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1 Division of Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; and 2 Division of Pulmonary and Critical Care Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
Correspondence and requests for reprints should be addressed to Gerard J. Criner, M.D., Pulmonary and Critical Care Medicine and Temple Lung Center, Temple University School of Medicine, 745 Parkinson Pavilion, 3401 North Broad Street, Philadelphia, PA 19140. E-mail: crinerg{at}tuhs.temple.edu
ABSTRACT
The change in FEV1 has been the traditional metric used to define the progression of chronic obstructive pulmonary disease in affected patients. Consequently, various treatments have "targeted" the accelerated decline in FEV1 in an attempt to modify or alter the disease process. We propose a broader definition for "disease modification" as any change in a metric related to the disease that is maintained over time. Available longitudinal and/or predictive data on several newer modalities are described that might be considered as alternative metrics to assess disease modification in chronic obstructive pulmonary disease. These include inspiratory capacity, exercise capacity, the 6-minute walk distance, dyspnea measures, health status, multidimensional indices, and acute exacerbations. Finally, we consider the impact of disease modifying therapies on some of these metrics.
Key Words: disease-modifying therapies • dyspnea • health status • multidimensional indices • physiologic parameters
The traditional metric used to define the progression of chronic obstructive pulmonary disease (COPD) has been the change in FEV1 (1). To date, smoking cessation is the only treatment that slows the accelerated decline in lung function (2). In fact, various randomized controlled trials have demonstrated that neither inhaled ipratropium bromide nor inhaled corticosteroids alter the change in FEV1 over time compared with placebo (3–5). These disappointing results have led to the consideration that alternative outcomes be used to define disease modification. Moreover, lung function is poorly related to clinical outcomes, including dyspnea, exercise performance, and exacerbations. These patient-centered metrics are clearly more important to individual patients than is FEV1.
In this article, we propose that "disease modification" be defined as any change in a metric related to the disease that is maintained over time. In particular, we review the available data on five unique measures or outcomes—inspiratory capacity (IC), dyspnea, health status, the multidimensional BODE (body mass index, airflow obstruction, dyspnea, exercise performance) index, and acute exacerbations of COPD—that might be used as alternative metrics to assess disease modification. Finally, we consider briefly the impact of various treatments on these metrics. We propose that any treatment given over time that changes one or more of the above metrics can be considered disease modification. This concept goes beyond the traditional approach of using lung function—in particular FEV1—to define disease modification.
ALTERNATIVE METRICS
Physiological Parameters
Although IC has been used widely to assess static and dynamic hyperinflation in patients with COPD (6, 7), to the best of our knowledge there are no published data on the longitudinal changes in IC over time.
Both cross-sectional and longitudinal data reveal that exercise capacity declines over time in healthy individuals (8–10). In patients with COPD, Oga and colleagues (11) have reported an annual decline in 
O2max of –0.5 (SD, ± 0.1) ml/kg/minute in 45 male patients (age 69 ± 1 yr; FEV1 = 46 ± 1% predicted), with a baseline peak O2max of 14.8 (SD, ± 0.3) ml/kg/minute.
The 6-minute walk test (6MW) has been used to quantify functional capacity. Pinto-Plata and colleagues (12) showed that patients with COPD experienced a –26 (SD, ± 37) m/year decline in the 6MW over 2 years, whereas healthy subjects of similar age exhibited an increase of +12 (SD, ± 25) m/year.
Dyspnea
Most patients with COPD report that their breathlessness with activities generally progresses over time. Instruments that have been used to measure the impact of daily activities on breathlessness include the Medical Research Council (MRC) scale, the UCSD Shortness of Breath Questionnaire (UCSD SOBQ), the Baseline and Transition Dyspnea Indices, and the dyspnea component of the Chronic Respiratory Questionnaire. Jones and colleagues (13), as well as Oga and colleagues (11), found that the MRC scale changed by 0.1 units per year in two different cohorts of patients. On the other hand, Ries and coworkers (14) showed little change in the UCSD SOBQ over 4 years in a control group of patients with COPD who were randomized to education alone rather than pulmonary rehabilitation.
In a cohort of 76 patients with COPD, Mahler and colleagues (15) described that the Transition Dyspnea Index declined by –0.7 (SD, ± 2.9) units over 2 years. Casaburi and colleagues (16) reported a similar declining slope in the Transition Dyspnea Index in 325 patients who received placebo therapy as part of a randomized controlled trial with tiotropium.
Health Status
Both generic and disease-specific instruments have documented that health status generally worsens over time in patients with COPD. For example, the physical functioning score of the Short Form 20-item questionnaire (15), the St. George's Respiratory Questionnaire (11), and the Chronic Respiratory Questionnaire (11, 17) have all demonstrated that health status declines with time. Based on data in a 3-year trial of inhaled corticosteroids, Calverley and colleagues (18) showed that patients randomized to placebo therapy who withdrew from the study (51%) had a greater decline in the St. George's Respiratory Questionnaire total score compared with those who completed the 3-year study (49%).
Multidimensional Indices
COPD is a diverse disease with multifaceted dimensions that uniquely define the patient's physiologic and functional performance, and morbidity and mortality. In addition, COPD is associated with clinical manifestations not closely related to FEV1: dyspnea; exercise intolerance; malnutrition; pulmonary hypertension; and peripheral muscle weakness. Airflow obstruction has less influence on mortality than many of the above. However, no single physiologic or functional parameter captures the patient's ultimate outcome, either functionally or in terms of survival. Recent information has highlighted the inadequacies of certain time-honored physiologic parameters, such as FEV1, as being the sole determinant of patient's outcome. Moreover, the importance of nonpulmonary factors influencing the patient's outcome has recently received greater scrutiny. Hence, several investigators have studied the predictive accuracy of composite indices that include nonpulmonary factors to determine whether they can predict outcome better than measurements of FEV1 alone.
Celli and colleagues (19) found that four factors predicted increased risk of death in 207 patients with COPD: body mass index (B), degree of airflow obstruction as measured by FEV1 (O), dyspnea (D), and exercise tolerance measured by 6MW distance (E) (BODE) (Table 1). These combined variables were used to construct the BODE index. The BODE index was then prospectively evaluated with all-cause mortality and respiratory cause of death as the primary outcome variables in 625 patients with COPD over a period of 52 months. Patients with higher BODE scores were at higher risk for death. Hazard ratio for all-cause mortality per 1 point BODE index increase was 1.34 (confidence interval [CI], 1.26–1.42; p < 0.001), hazard ratio for respiratory cause of death was 1.62 (CI, 1.48–1.77; p < 0.001), and C statistic for ability of BODE score to predict the risk of death was 0.74 compared with 0.65 for FEV1 alone. Figure 1 shows that the ability of the BODE index to discriminate the probability of survival among patients was stronger than that of the conventional standard of FEV1 assessment.
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Multidimensional indices, such as BODE, to assess COPD activity and response to therapy have the advantage of including nonpulmonary markers that indicate the impact of systemic factors on COPD outcome. Moreover, patient's symptoms as well as objective physiologic measures are included. On the other hand, we do not know, as yet, which are the most important variables to include in a multidimensional index in order to most appropriately characterize the activity or prognosis of systemic factors associated with COPD. A cautionary note should be made that, although these indices may predict outcome in a population of patients, they may not accurately predict outcome in individual patients. Finally, as of yet, no markers that capture the pathogenesis of COPD have been integrated into any multidimensional COPD index.
Acute Exacerbations
Exacerbations are a major cause of morbidity, mortality, and the need for hospitalization or urgent care, and are a significant contributor to the cost of care and lost work productivity encountered in patients with COPD. An exacerbation in a patient with COPD has been considered analogous to an acute coronary event in a patient with coronary heart disease.
Many descriptive features of an exacerbation could conceivably be used as endpoints to assess the effect of interventions. These include: the number of exacerbations; the type of exacerbation (e.g., outpatient versus inpatient versus emergency room visit); time to first exacerbation; the severity of an exacerbation (admitted to an intensive care unit versus general floor bed; the use of noninvasive or invasive mechanical ventilation); and the duration of an exacerbation.
Despite the obvious clinical importance of exacerbations on patient outcomes and their common clinical occurrence, exacerbations have been difficult to use as endpoints in outcomes analyses for a variety of factors. First, uniform definitions of what constitutes an exacerbation are not readily available. Although the definition of an exacerbation originally described by Anthonisen and colleagues (24), or a modification of it, is the type most frequently used, a consistent standard definition has not been prospectively validated.
In most cases, a change in dyspnea over baseline, cough, increased sputum production or a change in its consistency, accompanied by fever or signs of upper airway congestion, are variably included in most descriptions of an exacerbation. However, patients underreport exacerbations by 50% (25), and only a small percentage of patients (1.6%) know the meaning of the term "exacerbation" (26). Compounding the problem of underreporting of exacerbations is the fact that exacerbation profiles vary widely amongst patients (Figure 2).
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ASSESSING THE IMPACT OF DISEASE-MODIFYING THERAPIES
In selecting the appropriate measures to assess the impact of disease-modifying therapies in COPD, certain considerations need to be made. First, the category of assessment must be considered. Categories of assessment may include epidemiologic variables, physiologic measures, structure–function assessments, the collection of symptomatic measures, and, finally, biological variables. Second, a decision must be made as to whether the assessment will be focused solely on pulmonary variables, or whether nonpulmonary variables will be considered as well. Recently, there has been consideration of the assessment of free-living variables (e.g., measurement of parameters encountered during the patient's routine performance of the activities of daily living) as opposed to those measured strictly under laboratory conditions. Additionally, a decision must be made whether the assessment will be made based on a single physiologic, biological, or functional variable, or on a composite index that captures a change in patient condition with a variety of the above categories. Finally, the thresholds for significance of the magnitude in change of any chosen parameter to be clinically meaningful must be decided.
Potential examples of biological, physiologic, and symptomatic markers of disease activity for COPD are shown in Table 2, as presented by Jones and Agusti (27). Single or composite combinations of such markers show promise in not only signaling a change in response to a specific intervention, but also in detecting a potential mechanism for disease-modifying therapy.
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Such a marker or markers do not currently exist, and much future work will be required to create an independent or composite marker with such a profile.
CONSIDERATIONS FOR FUTURE RESEARCH
Longitudinal changes in various measures/outcomes have been described in cohort(s) of patients followed over time receiving standard therapy, and in group(s) of patients receiving placebo treatment in a randomized controlled trial.
Related questions include:
FOOTNOTES
Conflict of Interest Statement: D.A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.J.C. has served on the advisory boards of Sepracor, Schering-Plough, Ortho-Biotech, Ostuka, and has research grants from Boehringer-Ingelheim, GlaxoSmithKline, Schering-Plough, Altana, Novartis, Emphasys, and Aeris Therapeutics.
(Received in original form January 7, 2007; accepted in final form March 12, 2007)
REFERENCES
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