PULMONARY, SLEEP, AND

CRITICAL CARE UPDATE

Update in Chronic Obstructive Pulmonary Disease 2014

Terence A. R. Seemungal1 and Jadwiga A. Wedzicha2
1
The University of The West Indies, St. Augustine Campus, Trinidad and Tobago; and 2National Heart and Lung Institute, Imperial
College London, London, United Kingdom

Chronic obstructive pulmonary disease
(COPD) remains a leading cause of death
worldwide, with a rising prevalence in
newly developed and developing countries,
including China, the world’s most
populous country. This article focuses
on information on chronic obstructive
pulmonary disease published in the
American Journal of Respiratory and
Critical Care Medicine in 2014 and will
update the reader on pathophysiology,
imaging, natural history, treatment, and
prevention of this condition.
In homozygous alpha-1 antitrypsin
(AT) deficiency–associated COPD,
inflammation is now clearly linked to the
genetic lesion, as is impaired innate
immunity in the airway. This latter results
from lesions in both TNF-a– and
TGF-b–dependent pathways but also
involves a prolonged unfolded protein
response, proline-glycine-proline (PGP)
peptide fragments, and dysregulation of
T-cell subsets. COPD phenotypes may
depend on the type of particulate insult to
the airway but also on lipid expression in
the airways. Ethnicity-specific components
of COPD were discovered in 2014. In
applying the results of studies to clinical
practice, the phenotype of COPD studied
may be of greater importance, and in several
such patients the clinical trial reference
standard may not be adhered to. Treatment
may soon be available for the prevention of
pulmonary hypertension in COPD. The
research agenda being formulated by the
NHLBI will no doubt guide future research
in this field. The Journal’s contributions to
new information in the areas outlined herein
is summarized by author in Table 1.
Alpha-1 AT Deficiency
Alpha-1 AT–related COPD remains an
important model to help us to understand the
pathology of the underlying disease processes
in COPD. The normal variant is termed
M-AT, but severe deficiency of AT is usually
caused by homozygosity for the Z mutation.
The accepted mechanism for COPD causation
in homozygous Z-AT (ZZ-AT) is proteinase
excess leading to accelerated alveolar
destruction and early-onset emphysema (1).
Inflammation in Alpha-1 AT Deficiency
Using a mouse model of Z-AT, Alam and
colleagues (2) showed that, compared with
M-AT, transgenic ZZ-AT mice exposed
to cigarette smoke had higher levels of
pulmonary cytokines, neutrophils, and
macrophages and an exaggerated
endoplasmic reticulum (ER) stress. Next the
authors looked at explanted lungs of MM-AT
and ZZ-AT individuals and found that the
ER overload response was greater in lungs
from ZZ-AT homozygotes with COPD and
more so in epithelial cells of the lung.
Cigarette smoke increased intracellular Z-AT
polymers, ER overload response, and
proinflammatory cytokine release
(importantly TNF-a) in Z-AT–
expressing pulmonary epithelial cells. This
inflammatory response could be prevented
with inhibitors of polymerization or protein
kinase RNA–like ER kinase or by
antioxidants (2). Figure 1 summarizes
our current understanding, which is that the
major insult leading to COPD in ZZ-AT is
Z-AT polymers in pulmonary cells and that
the proinflammatory effects of this pathologic
phenomenon are worsened by environmental
stress, such as that produced by cigarette
smoke and other pollutants (3).
Hassan and colleagues showed that
a specific micro-RNA (miR-199a-5p) is
decreased in monocytes of symptomatic
MM and ZZ individuals compared with
their asymptomatic counterparts. miR-
199a-5p was the most up-regulated in
asymptomatic ZZ subjects compared with
MM subjects (4). However, in symptomatic
individuals, miR-99a-5p expression was
lower than in asymptomatic individuals.
The authors also showed that expression of
key components of the unfolded protein
response within the endoplasmic reticulum
were highly expressed in monocytes of
symptomatic versus asymptomatic subjects.
Cigarette-induced endoplasmic reticulum
stress leads to the unfolded protein
response, which is dysregulated in part due
to underexpression of miR-199a-5p. A
prolonged unfolded protein response has
been linked to prolonged inflammation and
development of COPD (Figure 1) (5).
These results were supported by
Geragthy and colleagues, who showed
that ZZ-AT patients have reduced
protein phosphatase 2A (PP2A). They
showed that PP2A down-regulates
inflammation, protease expression, and
apoptosis under smoking conditions in
the lung and that this proinflammatory

( Received in original form March 17, 2015; accepted in final form July 9, 2015 )
Author Contributions: Both authors contributed to the conception and design of this article.
Correspondence and requests for reprints should be addressed to Terence A. R. Seemungal, M.B. B.S., Ph.D., Department of Clinical Medical Sciences, The
University of The West Indies, St Augustine Campus, Trinidad and Tobago. E-mail: terence.seemungal@sta.uwi.edu
Am J Respir Crit Care Med Vol 192, Iss 9, pp 1036–1044, Nov 1, 2015
Copyright © 2015 by the American Thoracic Society
DOI: 10.1164/rccm.201503-0534UP
Internet address: www.atsjournals.org

1036 American Journal of Respiratory and Critical Care Medicine Volume 192 Number 9 | November 1 2015
PULMONARY, SLEEP, AND CRITICAL CARE UPDATE
Table 1. Summary of Discoveries in Chronic Obstructive Pulmonary Disease
Discussed in the Journal in 2014
Topic
Alpha-1 antitrypsin
Inflammation
Lung function changes
Airway lipidomics and immunology
Airway lipids
Immunology of epithelium
CD41 T-cell activity
Disorders in neutrophil activity
Particulates, pollutants, and COPD
Cigarettes
Biomass exposure
Traffic particulates
Occupation and COPD
Genomics
Ethnicity and emphysema
GWAS
Comorbidity and natural history
COPD as a risk factor
Weight gain and lung function
Progression to lung cancer
Genetics of COPD and lung cancer
Patent foramen ovale
Imaging and pathphysiology of COPD
Prevention strategies in COPD
Research and prevention
E-cigarettes
Prevention of exacerbations
Prevention of readmission
Therapeutics
Which COPD are we treating?
Systemic steroids
Progression to pHTN
Definition of abbreviations: COPD = chronic obstructive pulmonary disease; GWAS = genome-wide
association study; pHTN = pulmonary hypertension.
state is further regulated by TNF-a. Closing
the loop, they then showed that lower AT
levels lead to decreased relative PP2A activity
in neutrophils, monocytes, small airway
epithelial cells, and A549 cells, thus leading to
greater inflammation (6).
Lung Function and Alpha-1 AT Deficiency
A study of post-transplant COPD recipients
in the absence of alpha-1 AT deficiency
Pulmonary, Sleep, and Critical Care Update
Study/Studies
Alam et al. (2); Jenne (1); Blanco (3);
Geraghty et al. (6); Hassan et al. (4);
Nana-Sinkam and Choi (5)
Banga et al. (7); Molloy et al. (8)
Donnelly (10); Telenga et al. (9)
Gohy et al. (11)
Kalathil et al. (13); Lipman and Brown (15);
Popescu et al. (12); Singh (14)
Snelgrove and Kheradmand (17);
Wells et al. (16)
Hollams et al. (18); Johnson and
Wegienka (19)
Ramı́rez-Venegas et al. (20); Vestbo
and Celli (21)
Dimakopoulou et al. (23); Lepeule
et al. (22); Rice et al. (24)
Marchetti et al. (25)
Hansel and Mathias (27); Manichaikul
et al. (26)
Castaldi et al. (30); Pillai (29)
Burgel and Clini (32); Van Remoortel
et al. (31)
Sood et al. (33); Suratt (34)
Denholm et al. (35)
Yang et al. (36)
Shaikh et al. (37)
Coxson et al. (38); Marchetti et al. (25);
Pillai (29)
Kiley and Gibbons (39); Agustı́ et al. (40)
Brody (41)
Han et al. (43)
Feemster and Au (51)
Prieto-Centurion et al. (52); Kim
et al. (54); Kaplan and Jones (55)
Abroug and Krishnan (57); Kiser et al. (56)
Adnot and Kawut (61); Weissmann et al. (60)
(n = 231) and with ZZ-AT COPD (n = 45)
found that COPD lung transplant patients
with AT deficiency showed a more rapid
decline than their AT-replete counterparts for
double lung transplants but not single lung
transplants. The study found no difference
between patients with COPD with and
without alpha-1 AT deficiency in frequency
of acute cellular rejection or mortality. The
result is almost counterintuitive and may
have to do with differences in disease
expression (and thus inflammation) between
the two types of patients chosen for the less
and more extensive lung transplants (7).
Finally, a study of MZ-AT subjects
showed that there is a greater degree of
airways obstruction in MZ-AT subjects than
in MM-AT subjects with the same degree of
smoking (8).
Airway Lipidomics and
Immunology
Lipidomics refers to the pathways and
networks of cellular lipids in biological
systems. One study showed lipids may
have a diagnostic role in COPD. Lipids
also have an immunologic role because
they form the basis of several of
the immunoglobulins. One of the
immunoglobulin A receptors can control
bronchial epithelial cell differentiation.
Although a primary role for inflammation in
COPD is discharged by the neutrophil,
T regulatory (Treg) cells of the immune
system also influence the development of
COPD in HIV-positive subjects.
Airway Lipidomics
Telenga and colleagues examined the airway
lipidome using sputum from nonsmokers and
from smokers with and without COPD and
showed important differences in lipid
composition between those with and those
without COPD (9). A total of 1,500 lipid
compounds were identified in the sputum of
subjects with COPD, and lipids of the
sphingolipid class were found to be more
highly expressed in the sputum of smokers
with COPD compared with those without
COPD. Of the 210 lipids differentially
expressed between the three groups, 13 lipids
showed at least a 2.5-fold increase between
smokers with and without COPD (Figure 2).
For these lipids, lipid expression was correlated
with extent of obstruction (lower FEV1% and
higher residual volume/TLC%) and pack-years
of smoking. These findings indicate a
pathophysiologic and perhaps diagnostic role
of lipids in COPD and are an indication that
modification of the airway lipidome may have
therapeutic implications (10).
Immunology of the Epithelium
IgA is secreted by the respiratory epithelium
due to its innate immunity but may also be
adaptively constituted with high affinity
for antigen once immune recognition occurs.
Polymeric immunoglobulin receptor (pIgR) is
1037
 PULMONARY, SLEEP, AND CRITICAL CARE UPDATE

(1) (5)
ENVIRONMENTAL GENETIC AAT
FACTORS DEFICIENCY
Tobacco
smoke
MM LUNG ZZ LUNG
Indoor pollution Z-ATT liver polymers
from biomass (8) Oxidant-induced Z
fuel smoke AAT lung polymerization (6) Z-AAT polymer
Chemical vapors accumulation
Agricultural dusts (2) Lung → ER stress
inflammation → cell dysfunction → ER stress
→ Iiver damage
(3) AMPLIFIED Z-AAT
LUNG INFLAMMATION lung
polymers
Inflammatory cells (7) Decreased AAT concentration
and activity in serum and tissues →
Inflammatory mediator increased vulnerability of lungs
release: against proteases
Proinflammatory
Chemotactic factors
CD8+ Lymphocyte
Pro-inflammatory cytokines
Growth factors

Oxidative stress (9) Neutrophil chemotaxis also by free Z polymers →

Inflammation amplification → Increased lung damage
Macrophage

Protease release →
protease-antiprotease Neutrophils
Neutrophil imbalance

(4) LUNG
EMPHYSEMA

Figure 1. (1) In subjects without alpha-1 antitrypsin (AAT) deficiency (MM genotypes), inhaled cigarette smoke, occupational exposures to dusts, chemical
agents and fumes, and smoke from biomass fuels cause chronic lung inflammation (2), which is enhanced in patients who develop chronic obstructive
pulmonary disease, involving CD81 cytotoxic lymphocytes, macrophages, and neutrophils, which release several types of inflammatory mediators,
proteases, and oxidants (which are added to the smoke-inhaled ones) (3), finally causing lung destruction with emphysema (4). (5) In Pi*Z (ZZ genotypes)
subjects, misfolded Z-AAT molecules and Z-polymers are retained in the rough endoplasmic reticulum (ER) of hepatocytes, where they can induce
ER stress and liver damage (6). Lung disease is attributable to the decreased concentration and low activity of Z-AAT, which is unable to provide
adequate protection to the lungs when attacked by proteases (7), and to an oxidant-mediated aggregation of Z-AAT in pulmonary epithelial cells, causing
ER stress with proinflammatory cytokine release and amplification of lung inflammation (8). In addition, free Z polymers are chemotactic for activated
neutrophils, and this further increases the inflammation and lung tissue damage (9). Reprinted by permission from Reference 3.

expressed on the epithelium and affords
transepithelial crossing to IgA synthesized by
mucosal plasma cells (11). Gohy and
colleagues showed that the down-regulation
of pIgR previously observed in COPD was
worse in more severe COPD and was
controlled by transforming growth factor
(TGF)-b1. TGF-b has been shown to control
epithelial cell differentiation. pIgR expression
is reduced in COPD (11), and its down-
regulation correlates with disease severity.
Further, the bronchial epithelium
reconstituted in vitro from these patients
retains its aberrant imprinting for pIgR
expression. This study also links pIgR
down-regulation to TGF-b–driven
reprogramming of the bronchial
epithelium, which results in impaired lung
IgA immunity in patients with COPD.
Thus, in COPD the damaged epithelium
becomes less capable of defending itself
from external insults.
CD41 T Cells and COPD
HIV-infected smokers are known to be at
greater risk of accelerated lung function
decline. Popescu and colleagues showed
that one of the specific immunopathologic
features of HIV-associated COPD is the
Fas-dependent activation–induced death
of CD41 cells, which is associated with
impaired HIV-specific CD41 T-cell
immunity (12). Further, lung mucosal
CD41 (but not blood CD41) was
correlated with FEV1 (12). On the other
hand, Kalathil and colleagues studied
stable COPD and showed that a subset of
CD41 T cells (i.e., Treg cells) from
peripheral blood mononuclear cells are
highly suppressive and appear to be
responsible for the impaired immune
response to nontypeable Haemophilus
influenzae. The study found that Treg
cells are up-regulated and are more
abundant in COPD, whereas T effector
cells have reduced responses to bacterial
antigen and are further down-regulated
by the enhanced Treg cells (13). The end
result of this derangement of T-cell
regulatory and effector function is an
impaired adaptive immune response,
and this appears to apply to both HIV-
associated and HIV-independent
COPD (14, 15). Further, genome-wide
association studies (GWASs) appear to
indicate a role for CD41 T cells in
emphysema pathogenesis (see below).
Disorders in Neutrophilic
Inflammation
A study of the murine model of emphysema
showed that mice exposed to cigarette
smoke developed emphysema with
increased proline-glycine-proline (PGP)
peptides and acetylated PGPs, neutrophilic
inflammation, and selective inhibition of
LTA4H peptidase activity, indicating an

1038 American Journal of Respiratory and Critical Care Medicine Volume 192 Number 9 | November 1 2015
PULMONARY, SLEEP, AND CRITICAL CARE UPDATE

Dihydro- Phospho- Sphingosine-1P

sphingosine-1P ethanolamine

Phytosphingosine Phytoceramides Sphingosine

Cerami
CerS
-dase
Serine
CerS SGMSs
3-Dehydro- Dihydro-
Dihydroceramides DEGS Ceramides Sphingomyelins
sphinganine sphingosine
SMases
Palmitoyl-CoA
GTs

Higher expressed in smokers with COPD than in never-smokers GSLs

Lower expressed after smoking cessation

Complex GSLs

Figure 2. The sphingolipid pathway. CerS = ceramide synthases; COPD = chronic obstructive pulmonary disease; DEGS = dihydroceramide desaturase;
GSLs = glycosphingolipids; GTs = glycosyltransferases; SGMSs = sphingomyelin synthases; SMases = sphingomyelinases. Phosphoethanolamine can be
used for phosphatidylethanolamine (PE) biosynthesis. Phosphoethanolamine could not be detected using the methodology of this study (9), although PEs
are more highly expressed. Reprinted by permission from Reference 9.

unrestricted proinflammatory condition
(16). Applying the methods to smokers
with and without COPD, these authors
found similar results (16). These data
suggest that neutrophilic inflammation in
COPD involves generation of PGP and
acetylated PGP, both proinflammatory
peptides, and that this may be a site for
therapeutic action (17).
Particulates, Pollutants, and
COPD
The effects of cigarette smoke in adolescents,
biomass pathophysiology in COPD,
traffic-related black carbon air pollution,
and occupational exposures in relation to
GOLD grade were explored by the Journal
in 2014.
Cigarette Smoke
Hollams and colleagues showed that
maternal smoking was associated with
lower lung function values in adolescent
nonsmokers independent of the association
with asthma in this age group (18). In
this study, 8% of adolescents had to
be excluded because they voluntarily
identified themselves as being addicted to
smoking (19). These data, taken together
with the observation by the author of the
editorial that the habit has become more
fashionable for girls than for boys in some
countries, suggests that there will be an
increased burden of COPD in the future
(19).
Biomass and COPD
Ramı́rez-Venegas and colleagues found that
subjects with biomass-induced COPD had
lower lung volumes and a slower rate of
decline than those with tobacco-induced
COPD. However, both groups had more
rapid decline in FEV1 in GOLD stages 1
and 2 than in later GOLD stages (20).
The results of this study suggest that
biomass-induced COPD is of a different
phenotype from tobacco smoke–induced
COPD (21).
Traffic-related Air Pollutants,
Morbidity, and Mortality
A study of 858 men who had been in the
normative aging study showed that
a tracer of traffic emissions, black carbon,
is associated with worse lung function
and decline in lung function even
when pollutant levels were within the
Environmental Protection Agency
National Air Quality Standards (22). This
study is yet more evidence of the effects of
air pollutants on respiratory morbidity.
However, a large study involving 307,553
subjects from 16 ongoing cohort studies
and involving 1,559 respiratory deaths
over 6 to 19 years in Europe found no
relation between air pollutants (particulate
matter and nitrogen oxides but not
including ozone or black smoke) and
respiratory mortality (23). However, this
may have been because most of the
patients in the studies were less than
70 years of age, and most of the effects
on respiratory mortality reported in other
studies involve deaths in more elderly
patients. Despite efforts to reduce air
pollutant levels, the prediction for their
future effects on respiratory morbidity and
mortality are unfavorable because of their
synergistic interaction with rising
temperatures associated with global
climate change (24).
Occupational Exposures and COPD
A study of 9,614 subjects showed that
occupational self-reported exposures to
dusts or fumes or both for more than 1 year
are associated with higher GOLD stage
COPD, respiratory symptoms, greater
rate of emphysema, and air trapping as
estimated by quantitative computed
tomography (CT) (25). In women but not

Pulmonary, Sleep, and Critical Care Update 1039

 PULMONARY, SLEEP, AND CRITICAL CARE UPDATE

in men, there was also an association of Chinese subjects. a-Mannosidase Comorbidity and Natural
airway wall thickness and history of degrades A1AT, which this is the link History of COPD
exposures (25). between the GWAS findings and percent
emphysema (27). Comorbidity is common in established
COPD, but one study suggested that
Genomics the role of COPD in these comorbid
Genome-Wide Association Studies in
COPD conditions is not causative. Weight gain
Genome-wide studies showed linkages has differing effects on lung function
between CT-defined emphysema and Cho and colleagues looked at 6,633
subjects from the NETT Genetics, IGGN, depending on baseline body mass index.
ethnicity as well as in type of emphysema Future risk of cancer in COPD appears
and genetic variants (Table 2). Eclipse, and COPDGene Studies and
found three new genome-wide more strongly linked to emphysema than
significant associations with COPD: to chronic bronchitis. Patent foramen
Ethnicity and the Emphysema a locus near HHIP, one near MMP12, and ovale with large shunts is more common in
Phenotype one near TGFB2 (28). Another study COPD.
A study of 7,914 patients from the Multi- of 6,184 smokers versus 3,559 smokers
ethnic Study of Atherosclerosis Cohort with GOLD Stage 2 or greater COPD Is COPD a Risk Factor for
looked at genetic links to emphysema showed that there are genetic Comorbidity?
as assessed by CT scanning (26). associations with CT-based emphysema This hypothesis was challenged by Van
Two single-nucleotide polymorphisms patterns of centrilobular and panlobular Remoortel and coworkers in a study of
previously linked to lung function in disease (29). The emphysema pattern on smokers with and without COPD compared
white subjects were shown to be closely CT was associated with enhancer regions with age- and sex-matched control subjects
associated with percent emphysema for these genes: for panlobular (31). The authors recruited subjects with
across all ethnicities and therefore suggest emphysema the top GWAS hits occurred newly diagnosed COPD during a screening
that these genes contribute to emphysema. in lung-related cell lines of pulmonary study, which they called “preclinical
Further, common variants in genes fibroblasts, and for centrilobular COPD.” They found that physical inactivity
associated with a-mannosidase are emphysema the top hits occurred in and smoking were more strongly associated
associated with percent emphysema lymphoblastoid cell lines and CD41 with the presence of comorbidities than
in African American, Hispanic, and T cells (30). with COPD. The study suggests that these
two factors may represent useful areas for
primary and secondary intervention in the
early stages of COPD (32).
Table 2. Summary of Single-Nucleotide Polymorphisms and Their Related Phenotypes
in Chronic Obstructive Pulmonary Disease as Discussed in the American Journal of
Weight Gain and Lung Function in
Respiratory and Critical Care Medicine in 2014
Smokers
One 6-year study showed that weight gain
Single-Nucleotide had differential effects on lung function
Phenotype Polymorphisms Nearest Gene Locus Reference in smokers with and without COPD (mainly
GOLD Stages 1 and 2). The lean to
Emphysema rs7957346 (whites) SNRPF 26 underweight subset of patients and the
rs1997352 (whites) RARB morbidly obese subset both had the lowest
rs10947233 PPT2
rs10411619 (Hispanics) MAN2B1* FEV1 and worse health status (33). Further,
rs12130495 (African MAN1C1* over the study period, weight gain led to
Americans) improvements in these outcome measures
in the lean to underweight subset but
Moderate, rs114205691 (whites) IREB2/CHRNA3/CHRNA5 27
centrilobular rs56113850 (African CYP2A6/EGLN2/ADCK4 led to deterioration in FEV1 in the
Americans and whites) morbidly obese group; these changes were
rs17368582 (whites) MMP12 independent of smoking and ethnicity (33).
rs1690789 (whites) TGFB2 This nonlinear relationship suggests that
the effect of weight on lung function before
Severe, rs9788721 (whites and AGPHD1
centrilobular African Americans) or during early COPD is unlikely to be
rs379123 (whites and MYO1D a purely mechanical effect of obesity on the
African Americans) lung (34).
Panlolubar rs11852372 (whites and AGPHD1
African Americans) Progression to Lung Cancer
rs9590614 (whites and VWA8 A large case-control study by Denholm
African Americans) and colleagues showed that two COPD
Lung cancer c.353T.C Snai1 36 phenotypes—chronic bronchitis and
emphysema—were associated with lung

1040 American Journal of Respiratory and Critical Care Medicine Volume 192 Number 9 | November 1 2015
PULMONARY, SLEEP, AND CRITICAL CARE UPDATE
cancer, but the relation to lung cancer was
stronger for emphysema. The authors
admit that COPD was not considered as
a single entity; rather, they preferred to look
at the separate COPD phenotypes of
emphysema and chronic bronchitis because
of heterogeneity in their presentation, lung
function decline, and survival and also
because grouping them together may mask
different relationships to lung cancer.
Respiratory diagnoses were defined by
patient recall (from patient history), and
thus the study was subject to misreporting
and recall bias. The study suggests that
patients in the emphysema phenotype
should be selected for closer follow-up for
lung cancer (35).
Genetics, COPD, and Lung Cancer
Epithelial–mesenchymal transition
(EMT)-related genes such as Snai1 induce
and promote EMT (36). GWASs have
shown that some germline variants near to
EMT-related genes are associated with lung
cancer or COPD. Yang and colleagues
showed that the germline variant c.353T.
C(p.Val118Ala) of Snai1 was associated
with decreased risk of lung cancer and
COPD. The c.353C genotype weakened
Snai1-induced expression of EMT markers
and consistently decreased the probability
of lung cancer metastasis at diagnosis, but
other variants may increase the probability
of subjects with COPD developing lung
cancer (36). The study is important because
germline variants are transmitted to
offspring in humans.
Patent Foramen Ovale and COPD
Shaikh and colleagues showed that a patent
foramen ovale was of similar prevalence in
patients with COPD and control subjects
but that patent foramen ovale with large
shunts was more frequent in patients
with COPD than in control subjects (26 vs.
6%). There were no relationships in
patients with COPD between patent foramen
ovale and 6-minute-walk distance or exercise
performance during a maximal exercise test.
Thus, even where there are large shunts,
patent foramen ovale closure is unlikely to
improve exercise performance (37).
Imaging and Pathophysiology
of COPD
Since 1995, the Gold Standard for assessing
COPD severity has been FEV1. However,
Pulmonary, Sleep, and Critical Care Update
FEV1 does not allow us to capture the
different phenotypes of COPD. For
example, several studies have shown that
although exacerbation frequency is
correlated with FEV1, it is only weakly
so (38). CT imaging is now being
used successfully to differentiate the
emphysematous from the bronchitic
phenotype in COPD, and multidetector
CT chest scanning has begun to examine
the anatomy of small airways disease in
COPD (38) and the pathobiology of COPD
during occupational exposure (25) and has
been shown to differentiate between
different genotypes (25, 29). The high
cumulative radiation exposure associated
with serial CT scanning is being mitigated
by iterative reconstruction algorithms that
allow a radiation dose reduction ranging
from 20 to 80%. Future application in
COPD will depend on use of gases with
an unpaired proton: 19F, 129Xe, and 3He.
The unpaired proton is polarized, which
compensates for the low concentration
in lung air spaces, allowing easy detection.
Using these gases has allowed exploration
of regional differences in ventilation
within the lung in response to
bronchodilator (38).
Prevention Strategies and
Comorbid Conditions in
COPD
Research Goals in the Prevention of
COPD
The NHLBI is now set on reducing the
mortality rate due to chronic respiratory
disease. Key features of this approach would
be a critical need for better definitions of
lung health, preclinical states, and lung
disease. Measures of lung health must
extend beyond current physiologic tests and
must lead to measures applicable to both the
individual and the population as a whole
(39). This approach will support the current
thrust into personalized medicine for
COPD (40) and will inform current trends
in COPD research.
Smoking Cessation and E-Cigarettes
E-cigarettes are being championed in the
lay press for their presumed safety and
smoke-free properties (41). However,
nicotine is produced by e-cigarettes,
and nicotine is addictive and has been
implicated in a number of cancers and
been shown to provoke dysfunction of
the cystic fibrosis transmembrane
conductance regulator in the airway
epithelium, leading to disruption of airway
mucus transport (41).
Prevention of Exacerbations
Macrolides have been shown to reduce
exacerbation frequencies. In a randomized
controlled trial of azithromycin in COPD,
azithromycin-treated patients with
COPD had a reduced rate of exacerbations
requiring systemic steroids and/or
antibiotics compared with subjects
receiving placebo (42, 43). The
azithromycin group was more likely have
the less severe exacerbation (i.e., less need
for intense therapy). Subgroup analyses
showed that azithromycin may be more
effective in older patients with COPD
and in those in higher GOLD stages.
Azithromycin (500 mg thrice weekly) was
also found to achieve a 42% reduction in
exacerbation rates among frequent
exacerbators (44). Because frequent
exacerbators are more likely to have
rhinovirus infection (45), we speculate that
the effects in frequent exacerbators shown
above may be due to the previously proven
protective effect of macrolides against
rhinovirus infection. Acetylcysteine was
also found to cause a 22% reduction in
exacerbation frequency in moderate to
severe COPD, and roflumilast was found
to cause a 13% reduction in severe COPD
with chronic bronchitis (46, 47), but the
anti–leukin-5 receptor-a monoclonal
antibody benralizumab had no effect on
exacerbations (48). Finally, a SNP related
to proteinase-activated receptor-1 activity
(49) and polymorphisms of the b-2
adrenergic receptor linked to salmeterol
activity may protect against frequent
exacerbations (50)
Prevention of Exacerbation
Readmissions
In 2014, the U.S. Center for Medicare
and Medicaid Services expanded their
Hospital Readmission Reduction Program
to include COPD. This meant that
readmission for a COPD exacerbation
within 30 days would be met with
reimbursement penalties (51). Thirty-day
risk-adjusted readmission rates do not
directly identify which components of
hospital care need to be addressed;
therefore, this initiative is unlikely to lead
to improved COPD care (51).
1041

Therapeutics
Which COPD Are We Treating?
One thousand patients from the U.S. COPD
Outcomes-based Network for Clinical
Effectiveness and Research Translation
(CONCERT) DataHub were assessed using
three COPD case definitions: ICD-9 codes,
patient-reported physician diagnosis, and the
clinical trial reference standard of obstructive
spirometry with a history of smoking or
alpha-1 AT deficiency (52). Only 42% of
patients met all three criteria. In addition,
only 57% of patients who met the ICD-9
definition also met the clinical trial
reference standard. Further, only 61% of
patients with self-reported COPD met
the clinical trial standard, and thus
epidemiologic studies that rely on patient-
reported diagnosis of COPD may not
accurately reflect the risk factors or
prevalence of COPD (52) (Figure 3). For
example, the data from Denholm and
colleagues would more likely fit the ICD-9
codes than the clinical trial standard (35).
General Practice registers may be less
efficient for recruitment of patients for
COPD trials for these reasons (53).
One study suggested enlarging the
definition of chronic bronchitis to include
that suggested by the St. George’s
Respiratory Questionnaire because doing
so identified patients with similar clinical
features of more respiratory symptoms,
exacerbation, worse lung function, and
greater airway wall thickness (54). These
491.x – Chronic Bronchitis
(n=309)
490.x – Bronchitis NOS
3.2
(n=214)
0.4
1.0
0.7 0 6.3
2.1
0.3
1.3
10.7
Figure 3. Percentage of participants identified by each International Classification of Diseases, Ninth
Revision (ICD-9) code (n = 909). Most patients (84%) had multiple encounters, and ICD-9 codes may
have varied across these encounters. A total of 54% of patients were identified by more than one
ICD-9 code and 17% by three or more ICD-9 codes. NOS = not otherwise specified. Reprinted by
permission from Reference 52.
1042 American Journal of Respiratory and Critical Care Medicine Volume 192 Number 9 | November 1 2015
PULMONARY, SLEEP, AND CRITICAL CARE UPDATE
studies raise the issue of a need for
international standards for diagnosis and
coding for COPD (55).
Use of Systemic Steroids
A retrospective database study of 17,239
patients reported that 33% of ICU admissions
were treated with low-dose corticosteroids
(methylprednisolone <240 mg/d) and that,
compared with high doses, the low-dose
patients had reductions in hospital and ICU
length of stay, total hospital costs, length of
invasive ventilation, need for insulin therapy,
and rate of fungal infections (3.3 vs. 4.4%)
(56). Although the study is of great interest, it
should be interpreted with caution. However,
it is the best that we have until a large,
randomized, prospective study is performed
and suggests that higher-dose systemic
steroids are not safe in acute exacerbations of
COPD (57).
Cessation of Inhaled Steroids in
COPD
Magnussen and colleagues showed that in
patients on dual bronchodilator therapy,
inhaled steroids may be safely withdrawn in
severe COPD over an 18-week period
without exacerbations. However, a 38-ml
fall in FEV1 was observed over the last
phase of withdrawal (58).
Halting Progression to Pulmonary
Hypertension
The phosphodiesterase-5 inhibitor tadalafil,
though useful in idiopathic pulmonary
492.x – Emphysema
(n=231)
496.x – Chronic airway
4.4 obstruction NOS (n=815)
10.6
37.8
13.7
7.4
hypertension, had no effect on COPD-
associated pulmonary hypertension (59).
However, hope for treatment of this
debilitating complication in COPD is not
lost: Weissmann and colleagues showed
that guanylate cyclase stimulator (sGC)
may prevent pulmonary hypertension in
COPD. They showed that treatment with
two different sGCs prevented development
of emphysema, pulmonary hypertension,
and vascular remodeling in animals
(60). It has previously been shown
that vascular remodeling of pulmonary
hypertension precedes alveolar destruction
(61). Lesions in cyclic guanosine
monophosphate–dependent pathways are
important to the development of COPD
and associated pulmonary hypertension
and suggest that sGC stimulators may
attenuate the course of COPD. The studies
also showed that sGC may halt progression
to pulmonary hypertension in smokers
with COPD.
Concluding Comments—The
Future
In 2014, the Journal published a sizable body
of work on COPD. This work indicates
a substantial emphasis on understanding
the genetics of COPD and prevention of
complications. Future strategies in COPD
will share many common approaches to
other chronic diseases as envisioned by the
NHLBI, such as rigorous dissemination and
implementation of research approaches to
shorten the evidence-to-practice lag in
clinical and public health settings, the use
of novel multilevel strategies for improving
care in underserved vulnerable communities,
and the use of gene therapy and the
implementation of electronic medical records
to facilitate the delivery of personalized,
predictive, and preemptive clinical care (39).
However, COPD will demand certain
strategies peculiar to the disease, such
as newer antiinflammatory drugs that
retard or restore lung function decline
and prevent expression of the frequent
exacerbator phenotype. The link between
COPD and lung cancer now appears to
have a genomic basis, but the pathogenetic
mechanisms underlying this link need to be
unraveled so that useful preventive strategies
can be designed. n
Author disclosures are available with the text
of this article at www.atsjournals.org.
PULMONARY, SLEEP, AND CRITICAL CARE UPDATE
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