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Abstract
Background: It is unclear whether various bronchodilator reversibility (BDR) criteria affect the prognosis of chronic
obstructive pulmonary disease (COPD). The aim of this study is to evaluate the impact of positive BDR defined
according to various BDR criteria on the risk of severe acute exacerbation (AE) in COPD patients.
Methods: Patients from four prospective COPD cohorts in South Korea who underwent follow-up for at least 1 year
were enrolled in this study. The assessed BDR criteria included the Global Initiative for Chronic Obstructive Lung
Disease (GOLD), American Thoracic Society (ATS), American College of Chest Physicians, (ACCP), major criteria of the
Spanish definition of asthma-COPD overlap syndrome (ACOS), criteria compatible with ACOS in the Global Initiative
for Asthma (GINA), and European Respiratory Society (ERS). The rate of patients with severe AE who required
hospitalization within 1 year due to BDR results according to each set of criteria was analyzed using logistic
regression models.
Results: Among a total of 854 patients, the BDR-positive cases varied according to the criteria used. There was a 3.5%
positive BDR rate according to GINA and a 29.9% rate according to the ATS criteria. Positive BDR according to the
GOLD criteria was significantly associated with a decreased risk of severe AE (adjusted odds ratio (aOR) = 0.38; 95%
Confidence interval (CI) = 0.150.93). This result remained statistically significant even in a sensitivity analysis that
included only participants with a smoking history of at least 10 pack-years and in the analysis for the propensity
score-matched participants.
Conclusions: Among different criteria for positive BDR, the use of the GOLD ones was significantly associated with a
decreased risk of severe AE in COPD patients. Increase use of ICS/LABA may have affected this relationship.
Keywords: Bronchodilator reversibility, COPD, Severe acute exacerbation
* Correspondence: kauri670@empal.com
3
Division of Pulmonary and Critical Care Medicine, Department of Internal
Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu,
Seoul 03080, Republic of Korea
Full list of author information is available at the end of the article
The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Kim et al. Respiratory Research (2017) 18:107 Page 2 of 9
beta agonists (ICS/LABA) and long-acting muscarinic models. Crude odds ratios (cORs), adjusted ORs (aORs),
antagonist (LAMA), were calculated as the total days of 95% confidence intervals (CIs), and the Akaike Information
prescription days of each drug category divided by the Criterion (AIC) were used to evaluate the models that in-
total days of follow-up. All measurements for lung func- cluded each set of BDR criteria as a principal variable. We
tion were collected prospectively. carried out a sensitivity analysis for patients with a smoking
This study investigated the incidence of severe AE history 10 pack-years (PY). The effects of treatment drugs
within 1 year of enrollment. All participants were asked (ICS/LABA and LAMA) and FEV1% on the relationship
to answer a questionnaire regarding the experience of between each of the BDR criteria and severe AE were also
AE of COPD since the previous visit at every follow-up explored. A propensity score for a positive BDR was also
visit. The definition of severe AE was any event that re- calculated by using various covariates and an analysis was
quired an emergency room visit or hospital admission conducted in the propensity score-matched participants. A
due to acute aggravation of COPD symptoms. p-value < 0.05 was regarded as statistically significant. SPSS
We compared those who experienced at least one severe 20.0 (IBM Corp., Armonk, NY, USA) and STATA 14.1 (Sta-
AE event within 1 year to those without a severe AE event taCorp, TX, USA) were used for statistical analysis.
by using either a Mann-Whitney test or a Students t-test
for continuous variables and a chi-squared test for categor- Results
ical variables. Variables that showed a statistically significant Among the patients in the four cohorts, patients with
difference between groups were included as adjustment co- more than 1-year of follow-up data were selected. As
variates to investigate the effects of each set of BDR criteria shown in the flow chart for enrollment (Fig. 1), a total of
on the incidence of severe AE in multivariable logistic 854 patients were included in this study.
Fig. 1 Flow chart showing the enrollment process for participants. SNUH Seoul National University Hospital Cohorts, CODA COPD in Dusty Area,
KOCOSS Korean COPD Subgroup Study, KOLD Korean Obstructive Lung Disease Cohort
Kim et al. Respiratory Research (2017) 18:107 Page 4 of 9
The baseline characteristics of the patients are shown in experienced severe AE at least 1 year prior to cohort enroll-
Table 1. The mean CAT score was 15.4 (SD 7.9), and the ment. The initial mean value of FEV1 was 1.56 L (SD 0.55).
mean SGRQ and mMRC scores were 33.1 (SD 17.3) and Among the 854 patients, BDR positivity differed
1.61 (SD 1.01), respectively. About 10.9% of patients according to the criteria used for the response. The posi-
tive BDR rate ranged from 0.9 to 61.6% across the
Table 1 Baseline characteristics of the participants cohorts and according to BDR criteria. Among the cri-
Characteristics All participants (n = 854) teria, the criterion of BDR > 8% FEV1 yielded a relatively
Age (mean, SD) 68.3 (7.6) high positive rate (33.661.6%) in every cohort com-
Male (N, %) 776 (90.9) pared to the other positive BDR criteria. The major
Cohorts registration (N, %) criteria for ACOS in the Spanish guidelines (15% and
SNUH 101 (11.8) 400 ml in FEV1) showed the lowest rate of BDR positiv-
CODA 110 (12.9) ity among the criteria.
KOCOSS 325 (38.1) During the 1-year follow-up period, the MPR of ICS/
KOLD 318 (37.2) LABA was 0.52 (SD 0.44), and the MPR of LAMA was
BMI (mean, SD) 23.0 (3.4)
0.54 (SD 0.43). About 10% of patients experienced severe
Weight (mean, SD) 61.7 (10.7)
AE during the 1-year follow-up period, ranging from 5.5
Height (mean, SD) 163.6 (7.4)
to 12.0% in all cohorts. The highest rate of severe AE oc-
Smoking habits
curred in patients from the KOCOSS cohort. (Table 2)
Several factors including body mass index (BMI), comor-
None smoker 81/851 (9.5)
bidity of diabetes mellitus (DM), symptom scores, and the
Ex-smoker 538/851 (63.2)
experience of severe AE before cohort enrollment were re-
Current smoker 232/851 (27.3)
vealed to be significant in our analysis. Among the BDR
Pack-year (mean, SD) 43.3 (28.7)
criteria, GOLD (BDR >12% and 200 ml FEV1) and ATS
Comorbidities (N, %)
(BDR 12% and 200 ml FEV1 or FVC) showed a difference
Diabetes mellitus 111/825 (13.5)
in positive rates between the severe AE(+) group and the
Heart disease 67/841 (8.0)
severe AE(-) group (Additional file 1: Table S1). Adjusted
Cancer 24/519 (4.6) ORs were calculated by adjusting for BMI, symptom score
Symptom scores of mMRC (2 vs. < 2), comorbidity of DM, initial FEV1%
CAT (mean, SD) 15.4 (7.9) (50 vs. <50), ICS/LABA MPR, and severe AE before co-
CAT 10 (N, %) 455/614 (74.1) hort enrollment. Use of the GOLD and ATS criteria was
SGRQ (mean, SD) 33.1 (17.3) associated with a decreased risk of severe AE (aOR = 0.37,
SGRQ 25 (N, %) 258/418 (61.7) 95% CI = 0.150.91 for GOLD; aOR = 0.51; 95% CI = 0.28
mMRC (mean, SD) 1.61 (1.01) 0.96 for ATS). All seven BDR criteria increased the good-
mMRC 2 (N, %) 403/834 (48.3) ness of fit estimated by the AIC in each model, and the
Severe acute exacerbation within 1-year 93 (10.9) amounts of improvement were similar among the seven
before enrollment (N, %)
criteria. In the sensitivity analysis for patients with a smok-
Pulmonary function test, mean(SD) ing history 10 PY, BDR positivity from the GOLD criteria
Initial FVC post (L)/(%) 3.18 (0.82)/87.6 (18.6) still predicted a significantly decreased risk of severe AE in
Initial FEV1 post (L)/(%) 1.56 (0.55)/60.9 (19.7) COPD patients (aOR = 0.36, 95% CI = 0.140.95) (Table 3).
Initial FEV1 50% (N, %) 586 (68.6) We compared the rate of severe AE between BDR posi-
Initial FEV1/FVC ratio post, mean(SD) 49.2 (11.7) tive and BDR negative patients during 1 year of follow up
BDR criteria, N (%) using different BDR criteria. Patients who showed BDR
BDR >12% and 200 ml (FEV1) (GOLD) 167 (19.6) positivity experienced less severe AE than patients who
BDR 12% and 200 ml (FEV1 or FVC) (ATS) 255 (29.9) showed BDR negativity when evaluated using the GOLD
BDR 15% (FEV1) (ACCP) 187 (21.9) or ATS criteria (3.6% vs. 10.9%, p = 0.004 for GOLD, 5.9%
BDR >8% (FEV1) 383 (44.9) vs. 11.0%, p = 0.02 for ATS) (Fig. 2).
BDR 15% and 400 ml (FEV1) 30 (3.5) When we calculated the risk of severe AE according to
(Spanish ACOS) various BDR criteria stratified by ICS/LABA and LAMA
BDR >12% and 400 ml (FEV1) (ACOS GINA) 30 (3.5) MPR, there were significant interactions between ICS/
Post FEV1% - pre FEV1 % 10% (ERS) 124 (14.5) LABA MPR and the GOLD or ERS criteria (post
SNUH Seoul National University Hospital Airway Registry, CODA COPD in Dusty Area FEV1%-pre FEV1% 10%) (p = 0.044 and p = 0.018, re-
Registry, KOCOSS Korean COPD Subgroup Study, KOLD Korean Obstructive Lung
Disease Cohort, N number, SD standard deviation, NR not recorded, CAT COPD spectively). If patients were treated with ICS/LABA for
assessment test, SGRQ St. Georges respiratory questionnaire, mMRC modified more than 6 months (MPR over 0.5), the rate of severe
medical research council dyspnea scale, FEV1 forced expiratory volume in one
second, FVC forced vital capacity, BDR bronchodilator reversibility AE was reduced in cases of positive BDR according to
Kim et al. Respiratory Research (2017) 18:107 Page 5 of 9
Fig. 2 Proportion of patients with severe acute exacerbation according to BDR positivity. *with a statistical significance of p-value <0.05
BDR bronchodilator reversibility, AE acute exacerbation, FEV1 forced expiratory volume in one second, FVC forced vital capacity
standard definition has not been established [1, 1317], smokers and smokers with a history of less than 10 PY.
reports suggest that a 1215% increase in FEV1 com- Other criteria did not show a significant ability to pre-
pared to the baseline exceeds normal within-subject dict severe AE. However, all aORs for positive BDR and
variability and response to placebo inhalation [19, 20]. severe AE were below 1.0 (range of aOR = 0.370.94).
When baseline FEV1 is low, a high improvement in the The mechanism of how BDR positivity in COPD
percentage can be possible with only a small improve- patients leads to a decreased risk of severe AE has not
ment in the absolute volume. Because of this, use of an been fully established, and there are several possible ex-
absolute volume increase of 200 ml has emerged as an planations for this. First, it could be the case that many
alternative to using a percentage increase. asthma patients were misdiagnosed as positive BDR
The usefulness of BDR positivity as a prognostic factor COPD patients. However, the sensitivity analysis ex-
has been controversial [8, 11, 21]. BDR positivity favors cluded patients with a smoking history of less than 10
a good treatment outcome in some studies, but demon- PY showed similar results, which suggests that asthma
strates poor disease related outcomes in others. For contamination alone is not an adequate explanation.
example, Marin et al. reported a result similar to ours in Second, a positive BDR per se could predict a future
that a positive BDR was significantly associated with a positive response to drugs. Interestingly, in our study
prolonged time to first hospitalization. However, theirs there was a significant interaction between ICS/LABA
was a retrospective study [21]. Our results were some- treatment and the effect of BDR on severe AE. A posi-
what different from PLATINO study, in which a positive tive BDR according to the GOLD criteria predicted a
BDR according to the ATS criteria and wheezing in the decrease in the risk of severe AE only in patients
last 12 months showed a higher risk of hospitalization who had an ICS/LABA MPR >0.5 (aOR for ICS/
[11]. Self-reported wheezing might be a more severe LABA MPR >0.5 = 0.18; 95% CI = 0.040.78; aOR for
symptom or a reflection of exacerbation, which could ICS/LABA MPR 0.5 = 0.95, 95% CI = 0.293.10; p for
contribute to the worse outcome in these patients. This interaction = 0.044), although statistical significance was
inconsistency might be due to the different study designs not reached in a sensitivity analysis that included only
and ethnicity. subjects with 10 PY. Our results suggest that a positive
Our present study using prospective cohorts suggests BDR could predict a response to ICS/LABA treatment. In
that BDR positivity according to the GOLD criteria can support of this, it has been reported that increased revers-
predict a decreased risk of severe AE risk in univariate, ibility of short-acting beta-2 agonists is associated with an
multivariate, sensitivity and propensity score-matched increase in eosinophils and in exhaled nitric oxide (NO)
analyses. Although the ATS criteria showed a similar re- [22]. This reversibility could be a phenotype of a good re-
sult in all participants, statistical significance was not sponder to inhaled corticosteroids [2327]. We found
reached in a sensitivity analysis that excluded non- there to be no effect modification by LAMA treatment for
Kim et al. Respiratory Research (2017) 18:107 Page 7 of 9
Fig. 3 Risk of severe acute exacerbation according to BDR criteria including subgroup analysis according to ICS/LABA use. aOR adjusted odds
ratio, CI confidence interval BDR bronchodilator reversibility, MPR medication possession ratio, ICS/LABA inhaled corticosteroid/long-acting
beta-agonist, LAMA long-acting muscarinic antagonist, FEV1 forced expiratory volume in one second, FVC forced vital capacity *with a statistical
significance of p-value <0.05
the effect of BDR on the incidence of severe AE in our This study also has several limitations. First, we did
study (all p for interactions >0.05). not investigate long-term outcomes, including mortality,
This study has several key strengths. First, it is the first owing to the limitations of the follow-up periods in
prospective study to compare clinical outcomes in these cohorts. Second, we did not have access to a large
COPD patients using various BDR positivity criteria. number of patients who had experienced severe AE.
Second, this study was performed in a non-Western re- However, the number of patients with severe AE was
gion and therefore represents the characteristics of sufficient to establish a multiple logistic regression
COPD patients from non-Western countries. The results model. Third, as a pooled analysis of four different co-
of this study could be helpful in future clinical trials or horts, bias might have been present that rendered our
longitudinal studies. Third, a relatively large number of sample unrepresentative of the total South Korean popu-
COPD patients from four different COPD cohorts were lation. When we examined the patient demographic data
included in this analysis. The results of this study could of the four cohorts in this study, however, we found that
therefore provide clinically significant information in a they seemed to have similar baseline FEV1 and symptom
real-world setting. Last, we applied propensity score- scores. This allowed us to use a combined sample to
matched analysis to strengthen the results. represent COPD patients in South Korea. Fourth, small
Kim et al. Respiratory Research (2017) 18:107 Page 8 of 9
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