Ers 2012.full
Ers 2012.full
DOI: 10.1183/09059180.00005509
CopyrightERSJ Ltd 2012
PATHOPHYSIOLOGY
Cigarette smoking is the leading cause of COPD in Western
countries. Cigarette-associated noxious agents injure the airway epithelium and drive the key processes that lead to
specific airway inflammation and structural changes [2]. Once
these agents are removed, repair processes should, ideally,
bring the airways back to their normal structure and function.
In general, an inadequate repair process is thought to play a key
role in the development of chronic airflow obstruction in some,
but not all, smokers. Indeed, in many subjects most of the
inflammatory changes continue despite smoking cessation [3].
This failure of bronchial inflammation to resolve might
contribute to systemic changes and ongoing bronchial and
lung matrix degradation. In addition to persistent airway
inflammation, other major phenomena involved in the disease
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RESPIRATORY PHYSIOLOGY
During recent years, several major advances have occurred in
the comprehension of respiratory physiology in COPD. Many
may have significant clinical implications regarding the disease
definition and diagnosis, estimation of prognosis using functional indices, assessment of therapeutic indications and
response to treatments. They mostly relate to spirometry,
exercise testing, pulmonary mechanics and respiratory muscles.
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Spirometry
Optimal criteria to define COPD-related airflow obstruction
The definition of obstruction remains a highly controversial issue.
Current Global Initiative for Chronic Obstructive Lung Disease
(GOLD) guidelines continue to define airflow limitation by a
fixed FEV1/forced vital capacity (FVC) threshold of 0.7,
independently of age and sex. This is in marked contradiction
with American Thoracic Society (ATS)/European Respiratory
Society (ERS) guidelines, which clearly recommend that the
lower limit of normal (LLN) criterion is used. Several large series
in which investigators assessed lung function in adults challenge
the GOLD guidelines. The first study [27], performed in 14,506
adults, found that the fixed ratio (as compared to the 1993
European Community for Steel and Coal (ECSC) study [28]) has a
high negative but a low positive predictive value, particularly in
patients aged .50 yrs (fig. 1): the false positive rate was 33% in
the 6170 yr age range. Similarly, in the NHANES-III (Third
National Health and Nutrition Examination Survey) population,
the proportion of older adults misclassified by the fixed ratio
was nearly one-fifth, whereas nearly one-half of young adults
were false-negative with GOLD guidelines, in comparison
Post-bronchodilator FEV1/FVC
a) 1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Post-bronchodilator FEV1/FVC
b) 1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
50
FIGURE 1.
60
70
80
Age yrs
90
100
forced vital capacity (FVC) ratio in subjects aged .50 yrs. Red line corresponds to
the fixed 0.7 cut-off, the black line to the age- and sex-specific lower limit of normal
(LLN). Red circles represent false positive subjects with the fixed ratio, green ones
are true positive according to LLN. Reproduced and modified from [27] with
permission from the publisher.
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Reversibility in COPD
COPD is usually defined as a poorly reversible obstructive
disorder. However, previous data showed a wide range of
reversibility in clinically well-defined COPD. This hypothesis
was verified in the UPLIFT (Understanding Potential Longterm Impacts on Function with Tiotropium) trial data, which
included at baseline a reversibility test with a combination of
high-dose ipratropium (three puffs) and salbutamol (four
puffs) [32]. FEV1 and FVC responses were highly variable
according to chosen criteria (ATS/ERS: .200 mL and .12%
from baseline; .15%; .10% pred). A majority (53.9%) of
patients reached the ATS/ERS threshold for reversibility.
Older patients, those with a better St Georges Respiratory
Questionnaire (SGRQ) score or those with low number of packyears were less responsive with this criterion. The proportion
of patients with volume response only (FVC) increased with
the severity of airflow obstruction. Although this responsiveness was obtained in optimal conditions (high dose, adequate
withholding of previous drugs, spirometry at peak bronchodilation) and varied greatly according to applied criteria,
it appears larger than expected and precludes the use of these
reversibility criteria to differentiate COPD from asthma. In
clinical practice, reversibility is often assessed in COPD
patients by spirometry alone. However, thoracic gas compression during forced expiration is a major event and flow at the
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the authors, their COPD group may not be perfectly representative of mild COPD patients discovered by screening, as they
exhibited increased plethysmographic functional residual capacity, markedly decreased forced expiratory flow between 25%
and 75% of FVC and a low diffusing capacity of the lung for
carbon monoxide (DL,CO). In addition, gas exchanges were not
evaluated. In practice, dynamic hyperinflation should, therefore, be considered as a potential cause of dyspnoea even in
mild COPD patients. Besides ventilatory limitation, dynamic
hyperinflation may also have haemodynamic consequences
through changes in intrathoracic pressures. This hypothesis was
previously demonstrated in healthy subjects during experimental flow limited exercise [43]. It was tested in GOLD stage 3
and 4 patients characterised by a severe resting hyperinflation,
defined as an IC/total lung capacity (TLC) ratio ,25% [44],
which was previously shown by the same team to be a negative
prognostic factor [45]. Haemodynamic compromise was indirectly assessed by the oxygen pulse. It was significantly
decreased in COPD patients at rest and during exercise.
Oxygen pulse at peak exercise was also significantly correlated
to resting IC/TLC ratio in the whole population (fig. 2). The
relationship was, however, smaller in the COPD group alone
(r50.46). At isotime during the test, oxygen pulse was always
lower in patients with IC/TLC ratio .25%. However, in
multivariate analysis, handgrip force was the most significant
predictor of peak O2 pulse. Abnormal kinetics of cardiac output
during exercise were also demonstrated in COPD patients,
together with a lowered kinetics of peripheral microvascular O2
delivery [46]. Improvement of cardiac output during exercise
with Heliox [47] further supports the detrimental role of
hyperinflation, which increases intrathoracic pressures.
These studies confirm the complexity of mechanisms limiting
exercise in COPD, with a variable combination of central
(dynamic hyperinflation and cardiac output) and peripheral
(muscle atrophy and dysfunction) factors. Determination of the
predominant mechanism in individual patients might prove
25
20
15
10
0
10
FIGURE 2.
20
30
40
IC/TLC ratio %
50
60
(TLC) ratio and oxygen pulse at peak exercise in chronic obstructive pulmonary
disease (COPD) patients (#) and controls ($). r50.65; p,0.0001. Correlation is
lower in COPD patients (r50.46). Reproduced from [44] with permission from the
publisher.
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a)
UPDATE ON COPD
20
#
Values % pred
10
-10
-20
-30
FEV1 FEV1/ FVC
FVC
b)
IC
SVC
RV
TGV
TLC
+
+
cmH2OsL-1
1
+
0
-1
-2
-3
Rinsp
FIGURE 3.
Rexp
Rtot
Xinsp
Xexp
Xtot
Xrs R5R19
data at 5 Hz induced by bronchodilator in flow limited (h) and nonflow limited (&)
patients at baseline. % pred: % predicted; FEV1: forced expiratory volume in 1 s;
FVC: forced vital capacity; IC: inspiratory capacity; SVC: slow vital capacity; RV:
insp: mean
residual volume; TGV: thoracic gas volume; TLC: total lung capacity; R
tot: mean whole breath
exp: mean expiration resistance; R
inspiration resistance; R
resistance; Xinsp: mean reactance during inspiration; Xexp; mean reactance during
5-R
19:
tot: mean total reactance; DXrs: mean difference in reactance; R
expiration: X
mean difference in resistances at 5 and 19 Hz. #: p50.04; ": p50.05; +: p50.001;
1
Nitrogen washout
The single-breath nitrogen washout test (SBN2) is a classic test
of small airways involvement [55], although its prognostic
value in early COPD remains controversial [56, 57]. The
relationships between SBN2 and airway inflammation were
evaluated in COPD patients not taking corticosteroids [58]. The
slope of phase III increased with neutrophil inflammation as
assessed by bronchial biopsies, BAL and induced sputum. The
most significant relationship was found between the slope of
phase III and BAL neutrophil elastase/neutrophil ratio, even
after adjustment for FEV1 level. The SBN2 test was unrelated to
the presence of other inflammatory cell types. These results
confirm the role of neutrophilic inflammation in small airways
and/or alveolar dysfunction. Monitoring of SBN2 could be
useful for the evaluation of new anti-inflammatory strategies
in COPD, although multiple-breath washout might be more
sensitive in this context [59, 60].
EUROPEAN RESPIRATORY REVIEW
Respiratory muscles
Inspiratory muscle endurance
Although not routinely measured, inspiratory muscle endurance (IME) is probably more relevant than inspiratory muscle
strength (as measured by maximal inspiratory pressure (PI,max))
in COPD, particularly for the evaluation of the impact of
inspiratory muscle training (IMT). The test may be performed
with a constant threshold load or an incremental one. A
previous study showed a significant impact of a high-intensity
IMT on incremental endurance test, dyspnoea and walking
distance [61]. A second study compared the responsiveness of
the two techniques after IMT using interval training [62]. IMT
significantly improved the performance during both tests, but
the incremental test appeared more sensitive. However, patients
modified their breathing pattern during training, shortening
inspiratory time and duty cycle. Thus, a precise evaluation of
treatment effect justifies an adequate control of the breathing
pattern during the test. IME testing might also help to select the
best COPD candidates for IMT [63] or other innovative
approaches [64, 65].
Neural respiratory drive
Mechanical abnormalities (hyperinflation or increased work of
breathing) together with cellular and molecular alterations
lead to diaphragmatic dysfunction in COPD, although some
compensatory mechanisms exist [64]. Neural respiratory drive
may be assessed by diaphragmatic electromyogram (EMG) but
few data are available in COPD. LUO and co-workers [66, 67]
have developed a specific oesophageal catheter with multiple
electrodes, allowing an optimal sampling of diaphragm EMG
and neural drive. The same electrode was used in COPD
patients to enable a comparison to age-matched healthy
controls [68]. EMG during spontaneous breathing was normalised as the percentage of individual maximal EMG (defined as
the maximal EMG value obtained during inspiration to TLC,
PI,max, maximal sniff manoeuvres or maximum voluntary
ventilation) and thus expressed as EMGdi % max. In
comparison with controls, COPD patients exhibited a markedly increased neural drive (EMGdi % max) at rest (mean 28%
versus 9%). In COPD patients, EMGdi % max was inversely
correlated to FEV1 (fig. 4) and vital capacity. EMGdi % max
reached 51% in the most severe patient, indicating a major
increase in load/capacity ratio. Unfortunately, the relationships between these EMG data and dyspnoea, health-related
quality of life or relevant pulmonary function test parameters
(hyperinflation, airway resistance and exercise tolerance) were
not determined. Therefore, the clinical relevance of this
method remains to be assessed.
CLINICAL CONSEQUENCES OF COPD FROM A
PRIMARILY RESPIRATORY PERSPECTIVE
It is now widely acknowledged that COPD clinical manifestations are not restricted to the respiratory system: it is of utmost
importance to recognise that the impact of COPD on individuals
is the consequence of both respiratory and extra-respiratory
features of the disease, in order to offer the global and integrated
care that is required to improve the patients health status.
Extra-respiratory diseases associated (and possibly causally
linked with COPD) will be the topic of the following section of
this review. Here we will focus on the impact of exacerbations,
cough and sputum production and dyspnoea.
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UPDATE ON COPD
a)
A. BOURDIN ET AL.
b)
Electrode pair
Flow
Lmin-1
5
30
0
-30
c)
d)
Electrode pair
Flow
Lmin-1
5
30
0
-30
0
e)
15
Time s
f)
60
50
EMGdi % max
15
Time s
40
20
10
30
0
10
FIGURE 4.
20
30
40
50
FEV1 % pred
60
70
80
40
60
80
100
Vital capacity % pred
120
140
Representative diaphragm electromyogram (EMG) tracings at rest (a and b) and during maximum voluntary ventilation (c and d) in a healthy subject (a and c)
and in a severe chronic obstructive pulmonary disease patient (b and d). Relationship between diaphragm EMG (as a percentage of the maximum; EMGdi % max) and e)
forced expiratory volume in 1 s (FEV1; r250.4; p,0.001) or f) vital capacity (r250.61; p,0.001). Reproduced and modified from [68] with permission from the publisher.
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A. BOURDIN ET AL.
Exacerbations
The definition of exacerbations has been the topic of several
reviews, guidelines and consensus statements, which reflects
that it does not represent a trivial issue [6971]. This point is
illustrated by the finding that only half of diary-detected
exacerbations are reported to physicians [71]. One consequence
is that it may be difficult to compare data on exacerbations
from studies with various definitions of these events.
However, data on the long-term impact of COPD exacerbations provide quite convergent results.
Previous studies suggested that a subset of patients exhibit
exacerbations more frequently, which is not explained only by
the severity of airflow obstruction [71]: more recently, a study of
severe, early-onset COPD probands and their relatives found
that predictors of frequent exacerbations were chronic cough
and phlegm production, episodic wheezing, pneumonia, active
smoking, exertional dyspnoea and lower lung function [72]. A
familial aggregation of exacerbations was observed, suggesting
a genetic component of the frequent exacerbator phenotypes.
Obviously, the occurrence of an exacerbation is associated with
an increased risk of hospitalisation and death. However, it also
impairs patients health status quite dramatically, as demonstrated by BOURBEAU et al. [73] (fig. 5). In this study, patients
were instructed to report all increases in respiratory symptoms
that lasted o24 h. Despite these efforts towards early identification and care for exacerbations, these episodes were associated
with marked (up to a mean of 14 points) worsening in SGRQ
impact and activity domains. During the second week following
the onset of exacerbation, a clinically significant deterioration of
impact scores was still observed in 37% of patients. The change
in health status that accompanies exacerbations is largely
related to their impact on daily activity, which is itself the
consequence of airflow obstruction, dyspnoea and impaired
exercise tolerance (as illustrated by the 1.4-point increase in the
BODE (body mass index, FEV1 for airflow obstruction,
dyspnoea, and 6-min walk distance for exercise tolerance) index
that is observed during exacerbations).
UPDATE ON COPD
and 1 and 2 weeks later, as compared with baseline values. Data taken from [73].
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16
14
12
Units
10
8
6
4
2
0
Onset
FIGURE 5.
Week 1
Week 2
Questionnaire activity (h) and impact (&) domains scores at onset of exacerbations
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A. BOURDIN ET AL.
with a greater frequency of moderate-to-severe airflow obstruction and dyspnoea (Medical Research Council (MRC) grades 45)
in males, suggesting a sex effect influencing the impact of COPD
on health status. Another Spanish study in daily practice found
that the variable affecting the disease burden the most (as
assessed using the clinical COPD questionnaire) was dyspnoea,
followed by the degree of airflow obstruction [92]. Similar
findings were provided by several other studies, underlying the
major role of dyspnoea as a determinant of health status [93].
16
14
12
10
8
6
0
All
Moderate Severe
FIGURE 6.
All
Moderate Severe
Chronic cough and
sputum production
A. BOURDIN ET AL.
UPDATE ON COPD
a) 2.0
b)
c)
1.8
1.6
1.4
1.2
0
CB
FIGURE 7.
II
III
GOLD stage
IV
CB
2
34 510
BODE score
CB
2
3
MRC grade
Level of physical activity by Global Initiative for Obstructive Lung Disease (GOLD) stage, BODE (body mass index, FEV1 for airflow obstruction, dyspnoea,
and 6-min walk distance for exercise tolerance) score and dyspnoea Medical Research Council (MRC) grade in 163 patients with chronic obstructive pulmonary disease.
Physical activity level o1.70: active; 1.401.69: predominantly sedentary; ,1.40: very inactive. CB: chronic bronchitis. Reproduced and modified from [96] with permission
from the publisher.
COMORBIDITIES
COPD has been primarily considered as a respiratory disease
characterised by permanent and progressive airflow obstruction, but the importance of extrapulmonary manifestations has
not been acknowledged until recently [102, 103]. In recent years,
investigators have focused their attention on the findings that
many COPD patients suffer from other chronic illnesses. These
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UPDATE ON COPD
TABLE 1
A. BOURDIN ET AL.
Extrapulmonary disease
Possible consequences in
COPD patients
Cardiovascular disease
Increased mortality
Increased dyspnoea (chronic heart failure)
Reduced physical activity
Increased mortality
Malnutrition
Increased mortality
Low fat free (muscle) mass
Skeletal muscle weakness
Increased dyspnoea
Reduced exercise capacity
Anaemia
Increased dyspnoea
Possibly increased mortality
Osteoporosis
Fractures
Depression
Increased mortality
Diabetes
Sleepiness
Pulmonary hypertension
Hypoventilation
A. BOURDIN ET AL.
UPDATE ON COPD
STATEMENT OF INTEREST
None declared.
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