Background: The development of irreversible airway obstruction (IRAO) in asthma is related to lung/airway inflammatory and structural changes whose characteristics are likely influenced by exposure to tobacco smoke. Objective: To investigate the interplay between airway and lung structural changes, airway inflammation, and smoking exposure in asthmatics with IRAO. Methods: We studied asthmatics with IRAO who were further classified according to their smoking history, those with ≥20 pack-years of tobacco exposure (asthmatics with smoking-related IRAO [AwS-IRAO]) and those with <5 pack-years of tobacco exposure (asthmatics with nonsmoking-related IRAO [AwNS-IRAO]). In addition to recording baseline clinical and lung function features, all patients had a chest computed tomography (CT) from which airway wall thickness was measured and quantitative and qualitative assessment of emphysema was performed. The airway inflammatory profile was documented from differential inflammatory cell counts on induced sputum. Results: Ninety patients were recruited (57 AwS-IRAO and 33 AwNS-IRAO). There were no statistically significant differences in the extent of emphysema and gas trapping between groups on quantitative chest CT analysis, although Pi10, a marker of airway wall thickness, was significantly higher in AwS-IRAO (p = 0.0242). Visual analysis showed a higher prevalence of emphysema (p = 0.0001) and higher emphysema score (p < 0.0001) in AwS-IRAO compared to AwNS-IRAO and distribution of emphysema was different between groups. Correlations between radiological features and lung function were stronger in AwS-IRAO. In a subgroup analysis, we found a correlation between airway neutrophilia and emphysematous features in AwS-IRAO and between eosinophilia and both airway wall thickness and emphysematous changes in AwNS-IRAO. Conclusions: Although bronchial structural changes were relatively similar in smoking and nonsmoking patients with asthma and IRAO, emphysematous changes were more predominant in smokers. However, neutrophils in AwS-IRAO and eosinophils in AwNS-IRAO were associated with lung and airway structural changes.

1.
Lougheed
MD
,
Lemiere
C
,
Ducharme
FM
,
Licskai
C
,
Dell
SD
,
Rowe
BH
, et al
Canadian thoracic society 2012 guideline update: diagnosis and management of asthma in preschoolers, children and adults
.
Can Respir J
.
2012
;
19
(
2
):
127
64
.
2.
Boulet
LP
,
Turcotte
H
,
Turcot
O
,
Chakir
J
.
Airway inflammation in asthma with incomplete reversibility of airflow obstruction
.
Respir Med
.
2003
;
97
(
6
):
739
44
. .
3.
Ulrik
CS
,
Backer
V
.
Nonreversible airflow obstruction in life-long nonsmokers with moderate to severe asthma
.
Eur Respir J
.
1999
;
14
(
4
):
892
6
. .
4.
ten Brinke
A
,
Zwinderman
AH
,
Sterk
PJ
,
Rabe
KF
,
Bel
EH
.
Factors associated with persistent airflow limitation in severe asthma
.
Am J Respir Crit Care Med
.
2001
;
164
(
5
):
744
8
. .
5.
Ten Brinke
A
.
Risk factors associated with irreversible airflow limitation in asthma
.
Curr Opin Allergy Clin Immunol
.
2008
;
8
(
1
):
63
9
. .
6.
Alshabanat
A
,
Zafari
Z
,
Albanyan
O
,
Dairi
M
,
FitzGerald
JM
.
Asthma and COPD overlap syndrome (ACOS): a systematic review and meta analysis
.
PLoS One
.
2015
;
10
(
9
):
e0136065
. .
7.
Global initiative for asthma and Global initiative for
.
chronic obstructive lung disease. Diagnosis of diseases of chronic airflow limitation: Asthma, COPD, and Asthma-COPD overlap syndrome (ACOS) 2015
.
[updated 2015. Available from:
www.ginasthma.org].
8.
Cazzola
M
,
Rogliani
P
.
Do we really need asthma-chronic obstructive pulmonary disease overlap syndrome?
J Allergy Clin Immunol
.
2016
;
138
(
4
):
977
83
. .
9.
Zeki
AA
,
Jarjour
NN
.
The asthma-chronic obstructive pulmonary disease overlap syndrome: a new take on an old concept
.
Ann Am Thorac Soc
.
2016
;
13
(
9
):
1440
2
. .
10.
Rodrigo
GJ
,
Neffen
H
,
Plaza
V
.
Asthma-chronic obstructive pulmonary disease overlap syndrome: a controversial concept
.
Curr Opin Allergy Clin Immunol
.
2017
;
17
(
1
):
36
41
. .
11.
Global Obstructive Lung Disease (GOLD)
.
Global strategy for the diagnosis, management, and prevention of chornic obstructive pulmonary disease (2020 report)
.
2020
.
Available from:
https://goldcopd.org/wp-content/uploads/2019/12/GOLD-2020-FINAL-ver1.2-03Dec19_WMV.pdf.
12.
Thomson
NC
,
Chaudhuri
R
,
Heaney
LG
,
Bucknall
C
,
Niven
RM
,
Brightling
CE
, et al
Clinical outcomes and inflammatory biomarkers in current smokers and exsmokers with severe asthma
.
J Allergy Clin Immunol
.
2013
;
131
(
4
):
1008
16
. .
13.
Boulet
LP
,
FitzGerald
JM
,
McIvor
RA
,
Zimmerman
S
,
Chapman
KR
.
Influence of current or former smoking on asthma management and control
.
Can Respir J
.
2008
;
15
(
5
):
275
9
. .
14.
Eisner
MD
,
Iribarren
C
.
The influence of cigarette smoking on adult asthma outcomes
.
Nicotine Tob Res
.
2007
;
9
(
1
):
53
6
. .
15.
Kauppi
P
,
Kupiainen
H
,
Lindqvist
A
,
Haahtela
T
,
Laitinen
T
.
Long-term smoking increases the need for acute care among asthma patients: a case control study
.
BMC Pulm Med
.
2014
;
14
:
119
. .
16.
Lange
P
,
Parner
J
,
Vestbo
J
,
Schnohr
P
,
Jensen
G
.
A 15-year follow-up study of ventilatory function in adults with asthma
.
N Engl J Med
.
1998
;
339
(
17
):
1194
200
. .
17.
Boulet
LP
,
Lemière
C
,
Archambault
F
,
Carrier
G
,
Descary
MC
,
Deschesnes
F
.
Smoking and asthma: clinical and radiologic features, lung function, and airway inflammation
.
Chest
.
2006
;
129
(
3
):
661
8
. .
18.
Shimoda
T
,
Obase
Y
,
Kishikawa
R
,
Iwanaga
T
.
Influence of cigarette smoking on airway inflammation and inhaled corticosteroid treatment in patients with asthma
.
Allergy Asthma Proc
.
2016
;
37
(
4
):
50
8
. .
19.
St-Laurent
J
,
Bergeron
C
,
Pagé
N
,
Couture
C
,
Laviolette
M
,
Boulet
LP
.
Influence of smoking on airway inflammation and remodelling in asthma
.
Clin Exp Allergy
.
2008
;
38
(
10
):
1582
9
. .
20.
Boulet
LP
,
Boulay
ME
,
Dérival
JL
,
Milot
J
,
Lepage
J
,
Bilodeau
L
, et al
Asthma-COPD overlap phenotypes and smoking: comparative features of asthma in smoking or non-smoking patients with an incomplete reversibility of airway obstruction
.
COPD J
.
2018
;
14
:
6
.
21.
Boulet
LP
,
Boulay
ME
,
Milot
J
,
Lepage
J
,
Bilodeau
L
,
Maltais
F
.
Longitudinal comparison of outcomes in patients with smoking-related asthma-COPD overlap and in non-smoking asthmatics with incomplete reversibility of airway obstruction
.
Int J Chron Obstruct Pulmon Dis
.
2019
;
14
:
493
8
. .
22.
Wang
Y
,
Xu
J
,
Meng
Y
,
Adcock
IM
,
Yao
X
.
Role of inflammatory cells in airway remodeling in COPD
.
Int J Chron Obstruct Pulmon Dis
.
2018
;
13
:
3341
8
. .
23.
Konstantellou
E
,
Papaioannou
AI
,
Loukides
S
,
Patentalakis
G
,
Papaporfyriou
A
,
Hillas
G
, et al
Persistent airflow obstruction in patients with asthma: characteristics of a distinct clinical phenotype
.
Respir Med
.
2015
;
109
(
11
):
1404
9
. .
24.
Thomson
NC
,
Chaudhuri
R
,
Spears
M
,
Messow
CM
,
MacNee
W
,
Connell
M
, et al
Poor symptom control is associated with reduced CT scan segmental airway lumen area in smokers with asthma
.
Chest
.
2015
;
147
(
3
):
735
44
. .
25.
Kitaguchi
Y
,
Yasuo
M
,
Hanaoka
M
.
Comparison of pulmonary function in patients with COPD, asthma-COPD overlap syndrome, and asthma with airflow limitation
.
Int J Chron Obstruct Pulmon Dis
.
2016
;
11
:
991
7
. .
26.
Gao
Y
,
Zhai
X
,
Li
K
,
Zhang
H
,
Wang
Y
,
Lu
Y
, et al
Asthma COPD overlap syndrome on CT densitometry: a distinct phenotype from COPD
.
COPD
.
2016
;
13
(
4
):
471
6
. .
27.
Mauad
T
,
Silva
LF
,
Santos
MA
,
Grinberg
L
,
Bernardi
FD
,
Martins
MA
, et al
Abnormal alveolar attachments with decreased elastic fiber content in distal lung in fatal asthma
.
Am J Respir Crit Care Med
.
2004
;
170
(
8
):
857
62
. .
28.
Gelb
AF
,
Yamamoto
A
,
Mauad
T
,
Kollin
J
,
Schein
MJ
,
Nadel
JA
.
Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction
.
J Allergy Clin Immunol
.
2014
;
133
(
1
):
263
5 e13
. .
29.
Kondoh
Y
,
Taniguchi
H
,
Yokoyama
S
,
Taki
F
,
Takagi
K
,
Satake
T
.
Emphysematous change in chronic asthma in relation to cigarette smoking. Assessment by computed tomography
.
Chest
.
1990
;
97
(
4
):
845
9
. .
30.
Juniper
EF
,
Bousquet
J
,
Abetz
L
,
Bateman
ED
.
Identifying “well-controlled” and “not well-controlled” asthma using the asthma control questionnaire
.
Respir Med
.
2006
;
100
(
4
):
616
21
. .
31.
Reddel
HK
,
Taylor
DR
,
Bateman
ED
,
Boulet
LP
,
Boushey
HA
,
Busse
WW
, et al
An official American thoracic society/European respiratory society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice
.
Am J Respir Crit Care Med
.
2009
;
180
(
1
):
59
99
. .
32.
Standardization of spirometry, 1994 update. American thoracic society
.
Am J Respir Crit Care Med
.
1995
;
152
(
3
):
1107
36
.
33.
Quanjer
PH
,
Stanojevic
S
,
Cole
TJ
,
Baur
X
,
Hall
GL
,
Culver
BH
, et al
Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations
.
Eur Respir J
.
2012
;
40
(
6
):
1324
43
. .
34.
Quanjer
PH
,
Brazzale
DJ
,
Boros
PW
,
Pretto
JJ
.
Implications of adopting the global lungs initiative 2012 all-age reference equations for spirometry
.
Eur Respir J
.
2013
;
42
(
4
):
1046
54
. .
35.
Wanger
J
,
Clausen
JL
,
Coates
A
,
Pedersen
OF
,
Brusasco
V
,
Burgos
F
, et al
Standardisation of the measurement of lung volumes
.
Eur Respir J
.
2005
;
26
(
3
):
511
22
. .
36.
Macintyre
N
,
Crapo
RO
,
Viegi
G
,
Johnson
DC
,
van der Grinten
CP
,
Brusasco
V
, et al
Standardisation of the single-breath determination of carbon monoxide uptake in the lung
.
Eur Respir J
.
2005
;
26
(
4
):
720
35
. .
37.
Pin
I
,
Gibson
PG
,
Kolendowicz
R
,
Girgis-Gabardo
A
,
Denburg
JA
,
Hargreave
FE
, et al
Use of induced sputum cell counts to investigate airway inflammation in asthma
.
Thorax
.
1992
;
47
(
1
):
25
9
. .
38.
Pizzichini
E
,
Pizzichini
MM
,
Efthimiadis
A
,
Evans
S
,
Morris
MM
,
Squillace
D
, et al
Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements
.
Am J Respir Crit Care Med
.
1996
;
154
(
2 Pt 1
):
308
17
. .
39.
Belda
J
,
Leigh
R
,
Parameswaran
K
,
O’Byrne
PM
,
Sears
MR
,
Hargreave
FE
.
Induced sputum cell counts in healthy adults
.
Am J Respir Crit Care Med
.
2000
;
161
(
2 Pt 1
):
475
8
. .
40.
Gibson
PG
.
Inflammatory phenotypes in adult asthma: clinical applications
.
Clin Respir J
.
2009
;
3
(
4
):
198
206
. .
41.
Schroeder
JD
,
McKenzie
AS
,
Zach
JA
,
Wilson
CG
,
Curran-Everett
D
,
Stinson
DS
, et al
Relationships between airflow obstruction and quantitative CT measurements of emphysema, air trapping, and airways in subjects with and without chronic obstructive pulmonary disease
.
AJR Am J Roentgenol
.
2013
;
201
(
3
):
W460
70
. .
42.
Grydeland
TB
,
Dirksen
A
,
Coxson
HO
,
Pillai
SG
,
Sharma
S
,
Eide
GE
, et al
Quantitative computed tomography: emphysema and airway wall thickness by sex, age and smoking
.
Eur Respir J
.
2009
;
34
(
4
):
858
65
. .
43.
Tan
WC
,
Hague
CJ
,
Leipsic
J
,
Bourbeau
J
,
Zheng
L
,
Li
PZ
, et al
Findings on thoracic computed tomography scans and respiratory outcomes in persons with and without chronic obstructive pulmonary disease: a population-based cohort study
.
PLoS One
.
2016
;
11
(
11
):
e0166745
. .
44.
Hansell
DM
,
Bankier
AA
,
MacMahon
H
,
McLoud
TC
,
Müller
NL
,
Remy
J
.
Fleischner society: glossary of terms for thoracic imaging
.
Radiology
.
2008
;
246
(
3
):
697
722
. .
45.
Hartley
RA
,
Barker
BL
,
Newby
C
,
Pakkal
M
,
Baldi
S
,
Kajekar
R
, et al
Relationship between lung function and quantitative computed tomographic parameters of airway remodeling, air trapping, and emphysema in patients with asthma and chronic obstructive pulmonary disease: a single-center study
.
J Allergy Clin Immunol
.
2016
;
137
(
5
):
1413
e12
. .
46.
Cosentino
J
,
Zhao
H
,
Hardin
M
,
Hersh
CP
,
Crapo
J
,
Kim
V
, et al
Analysis of asthma-chronic obstructive pulmonary disease overlap syndrome defined on the basis of bronchodilator response and degree of emphysema
.
Ann Am Thorac Soc
.
2016
;
13
(
9
):
1483
9
. .
47.
Qu
Y
,
Cao
Y
,
Liao
M
,
Lu
Z
.
Sagittal-lung CT measurements in the evaluation of asthma-COPD overlap syndrome: a distinctive phenotype from COPD alone
.
Radiol Med
.
2017
;
122
(
7
):
487
. .
48.
Suzuki
T
,
Tada
Y
,
Kawata
N
,
Matsuura
Y
,
Ikari
J
,
Kasahara
Y
, et al
Clinical, physiological, and radiological features of asthma-chronic obstructive pulmonary disease overlap syndrome
.
Int J Chron Obstruct Pulmon Dis
.
2015
;
10
:
947
54
. .
49.
Meijer
M
,
Rijkers
GT
,
van Overveld
FJ
.
Neutrophils and emerging targets for treatment in chronic obstructive pulmonary disease
.
Expert Rev Clin Immunol
.
2013
;
9
(
11
):
1055
68
. .
50.
Polverino
E
,
Rosales-Mayor
E
,
Dale
GE
,
Dembowsky
K
,
Torres
A
.
The role of neutrophil elastase inhibitors in lung diseases
.
Chest
.
2017
;
152
(
2
):
249
62
. .
51.
Gelb
AF
,
Yamamoto
A
,
Verbeken
EK
,
Schein
MJ
,
Moridzadeh
R
,
Tran
D
, et al
Further studies of unsuspected emphysema in nonsmoking patients with asthma with persistent expiratory airflow obstruction
.
Chest
.
2018
;
153
(
3
):
618
29
. .
52.
Doyle
AD
,
Mukherjee
M
,
LeSuer
WE
,
Bittner
TB
,
Pasha
SM
,
Frere
JJ
, et al
Eosinophil-derived IL-13 promotes emphysema
.
Eur Respir J
.
2019
;
53
(
5
):
1801291
.
53.
Boulet
LP
.
Irreversible airway obstruction in asthma
.
Curr Allergy Asthma Rep
.
2009
;
9
(
2
):
168
73
. .
54.
Boulet
LP
.
Airway remodeling in asthma: update on mechanisms and therapeutic approaches
.
Curr Opin Pulm Med
.
2018
;
24
(
1
):
56
62
. .
55.
Kirby
M
,
Tan
WC
,
Hague
CJ
,
Leipsic
JA
,
Bourbeau
J
,
Hogg
JC
, et al
Computed tomography visual emphysema scoring and quantitative measurements provide independent and complementary information in COPD
.
Am J Respir Crit Care Med
.
2017
:
A6477
.
56.
Gietema
HA
,
Müller
NL
,
Fauerbach
PV
,
Sharma
S
,
Edwards
LD
,
Camp
PG
, et al
Quantifying the extent of emphysema: factors associated with radiologists’ estimations and quantitative indices of emphysema severity using the ECLIPSE cohort
.
Acad Radiol
.
2011
;
18
(
6
):
661
71
. .
57.
Sorino
C
,
D’Amato
M
,
Steinhilber
G
,
Patella
V
,
Corsico
AG
.
Spirometric criteria to diagnose airway obstruction in the elderly: fixed ratio vs lower limit of normal
.
Minerva Med
.
2014
;
105
(
6 Suppl 3
):
15
21
.
58.
Swanney
MP
,
Ruppel
G
,
Enright
PL
,
Pedersen
OF
,
Crapo
RO
,
Miller
MR
, et al
Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction
.
Thorax
.
2008
;
63
(
12
):
1046
51
. .
59.
Xie
M
,
Wang
W
,
Dou
S
,
Cui
L
,
Xiao
W
.
Quantitative computed tomography measurements of emphysema for diagnosing asthma-chronic obstructive pulmonary disease overlap syndrome
.
Int J Chron Obstruct Pulmon Dis
.
2016
;
11
:
953
61
. .
60.
Saba
M
,
Dan
E
,
Bittoun
R
,
Saini
B
.
Asthma and smoking: healthcare needs and preferences of adults with asthma who smoke
.
J Asthma
.
2014
;
51
(
9
):
934
42
. .
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.