[

Commentary

Unraveling the Pathophysiology of the Asthma-COPD

Overlap Syndrome
Unsuspected Mild Centrilobular Emphysema Is Responsible
for Loss of Lung Elastic Recoil in Never Smokers With
Asthma With Persistent Expiratory Airflow Limitation
Arthur F. Gelb, MD, FCCP; Alfred Yamamoto, MD; Eric K. Verbeken, MD; and Jay A. Nadel, MD

Investigators believe most patients with asthma have reversible airow obstruction with
treatment, despite airway remodeling and hyperresponsiveness. There are smokers with
chronic expiratory airow obstruction despite treatment who have features of both asthma
and COPD. Some investigators refer to this conundrum as the asthma-COPD overlap
syndrome (ACOS). Furthermore, a subset of treated nonsmokers with moderate to severe
asthma have persistent expiratory airow limitation, despite partial reversibility. This residuum has been assumed to be due to large and especially small airway remodeling. Alternatively, we and others have described reversible loss of lung elastic recoil in acute and
persistent loss in patients with moderate to severe chronic asthma who never smoked and its
adverse eect on maximal expiratory airow. The mechanism(s) responsible for loss of lung
elastic recoil and persistent expiratory airow limitation in nonsmokers with chronic asthma
consistent with ACOS remain unknown in the absence of structure-function studies. Recently
we reported a new pathophysiologic observation in 10 treated never smokers with asthma
with persistent expiratory airow obstruction, despite partial reversibility: All 10 patients with
asthma had a signicant decrease in lung elastic recoil, and unsuspected, microscopic mild
centrilobular emphysema was noted in all three autopsies obtained although it was not easily
identied on lung CT scan. These sentinel pathophysiologic observations need to be conrmed to further unravel the epiphenomenon of ACOS. The proinammatory and proteolytic
mechanism(s) leading to lung tissue breakdown need to be further investigated.
CHEST 2015; 148(2):313-320
ABBREVIATIONS:

ACOS 5 asthma-COPD overlap syndrome; HU 5 Hounsfield units; TLC 5 total lung

capacity

Manuscript received October 7, 2014; revision accepted January 5,

2015; originally published Online First May 7, 2015.
AFFILIATIONS: From the Pulmonary Division, Department of Medicine
(Dr Gelb) and the Department of Pathology (Dr Yamamoto), Lakewood
Regional Medical Center, Lakewood, CA; the Geffen School of Medicine at UCLA Medical Center (Dr Gelb), Los Angeles, CA; the Department of Pathology (Dr Verbeken), Katholieke Univeritair Ziekenhuis
Gasthuisberg, Leuven, Belgium; and the Departments of Medicine
(Dr Nadel), Physiology (Dr Nadel), and Radiology (Dr Nadel), University
of California, San Francisco Medical Center, San Francisco, CA.

CORRESPONDENCE TO: Arthur F. Gelb, MD FCCP, 3650 E South St,

Suite 308, Lakewood, CA 90712; e-mail: afgelb@msn.com
2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of
this article is prohibited without written permission from the American
College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.14-2483

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313

There are some former or current smoking patients with

chronic expiratory airflow obstruction despite therapeutic intervention who have features of both asthma and
COPD.1-5 This conundrum has been labeled the asthmaCOPD overlap syndrome (ACOS).5-9 In 2014, a document
endorsed by both GINA (Global Initiative for Asthma)
and GOLD (Global Initiative for Chronic Obstructive
Lung Disease) provided in-depth analyses, with diagnostic
and therapeutic recommendations for ACOS.10 The
clinical course of these patients is often compounded
by frequent exacerbations, especially in patients with
asthma who continue to smoke. Furthermore, investigators have also identified never smoked asthma phenotypes or subgroups with shared characteristics. This has
allowed stratification of patients with moderate to severe
asthma using input from multiple sources: clinical data,
BAL, large airways pathology, blood inflammatory biomarkers, genetic markers, lung function, demographics,
lung CT scan, and medication response.11-14 A recent
study demonstrated the potential therapeutic limitation
using cluster analysis and variable response in Cluster 5,
which is best aligned with ACOS.14 And, genetic studies
have suggested less than a firm overlap between asthma
and COPD.8,9,15 However, these asthma cluster studies
have not specifically addressed ACOS and the pathophysiologic mechanism(s) responsible for persistent
expiratory airflow limitation.
In patients with asthma who are nonsmokers, we16 and
several other investigators17-24 have previously reported
reversible loss of lung elastic recoil and hyperinflation
at total lung capacity during acute attacks of asthma that
were either spontaneous16-20 or induced by exercise21,22
or by antigen challenge.23,24 Furthermore, loss of lung
elastic recoil has been reported in chronic asthma with
only partially reversible airway obstruction despite
treatment17,18,20,25-28 and also in mild asthma.29 The sentinel study by Gold et al16 in 1967 reported the reversible
loss of lung elastic recoil in acute asthma. And, the sentinel study by Woolcock and Read17 in 1968 demonstrated the unexpected chronic loss of lung elastic recoil
in patients with stable asthma with expiratory airflow
limitation and partially reversible, nearly parallel left
shift in the pressure-volume curve with exacerbation.
This unexpected loss of lung elastic recoil contributes
greatly to exaggerate airflow limitation due to intrinsic
peripheral airway bronchoconstriction.30 These nonsmokers with asthma with loss of lung elastic recoil
and persistent limitation of maximal expiratory airflow
have normal diffusing capacity corrected for alveolar
volume. They have normal or only mild parenchymal

314 Commentary

attenuation of lung density using voxel quantification

on high-resolution thin-section (1 mm) lung CT scan at
full inspiration,25-27 with trivial Thurlbeck emphysema
scores 15.31,32 However, the limited resolution of lung
FOR EDITORIAL COMMENT SEE PAGE 297

CT scan may not be capable of discriminating between

mild emphysema and hyperinflation.33-35 Because wellperformed structure-function studies of the lungs in
asthma are rarely published, the pathophysiologic
mechanism(s) responsible for the loss of lung elastic
recoil in acute16-24 and chronic asthma17,18,20,25-29 remain
an enigma. Here, we review our pathologic and physiologic data36 in never smokers with asthma with
persistent expiratory airflow limitation consistent with
asthma guidelines,37 which we hope will begin to
unravel the paradigm of ACOS.5-10

Pathophysiologic Correlative Study

Study Design and Selection of Patients With
Asthma

We have studied many adult nonsmokers with asthma

followed in a tertiary referral asthma clinic for moderate to severe cases37 with persistent maximal expiratory airflow limitation despite treatment and partial
reversibilty.25-27,36 All patients with asthma were clinically stable at the time of lung function studies and had
tapered off oral corticosteroid for 6 weeks. Most of
the patients with asthma studied had nearly lifelong
history of asthma and had never smoked. None had
chronic bronchitis or history of exposure to potential
agents that might cause lung injury, including exposure
to secondhand smoke.
In our sentinel pilot pathophysiologic study initiated
nearly 10 years ago, only two of 10 patients with asthma
had recurrent chronic rhinosinusitis.36 All had normal
serum values for a1-antitrypsin. Two of the 10 patients
with asthma had experienced acute exacerbations in the
past that required hospitalization including endotracheal intubation and short-term mechanical ventilation.
Within the previous 2 years of study, all patients with
asthma satisfied the spirometric criteria for at least
partial reversibility, with an increase in FEV1 . 200 mL
and 12% following 270 mg aerosolized albuterol sulfate
via spacer chamber when not using any long-acting
and short-acting b2-agonist and muscarinic antagonist
metered dose inhalers for 24 and 6 h, respectively. Results
in the 10 patients in our pilot study36 have not been
included in our previous studies.25-27

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Lung CT Scan, Asthma Control Test, Serum

IgE, and Eosinophil Count Results

In 10 adult treated patients with asthma (five women)

aged 52 14 years (mean SD), the BMI was 27 6,
total blood eosinophil values were 206 (131-260) cells/mL
(median, 1-3 interquartile range), and IgE level was
280 (31-500) km/L.36 The Asthma Control Test38 score
was 16 to 19 when both clinical status and spirometry
were optimally improved by maximizing therapeutic
intervention. This included both short- and long-acting
b2 agonist, muscarinic receptor antagonist, inhaled
beclomethasone equivalent 0.4 mg/d, and tapering oral
corticosteroid as needed. Thurlbeck lung CT scan
emphysema score32 was 10, consistent with trivial or
no emphysema in seven patients with asthma. In the
three patients with asthma with loss of lung elastic
recoil and persistent expiratory airflow limitation who
died, all had mild, diffuse centrilobular emphysema at
autopsy, The Thurlbeck lung CT scan emphysema score
(0 5 none to 100 5 very extensive lung tissue breakdown)32
was between 10 and 20, consistent with trivial to mild
emphysema as per radiologist Mark J. Schein, MD,
by this criterion.36 In one patient with asthma with a
Thurlbeck emphysema score32 of 10 who was autopsied, the lung CT scan voxel quantification score
for 2950 Hounsfield units (HU) was 6.5% for right
lung and 0.9% for left lung. This is consistent with
hyperinflation and air trapping but not diagnostic for
emphysema ( 10% lung voxel 2950 HU).33-35
Lung Function Studies

In 10 patients with asthma, the postbronchodilator

(270 mg albuterol sulfate metered dose inhaler with
spacer) vital capacity was 4.2 1.1 L (90% 14% predicted) (mean SD), FVC was 4.0 1.0 L (88%
13% predicted), FEV1 was 2.5 0.4 L (69% 14% predicted), and FEV1/FVC ratio was 63% 9% (Table 1).
Specific airway conductance was markedly reduced
(0.06 [0.05-0.08] lps/cm H2O/L [median, 1-3 interquartile range], 123 [100-142]% predicted. Hyperinflation
and air trapping were marked at both functional residual
capacity 4.3 (3.5-4.4) L, 123 (109-142)% predicted, and
residual volume 3.4 (2.8-3.5) L, 143 (141-176)% predicted
This was probably caused by premature airway closure
as a result of both intrinsic airway obstruction and loss of
lung elastic recoil. Total lung capacity (TLC) was mildly
elevated at 7.3 (6.8-7.5) L, 112 (110-119)% predicted. Static
lung elastic recoil pressure at TLC was 15 (13-18) cm H2O,
63 (50-70)% predicted. Diffusing capacity after correction for alveolar volume was normal or increased
(5.5 [4.6-6.0] mL/min/mm Hg/L 130 [112-141]% predicted).

This implies integrity of alveolar-capillary surface area

when using an underestimated alveolar lung volume
compared with plethysmographic derived values. All
10 patients with asthma had measured loss of static lung
elastic recoil compared with age-matched control subjects (Fig 136,39). Furthermore, the reduction in both
lung elastic recoil and in airway conductance had a similar contribution to the decrease in expiratory maximal
expiratory airflow at 90% predicted TLC (78% observed
TLC) (Fig 2). Measurement of large airways and peripheral airways/alveolar exhaled nitric oxide was normal.40
The clinical, laboratory, and physiologic studies in
these 10 patients with asthma were similar to those we
reported previously.25-27
Autopsy Findings

In three autopsied cases, as previously reported,36 all

had significant maximal expiratory airflow limitation
with hyperinflation and air trapping, normal diffusing
capacity, and trivial to mild Thurlbeck lung CT scan
emphysema score32 of 10, 15, and 20. Transaxial
macroscopic section of autopsy obtained of formalinfixed and inflated lungs to 15 cm H2O revealed trivial to
mild emphysema by Thurlbeck emphysema scores32 of
10 (case 10), 15 (case 4), and 20 (case 9). However,
microscopic examination revealed mild, diffuse, centrilobular emphysema in all three cases. Intraalveolar
chord diameter in areas of normal lung parenchyma
was 300 mm, whereas it was much greater in emphysematous parenchyma in cases 9 and 10 (Figs 3A-D). In case 10,
there were also areas of alveolar ductal ectasia and nearly
homogeneous alveolar hyperinflation consistent with
senile lung alterations as described by Verbeken et al.41,42
In all three patients with asthma, there were also
concurrent microscopic findings of typical asthma
in large and small airways, including mucosal goblet cell
metaplasia and thickening of both the basement membrane and airway smooth muscle layers. Mucin deposition (identified by Alcian blue/Periodic acid-Schiff
stain) and mucous plugs were noted in lumens of conducting airways and extending to terminal bronchioles
and were laden predominantly with recruited neutrophils (CD15 stain), especially in cases 9 and 10. The typical asthma airway remodeling changes were consistent
with previous studies,43-47 including decrease in airway
remodeling in older patients with fatal asthma when
compared with age-matched control subjects.48 In a
control case with asthma (Fig 3E), an 80-year-old
woman with reversible airway obstruction on treatment, there was no evidence for lung parenchymal
tissue breakdown, but typical airway remodeling and

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315

TABLE 1

] Studies in Four Never Smokers With Asthma With Loss of Lung Elastic Recoil and Persistent

Expiratory Airflow Obstruction Who Had Unsuspected Microscopic Mild Centrilobular Emphysema at
Autopsy
Case 4, 42-y-Old
Man

Case 9, 72-y-Old
Woman

FEV1, L (% predicted)

3.3 (63)

0.7 (42)

0.82 (52)

1.6 (72)

FVC, L

6.2 (104)

1.3 (60)

1.7 (81)

3.0 (99)

49

48

56

Test

FEV1/FVC, %

53

Case 10, 82-y-Old

Woman

Case 11, 83-y-Old

Man

VC, L

6.6 (110)

1.3 (60)

1.7 (81)

3.0 (99)

FRC, L

6.0 (123)

2.8 (122)

3.6 (171)

4.6 (141)

RV, L

3.2 (143)

2.4 (170)

2.9 (177)

3.4 (137)

TLC, L

9.8 (119)

3.7 (101)

4.6 (123)

6.3 (118)

DLCO/VA, mL/mm Hg/min/L

SGaw, L/s/cm H2O/L

4.3 (95)

3.0 (81)

0.06 (24)

0.05 (21)

6.5 (194)
0.04 (16)

4.0 (120)
0.07 (31)

Lung CT scan Thurlbeck emphysema

score31 and % lung , 2950 HU

15

20

10

VQ

6.5% R lung

7.0% R lung

0.9% L lung

14% L lung

10

10

Inated lung macroscopic emphysema

score31

15

20

All values are post 270 mg albuterol metered dose inhaler, with normal prediction values previously noted.25-27,39 Results demonstrate moderate to
severe expiratory airow limitation on spirometry, with marked reduction in specic airway conductance. There is hyperination (trapped gas) at
static lung volumes including FRC, RV, and TLC. The hyperination at TLC is presumably due to loss of lung elastic recoil. The increase in RV and
evidence of airway narrowing suggests early airway closure during expiration (trapped gas). Expiratory airow limitation and hyperination at FRC
and RV are interpreted as due to a combination of loss of lung elastic recoil and decreased intrinsic airway conductance. The latter is due to intrinsic
airway remodeling, including mucous plugging and bronchoconstriction, with resultant premature airway closure. The normal DLCO/VA suggests the
presence of an alveolar-capillary surface area within normal limits. The Thurlbeck scores32 on lung CT scan suggest trivial/mild emphysema. However,
microscopic sections of formalin-inated lung demonstrated mild diuse breakdown of lung tissue (emphysema in Figure 3). DLCO/VA 5 diusing capacity
corrected for alveolar volume; FRC 5 functional residual capacity; HU 5 Hounseld units; L 5 left; R 5 right; RV 5 residual volume; SGaw 5 specic airway
conductance; TLC 5 total lung capacity; VC 5 vital capacity; VQ 5 voxel quantication for % lung , 2950 HU. Cases 4, 9, and 10 were previously
reported; case 11 has not been reported previously. Case numbers refer to dashed lines in Figure 1. (Adapted with permission from Gelb et al.36)

senile hyperinflation and ductal ectasia changes were

noted.41,42 Figure 3F demonstrates normal lung parenchyma in a healthy elderly man. Since publication of the
initial study,36 a fourth never smoker with lifelong asthma
with microscopic mild emphysema (case 11), and senile
lung alterations41,42 on autopsy has been confirmed and
is included in Table 1. Case numbers refer to Figure 1.

Physiologic Studies
Loss of lung elastic recoil has been reported in chronic
asthma with only partially reversible airway obstruction
despite treatment17,18,20,25-28 and also in mild asthma.29
However, no pathologic data have been obtained.
Originally, we studied 18 nonsmokers with asthma aged
59 15 years (mean SD) with persistent expiratory
airflow limitation.25 Despite normal diffusing capacity
corrected for alveolar volume and lung CT scan, there
was a significant fixed loss of lung elastic recoil in three
of four patients with asthma aged 30 to 49 years, in all
five patients with asthma aged 51 to 60 years, and in
seven of nine patients with asthma aged 61 to 82 years.
316 Commentary

The fixed loss of lung elastic recoil was responsible for

35% reduction in maximal expiratory airflow at 80%
TLC and 55% reduction at 70% of TLC.25 In another
study, we noted fixed loss of lung elastic recoil in all
11 patients with asthma aged 64 11 years with persistent post 270 mg albuterol FEV1 of 60% to 79% predicted,
and in five patients with asthma aged 55 16 years
with persistent FEV1 of , 60% predicted, but no loss in
five patients with asthma aged 51 17 years with
FEV1 . 80% predicted.26 The fixed loss of lung elastic
recoil was responsible for an average of 34% of decreased
maximal expiratory airflow at 80% TLC and 50% decrease
at 70% TLC.26 In a study of 43 patients with chronic
asthma, we reported that fixed loss of lung elastic recoil
was associated with increasing age, duration of disease,
and progressive expiratory airflow limitation and was a
risk factor for near-fatal asthma.27

Lung CT Scan Studies

Busacker et al33 and Biernacki et al34 noted significant lung
attenuation in nonsmokers with severe asthma using

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good correlation between surgically obtained lung specimens scored for emphysema with voxel scored lung
attenuation , 2950 HU. However, no correlative physiologic studies including measurements of static lung elastic
recoil pressures were obtained, and only one study showed
a correlation with lung parenchymal structure.35 From
the historical perspective, the editorial by Paganin et al49
traces the significance of lung CT scan diagnosis of
emphysema in patients with asthma with lung pathology. Unfortunately, many of the patients with asthma
studied were chronic smokers with comorbidities.

Pathology Studies
Figure 1 Static lung elastic recoil pressure (Pst[l]) was measured in a
subgroup of 10 (five women) treated never smokers with asthma aged
52 14 y (mean SD) with persistent expiratory airflow limitation.36
All had significant loss of lung elastic recoil compared with normal
values. The dashed lines represent four cases which all had autopsyproven mild diffuse emphysema; three cases (4, 9, 10) were previously
reported, and case 11 was not previously reported.36 The individual
curves are clearly shifted to the left of lower limit of age-matched normal
subjects39 with mild increase in compliance. TLC was mildly elevated at
7.3 (6.8-7.5) L, 112 (110-119)% predicted (median, 1-3 interquartile
range). Pst(l) at TLC was 15 (13-18) cm H2O, 63 (50-70)% predicted.
TLC 5 total lung capacity. (Adapted with permission from Gelb et al.36)

quantitative lung CT scan density voxels , 2850 HU.

This is more consistent with hyperinflation as opposed
to lung tissue breakdown (emphysema). Alternatively,
. 10% lung parenchyma with quantitative lung CT scan
density voxels , 2950 HU is more consistent with
emphysema.33 Moreover, Madani et al35 have reported

One previous sentinel autopsy study by Mauad et al44

in nonsmokers with fatal asthma has reported lung
tissue breakdown and localized emphysema, and no
study measured lung function including lung elastic
recoil.43-50 In fatal asthma, Mauad et al44 noted cleavage
of bronchiolar-alveolar tethering attachments with
fragmented and decreased adventitial elastic fibers, and
localized periterminal bronchiolar parenchymal emphysema. Dolhnikoff et al45 and de Magalhes Simes et al50
emphasized the surrounding inflammatory response,
including fibronectin, matrix metalloproteases, mast
cells, eosinophils, and neutrophils. Baines et al51 reported
increased neutrophil elastase was detected in the plasma
of patients with asthma with neutrophilic airway inflammation, suggesting systemic neutrophil activation.
Andersson et al52 also emphasized mast cell-associated
alveolar inflammation in uncontrolled asthma.

Proposed Mechanism(s) for Emphysema

in Asthma

Figure 2 At any effort independent lung volume, VmaxE 5 Pst(l) 3 Gus

(conductance of upstream airways).30 At 90% predicted TLC (78%
observed TLC) the loss of lung elastic recoil contributes to airflow
limitation to a similar extent as the reduction in peripheral airway conductance. Cases 1 to 10 were recently reported, as noted in Figure 1.36
Results in case 11 are similar. Gus 5 conductance of upstream airways;
VmaxE 5 maximal expiratory flow. See Figure 1 legend for expansion of
other abbreviations. (Reprinted with permission from Gelb et al.36)

The original description of emphysema by Leopold and

Gough53 included inflammatory mucous plugs in the
terminal bronchioles and suggested that this was the
nascent site of lung tissue breakdown that led to centrilobular emphysema. We suggest that recurrent asthma
attacks may produce bronchiolar inflammation with
activation of a proinflammatory pathway. This may
be mediated by an autocrine epidermal growth factor
receptor signaling cascade stimulated by inhaled invaders
in epithelial cells as we previously suggested.54 Subsequently, specific protective mucociliary responses occur
in the airway epithelium via IL-17 and IL-18, which
activate IL-8 to induce mucin production and neutrophil
recruitment, especially in mild to moderate asthma.54
Moreover, proteases such as neutrophil elastase and
cathepsin G, activated eosinophils, macrophages, and
mast cells may all induce mucin production via activation of the epidermal growth factor receptor ligandinitiated signaling cascade. Furthermore, neutrophil

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317

Figure 3 A-D, Note emphysema

(A, B, case 9; and C, D, case 10 from
Table 1), including not only disorganization and unevenly distributed
enlarged airspaces but also disrupted
alveolar septa even visible at this
magnification, as previously reported.36
In these cases, Alcian blue/Periodic
acid-Schiff (PAS stain) showed
mucin in terminal bronchioles with
plugging, especially in cases 9 and
10, and the plugs contained 70%
recruited neutrophils. E, Control
asthma case was an 80-y-old
woman with asthma with reversible
expiratory airflow limitation with
treatment. Microscopic morphometry was consistent with senile lung,
with nearly homogenous acinar
hyperinflation and alveolar ductal
ectasia but without unevenly distributed airspace enlargement or septal
disruption and with no free septal
fragments detached from the surrounding structures.41,42 F, Sample
from a 71-y-old man with normal
lung function. AD 5 alveolar duct;
BV 5 blood vessel; RB 5 respiratory
bronchiole; TB 5 terminal bronchiole.
(Hematoxylin and eosin stain.)

elastase and cathepsin G are potent secretagogues for

submucosal gland epithelial cells. Together with activated matrix metalloproteases, this proteolytic cascade
has the potential to cleave and disrupt the normal connective tissue integrity of lung parenchymal-terminal
bronchiole attachments, leading to potential loss of anatomic and physiologic interdependence. Bronchiolar
instability can lead to air trapping and hyperinflation
and negative effort dependence during forced exhalation. We suggest that the epiphenomenon of asthmarelated lung tissue breakdown leading to mild emphysema
can be explained by a proinflammatory proteolytic cascade. This is similar to terminal bronchiolar-lung parenchymal uncoupling in smokers with loss of lung elastic
recoil in early emphysema as described by Saetta et al55
and by Gelb et al.56,57 In normal aging lungs compared
with younger lungs, the loss of lung elastic recoil39 may
be related to nearly homogeneous acinar hyperinflation
and alveolar ductal ectasia without alveolar breakdown
and/or fracture.41,42 Similar lung CT scan densitometry
studies in an aging population by Bellia et al58 have also
confirmed these findings, and the lower limit of normal
was 2901 HU. Additional voxel quantitative lung
CT scan studies, including measurements of distal airway
wall thickness as identified by Rutten et al59 in COPD
and by Gupta et al60 in asthma subphenotypes, may also
318 Commentary

be helpful. Furthermore, as in COPD, loss of small airways and terminal bronchioles in asthma can further
magnify expiratory airflow limitation.36,61

Conclusions
We hope this commentary may help begin to explain the
clinical conundrum of ACOS in a subset of nonsmokers
with chronic asthma,1-10 often but not necessarily beginning
in childhood, with persistent expiratory airflow obstruction despite treatment, and most often noneosinophilic.62
These patients with asthma are at risk for COPD due to a
proinflammatory and proteolytic cascade. This may lead
to lung tissue breakdown and unsuspected diffuse, mild
centrilobular emphysema that is not easily detected clinically, physiologically, or with lung CT scan.36 We need
more structure-function studies that include physiologic
measurements of static lung elastic recoil pressure with
maximal expiratory flow-static lung elastic recoil pressure
curves and correlation with formalin-inflated whole-lung
specimens as well as analyses of small and large airway
pathology. These also need to be correlated with highresolution thin-section lung CT scan with voxel quantification and other cogent parameters as identified by
phenotype cluster analyses. Furthermore, the proinflammatory and proteolytic mechanism(s) leading to lung tissue
breakdown need to be further investigated and inhibited.

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Acknowledgments
Financial/nonfinancial disclosures: The authors have reported to
CHEST that no potential conflicts of interest exist with any companies/
organizations whose products or services may be discussed in this article.
Other contributions: We thank Ranna Patel, BS, HT, ASCP, for pathology
technical assistance; Colleen Flynn Taylor, MA, and Randy Newsom,
RCP, CPFT, for initial lung function testing; Jennifer Klotchman, PhD,
Bob Ward, MSEE, professor at California State University, Long Beach
(Computer Science), and Stuart Green, MD, professor at University of
California, Irvine Medical Center (Orthopedic Surgery), for graphics;
Ouided Rouabhi, BS, and Susan Wood, PhD, of Vida Diagnostics, Inc,
Cupertino, California and Coralville, Iowa (vidadiagnostics.com) for
lung CT scan voxel quantification; Tracy Dyer, MD, who performed
the autopsy in case 1 at Dallas County Southwestern Institute of
Forensic Sciences, Dallas, TX; Noe Zamel, MD, professor of medicine,
University of Toronto Faculty of Medicine, for collaborative physiologic
studies25-27,31,56,57; Christine Fraser, RCP, CPFT, Roxanna Moridzadeh,
BS, of UCLA, Dallas Beaird, BS, of UC Santa Barbara, Diem Tran, BA,
of UC Berkeley, and Capt Lisa Maginot, of West Point, for additional
lung function studies; and Michelle Bolling, RN, for patient care.

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