish between severity and activity, which are different. As an example, a 45-year-old with an FEV1 of 55% of predicted normal and thus moderate disease according to the Global Initiative for Obstructive Lung Diseases (GOLD) may have more disease activity than an 85-year-old with an FEV1 of 45% predicted and severe COPD, as the former will have had a greater loss of lung function over time than the latter.

However, the FEV1 is still extraordinarily useful. Guidelines for treatment of COPD exist in most parts of the world, and most of them are based on the GOLD Initiative report (1). Similar to what is seen for other—but not all—chronic diseases, guidelines universally recommend increasing medical treatment with increasing severity. This is exemplified by the treatment steps advocated by GOLD, wherein classes of drugs are added as patients progress from GOLD stage 1, mild COPD, to GOLD stages 3 and 4, severe and very severe disease. This seems fully justified for drugs with mainly symptomatic effect. However, a major goal in COPD treatment is to prevent disease progression. Because current concepts suggest that an abnormal inflammatory response causes disease progression, antiinflammatory drugs, such as inhaled corticosteroids and phosphodiesterase-4 inhibitors, hold the promise of modifying disease progression in addition to relieving symptoms (5). The benefits of current pharmacologic therapy in modifying disease progression in COPD are uncertain, but we do have recent evidence that treatment with inhaled corticosteroids and long-acting bronchodilators at least have some impact on FEV1 decline (6, 7). Several companies have compounds at various stages of development in their pipeline with novel antiinflammatory properties, and these drugs will potentially be able to modify the underlying disease mechanisms driving disease progression (8).

How do we then currently use these drugs? Today, we advocate the use of these drugs in patients with severe or very severe COPD with a history of previous exacerbations (1). By using this recommendation we treat patients with severe disease who experience considerable morbidity. This is clinically logical as these are the patients most burdened by disease and those who—as a result of their symptomatology—most frequently will visit the doctor and ask for help.

However, activity and severity are not the same. Intuitively, it would make sense to initiate treatment earlier, in less severe disease. Indeed, the one strategy that has been accepted as an intervention to reduce disease progression is smoking cessation. Its benefits were demonstrated in the Lung Health Study (9), which adopted just such a strategy evaluating patients with moderate disease. Increased disease activity in milder disease is also suggested from subgroup analyses of large long-term trials. A secondary analysis of data from TORCH (10) has shown that among patients in the group allocated to placebo in GOLD stage 2 (moderate COPD), the average decline in FEV1 was 60 ml/yr, whereas it was 56 ml/yr in GOLD stage 3 and only 34 ml/yr in GOLD stage 4 (very severe COPD) (6). As the normal decline in FEV1 is 25 and 30 ml/yr in women and men, respectively, this indicates that many patients with moderate COPD are “rapid decliners” and that a large proportion of patients with severe and very severe disease no longer have increased disease activity. The same phenomenon was seen in the UPLIFT trial, wherein the average decline in the total study population was 41 ml/yr (11), in contrast to 49 ml/yr in GOLD stage 2 as presented in a recent subgroup analysis (7). Although some of these differences may be the result of study subject recruitment bias, these studies underline the fact that FEV1 is a measure of disease severity but is not a surrogate for disease activity. Rate of change of FEV1, which is a measure of activity, unfortunately requires very large and long-term studies making it impractical for assessment of new treatments. Perhaps even more important, there may be several distinct “activities” in COPD. Exacerbations, as assessed by health care use, for example, are more frequent in patients with severe disease. This suggests that the activities that lead to exacerbation risk may be independent, at least in part, from those that cause lung function loss. Using severity to select subjects may be very useful for some purposes, but its use in studies of interventions with a potential for disease modification may achieve relatively little and may be counterproductive.

We know that presence of bronchial hyperresponsiveness in patients with asymptomatic COPD is a marker of disease progression (12), and that presence of symptoms predicts decline in FEV1 in mild COPD (13), but these “markers” are not specific and are difficult to quantify. We also use frequent exacerbations as an indicator of disease activity, particularly as a measure of exacerbation susceptibility. This is particularly important as exacerbations are major clinical problems, convey a poor prognosis, and are major drivers of cost associated with this disease. In addition, exacerbations are associated with an excess FEV1 decline, although they account only for a small portion of the excess (14), and patients will decline for a number of other reasons as well. Importantly, as noted above, the patients who decline most rapidly (i.e., those with milder disease) will not experience many exacerbations. As a result, the development of future treatment options for COPD is in a limbo. A pharmaceutical company is likely to think twice before taking potentially disease-modifying agents forward in an area where no tools exist for identifying the subjects most likely to benefit. As there are no tools for evaluating the impact of a promising therapeutic candidate on disease activity in early-phase drug trials, it seems highly likely that a number of potentially valuable drugs have been missed in recent years as the clinical tools available for their assessment over 4- to 12-week time frames—changes in lung function, symptoms, or currently available biomarkers of inflammation—are inadequate for the task.

There is therefore an urgent need for the development of disease activity biomarkers for use in COPD. These are needed not just for the sake of drug development; they are also strongly needed to advance understanding of the heterogeneity of COPD and its natural history. Like in many other fields in medicine currently, biomarkers are a topic of major interest in COPD research. Large studies are on their way, including the ECLIPSE study (15) and two large U.S. cohort studies with the common aim of further disentangling COPD, COPDgene, and SPIROMICS. Many studies have evaluated biomarkers, most commonly as predictors of exacerbations (16). What is urgently needed now is for the work on biomarkers to be applied to disease activity.

1. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD Executive Summary. Am J Respir Crit Care Med 2007;176:532–555.
2. Murray CJL, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997;349:1498–1504.
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7. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP, for the UPLIFT investigators. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomized controlled trial. Lancet 2009;374:1171–1178.
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10. Calverley PMA, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J, on behalf of the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789.
11. Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M, for the UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543–1554.
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13. Bridevaux P-O, Gerbase MW, Probst-Hensch NM, Schindler C, Gaspoz J-M, Rochat T. Long-term decline in lung function, utilisation of care and quality of life in modified GOLD stage 1 COPD. Thorax 2008;63:768–774.
14. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847–852.
15. Vestbo J, Anderson W, Coxson HO, Crim C, Dawber F, Edwards L, Hagan G, Knobil K, Lomas DA, MacNee W, et al. the ECLIPSE investigators. Evaluation of COPD longitudinally to identify predictive surrogate endpoints (ECLIPSE). Eur Respir J 2008;31:869–873.
16. Sin DD, Vestbo J. Biomarkers in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2009;6:543–545.


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