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The Proceedings of the American Thoracic Society 2:267-271 (2005)
© 2005 The American Thoracic Society

Chronic Obstructive Pulmonary Disease Outcome Measurements

What's Important? What's Useful?

Nicholas J. Gross

Stritch-Loyola School of Medicine, Hines VA Hospital, Chicago, Illinois

Correspondence and requests for reprints should be addressed to Nicholas J. Gross, M.D., PO Box 1485, Hines Hospital, Bldg 1, Room E438 Roosevelt & 5th Avenues, Hines, IL 60141. E-mail: Nicholas.gross{at}med.va.gov


   ABSTRACT
TOP
 ABSTRACT
PHYSIOLOGIC OUTCOMES
 FUNCTIONAL OUTCOMES
 GLOBAL-CLINICAL OUTCOMES
 MISCELLANEOUS OUTCOMES
 REFERENCES
 
The severity of chronic obstructive pulmonary disease (COPD) and patients' response to therapy are difficult to assess. The traditional measure, spirometry, correlates poorly with important clinical features of the disease, such as survival and quality of life (QOL). Moreover, COPD has recently been recognized as a systemic disease, and its systemic manifestations, such as weight loss and muscle weakness, are only poorly related to lung function. Therefore, although lung function remains an important outcome, other outcomes must be included in any overall assessment of disease severity or response to interventions. Examples include refinements of spirometry, such as measurement of FEV6 and inspiratory capacity; functional outcomes, such as dyspnea indexes and exercise tests; and global-clinical outcomes, such as QOL questionnaires and assessment of frequency and severity of acute exacerbations. For scoring disease severity, making a prognosis, or determining the outcome of novel interventions, composite measures need to be developed that take into account as many aspects of COPD as practicable.

Key Words: composite outcomes • dyspnea indexes • exacerbations • exercise capacity • quality of life

Chronic obstructive pulmonary disease (COPD) is now extremely common (1). Its incidence and associated mortality are increasing rapidly, not only in the United States but also in developing countries (2). Almost all our current therapy is symptomatic and does not alter the progression of the disease or the survival of its victims. To address this crisis, several new therapies are being developed, and existing therapies are being modified. A major question that emerges from these efforts is how we may best evaluate the efficacy of these novel therapeutic interventions.

Spirometric measures of pulmonary function (typically FEV1 and FEV1/FVC) have been used to determine the efficacy of a treatment. However, it has become clear in the last decade that spirometry neither predicts survival well (3, 4) nor correlates well with clinical status measures, such as quality of life (QOL) (5). Nor has it been shown that an improvement in pulmonary function achieved by any intervention other than smoking cessation is associated with an improvement in survival; this includes surgery (6). A lack of improvement in spirometry may be associated with other clinically important improvements in symptomatology; therefore, spirometry may provide a less-than-complete measure of the efficacy of an intervention.

A further consideration is the recent realization that COPD is not just a pulmonary disorder but is a systemic disease that has systemic effects that can contribute substantially to its morbidity and mortality (7). Weight loss, muscle weakness, and osteoporosis are among a variety of common features of advanced COPD, each of which contributes to the symptoms, morbidity, and probably the mortality of COPD. The mechanisms of these systemic effects are poorly understood but may be related to persistent airways inflammation (8) and elevated levels of circulating inflammatory mediators, such as tumor necrosis factor-{alpha} (TNF-{alpha}) (9). Spirometry alone provides little or no information about the extrapulmonary effects of COPD.

This review summarizes the utility of a variety of outcome measurements in the assessment of therapeutic interventions for COPD. As in a previous review (10), these outcomes are grouped into categories or dimension: physiologic, functional, global-clinical, and miscellaneous. Where possible, the minimal clinically important difference (MCID) in an outcome is mentioned. Because almost any outcome in COPD is a matter of degree (e.g., improvement in FEV1 or exercise capacity after an intervention), MCIDs have been proposed for several comes (59). These MCID, which are often based on "soft" data, represent a general consensus among authors of the minimal change in an outcome that seems to result in a clinically meaningful improvement.


   PHYSIOLOGIC OUTCOMES
TOP
 ABSTRACT
 PHYSIOLOGIC OUTCOMES
FUNCTIONAL OUTCOMES
 GLOBAL-CLINICAL OUTCOMES
 MISCELLANEOUS OUTCOMES
 REFERENCES
 
Where the intervention may be expected to have an effect on lung function, it is appropriate to measure it. The most useful, discriminatory, and reproducible measurements are those obtained by spirometry: FEV1, FVC, and their ratio (11, 12). Where the intervention is a bronchodilator, serial spirometry is performed before and for an appropriate time span after administration of the agent. The results can be evaluated in many ways (e.g. peak FEV1 and area under the FEV1 curve). Other results can be measured from the same data, usually as secondary outcomes (e.g., time to onset and duration of bronchodilation action, both typically being arbitrarily taken to be an increase in FEV1 of 15% increase over its baseline value). How much must the FEV1 improve to be considered clinically significant (i.e., the MCID)? The within-subject variability of FEV1 has been estimated to be 160 ml (16). A change in FEV1 of this amount can thus be taken as evidence of physiologic efficacy, but a threshold for clinical efficacy has not been definitively established. The American Thoracic Society and Global Initiative for Chronic Obstructive Lung Disease guidelines considered an absolute increase in FEV1 of 200 ml plus a relative increase of 12% above baseline to be the threshold of clinical significance.

The technical performance of spirometry is important, and standards have been published (13). Because these standards are rarely met in clinical practice, retrospective data from routine clinic data are usually inadequate for research purposes. Fortunately, most, if not all, contemporary spirometers have built-in quality control software that alerts the operator to unacceptable data. One of the common technical problems of spirometry relates to the duration of expiration. Due to the prolonged and low expiratory flow rate in COPD, the FVC is dependent on the motivation and breath-holding capacity of the subject. To avoid the uncertainty this creates, the FEV6 (the volume expired in the first 6 s of a forced expiration) has been advocated as a surrogate for FVC (14).

One other refinement of routine spirometry, the inspiratory capacity (IC), should be considered. FEV1 and the FEV1/FVC ratio may not detect significant changes in lung physiology after bronchodilation because the spirogram is performed at lower lung volumes where flow rates are decreased (Figure 1). Thus, lung hyperinflation and its reduction in response to a bronchodilator are often not apparent on routine spirometry. IC is a surrogate for lung hyperinflation that is easily derived from spirometry (15). IC should be included in all COPD outcomes, particularly where changes in lung physiology are expected.



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  		Figure 1. Flow-volume loops before and after bronchodilator in a patient with COPD. The smaller loops are the tidal loops; the larger ones are maximal loops. Both are positioned at absolute lung volumes to show the shift toward lower lung volumes after bronchodilator. The FEV1 values (vertical arrows at 1 s) increased by only 10% of baseline (not significant). However, IC increased by 23% (> 0.5 L). Thus, even if absolute volumes had not been measured, the increase in IC could be taken as evidence that a significant bronchodilator response had occurred. Reprinted with permission from Reference 10.

 
As an outcome of long-term studies, spirometry has been used to study the effects of age (17) and several therapeutic interventions (18, 19). The age-related decline in FEV1 of never-smokers (~25 ± 5 ml/yr) is well known (20). The effect of an intervention can be gauged against this historic value or, better, a control group. For current studies of this effect, the postbronchodilator FEV1 (rather than prebronchodilator FEV1) is the preferred parameter because of its greater reproducibility (11).

Other physiologic outcomes include tests of static lung volumes, airway resistance, compliance, diffusion (gas transfer) capacity, and arterial blood gases. Arterial blood gases are a relevant outcome in studies of interventions that might affect respiratory drive or impair ventilation-perfusion relationships in the lungs. The other physiologic outcomes may be of value in special circumstances (e.g., in lung volume reduction surgery) but are otherwise rarely useful.


   FUNCTIONAL OUTCOMES
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 ABSTRACT
 PHYSIOLOGIC OUTCOMES
 FUNCTIONAL OUTCOMES
GLOBAL-CLINICAL OUTCOMES
 MISCELLANEOUS OUTCOMES
 REFERENCES
 
Functional outcomes fall into subjective and objective categories. There are validated and reproducible methods to measure each. The most common and distressing symptoms of COPD include dyspnea on effort, wheeze, cough, and sputum production. Dyspnea can be assessed by a variety of instruments, the simplest of which are the Borg scale (21) and the Medical Research Council (MRC) dyspnea scale (22). The Borg scale is a 10 point scale representing the entire range of severity of dyspnea; the subject is requested to select a point on this scale that corresponds to his perception of dyspnea. A change of 1 cm is believed to be the MCID. The MRC dyspnea scale is a set of five statements about dyspnea. The subject is asked to select the statement that most closely applies. Both scales are easy to use and quick to perform and are capable of detecting long- and short-term changes. The MRC scale is one of the components of the BODE index described below (3). Because the MRC scale has only five grades, it lacks sensitivity and does not take account of the effort expended to perform the task in each grade. More complete subjective estimates of dyspnea that avoid this drawback are provided by questionnaires such as Mahler's Baseline- and Transition-Dyspnea Indexes (23). Both questionnaires are validated, take longer to perform, and require more from the subjects and are thus better suited to research than to routine clinical practice. An MCID of 1 unit is suggested by the authors.

Objective estimates of functional capacity are provided by exercise tests, of which a considerable number are available (24–26). Among a variety of field tests, the most widely used is the 6-minute Walk Test (6-MWT) (27, 28), a supervised measurement of the distance the patient can walk on the level in 6 minutes. Reference values are 576 m for healthy male subjects and 494 m for healthy female subjects (29). The distances for patients with COPD are generally less but are variable (30). The threshold of clinically significant change as a result of an intervention (MCID) (e.g., a rehabilitation program) has been reported to be about 55 m for groups (30, 31) and 86 m for individuals (60). Guidelines for its performance have been provided (32). A similar but more exhaustive test is the Incremental Shuttle Walk Test (33). The patient walks around a 10-m circuit at a pace set by an audible signal. The pace and signal are ramped up each minute. The end-point is the distance that the patient has walked when they can no longer keep pace with the signal. The relative advantages of each have been discussed (10). All such tests are easy to perform and require a minimum of apparatus but impose some demands on the subjects and the investigator (a training effect over the first few tests a subject performs is one of the caveats in their interpretation).

More formal tests of exercise capacity are laboratory based, using treadmills or stationary bicycles. These tests fall into two categories: those that use a steady state of work output and those that use an incremental increase in work output. The endpoint is typically the maximal workload (in Watts) that the subject can achieve. In the National Emphysema Treatment Trial (NETT) (6), a change of 10 Watts was taken as the threshold of clinically significant improvement. Such tests of exercise capacity require a dedicated facility and trained staff and are relatively expensive. They are thus generally less practical for routine studies than the field tests.


   GLOBAL-CLINICAL OUTCOMES
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 ABSTRACT
 PHYSIOLOGIC OUTCOMES
 FUNCTIONAL OUTCOMES
 GLOBAL-CLINICAL OUTCOMES
MISCELLANEOUS OUTCOMES
 REFERENCES
 
QOL
Health status measurements are indispensable in formal studies of interventions, although they are not in clinical practice. The American Thoracic Society website provides an index to several of these that are more or less specific to subjects with pulmonary disorders (http://www.thoracic.org). Two QOL indexes have been validated and are widely used in COPD: the Saint George's Respiratory Questionnaire (SGRQ) (34) and the Chronic Respiratory Questionnaire (CRQ) (35). Both indexes have been validated and are sensitive to changes resulting from interventions and from natural events, such as acute exacerbations of COPD. The SGRQ has three components: Symptoms, Activity, and Impacts. Its total score ranges from 0 (perfect health) to 100 (most severe status). A change in four units is the minimal clinically significant change (61). The CRQ has four components: Dyspnea, Fatigue, Emotional Function, and Mastery. The current version of this instrument is scored on a seven-point scale; higher scores signify better health status, and a difference of 0.5 units or more is considered to be the MICD (36). For each instrument, the total score is probably the most reliable end-point; however, one or more components can be presented to indicate a field in which the event or intervention seems to be particularly beneficial or harmful.

QOL outcomes such as these are regarded as important in all aspects of COPD because they are felt to represent changes that are clinically most relevant to patients and that may not be measurable by other more conventional parameters.

Acute Exacerbations of COPD
Acute exacerbations can be measured in many ways (e.g., time to first exacerbation, number of exacerbations, number of unscheduled and emergency department visits for COPD, number of hospitalizations for COPD, and number of ICU admissions for COPD). Each of these outcomes should be captured, and, for confidence in the effect of the intervention, the results of these outcome measures should be in the same direction and statistically significant.

Mortality
Mortality can be recorded as all-cause and disease related. Although mortality is probably the most robust and definitive outcome, it has rarely been measured as a primary outcome in COPD; the two long-term oxygen therapy trials (43, 44) and the NETT (6) are notable exceptions. Studies in which mortality is the primary outcome are likely to require relatively large numbers of subjects and long observation times and are consequently expensive.


   MISCELLANEOUS OUTCOMES
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 ABSTRACT
 PHYSIOLOGIC OUTCOMES
 FUNCTIONAL OUTCOMES
 GLOBAL-CLINICAL OUTCOMES
 MISCELLANEOUS OUTCOMES
REFERENCES
 
Radiology
Traditional radiologic examination of the lungs is insensitive to the presence and severity of COPD. However, computed tomography (CT) is able to detect and objectively quantify the density of lung regions, and the measurements correlate reasonably well with subsequently obtained lung histology (45, 46). In addition to lung parenchymal density measurements, progress is being made toward measurement of airway dimensions and wall thickness by high-resolution CT scans (47, 48). Radiologic outcome has not been widely applied in clinical studies, although it has been appropriately use in as an outcome of lung volume reduction surgery (49).

Markers of Airway Inflammation
These are receiving increased attention, with the realization that the pathogenesis and cellular pathology of inflammation is distinctive in COPD (50). A variety of studies have used biopsies of airways (e.g., scoring interleukin [IL]-8 and numbers of CD-8 lymphocytes [51]), bronchoalveolar lavage (52), exhaled breath condensates (e.g., 8-isoprostane and leukotriene B4 [53, 54]), and circulating inflammatory markers (e.g., TNF-{alpha} and its soluble receptors and IL-6) (56, 56). Although these markers have been used as outcomes of interventions (57), their role in clinical research is only beginning to reach its potential. With better understanding of the COPD inflammatory process, one hopes that the most relevant markers of inflammation will emerge and that reliable, simple assays will become widely included in clinical studies.

Soft Outcomes
It is conventional in clinical studies to include, as secondary outcomes, data that one regards as soft. Soft data include diary cards, the use of rescue mediations, and global evaluations by subjects or physicians. These data can be misleading (58) and add little value to the study, except possibly to corroborate the primary outcome.

Composite Outcomes
COPD is a protean condition; each of the outcomes discussed previously focuses on a different dimension of the disease, and none by itself gives a reliable account of the disease state or a complete result of an intervention. It is appropriate, therefore, that attempts are made to devise a method to score disease severity, make a prognosis, or determine the outcome of an intervention that takes account of as many aspects of the disease as is practicable. All or most clinical studies should include not only a physiologic outcome (e.g., based on spirometry) but also subjective and objective functional scores (e.g., a dyspnea index and a 6-MWT) and a QOL index (e.g., SGRQ or CRQ); these should be co-primary outcomes (10). More specific outcomes (e.g., lung density by CT scan or inflammatory markers) should be included where appropriate.

Celli and colleagues (3) have devised, prospectively tested, and validated a composite index that they call the BODE index from its four components: Body mass index, degree of airflow Obstruction, the modified MRC Dyspnea scale, and Exercise capacity based on the 6-MWT. The sum of components provides a score from 0–10. The prospective, validation phase of the study examined two robust outcomes, all-cause mortality, and mortality due to respiratory failure. For both outcomes, the BODE index was a better predictor of mortality than FEV1 (Figure 2). Major advantages of the index are that it is widely applicable, simple, and requires no special equipment.



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  		Figure 2. Survival of patients with COPD based on the BODE index (A) or stages of COPD as defined by American Thoracic Society standards (B). Reprinted with permission from Reference 3.

 

   FOOTNOTES
 
Research for this report has been provided by Veterans Affairs Research

Conflict of Interest Statement: N.J.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form April 13, 2005; accepted in final form July 14, 2005)


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