Review
Bronchodilator reversibility in chronic obstructive
Lancet Respir Med 2013;
1: 564–73
Published Online
June 18, 2013
http://dx.doi.org/10.1016/
S2213-2600(13)70086-9
School of Ageing and Chronic
Disease, University of
Liverpool, Liverpool, UK
(Prof P M A Calverley DSc); and
Aintree Chest Centre,
University Hospital Aintree,
Liverpool, UK (P M A Calverley,
P Albert MD, P P Walker MD)
Correspondence to:
Prof Peter M A Calverley, Clinical
Science Centre, University
Hospital Aintree, Longmoor
Lane, Liverpool L9 7AL, UK
pmacal@liverpool.ac.uk
564
pulmonary disease: use and limitations
Peter M A Calverley, Paul Albert, Paul P Walker
The change in forced expiratory volume in 1 s (FEV₁) after administration of a short-acting bronchodilator has been
widely used to identify patients with chronic obstructive pulmonary disease (COPD) who have a potentially different
disease course and response to treatment. Despite the apparent simplicity of the test, it is difficult to interpret or rely
on. Test performance is affected by the day of testing, the severity of baseline lung-function impairment, and the
number of drugs given to test. Recent data suggest that the response to bronchodilators is not enhanced in patients
with COPD and does not predict clinical outcomes. In this Review we will discuss the insight that studies of
bronchodilator reversibility have provided into the nature of the COPD, and how the abnormal physiology seen in
patients with this disorder can be interpreted.
Introduction FEV1 falls below the predicted normal value has been
Chronic obstructive pulmonary disease (COPD) is the used as a marker of disease severity, although recent
term used to describe a persistent and generally treatment guidance has emphasised the need to base
progressive illness that results from a respiratory decisions about management on clinical factors as well
bronchiolitis, beginning in the most peripheral airways,1 as spirometric impairment.7 Theoretically, spirometric
and that is often accompanied by alveolar loss data should be measured after an inhaled bronchodilator
(emphysema).2 These pathological changes delay lung is given. This approach has been applied in recent
emptying at rest and even more so during exercise3 and international studies of COPD prevalence8,9 and remains
are characterised by the presence of abnormal obstructive the recommended method to assess disease severity.7
spirometry, customarily defined as a reduction in the COPD differs from bronchial asthma, which is also
forced expiratory volume in 1 s (FEV1)/forced vital associated with obstructive spirometry, because patients
capacity (FVC) ratio to 0·7 or less. However, this criterion with COPD do not show substantial variability in lung
is inappropriate for use in elderly patients4 and has led function either spontaneously or in short-term response
some experts to advocate the use of an age-related lower to treatment. However, this has not prevented many
limit of normal for this ratio.5,6 The degree to which the clinicians and investigators10 from trying to identify
discrete phenotypes of patients with COPD who show a
greater than anticipated change in spirometry after
Key messages treatment with a short-acting bronchodilator drug.
• Small changes in FEV1 after a bronchodilator in individuals A positive response in the bronchodilator reversibility
with mild chronic obstructive pulmonary disease (COPD) test has been suggested to identify differences in the
can challenge the diagnosis of COPD clinical course and therapeutic response of patients with
• The absolute change in FEV1 post-bronchodilator varies COPD that have not been prospectively established.
with the day of testing, the number of bronchodilator Nobel prize-winning psychologist Daniel Kahneman
drugs used to test, and drug dose noted that it is easier to substitute the answer to an easy
• The absolute increase in FEV1 post-bronchodilator is question when a hard one is asked. 11 In this case, doctors
similar in individuals with moderate COPD and healthy have extrapolated their observation of an immediate
smokers change in lung function after administration of
• The absolute increase in FEV1 post-bronchodilator bronchodilators into an expectation that this will predict
decreases as baseline FEV1 decreases and so does the clinical outcome. We believe that there is now good
chance of being classified as reversible evidence that this is not the case. The topic of
• Although the average number of reversible patients in a bronchodilator reversibility in patients with COPD has
COPD population is stable over time, individuals change been reviewed previously,12,13 but recently published data
their reversibility status on repeat testing allow this commonly used mode of testing to be set into
• Reversibility status does not identify patients with a a wider context. We clarify what can and cannot be
different clinical course or response to treatment nor does ascertained with confidence from this widely used but
it add to the baseline FEV1 in the prediction of patients surprisingly confusing test.
with more rapid disease progression
• In patients with clinical and spirometric evidence of COPD, How to define bronchodilator reversibility
reversibility testing adds little to management. However, The term bronchodilator reversibility implies the complete
in patients who have atypical clinical features, reversibility or near complete correction of an obstructive spirometric
testing is still warranted abnormality. Such changes can occur in patients with
bronchial asthma but are not always seen. Normalisation
www.thelancet.com/respiratory Vol 1 September 2013
 Review

of spirometry after administration of a bronchodilator is reported the response to inhaled salbutamol in

not seen in patients with COPD unless the baseline FEV1 representative population samples from 14 centres
is close to the predicted normal value before the drug is worldwide. The results of the study suggest that an
given. In this case, a small absolute increase in FEV1 can increase in FEV1 of more than 300 mL is very unlikely to
mean that the post-bronchodilator value is no longer arise by chance, and that this equates to a 12% increase from
below the predicted normal value or associated with an baseline in people with normal lung function, as suggested
FEV1/FVC ratio less than 0·7. This effect has been noted in earlier by expert groups.18 A high degree of variation in
population studies that identified many people with mild FVC measurements was noted between centres, which
airflow obstruction.14 These data show how small changes increases the uncertainty of the significance of a positive
in absolute volume can affect a binary categorical variable test based on this measurement. Similar absolute changes
such as reversibility in patients with an FEV1/FVC ratio in FEV1 were seen in the healthy comparator data reported
close to the threshold value. Such a complete normalisation by the Evaluation of COPD Longitudinally to Identify
of lung function is not (by definition) recorded in more Predictive Surrogate Endpoints (ECLIPSE) investigators.19
advanced disease because a patient showing this response However, in the ECLIPSE study, the change in FEV1
on spirometric testing would be regarded as asthmatic. recorded in the healthy smoker group was similar to that
However, many patients with COPD show some reported in the patients with COPD who were the main
improvement in FEV1, FVC, or both, after a bronchodilator, focus of the ECLIPSE programme (figure 1).
and this response to treatment can reach the thresholds The definition of bronchodilator reversibility has three
believed to represent reversibility. Moreover, almost all components. The first is the assessment of the short-term
studies of COPD have focused on FEV1 as the defining (<60 min after the test) change in lung function, usually
variable rather than in conjunction with changes in other FEV1, after inhalation of a short-acting bronchodilator
variables such as FVC or the FEV1/FVC ratio. drug. The short-acting β agonist salbutamol or the
In the past, it has been difficult to determine the size of a short-acting antimuscarinic agent ipratropium, or both,
change in lung function after a bronchodilator in healthy are the most common test drugs. Second, the change in
individuals. Initial estimates were derived from patients FEV1 needs to be greater than what would be expected by
with less severe COPD or modest sized Caucasian chance; the usual way to express this is as a change
population samples.15,16 This problem has been overcome greater than 12% of the baseline value. However, this
by the Burden of Obstructive Lung Disease study,17 which calculation implies that the change in FEV1 after a

35
Patient with COPD (%)

30
25
20
15
10
5
0

35
30
Smoker controls (%)
Patient group

25
20
15
10
5
0

35
Non-smoker controls (%)

30
25
20
15
10
5
0
–0·65 –0·55 –0·45 –0·35 –0·25 –0·15 –0·05 0·05 0·15 0·25 0·35 0·45 0·55 0·65 0·75 0·85 0·95 1·05 1·15 1·25 1·35
Change in FEV1 (L) post-bronchodilator

Figure 1: Distribution of absolute changes in FEV1 after salbutamol in ECLIPSE participants

Frequency distribution of change in FEV1 after 400 μg inhaled salbutamol in 1831 patients with chronic obstructive pulmonary disease (top), 285 healthy smokers
(mid), and 228 non smokers (lower). Data from Albert and colleagues.19 FEV₁=forced expiratory volume in 1 s. FVC=forced vital capacity.

www.thelancet.com/respiratory Vol 1 September 2013 565

 Review
bronchodilator will vary with lung size, something for
which no real supporting data exist. Hence, if the
baseline value is high, a large absolute change in FEV1 is
needed for a positive response, but small changes close
to the between-test variability in the measurement can be
enough to suggest reversibility when the pre-test FEV1 is
low. To overcome this requirement, a third pragmatic
component was added and after the Intermittent Positive
Pressure Breathing (IPPB) study,20 namely a requirement
of at least a 12% baseline increase plus an additional
200 mL absolute change.
Concerns about the overdiagnosis of reversibility on the
basis of a percentage change from baseline in COPD led
to a proposal by European investigators that reversibility
is present when the FEV1 changes by 9% of the predicted
value for that patient. This approach was initially
supported by the European Respiratory Society21 because
the use of a simple percentage increase removes the
dependence of the result on the pre-test value of FEV1.
However, partly because of the relative complexity of the
definition, recommendations have reverted to the original
definition described above.22
The absence of bronchodilator reversibility has been an
important feature in COPD treatment trials in Europe23,24
but not North America.25,26 In North America, patients
have previously been selected for trials because they
showed an acute response to treatment.27 Patients with
reversible COPD were more likely to report a response to
oral corticosteroids than were patients without reversible
COPD;28 however, this form of response testing was not a
specific marker of disease progression on longer term
follow up.29 Reversibility status has been linked to specific
chromosomes in genetic studies of COPD,30 and findings
from some studies show that patients with reversible
COPD have an accelerated loss of lung function
compared with those who do not have reversible
COPD.31-33 However, to understand these associations and
develop clinically useful recommendations based on the
results of reversibility testing in individual patients has
proven to be much harder than first believed.
Drawbacks of reversibility tests in COPD
Large clinical studies have examined the usefulness and
performance characteristics of bronchodilator reversibility
testing across a wide range of COPD severities defined by
spirometry.14,17,19,20,31,33–38 The table describes the
characteristics of several of the most important studies.
These studies have identified issues in many key areas,
which are discussed in turn.
Drug, drug dose, and timing of test
The most widely used drug is salbutamol in a dose of
200–400 μg with a 15 min delay before re-testing. This
approach is pragmatic and uses the shortest time between
tests consistent with the known pharmacological actions
of this drug. However, larger doses of β agonist will
produce small additional increments in FEV1 and will
566
thereby change the number of patients with a reversible
response.39 Similar considerations apply to short-acting
antimuscarinics that have slightly slower onsets of action
and therefore necessitate a greater delay before repeating
spirometry testing.40 Combination of drugs from each drug
class further increases the responder rate (figure 2).34,41
Waiting longer before re-testing FEV1 after the test dose
will probably result in the detection of a greater change in
FEV1 in some patients and hence increase the number of
patients regarded as having a reversible response. How
often this situation arises and what effect it might have
with different drugs and different background disease
severity has not been systematically explored. Differences
in test protocol contribute to differences in the reported
prevalence of reversible disease, which varies between
5% in the Lung Health Study population33 to more than
50% in the UPLIFT trial.42 Another important factor to
consider in the interpretation of clinical trial data is how
well patients adhere to omitting their normal
bronchodilator therapy before spirometric testing. If the
test drug is given on top of an active bronchodilator, the
FEV1 change is likely to be less than the change seen in a
patient who has successfully omitted their usual
bronchodilator treatment. The importance of this effect
has not been explored. However, patients in the ECLIPSE
study who were asked to omit their usual tiotropium for
24 h did not show any differences in response from those
not taking this drug.19
Reproducibility of reversibility status
To be clinically useful, the attribution of a characteristic
to an individual (the phenotype) needs to be stable from
day to day, and in this regard bronchodilator reversibility
fails. Although the percentage of patients classified as
responders in any population is stable when re-tested
over 2–12 months, figure 3 shows how the individual
response varies between occasions.34 Changes in the
definition of a positive response, whether by using the
percentage predicted method described previously or
methods requiring a larger change in absolute volume
(eg, a 400 mL change in FEV1), do not eradicate this
tendency to individual variation. However, the definition
used will determine the percentage of the population
regarded as responsive.19 Therefore, treatment guidelines
and management strategies no longer advocate
bronchodilator testing as part of routine assessment of
patients with COPD.32,43
Prediction of bronchodilator-responsiveness
The most consistent predictor of reversibility status is the
pre-test FEV1. Generally, the lower the FEV1, the lower the
chance a patient has of having a positive reversibility test,
irrespective of whether one or two drugs are used in
testing.19,34,35 Data from the ECLIPSE study19 showed that
although having a lower pre-test FEV1 increased the
chance of exceeding the 12% change threshold, few of
the patients with the worst pre-test spirometry had a
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 Review

Number of Method of COPD severity Reversibility criteria Clinical predictors of reversibility Clinical outcomes associated with
patients reversibility reversibility
ECLIPSE19,32 1831 15 min after Mean pre- ATS/ERS: FEV₁ increase ≥12% GOLD stage: GOLD II mean 0·16 mL Decreased FEV₁: additional 17 mL (SD 4)
400 μg bronchodilator plus 200 mL (SD 0·17) FEV₁ increase; GOLD III mean annual decrease in FEV₁ in reversible patients
salbutamol FEV₁=1·25 L (SD 0·49), 0·1 mL (SD 0·13) FEV₁ increase; GOLD IV but mean baseline FEV₁ 220 mL (SD 22)
45% (SD 15) predicted; 0·05 mL (SD 0·08) FEV₁ increase higher
GOLD II=848 (46%) Gender mean for men 0·13 mL (SD 0·16)
GOLD III=750 (41%) FEV₁ increase vs women 0·1 mL (SD 0·12)
GOLD IV=233 (13%) increase; odds ratio (OR) 1·79 (95% CI
1·37–2·31)
Extent of emphysema on CT: association
r=0·09; p<0·001; no association with age,
smoking status, or cigarette pack-years
LUNG 4194 10 min after Mean pre-bronchodilator Three criteria used: FEV₁ absolute Methacholine reversibility: p<0·001 on all Decreased FEV₁, no association when
HEALTH33 200 μg FEV₁=2·64 L (SD 0·6), change in m, change expressed as three criteria; age: p<0·001 all three baseline data excluded from assessment
isoprotenerol 75% (SD 9) predicted; a percentage criteria; pack-years: p<0·001 all three
mean post- of the pre-bronchodilator criteria; gender: no association; no
bronchodilator value, and change association with quit status (sustained
FEV₁=2·75 L (SD 0·6), expressed as a percentage quitter, intermittent quitter, and
79% (SD 9) predicted of predicted normal FEV₁ continued smoker)
ISOLDE34 660 30 min after Mean pre- Three criteria used: FEV₁ absolute No association between absolute change No association between absolute change in
400 μg bronchodilator change in mL, change expressed in FEV₁ (mL) vs smoking status, atopy, or FEV₁ (mL) vs FEV₁ decrease, worsening of
salbutamol, FEV₁=1·28 L (SD 0·46), as a percentage of the gender health status measured by SGRQ, or
then 30 min 46% (SD 15) predicted pre-bronchodilator value, and exacerbation rate
after 80 μg change expressed as a percentage
ipratropium of predicted normal FEV₁
UPLIFT35,37 5756 60 min after Mean Three criteria used: criteria a FEV1 Criteria a: age 64 years (SD 8) reversible Criteria a: health status measured by SGRQ
80 μg pre-bronchodilator increase ≥12% plus 200 mL (52% group vs 65 years (SD 8) irreversible 44 (SD 17) reversible patients vs 48 (SD 17)
ipratropium FEV₁=1·1 L, 39% (SD 12) reversible by this criteria), criteria (p<0·001); gender 79% reversible irreversible (p<0·001); exacerbation rate
then 30 min predicted; mean b FEV₁ increase by more than patients male vs 69% irreversible patients 1 year or longer 67·9% reversible patients vs
after 200 μg post-bronchodilator 15% over baseline (66% male (p<0·001); pack-years 50 years (SD 68·5% irreversible; all-cause mortality 10·8%
salbutamol FEV₁=48% (SD 13) reversible by this criteria), criteria 29) reversible patients vs 47 years (SD 27) reversible group vs 16·2% irreversible
predicted; GOLD II=47%, c ≥10% absolute increase in % irreversible (p<0·001) Criteria b: health status measured by SGRQ
GOLD III=45%, predicted FEV₁ (39% reversible Criteria b: BMI 25·9 (SD 5) reversible no association; exacerbation rate 1 year or
GOLD IV=9% by this criteria) patients vs 26·3 (SD 5·2) irreversible longer 67·6% reversible patients vs 68·5%
(p<0·001); present smoking status 29% irreversible; all-cause mortality 12·5%
reversible patients smoked vs 34% reversible group vs 15·1% irreversible
irreversible (p<0·001) Criteria c: health status measured by SGRQ
Criteria c: no significant association 44 (SD 17) reversible patients vs 47 (SD 17)
including duration of COPD irreversible (p<0·001); exacerbation rate
1 year or longer 67·5% reversible patients vs
69·3% irreversible; all-cause mortality 9·4%
reversible group vs 15·9% irreversible
PLATINO38 5571 15 min after Mean FEV₁ 2·49 L, ATS/ERS: FEV₁ increase ≥12% 15% patients taking inhaled therapy ..
200 μg 378 of 5571 (7%) plus 200 mL (defined as having taken a bronchodilator
salbutamol patients reversible or inhaled corticosteroid within the
previous 1 year) reversible vs 7% patients
not taking therapy (p<0·001)
NETT36 544 15 min after Mean pre- ATS/ERS: FEV₁ increase ≥12% Patients who met ATS/ERS reversibility ..
116 μg bronchodilator plus 200 mL (121 of 544 [22%] criteria on one or more occasions
salbutamol FEV₁=24% (SD 7) patients met criteria on at least (reversible) vs those who were never
predicted one occasion); FEV₁ ≥400 mL reversible: no association with age; TLC
(10 of 544 [2%] patients met (post-bronchodilator; 126% predicted in
criteria on at least one occasion) reversible patients vs 130% irreversible,
p<0·005); gender (11% female reversible vs
29% male reversible) OR 2·37 (1·37–4·12);
p=0·002; DLco 32% (SD 10) reversible
patients vs 28 (10)% irreversible (p<0·001);
no association with pack-years or extent of
emphysema on CT
IPPB20 985 250 μg Pre-bronchodilator FEV₁ increase >12% .. Patients who showed >12% improvement in
isoproterenol FEV₁=1·03 L (36·1% FEV₁ (reversible): FEV₁ decrease: mean 52 mL
predicted), mean FEV₁ annual decrease in FEV₁ in irreversible patients
improvement with vs 27 mL annual decrease in reversible; no
bronchodilator=14·5% association with mortality or hospitalisation

Results from and response criteria used in selected studies of bronchodilator reversibility in patients with COPD, including the association between bronchodilator reversibility status and subsequent clinical
outcomes. The missing data in the right columns is because these studies did not relate reversibility testing to clinical outcomes. COPD=chronic obstructive pulmonary disease. FEV1=forced expiratory volume in
1 s. ATS/ERS=American Thoracic Society/European Respiratory Society. SGRQ=St George’s Respiratory Questionnaire. TLC=total lung capacity. DLco=diffusion coefficient for carbon monoxide.

Table: Selected studies reporting bronchodilator reversibility testing in chronic obstructive pulmonary disease

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 Review
1·6 FEV1 pre-bronchodilator
FEV1 post salbutamol or ipratropium
FEV1 post both
1·5
1·4
FEV1 (L)
1·3
1·2
1·1
Visit 0 Visit 1 Visit 2
(salbutamol) (ipratropium) (both)
Figure 2: Absolute change in FEV1 after salbutamol and ipratropium
Mean (SE) FEV1 before and after 400 μg salbutamol, 80 μg ipratropium, or both on
three occasions at monthly intervals in 660 stable patients with chronic
obstructive pulmonary disease. Reproduced with permission from Calverley and
colleagues,34 by permission of the BMJ Group. FEV₁=forced expiratory volume in 1 s.
200 mL increase in FEV₁ post salbutamol, the absolute
change in FEV₁ ranging from 160 ml in GOLD grade 2
patients to 50 mL in GOLD 4. Findings from other
studies have shown a similar GOLD grade-related
reduction in reversibility.17,35
Many other variables may be useful for the identification
of patients likely to respond to bronchodilator drugs. The
presence of sputum eosinophilia might identify patients
with COPD who are more likely to respond to oral
corticosteroids,44 although whether such a response
predicts longer term clinical outcomes has been
challenged.29 No consensus exists on the prevalence of
sputum or blood eosinophilia or both in clinically
diagnosed patients with COPD. Furthermore, extensive
data are not available in patients with COPD on the day
to day variation of measures of eosinophilia. Neither
gender, present smoking status, nor atopy consistently
distinguish responsive from unresponsive patients.34 The
National Emphysema Treatment Trial (NETT)36
investigators found that the presence of CT-defined
emphysema reduced the chance of a patient being
classed as reversible. However, this study recruited
patients with a much lower baseline FEV1 and a high
likelihood of emphysema. The relation between
reduction in CT-defined lung density and reversibility
status was much weaker in the ECLIPSE study of patients
in secondary care clinics.19 The table shows a selection of
studies that examined predictors of bronchodilator
responsiveness. These data clearly suggest that apart
from pre-bronchodilator FEV1, no consistent or reliable
predictor of response, and certainly no predictor that is
useful in day-to-day clinical practice exists.
Clinical implications of reversibility testing
In view of the poor day to day reproducibility of
reversibility status, the fact that reversibility status does
not predict clinical progress in patients with COPD is
not surprising.19,34 The table shows the main outcomes of
reversibility testing in stable COPD considered together
568
with the studies in which they were reported. Two of
these merit special attention. First, to see if patients who
never showed a reversible response to bronchodilators
differed from those who sometimes had a positive
reversibility test, the ECLIPSE investigators compared
1362 patients who never met the standard criterion of
reversibility in 4 tests over 1 year with 227 who did show
a response to bronchodilators on one or more occasions.
With this strict and rather clinically impractical
definition, no association existed between reversibility
and either baseline health status, change in health status
over time, or mortality. However, patients who never
responded were more likely to exacerbate in the 2 years
of follow up after testing. This finding was attributable
to the confounding effects of pre-bronchodilator lung
function because the patients with decreased pre-test
FEV1 were also less likely to reverse and had more
exacerbations than patients not showing reversibility.
The relation between reversibility status and exacer-
bations was lost when allowance was made for baseline
FEV₁. Data from earlier studies suggested that
reversibility status predicted the rate of decrease in FEV1,
but this was only true for decrease in pre-bronchodilator
FEV1.31,45 The ECLIPSE data suggest that the association
between decrease in post-bronchodilator FEV1 over time
and reversibility was more robust, but was again
confounded by patients with less severe lung function
impairment showing both a more rapid loss of lung
function and an increased chance of being classed as
reversible.32,46 The poor clinical stability of the reversibility
test in patients in GOLD 2 (unpublished data) makes it
more likely that decline in lung function is mainly
driven by pre-bronchodilator FEV1 rather than
reversibility status.
Physiological mechanisms associated with
bronchodilator responsiveness
Whatever their mode of action, inhaled bronchodilators
produce rapid relaxation of airway smooth muscle and
improve the expiratory flow rate. In COPD, in which
increased peripheral airways resistance and a variable loss
of lung elastic recoil exists, expiratory flow limitation (a
disorder in which the expiratory flow rate cannot be
increased or falls despite increasing effort) often occurs
during tidal breathing.47,48 Flow limitation develops earlier
during a forced expiratory manoeuvre in patients with
COPD than in healthy individuals who only have flow
limitation at low lung volumes. In patients with COPD,
inhaled bronchodilators decrease both total and respiratory
system resistance, as shown during tidal breathing with
the effort-independent forced oscillation method.49,50
However, bronchodilators have much less effect on
expiratory than inspiratory resistance, and hence FEV1,
when flow limitation is present and so seem to be less
effective in these patients.50 The most important
physiological effect of bronchodilators is to decrease
end-expiratory lung volume usually without any effect on
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Visit 1: 76% not reversible
Visit 2: 77% not reversible 1167
Visit 3: 77% not reversible 1019 148
Visit 4: 79% not reversible 923 96 109
Figure 3: Repeated reversibility testing over one year in stable COPD
Reproducibility of reversibility classification (American Thoracic Society/European Respiratory Society criteria) in 1831 patients with chronic obstructive pulmonary
disease on four occasions over 1 year. The percentage not reversible at each visit is shown on the left. Reproduced from Albert and colleagues,19 by permission of the
BMJ Group.
tidal expiratory flow limitation.39,50,51 This fall in lung
volume allows patients to exercise for longer before
dynamic hyperinflation reaches the critical point where
inspiratory reserve volume is compromised and dyspnoea
becomes severe.52,53
These more subtle physiological effects help to explain
why changes in FEV1 after a bronchodilator that fall
within the between-test reproducibility of the
measurement can translate into the clinically relevant
improvements in exercise capacity, health status,
exacerbation frequency, and even in symptom intensity
during exacerbations.42,54–56 In fact, changes in
end-expiratory lung volume after administration of a
short-acting bronchodilator track changes in residual
volume and the change in FVC, irrespective of GOLD
grade. This contrasts with FEV1 change which, as noted
above, decreases in magnitude as the percent predicted
pre-test value falls.19 Thus, change in FEV1 is an indirect
marker of the physiologically important effect of the
bronchodilator, and as disease becomes more severe,
the change in end-expiratory lung volume and FEV1
become less closely related. Moreover, this differential
effect on FEV1 and FVC can produce a seemingly
paradoxical decrease of FEV1/FVC ratio as shown in
figure 4. This discrepancy results in some patients
having an isolated FVC response,57,58 which has been
associated with emphysema59 as was seen in the NETT
data.36 In these circumstances, the improvement in lung
volume outweighs the deterioration in forced lung
emptying in terms of clinical benefit. In view of the
complexity of these processes, the fact that acute
changes in one indirect measure of lung function
post-bronchodilator do not predict clinical benefit is
not surprising.
The absolute change in FEV1 after a bronchodilator
might decrease slightly with baseline FEV₁, but no
evidence exists for an asthmatic subset of patients with
COPD defined by an unexpectedly large change in lung
function. Figure 1 shows the frequency distribution of
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Review
1831 Not reversible
Reversible
1394 437
227 238 199
147 80 162 76 76 123
39 111 36 37 43 123 39 43 33 48 28 51 72
FEV₁ change after treatment with salbutamol in the
patients with COPD in the ECLIPSE study.19 Similar
results were also reported from the UPLIFT and LHS1
studies.33,35 ECLIPSE included comparator groups of
slightly younger healthy smokers and non-smokers. As
noted above, no significant difference was found in the
mean FEV1 change between the smokers and GOLD
grade 2 patients with COPD (160 mL vs 140 mL), but the
healthy individuals in ECLIPSE and other trials showed
a smaller change in mean lung function in keeping with
the BOLD data.17 There are several possible explanations
for this finding. Airway smooth muscle tone is
cholinergically mediated60 and airway inflammation,
which is increased in both smokers and in patients with
COPD,61,62 might enhance this neural mechanism and
reduce resting airway calibre. However, many other
processes, including airway wall oedema and vascular
congestion, can result from an airway inflammation. In
the ECLIPSE study,19 the pre-test FEV1 in the smoking
group was lower than in the healthy non-smoker
individuals, which supports this idea. Alternatively, the
presence of panacinar emphysema might influence
airway responsiveness as suggested in recent
pathological studies.63 The mechanism, whatever it
might be, seems to become less important as COPD
worsens, probably because of the onset of fibrotic
changes in the peripheral airways.2
Methodological challenges with spirometry data
The measurement of spirometry involves patient
cooperation, is effort dependent, and has a known
within-day reproducibility in COPD.64 The 200 mL
threshold incorporated as part of the reversibility
definition is designed to take into account the variation
in spirometric measurement and to ensure that any
change reported has not happened because of chance
variation in the test itself.15,65 Nonetheless, some positive
tests can arise by chance, especially when the baseline
FEV1 value is low. This situation will contribute to the
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between day instability of the reversibility classification
in the scientific literature. A more important factor
identified in both the ISOLDE34 and ECLIPSE19,32
populations is spontaneous variation in the pre-test
FEV1 between test days. When spirometry was
measured repeatedly, an average FEV1 value could be
identified for each patient. If the FEV1 was low relative
to its average value, a positive reversibility test was
more likely to be reported. Conversely, there is less
room for improvement after treatment in patients with
a high baseline FEV1, and this was associated with a
decreased chance of being classed as reversible. These
data suggest that the between day variation in responder
status probably results from normal physiological
changes in pre-test airway calibre on a background of a
low FEV1 rather than clinically important changes in
airway responsiveness.
A Post-bronchodilator FEV1 change by GOLD status
0·4
p<0·001
p<0·001
0·3
FEV1 change (L)
Clinical and research lessons for the future
Several decades of intensive study of reversibility testing
in COPD has highlighted some important truths about
COPD and our general approach to interpretation of
spirometry data in clinical settings. First, the apparent
simplicity of classification of a patient as either reversible
or not on the basis of one test has proven to be an illusion.
Without an understanding of the between and within test
variability in FEV1, this apparently straightforward test of
lung function can easily be misinterpreted. The failure to
identify a consistently responsive subgroup of patients
with COPD, despite repeated attempts in large
populations over several decades, shows that this
approach is unlikely to be of benefit in routine clinical
practice, whatever the threshold chosen for significant
FEV1 change or even if other volume-based measurements
are substituted. In fact, the real importance of these
findings is that a clinical diagnosis of COPD supported by
a measurement of lung function is a robust way to
identify this disorder. In an era of protocolised medicine,
it is important to stress that in all studies of reversibility,
patients were selected for inclusion because their
physicians believed them to have COPD on the basis of

p<0·001
clinical examination and spirometry testing. Patients who
0·2
have atypical features in their history, either in terms of
age of onset, family history, or in the timing of associated
0·1
symptoms, might exhibit the kind of dramatic responses
to treatment that are so clinically memorable. Just
0
because reversibility assessment adds little to routine
B Post-bronchodilator FVC change by GOLD status clinical practice, does not mean that the assessment is
0·8 p=0·983 uninformative in specific situations. However, in general,
p=0·865 the between test variability in classification of reversibility
0·6 status makes this reversibility test a poor way to classify
p=0·877
FVC change (L)

patients or select their bronchodilator treatment.

0·4 Likewise, the value of post-bronchodilator spirometry
in determining the population-based prevalence of
0·2 COPD is considerable when the prevalence of GOLD
grade 1 disease (FEV1/FVC<0·7 with an FEV1 more than
0
80% predicted) is high because the number of patients
identified as having COPD varied significantly between
C Post-bronchodilator FEV1/FVC change by GOLD status pre-bronchodilator and post-bronchodilator spirometry
p<0·001 assessments14 (ie, the use of pre-bronchodilator data only
p<0·001
5·0
will exclude many patients with apparent COPD). Most
p<0·001
data have been obtained through the study of patients
FEV1/FVC change (%)

who already have a diagnosis of COPD. Reversibility

testing might be more helpful in truly treatment-naive
0 individuals, although it seems likely that the same issues
of between-test variability in lung function will still apply.
Alternative tests that show the effect of spontaneous
–5·0 variations in airway calibre in disorders of tidal breathing
might prove more helpful. The measurement of
Gold II Gold III Gold IV
respiratory system resistance with forced oscillation
Figure 4: Changes in spirometry after salbutamol in patients with COPD methods has already identified substantial spontaneous
grouped by GOLD grade variability in patients with asthma66,67 and recent advances
Changes (SD) in FEV₁ (top), FVC (middle), and FEV1/FVC (bottom) after
treatment with salbutamol by GOLD grade at the first visit reported in figure 3.
in the technique mean that it might become a useful test
Data from Albert and colleagues.19 FEV₁=forced expiratory volume in 1 s. in a research setting. In this context, this method could
FVC=forced vital capacity. be applied to patients with COPD to confirm or refute

570 www.thelancet.com/respiratory Vol 1 September 2013


the existence of patients who have more asthmatic
disease features; neither reversibility testing nor
provocation challenge to induce bronchoconstriction can
conclusively solve this issue.68 However, the available
data do not point to coexisting asthma as an explanation
for the response to treatment in COPD.
A further result of these studies of reversibility in
COPD is the light they throw on COPD pathology.
Changes in inflammatory cells, especially mast cells,
have been reported in airway smooth muscle in patients
with less advanced COPD and in patients with asthma.63,69
However, the response to anti-inflammatory treatment in
these diseases is very different. Airway smooth muscle
thickness is markedly increased in patients with asthma
but much less so in patients with COPD;70 this difference
provides a physiologically plausible explanation for the
difference in bronchodilator response seen in these two
disorders. The similarity in absolute FEV1 improvement
in response to bronchodilator in patients with moderate
COPD and in healthy smokers of similar gender
composition (and hence lung size) is striking, as is the
similarity in spontaneous variation of the pre-test FEV1.19
These data suggest that airway smooth muscle behaves
normally in patients with COPD without the lability that
characterises patients with asthma. Further, the main
abnormality in COPD is persistent airway narrowing,
whether in the peripheral airways or as a result of
emphysema.
If, as seems to be the case, acute variation in lung
function is indicative of the abolition of preserved
airway smooth muscle tone, then a ceiling probably
exists for the effects of bronchodilator treatment in
patients with COPD, however treatment is
administered. Optimisation of bronchodilator treat-
ment with one or more drugs of different classes is an
area of great interest, but this approach has restricted
potential. Likewise, because of the ceiling effect, the
addition of anti-inflammatory treatment can improve
lung function independent of and in addition to any
improvement due to bronchodilators; however, reliance
on changes in the FEV1 over a few months of treatment
to establish the efficacy of anti-inflammatory treatment
Search strategy and selection criteria
This Review combines the research of the authors over many
years with a search of Medline and Embase for articles
published in English from Jan 1, 2003, to Oct 30, 2012, using
the search terms “bronchodilator reversibility”, “chronic
obstructive pulmonary disease” OR “chronic bronchitis” OR
“emphysema”, and “reversibility testing”. Relevant
references published before the search period were also
included and references from relevant articles were also
searched. Review articles and book chapters are cited to
provide readers with more details and more references than
this Review can report.
www.thelancet.com/respiratory Vol 1 September 2013
Review
might be misplaced. Future treatment needs to address
the effect of loss of airways early in the natural history
of COPD when lung function declines most rapidly71
rather than focusing on the few gains in function that
can be achieved by manipulation of airway smooth
muscle tone.
A better understanding of bronchodilator respon-
siveness in COPD will also lead to an improvement in
the ability to interpret the clinical trial data that form
the evidence base for treatment frameworks. In view of
the failure of reversibility testing to identify patients
with a different clinical course, the exclusion of
reversible patients from clinical trials in which clinical
outcomes such as exacerbation rates, health status, or
mortality are the main outcomes is not sensible.
Experience with bronchodilator testing has shown that
the absolute increase in FEV1 after a bronchodilator is
greater when the baseline FEV1 is higher. Similar effects
have been reported in drug trials, even when
anti-inflammatory drugs are being tested.72,73
Aggregation of studies with small but significant
differences in baseline function and degree of
reversibility can be misleading and emphasises the
need to look at endpoints other than just FEV1 in the
assessment of treatment response.
Conclusion
Bronchodilator reversibility in patients with COPD is a
normally distributed continuous variable and the
application of specific criteria defining significant and
insignificant reversibility is arbitrary. Careful study has
revealed that bronchodilator reversibility varies between
tests, often as a function of baseline FEV1—ie, for an
individual on a specific testing day, a decreased baseline
FEV1 is associated with an increased chance of significant
reversibility. This finding is independent of the chosen
definition of significant reversibility and associations
with clinical outcomes have not been consistently shown;
therefore, the presence of a positive bronchodilator
response does not identify a useful phenotype.
Reversibility testing should not be used to determine
which patients with COPD should be prescribed either
short-acting or long-acting bronchodilators, and the
presence or absence of significant bronchodilator
reversibility should not be used to select patients with
COPD for participation in clinical trials.
Contributors
The authors of this Review conceived, conducted, and wrote this paper and
take responsibility for its content. This Review was done independently of
any pharmaceutical input and without the aid of a medical writer. This
Review was not directly funded nor was ethical approval sought for this
work. PMAC conceived the Review and was responsible for its overall
content. PA assisted with writing, editing, and created the figures. PW
assisted with writing, editing, and created the table.
Conflicts of interest
PMAC has in the past received funding from several pharmaceutical
companies for studies of patients with COPD. PA and PW have not
received any funding. All authors declare that they have no conflicts of
interest in relation to this Review.
571
 Review
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