Chronic Obstructive Pulmonary Disease
Outcome Measurements
Whats Important? Whats Useful?
Nicholas J. Gross
Stritch-Loyola School of Medicine, Hines VA Hospital, Chicago, Illinois
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 fea-
tures of the disease, such as survival and quality of life (QOL).
Moreover, COPD has recently been recognized as a systemic dis-
ease, and its systemic manifestations, such as weight loss and muscle
weakness, are only poorly related to lung function. Therefore, al-
though lung function remains an important outcome, other out-
comes must be included in any overall assessment of disease severity
or response to interventions. Examples include refinements of spirome-
try, 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.
Keywords: composite outcomes; dyspnea indexes; exacerbations; exer-
cise capacity; quality of life
Chronic obstructive pulmonary disease (COPD) is now extremely
common (1). Its incidence and associated mortality are increas-
ing 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 cessa-
tion is associated with an improvement in survival; this includes
surgery (6). A lack of improvement in spirometry may be associ-
ated with other clinically important improvements in symptom-
atology; 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 mor-
(Received in original form April 13, 2005; accepted in final form July 14, 2005)
Research for this report has been provided by Veterans Affairs Research
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@med.va.gov
Proc Am Thorac Soc Vol 2. pp 267271, 2005
DOI: 10.1513/pats.200504-036SR
Internet address: www.atsjournals.org
bidity and mortality (7). Weight loss, muscle weakness, and os-
teoporosis 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 circu-
lating inflammatory mediators, such as tumor necrosis factor-
(TNF-) (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-clin-
ical, and miscellaneous. Where possible, the minimal clinically
important difference (MCID) in an outcome is mentioned. Be-
cause 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
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 ob-
tained by spirometry: FEV1, FVC, and their ratio (11, 12). Where
the intervention is a bronchodilator, serial spirometry is per-
formed before and for an appropriate time span after administra-
tion 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 out-
comes (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 esti-
mated 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 in-
crease 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. Fortu-
nately, 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 re-
lates 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
268
Figure 1. Flow-volume loops before and after bronchodilator in a pa-
tient 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.
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 broncho-
dilator are often not apparent on routine spirometry. IC is a
surrogate for lung hyperinflation that is easily derived from spi-
rometry (15). IC should be included in all COPD outcomes,
particularly where changes in lung physiology are expected.
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 postbron-
chodilator FEV1 (rather than prebronchodilator FEV1) is the
preferred parameter because of its greater reproducibility (11).
Other physiologic outcomes include tests of static lung vol-
umes, airway resistance, compliance, diffusion (gas transfer) capac-
ity, 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 cir-
cumstances (e.g., in lung volume reduction surgery) but are other-
wise rarely useful.
FUNCTIONAL OUTCOMES
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. Dys-
pnea 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 corre-
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 2 2005
sponds 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 state-
ments 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 Mahlers Baseline- and Tran-
sition-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
(2426). Among a variety of field tests, the most widely used is
the 6-minute Walk Test (6-MWT) (27, 28), a supervised measure-
ment 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 pro-
vided (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 appara-
tus but impose some demands on the subjects and the investiga-
tor (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
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 Georges
Respiratory Questionnaire (SGRQ) (34) and the Chronic Respi-
ratory Questionnaire (CRQ) (35). Both indexes have been vali-
dated 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 Im-
pacts. 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: Dys-
Gross: Outcome Measures in COPD
pnea, 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 benefi-
cial 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 un-
scheduled 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. Al-
though mortality is probably the most robust and definitive out-
come, 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 num-
bers of subjects and long observation times and are consequently
expensive.
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.
269
MISCELLANEOUS OUTCOMES
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 dis-
tinctive 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- 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 sever-
ity, make a prognosis, or determine the outcome of an intervention
that takes account of as many aspects of the disease as is practica-
ble. All or most clinical studies should include not only a physio-
logic 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 010. 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.
270
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.
References
1. National Center for Health Statistics. Plan and Operation of the Third
National Health and Nutrition Examination Survey, 19881994. US
Department of Health and Human Services publication PHS 94-1308.
Washington, DC: USDHHS.
2. Murray CJL, Lopez AD. Mortality by cause for eight regions of the
world, Global Burden of Disease Study. Lancet 1997;349:12691276.
3. Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruc-
tion, dyspnea, and exercise capacity index of chronic obstructive pul-
monary disease. N Engl J Med 2004;350:10051012.
4. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis of factors
related to mortality in chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2003;167:544549.
5. Domingo-Salvany A, Lamarca R, Ferrer M, Garcia-Aymerich J, et al.
Health-related quality of life and mortality in male patients with
chronic obstructive pulmonary disease. Am J Respir Crit Care Med
2002;166:680685.
6. National Emphysema Treatment Trial Research Group. A randomized
trial comparing lung-volume-reduction surgery with medical therapy
for severe emphysema. N Engl J Med 2003;348:20592073.
7. Gross NJ. Extrapulmonary effects of COPD. Curr Opin Pulm Med 2001;
7:8492.
8. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruc-
tion in chronic obstructive pulmonary disease. N Engl J Med 2004;
350:26452653.
9. Schols AM, Buurman WA, Staal van den Brekel AJ, Dentener MA,
Wouters EF. Evidence for a relation between metabolic derangements
and increased levels of inflammatory mediators in a subgroup of pa-
tients with chronic obstructive pulmonary disease. Thorax 1996;51:
819824.
10. Gross NJ. Outcome measures for COPD treatments, a critical evaluation.
COPD: J Chronic Obstructive Pulmonary Dis 2004;1:4157.
11. Enright PL, Johnson LR, Connett JE, Voelker H, Buist AS. Spirometry
in the Lung Health study. 1: methods of quality control. Am Rev
Respir Dis 1991;143:12151223.
12. Enright PL, Lebowitz MD, Cockroft DW. Physiologic measures, pulmo-
nary function tests. Am J Respir Crit Care Med 1994;149:S9S18.
13. American Thoracic Society. ATS standardization of spirometry 1994
update. Am J Respir Crit Care Med 1994;152:11071136.
14. Enright RL. The FEV1/FEV6 predicts lung function decline in adult
smokers. Respir Med 2002;96:444449.
15. ODonnell DE. Assessment of bronchodilator efficacy in symptomatic
COPD. Chest 2000;117:42S47S.
16. Tweedale PN, Alexander F, McHardy GJR. Short-term variability of
FEV1 and bronchodilator responsiveness in patients with obstructive
ventilatory defects. Thorax 1997;42:48790.
17. Traver GA, Cline MG, Burrows B. Predictions of mortality in COPD,
a 15 year follow-up study. Am Rev Respir Dis 1979;119:895902.
18. Anthonisen NR, Wright EC, IPPB Trial Group. Bronchodilator response
in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986;133:
814819.
19. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking interven-
tion and the use of an inhaled anticholinergic bronchodilator of the rate
of decline of FEV1, the Lung health study. JAMA 1994;272:14971505.
20. Fletcher C, Peto R, Tinker C. The natural history of chronic bronchitis
and emphysema. New York: Oxford University Press; 1976. pp. 1272.
21. Burdon GW, Juniper EF, Killian KJ, et al. The perception of breath-
lessness in asthma. Am Rev Respir Dis 1982;126:825828.
22. Fletcher CM. Standardized questionnaire on respiratory symptoms: a
statement prepared and approved by the MRC Committee on the
aetiology of chronic bronchitis. BMJ 1960;2:1665.
23. Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement
of dyspnea, contents, interobserver agreement, and physiologic corre-
lates of two new clinical indexes. Chest 1984;85:751758.
24. Weisman IM, Zebalos RJ, editors. Clinical exercise testing; progress in
respiratory research. Karger, Basel, New York: 2002.
25. Montoye HJ, Kemper HCG, Saris WHM, Washburn RA. Measuring
physical activity and energy expenditure. Champaign, IL: Human Ki-
netics; 1996.
26. Cooper CB, Storer TW, editors. Exercise testing and interpretation, a
practical approach. Cambridge, UK: Cambridge University Press; 2001.
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 2 2005
27. Butland RJA, Pang J, Gross ER, Woodcock AA, Geddes DM. Two-,
6-, and 12-minute walking tests in respiratory disease. BMJ 1982;284:
16071608.
28. Solway S, Brooks D, Lacasse Y, Thomas S. A qualitative systematic
overview of the measurement properties of functional walk tests used
in the cardiorespiratory domain. Chest 2001;119:256270.
29. Enright PL, Sherrill DL. Reference equations for the six-minute walk
test in healthy adults. Am J Respir Crit Care Med 1998;158:13841387.
30. Redelmeier DA, Bayoumi AM, Goldstein RS, Guyatt GH. Interpreting
small differences in functional status, the 6-minute walk test in chronic
lung disease patients. Am J Respir Crit Care Med 1997;155:12781282.
31. Lacasse Y, Wong E, Guyatt GH, King D, Cook DJ, Goldstein RS. Meta-
analysis of respiratory rehabilitation in chronic obstructive pulmonary
disease. Lancet 1996;348:11151119.
32. ATS Committee on Proficiency Standards for Clinical Pulmonary Func-
tion Laboratories. ATS Statement: guidelines for the 6-minute walk
test. Am J Respir Crit Care Med 2002;166:111117.
33. Singh SJ, Morgan MDL, Scott S, Walters D, Hardman A. Development
of a shuttle walking test of disability in patients with chronic airways
obstruction. Thorax 1992;47:10191024.
34. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete
measure for chronic airflow limitation: the St Georges Respiratory
Questionnaire. Am Rev Respir Dis 1992;145:13211327.
35. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A
measure of the quality of life for clinical trials in chronic lung disease.
Thorax 1987;42:773778.
36. Schunemann HJ, Puhan M, Goldstein R, Jaeschke R, Guyatt GH. Mea-
surement properties and interpretability of the Chronic Respiratory
Disease Questionnaire (CRQ). COPD: J Chronic Obstructive Pulmo-
nary Dis 2005;2:8189.
37. Cydulka RK, McFadden ER Jr, Emerman CL, et al. Patterns of hospital-
ization in elderly patients with asthma and chronic obstructive pulmo-
nary disease. Am J Respir Crit Care Med 1997;56:18071812.
38. Vilkman S, Keistinen T, Tuuponen T, Kivela SL. Survival and cause of
death among elderly chronic obstructive pulmonary disease patients
after first admission to hospital. Respiration (Herrlisheim) 1997;64:281
284.
39. Hilleman DE, Dewan N, Malesker M, Friedman M. Pharmacoeconomic
evaluation of COPD. Chest 2000;118:12781285.
40. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in
exacerbations of chronic obstructive pulmonary disease. Ann Intern
Med 1987;106:196204.
41. Rodriguez-Roisin R. Toward a consensus definition for COPD exacerba-
tions. Chest 2000;117:S398S401.
42. Niewoehner D, et al. (in preparation), data on file (Boehringer-Ingleheim
Pharmaceuticals)
43. Medical Research Council Working Party. Long term domiciliary oxygen
therapy in chronic hypoxic cor pulmonale complicating chronic bron-
chitis and emphysema. Lancet 1981;1:681686.
44. Nocturnal Oxygen Therapy Group. Continuous or nocturnal oxygen ther-
apy in hypoxemic chronic obstructive pulmonary disease. Ann Intern
Med 1980;93:391398.
45. Spouge D, Mayo JR, Cardoso W, Muller NL. Panacinar emphysema, CT
and pathologic findings. J Comput Assist Tomogr 1993;17:710713.
46. Genevois PA, de Maertelaer V, De Vuyst P, Zanen J, Yernault JC.
Comparison of computed density and macroscopic morphometry in
pulmonary emphysema. Am J Respir Crit Care Med 1995;152:653657.
47. Nakano Y, Muro S, Sakai H, et al. Computed tomographic measurements
of airway dimensions and emphysema in smokers. Am J Respir Crit
Care Med 2000;162:11021108.
48. King GG, Muller NL, Whittall KP, Xiang S, Pare PD. An analysis algo-
rithm for measuring airway lumen and wall areas from high-resolution
computed tomographic data. Am J Respir Crit Care Med 2000;161:574
580.
49. Bae KT, Slone RM, Gierada DS, Yusen RD, Cooper JD. Patients with
emphysema, quantitative CT analysis before and after lung volume
reduction surgery. Radiology 1997;203:705714.
50. Barnes PJ. New concepts in chronic obstructive pulmonary disease. Annu
Rev Med 2003;54:113129.
51. DiStefano A, Capelli A, Lusuardi M, et al. Severity of airflow limitation
is associated with severity of airway inflammation in smokers. Am J
Respir Crit Care Med 1998;158:12771285.
52. Saetta M, Turato G, Maestrelli P, Mapp CE, Fabbri LM. Cellular and
structural bases of chronic obstructive pulmonary disease. Am J Respir
Crit Care Med 2001;163:13041309.
53. Montuschi P, Barnes PJ. Analysis of exhaled breath condensates for
Gross: Outcome Measures in COPD
monitoring airway inflammation. Trends Pharmacol Sci 2002;23:232
237.
54. Paredi P, Kharitonov SA, Barnes PJ. Analysis of expired air for oxidation
products. Am J Respir Crit Care Med 2002;166:S31S37.
55. Schols AM, Buurman WA, Staal van den Brekel AJ, Dentener MA,
Wouters EF. Evidence for a relation between metabolic derangements
and increased levels of inflammatory mediators in a subgroup of pa-
tients with chronic obstructive pulmonary disease. Thorax 1996;51:
819824.
56. Roland M, Bhowmik A, Sapsford RJ, et al. Sputum and plasma
endothelin-1 levels in exacerbations of chronic obstructive pulmonary
disease. Thorax 2001;56:3035.
57. Gizycki MJ, Hattotuwa KL, Barnes N, Jeffery PK. Effects of fluticasone
271
propionate on inflammatory cells in COPD, an ultrastructural exami-
nation of endobronchial biopsy tissue. Thorax 2002;57:799803.
58. Rand CS, Wise RA, Nides M, et al. Inhaler adherence in a clinical
trial, comparison of self-report and canister weighing to the nebulizer
chronology. Am Rev Respir Dis 1992;146:15591564.
59. Make B, Casaburi R, Leidy NK. Interpreting results from clinical trials,
understanding minimal clinically important differences in COPD out-
comes. COPD: J Chronic Obstructive Pulmonary Dis 2005;2:15.
60. Wise RA, Brown CD. Minimal clinically important differences in the
six-minute walk test and the incremental shuttle walking test. COPD:
J Chronic Obstructive Pulmonary Dis 2005;2:125129.
61. Jones PW. St Georges Respiratory Questionnaire: MCID. COPD: J
Chronic Obstructive Pulmonary Dis 2005;2:7579.