STAT E O F T H E A RT R E V I E W

Asthma-COPD overlap syndrome:

pathogenesis, clinical features, and
therapeutic targets
Janice M Leung, Don D Sin
Division of Respiratory Medicine
and Centre for Heart Lung A B S T RAC T
Innovation, St Paul’s Hospital,
University of British Columbia,
Asthma-COPD overlap syndrome (ACOS) or asthma-COPD overlap captures the
Vancouver, BC, Canada subset of patients with airways disease who have features of both asthma and
Correspondence to: D Sin
don.sin@hli.ubc.ca chronic obstructive pulmonary disease (COPD). Although definitions of ACOS vary, it
Cite this as: BMJ 2017;358:j3772 is generally thought to encompass persistent airflow limitation in a patient older than
doi: 10.1136/bmj.j3772
40 years of age with either a history of asthma or large bronchodilator reversibility.
Series explanation: State of the
Art Reviews are commissioned ACOS affects about a quarter of patients with COPD and almost a third of patients
on the basis of their relevance to
academics and specialists in the US
who previously had asthma. Compared with their counterparts with asthma or COPD
and internationally. For this reason alone, patients with ACOS have significantly worse respiratory symptoms, poorer
they are written predominantly by
US authors quality of life, and increased risk of exacerbations and hospital admissions. Whether
this condition emerges after gradual shifts in airway remodelling and inflammation
in a patient with COPD, as the result of noxious exposures in a patient with asthma,
or even as a de novo disease with its own pathology is yet to be determined.
Nevertheless, using treatments developed for asthma or COPD that target
eosinophilic, neutrophilic, or paucigranulocytic airway inflammation may be a helpful
approach to these patients until further clinical trials can be performed.

Introduction and neutrophilic mediated inflammation, proteolysis,

In 1961 at a bronchitis symposium in Groeningen, the
Netherlands, Orie and Sluiter proposed what has since
become known as the Dutch hypothesis, a paradigm
under which asthma and chronic obstructive pulmo‑
nary disease (COPD) share a common origin with their
divergence explained by an individual’s unique genetic
make-up and environmental exposures.1 Despite the
lasting influence of this paradigm, it was and continues
to be vigorously contested,2‑4 and, in reality, clinicians
have practised for decades under the rubric of a fixed
dichotomy between asthma and COPD. Only recently
has a more fluid understanding of these two conditions
re-emerged, existing instead along a continuum with
a subset of patients showing features of both. Asthma-
COPD overlap syndrome (ACOS) or asthma-COPD overlap
is now thought to affect up to a quarter of patients previ‑
ously thought to have COPD and up to a third of patients
previously thought to have asthma.5‑8
In this review, we present the case for ACOS as a clini‑
cally important phenotype among airways diseases and
advocate for the continued pursuit of its underlying
pathophysiology. Our main focus is the potential mecha‑
nisms of disease, whether ACOS is merely an evolution
from longstanding COPD or asthma or is its own disease
entity with a unique pathogenesis. In particular, we eval‑
uate the effects of smoking, air pollution, eosinophilic
genetics, and childhood lung development and how these
factors might lead to ACOS. Although much remains to be
determined about any of these factors in the development
of ACOS, they provide a framework of understanding as
to how features of asthma might develop in patients
with COPD and vice versa. The latter part of the review
will then use this framework to speculate on treatments
that may benefit patients with ACOS and ultimately to
establish priorities for the development of novel ACOS
therapeutics.
Rationale
The concept of ACOS is controversial, and even the use
of the term “syndrome” may meet with some resistance
as we do not yet know whether this is a single, unifying
disease.9 We urge the medical community, however, to
consider that many patients do not fall neatly within the
categories of asthma and COPD and that many have a
mix of features from both. Importantly, multiple studies
have now shown that, compared with those with asthma
or COPD alone, these patients face increased symptom
burdens and higher rates of hospital admission and exac‑
erbation,10‑16 indicating that ACOS is a distinct phenotype
in the airways disease spectrum and may have its own
clinical trajectory. Unfortunately, treatments specifically
targeted at this mixed phenotype are noticeably lack‑

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 STAT E O F T H E A RT R E V I E W
ing. Patients with ACOS are often overlooked or simply
excluded in clinical trials investigating novel treatments
for asthma and COPD.17 18 In addition, the paucity of data
on the mechanistic drivers of ACOS and how these might
differ from those of asthma or COPD has limited the dis‑
covery of ACOS specific treatments. As a result, how to
identify and manage these patients remains a puzzle for
clinicians. Investigation of this subset of patients with
airways disease is imperative.
Sources and selection criteria
We obtained references through a PubMed search inclu‑
sive of publications from 2000 to March 2017. Search
terms included “asthma COPD overlap syndrome”,
“ACOS”, and “mixed asthma COPD phenotype”. We
added additional references on the basis of the reference
lists of recent review papers, including the 2016 consen‑
sus statement from Sin et al.17 We retrieved randomised
controlled trials, observational cohort studies, systematic
reviews, meta-analyses, and case series and reports for
further review. We prioritised larger randomised con‑
trolled trials, observational cohort studies, and meta-
analyses that were published most recently. We filtered
search results for relevance to definition, epidemiology,
mechanisms, and treatment. We considered only Eng‑
lish language publications. For the section on emerging
treatments, we searched Clinicaltrials.gov for studies on
ACOS, neutrophilic asthma, and eosinophilic COPD.
Definition and diagnosis
Given the nascence of ACOS, no single accepted defini‑
tion for ACOS exists. Although it coined the term ACOS in
its 2015 update on asthma management and prevention,
the Global Initiative for Asthma (GINA) and the Global
Initiative for Chronic Obstructive Lung Disease (GOLD)
declined to put forth an overarching definition, citing
the need for better phenotyping and further mechanistic
work.19 More recently, the American Thoracic Society and
the National Heart, Lung, and Blood Institute issued a
workshop statement concluding that ACOS should not
be considered a discrete disease entity, but rather an
airways disease phenotype of mixed features.9 Nonethe‑
less, GINA/GOLD identified diagnostic clues that suggest
ACOS, including persistent yet reversible airflow limita‑
tion (post-bronchodilator forced expiratory volume in
1 s (FEV1) to forced vital capacity (FVC) ratio of <70%
and FEV1 improvement of >12% and >400 mL from base‑
line after bronchodilator therapy); a history of asthma
diagnosed by a doctor, atopy, allergies, or exposure to
noxious agents; either sputum neutrophilia or eosino‑
philia; and age 40 years or older. Other groups, working
largely through consensus opinion, have offered systems
of major and minor criteria by which to identify patients
who may have ACOS (fig 1).17‑23 Although subtleties exist
between these proposed systems, they share several key
obligatory features: that patients should be 40 years or
older, have persistent airflow obstruction, and a history of
asthma or evidence of bronchodilator reversibility. Curi‑
ously, many of these systems have not featured environ‑
mental exposures (either cigarette smoke or biomass fuel)
as a key component despite the clear links between such
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exposures and the development of COPD. We propose that
cigarette smoking or exposure to biomass fuel should be
an integral component of the definition of ACOS, to avoid
including patients with asthma who have developed air‑
way remodelling and fixed airflow limitation. Given the
lack of an accepted gold standard for the diagnosis of
ACOS, none of the diagnostic schemes in fig 1 has been
officially validated.
Of lesser importance in the diagnostic algorithm are
biomarkers commonly used in the diagnosis and manage‑
ment of asthma. Although helpful in identifying COPD
patients with possible asthma overlap, immunoglobulin
E (IgE), sputum or peripheral blood eosinophil count,
and fractional exhaled nitric oxide (FeNO) are not suf‑
ficiently sensitive or specific on their own for diagnosis
of ACOS. Elevated IgE concentrations are found in up to
half of patients with COPD,24 25 and eosinophilic sub‑
types of COPD are well described in the literature.26‑30
The debate about which level of peripheral eosinophil
count to ascribe to ACOS, whether above 2%, 3%, 5%,
or instead using an absolute measurement, has also
not been resolved.21‑33 A FeNO cut-off of above 35 ppb
may correlate with a post-bronchodilator FEV1 response
greater than 200 mL and atopy in patients with COPD,25 34
but the few studies that have looked at FeNO in ACOS
seem to offer conflicting evidence of the test’s discrimina‑
tory power.6 35 Moreover, like sputum eosinophil measure‑
ments,36 37 FeNO is neither widely available at all sites
nor standardised across instruments or centres.38 39 These
factors remain adjunctive tools in the diagnosis of ACOS
until further studies can be performed.
Epidemiology and clinical features
Without a standard definition or diagnostic system in
place, the fact that population estimates of ACOS are
highly variable comes as no surprise. Epidemiological
studies have used definitions as disparate as the major-
minor criteria system, self reported physician diagnoses,
and combinations of spirometry results and symptom
descriptions. Estimates of ACOS in the general popula‑
tion, using either self reported physician diagnoses or
a combination of airflow obstruction on spirometry and
symptom report, fall roughly between 2% and 3%.12‑46 In
comparison, estimates of asthma and COPD in these same
populations tend to be higher, around 5-17% for asthma
and 2-12% for COPD. However, the prevalence of ACOS
may vary according to geographic region, with estimates
ranging anywhere from 0.61% in China to 3.7% in the
United States.7 47 In cohorts of COPD patients specifically,
the prevalence of ACOS ranges from 6% to 55%,6‑58 with
pooled estimates from a meta-analysis suggesting a preva‑
lence of just over 25%.5 In cohorts of asthma patients, the
prevalence ranges from 10% to 31%.7‑59 In studies looking
at patients with any airway obstruction (defined by either
patient report or diagnosis in the medical record of asthma
or COPD or through spirometry), the prevalence ranges
from 15% to 56%.11‑62 Moving forward, comparisons of
prevalence across regions and time will ultimately require
a standardised definition for ACOS. Nevertheless, no mat‑
ter which definition is used, ACOS seems to account for a
considerable portion of all airways diseases.
 STAT E O F T H E A RT R E V I E W

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Fig 1 |  Consensus diagnostic criteria for asthma-COPD overlap syndrome (ACOS) in patients with airflow limitation. COPD=chronic obstructive pulmonary disease;
CT=computed tomography; FeNO=fractional exhaled nitric oxide; FEV1=forced expiratory volume in 1 s; FVC=forced vital capacity; LLN=lower limit of normal

Many case-control studies comparing ACOS with
asthma and COPD suggest a specific demographic
type: patients with ACOS tend to be younger,5‑64 to be
female,56 63 and to have higher body mass index,5‑64
lower socioeconomic status,41 42 and lower education
levels.41 42 ACOS patients also carry a higher burden of
comorbidities, particularly for conditions such as gas‑
tro-oesophageal reflux disease, osteoarthritis, osteopo‑
rosis, depression, and anxiety.42‑63 Importantly, despite
divergent definitions and methods, these studies con‑
sistently show a distinct clinical trajectory for ACOS,
one whose severity seems to exceed that of asthma or
COPD alone. By various disease control measures—
pulmonary function,15‑66 respiratory symptoms,43‑67

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Table 1 | Lung function decline in asthma-COPD overlap syndrome (ACOS)

Mean
duration of
Citation No Definition of ACOS follow-up FEV1 decline*
Fu, 201362 Asthma 8 Respiratory symptoms; increased 4 years Asthma 140 (230)
COPD 36 airflow variability; post- COPD 100 (130)
bronchodilator FEV1/FVC<70% and
ACOS 55 ACOS 60 (190)
FEV1<80%
de Marco, Neither 5659 Diagnosis of asthma or asthma-like 9 years Neither 26.2 (31.1-21.3)
201540 Asthma 941 symptoms + pre-bronchodilator Asthma 25.3 (30.5, 20.1)
chronic airflow obstruction,
COPD 166 COPD 37.3 (44, 30.6)
symptoms, history of active
ACOS 218 smoking or occupational exposure ACOS 25.9 (32.2, 19.6)
to vapours, dust, gas, or fumes
Lange, Asthma 124 Self reported asthma + post- 18 years Asthma 26 (29)
201668 COPD 303 bronchodilatory FEV1/FVC<0.70 COPD 46 (28)
ACO with early onset asthma† 62 ACO with early onset asthma 31 (37)
ACO with late onset asthma‡ 188 ACO with late onset asthma 51 (38)
Tkacova, COPD 4453 COPD + positive methacholine 5 years Difference in FEV1 decline between ACOS and
201648 ACOS 1434 challenge test COPD=−10.3 mL/year
COPD=chronic obstructive pulmonary disease; FEV1=forced expiratory volume in 1 s; FVC=forced vital capacity.
*Measured as mL/year with standard deviation or interquartile range, except for Fu et al, which showed results as change in FEV1 over entire four year period.
†Defined as onset before age 40 years.
‡Defined as onset after age 40 years.

exacerbation rates,14‑68 use of respiratory drugs,43‑69
overall health status,7‑43 quality of life,5‑55 and disabil‑
ity12‑61—ACOS patients have greater decrements than
their counterparts with asthma or COPD alone. Specifi‑
cally, as high as a 20% decrement in per cent predicted
FEV1 has been shown in ACOS patients compared with
asthma patients,41 43 and up to a 10% difference has been
shown between ACOS and COPD patients.43 Exacerbation
rates are up to four to five times higher in ACOS patients
compared with asthma and COPD patients.43 58 Emer‑
gency department visits,41‑61 hospital admissions,12‑61
and healthcare use7‑61 are also significantly higher in
ACOS patients, who incur twice the health related costs
of asthma and COPD patients,70 71 mainly through out‑
patient visits and drugs.72 The rate of physician visits,
for example, is approximately 1.3 to 1.5 times higher in
ACOS patients than in COPD patients.7 8
Data on excess decline in lung function (table 1)
and excess mortality (table 2) in ACOS remain mixed.
In a cohort of asthma, COPD, and ACOS patients, ACOS
patients with late onset asthma (onset over the age of
40 years) had the greatest FEV1 decline (49.6 mL/year
versus 27.3 mL/year in ACOS patients with early onset
asthma and 39.5 mL/year in COPD patients).68 However,
other studies have found that FEV1 decline in ACOS was
similar to that in asthma but better than in COPD,40 or
that no difference existed between ACOS, asthma, and
COPD groups.62 Similarly, studies have shown increased
mortality,45‑68 decreased mortality,14 73 and no difference
in mortality55 56 when comparing ACOS with asthma and
COPD. Discrepancies in case definition and variable fol‑
low-up times may account for these discordant results;
in any case, the natural history of ACOS is still very much
a question to be answered.
Mechanisms of disease
The clinical presentation of ACOS in a manner that
exceeds the expected disease burdens of either asthma
or COPD alone raises an important question as to its ori‑
gin: is ACOS the manifestation of a unique pathogenic

Table 2 | Survival and mortality in asthma-COPD overlap syndrome (ACOS)

Duration of
Citation No Definition of ACOS follow-up Survival and mortality statistics
Diaz-Guzman, Asthma 709 Self report of both asthma and COPD 18 years Odds ratio (95% CI) for death: asthma 3.70 (2.67 to 5.13);
201145 COPD 815 COPD 3.50 (2.52 to 4.85); ACOS 7.64 (5.08 to 11.49)
ACOS 357
Yamauchi, Asthma 19 865 Admission for asthma exacerbation + history of COPD OR admission for COPD Hospital In-hospital mortality: asthma 1.2%; COPD 9.7%; ACOS 2.3%
201573 COPD 4261 exacerbation + history of asthma stay
ACOS 6279
Sorino, 201655 Asthma 159 Post-bronchodilator FEV1/FVC<LLN + history of asthma or very positive 15 years 15 year survival: asthma 47%; COPD 25%; ACOS 35%
COPD 205 bronchodilator test (increase in FEV1≥15% and ≥400 mL) + personal history of
atopy + personal history of wheezing
ACOS 118
Wurst, 201656 COPD 1483 Self report of asthma in COPD patients Not Mortality rate: COPD 10%; ACOS 9%
ACOS 493 available
Tkacova, COPD 4453 COPD + positive methacholine challenge test 5 years Respiratory related mortality rate: COPD 0.77%; ACOS 1.69%
201648 ACOS 1434
Bai, 201714 COPD 65 Post-bronchodilator FEV1/FVC<70% + either smoking ≥10 pack years or long term Median: 45 Mortality rate: COPD 20%; ACOS 4.6%
ACOS 65 exposure to inhaled dust + positive bronchodilator test (improvement of months
FEV1≥12% and 200 mL)
COPD=chronic obstructive pulmonary disease; FEV1=forced expiratory volume in 1 s; FVC=forced vital capacity; LLN=lower limit of normal.

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Fig 2 |  Possible mechanisms for the development of asthma-COPD overlap syndrome (ACOS). Two mechanisms by which ACOS might develop are presented.
According to the Dutch hypothesis, asthma and chronic obstructive pulmonary disease (COPD) exist along a continuum with a shared origin. ACOS may fit along
this continuum if, for instance, a patient with asthma is exposed to the usual inhalants that cause COPD, such as cigarette smoke or air pollution. In both humans
with asthma and mouse models of asthma, these exposures lead to neutrophilic inflammation, cytokine release, oxidative stress, DNA methylation changes,
and matrix metalloproteinase mediated proteolysis. Such changes may then shift the asthmatic airway to features of COPD, including fixed airways obstruction
and emphysema. Conversely, the British hypothesis considers asthma and COPD to be unique diseases. Accordingly, ACOS may have its own origins in genetic
predisposition or early childhood events. Whereas single nucleotide polymorphisms in CSMD1 and GPR65 show marginal genome-wide significance for ACOS
compared with COPD alone, recent data suggest that attenuated lung development in early childhood may contribute to future development of ACOS

mechanism, is it simply the additive (or synergistic) result
of two distinct pathologies combined together, or is it the
end result of various environmental stimuli and insults
applied to a patient already affected by asthma or COPD?
To answer this question, revisiting the principles of the
Dutch hypothesis (and, conversely, its longstanding rival
the British hypothesis) may be helpful. Fundamentally,
the Dutch hypothesis posits that asthma and COPD are a
single disease of diffuse airway obstruction (termed by
Orie and Sluiter as “chronic non-specific lung disease”),
but that both endogenous and exogenous factors help to
steer patients into distinguishable phenotypes that we
understand better today as asthma or COPD.74 These fac‑
tors may include, but are certainly not limited to, genet‑
ics, sex, age, allergens, smoking, air pollution, biomass
fuel, concomitant pulmonary diseases, and infections. On
the other hand, the British hypothesis maintains separate
origins for asthma and COPD, underscored by the fact
that each disease has its own characteristic inflammatory
profile, genetic polymorphisms, response to treatment,
and clinical course.2 4
In this section, we consider ACOS within the prism of
these two schools of thought (fig 2). If the Dutch hypoth‑
esis holds true, this would suggest that ACOS should take
its place alongside asthma and COPD in the single disease
continuum, emerging only through the confluence of spe‑
cific patient related and environmental factors. Under this
scheme, one could consider these three diseases as being
somewhat in flux, that asthma leading to ACOS and COPD
leading to ACOS are two potential pathways by which
ACOS can develop. The British hypothesis as applied to
ACOS would instead suggest that this is in fact its own
disease with a unique genetic and molecular profile
distinguishing it from asthma and COPD. Suffice to say,
neither of these theories has yet been definitively proven
or disproven when considering the conundrum of ACOS.
We provide evidence that might support either side, but
ultimately the message here is that further mechanistic
work is desperately needed to unravel the pathogenesis
of ACOS.
How might asthma become ACOS?
The gradual shift of a patient with asthma to one with
features of both asthma and COPD requires several
physiological adjustments to occur. Whereas asthma is
conventionally viewed as a disease of variable airflow
obstruction, often in response to allergen hypersensi‑
tivity,19 the obstruction in COPD is thought to be incom‑

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 STAT E O F T H E A RT R E V I E W
pletely reversible and the product of environmental
exposures such as tobacco or biomass fuel.75 Patients
with asthma who are exposed to noxious inhalants
traditionally associated with COPD could conceivably
develop this degree of fixed obstruction over time. Sec‑
ondly, in contrast to asthma, emphysema and the loss of
lung elastic recoil is an important phenotype of COPD.76
Autopsy studies, however, suggest that these processes
may have been overlooked in asthma.77 78 Here, we review
both aspects of COPD that may develop in patients with
asthma.
Smoking
A quarter of patients with asthma are current ciga‑
rette smokers,79 and in comparison with non-smoking
patients with asthma, they carry a significantly greater
risk for developing fixed airflow obstruction and
ACOS.41‑82 Exposure to cigarette smoke in asthma seems
to remodel the airway in a way that may worsen small
airways obstruction. Firstly, although goblet cell hyper‑
plasia and mucus hypersecretion are well described
pathological findings in both asthma and COPD,
these features are aggravated in current smokers with
asthma compared with ex-smokers or non-smokers with
asthma.83 Secondly, multiple studies using both induced
sputum samples and endobronchial biopsies have now
shown that smoking in asthma increases airway neu‑
trophilia, shifting the predominantly eosinophilic cell
pattern typically observed in asthma towards a neutro‑
philic COPD pattern.84‑88 This process may be mediated
by cytokines, as interleukin (IL)-6, IL-8, and IL-17A have
all been implicated in n­eutrophil chemotaxis in smokers
with asthma.85‑89 In addition, smoking may induce CD8+
T cell proliferation in the asthmatic airway,90 similar to
COPD.91 92 Studies have shown that both neutrophil and
CD8+ T cell numbers correlate well with increasing air‑
flow obstruction.85 93 Increases in CD8+ T cells in par‑
ticular may relate to faster decline in lung function,93 as
well as incomplete reversibility of airflow obstruction.94
Experimental models in which allergen sensitised mice
are exposed to cigarette smoke seem to confirm these
findings, with attenuation of eosinophilic inflammation
in favour of increases in neutrophils, CD4+ and CD8+ T
cells, and total cells.95‑98
The recent application of new ’omics platforms to
asthmatic smokers has shed light on novel genes and
proteins that may play a role in shifting asthma to ACOS,
although the direct connection from these findings to
disease pathogenesis is still being clarified. Proteomic
analysis of induced sputum samples in four different
asthma phenotypes found that, compared with non-
smoking patients with severe asthma, smokers and
ex-smokers with severe asthma had decreased sputum
abundance of tyrosine protein kinase Lyn (involved in
mast cell degranulation).99 Genes up-regulated in the
smoking group predominantly reflect actin cytoskeleton
function. Validation of these target proteins and genes
in independent cohorts and deeper interrogation of the
mechanistic pathways underlying their role in smoking
related changes in the asthmatic airway may provide fur‑
ther insight into the origins of ACOS.
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Air pollution
Ambient air pollution—a mixture of particulate matter,
carbon monoxide, lead, sulphur dioxide, nitrogen oxides,
and ozone—is a well known mediator of airways disease,
and multiple large population studies have shown that
long term exposure to air pollution is detrimental for lung
function. The Framingham Offspring or Third Generation
studies, made up of more than 6000 participants, showed
that proximity to a major roadway and exposure to fine
particulate matter (PM2.5) decreased FEV1 and acceler‑
ated decline in FEV1.100 Other components of air pollu‑
tion, such as nitrogen oxides and PM10, have also been
associated with low FEV1.101 Conversely, improvements in
PM10 and PM2.5 levels over time increased FEV1 and FVC
in children residing in southern California.102 For patients
with asthma in particular, exposure to excess air pollu‑
tion has considerable deleterious effects, with exacerba‑
tions, emergency room visits, and hospital admissions
all closely associated with levels of air pollution.103‑107
The effect of air pollution on the asthmatic airway has
multiple facets: impaired regulatory T cell function,108
activation of toll-like receptor (TLR)-2 and TLR-4 medi‑
ated innate immune responses,109 increased oxidative
stress,110‑113 cytokine mediated airway inflammation,114 115
and alterations in DNA methylation.116 117
Any or all of these mechanisms could conceivably
induce the phenotypic switch from asthma to ACOS,
although data confirming this hypothesis are notably
lacking. Nonetheless, a study investigating the develop‑
ment of COPD in Ontario’s asthma population provides
the most convincing evidence to date for a link between
air pollution and ACOS.8 In this study, 6040 adults in
Ontario, Canada, with asthma were followed between
1996 and 2014, with a diagnosis of COPD by a physician
during that time period used as the definition of ACOS. Air
quality data were provided from 49 continuous fixed site
monitors throughout Ontario. For every increase in PM2.5
of 10 μg/m3, the adjusted hazard ratio for developing
ACOS was 2.78 (95% confidence interval 1.62 to 4.78).
Environmental exposures may thus be one important trig‑
ger in the pathogenesis of ACOS.
Loss of lung elastic recoil and development of
emphysema in asthma
Emphysema, hyperinflation, and the loss of lung elastic
recoil are often associated with COPD, but they may also
play an integral role in the later stages of severe asthma.
Recognition of the loss of lung elastic recoil dates back
to 1967 when Gold, Kaufman, and Nadel showed that
patients with severe asthma lasting longer than five years
had significantly reduced lung elastic recoil compared
with healthy people.118 Initially, this was not thought to
be related to emphysematous tissue destruction, as elas‑
tic recoil would return to normal following treatment with
bronchodilators. However, subsequent studies showed
that the loss of lung elastic recoil was more durable than
anticipated and that this loss can still be observed in sta‑
ble clinical states.119‑121 Normal diffusing capacity and
computed tomography imaging again argued against the
presence of significant emphysema as a cause of elastic
recoil abnormalities.120
 STAT E O F T H E A RT R E V I E W
Two autopsy studies have since shifted our understand‑
ing of the structural lung changes in asthma. A study in
2004 found a decrease in elastic fibres and an increase
in the number of abnormal alveolar attachments in fatal
asthma compared with controls.78 A subsequent study in
2014 reported the autopsy findings of three patients with
asthma, which showed that although macroscopic evalu‑
ation of the lungs did not show emphysema, microscopic
examination showed diffuse upper lobe predominant
mild centrilobular emphysema.122 More recently, it has
been suggested that recurrent exacerbations of asthma
induce bronchiolar inflammation, with activation of
proteases such as neutrophil elastase, cathepsin G, and
matrix metalloproteases (MMP), all of which conspire to
break down the lung parenchyma.77 In vitro work has
implicated IL-13 as a potent suppressor of elastin mRNA
expression through a pathway that involves the secretion
of MMP-1 and MMP-2.123 The later stages of asthma may
thus start to resemble emphysema, shifting asthma down
the airways spectrum to ACOS.
How might COPD become ACOS?
The reverse scenario, in which a patient with COPD devel‑
ops features of asthma, is admittedly less compelling.
This would require the development of three important
pathological traits of asthma in a patient with COPD:
allergen sensitisation, airway hyper-responsiveness, and
eosinophilic and type 2 (Th2) mediated airway inflam‑
mation. Allergen sensitisation has been known to occur
in COPD, particularly in older people,124 and upwards of
25-30% of COPD patients report allergic upper airway
symptoms or show IgE sensitisation to perennial aller‑
gens.125 Among smokers, allergen sensitisation has also
been associated with faster decline in lung function and,
among COPD patients, with increased respiratory symp‑
toms and COPD exacerbations.125 126 Whether allergen
sensitisation ultimately remodels the airway in the man‑
ner of asthma has yet to be demonstrated, however, and
little research on this has been done. Similarly, airway
hyper-responsiveness and eosinophilic/Th2 mediated
inflammation also occur in COPD. However, for the for‑
mer it is by no means certain whether the pathological
process is the same as in asthma, and for the latter it is
conceivable that similar inflammatory changes also occur
in patients with asthma who develop ACOS. Below, we
review the mechanisms by which these two features may
emerge or worsen over the course of COPD.
Airway hyper-responsiveness and airway remodelling
Airway hyper-responsiveness is the acute response of an
airway to a bronchial challenge, often in the form of an
agent such as methacholine or histamine. Airway hyper-
responsiveness affected up to a quarter of participants
in the Lung Health Study and was associated with faster
decline in FEV1 and higher respiratory related mortality.48
The response to a bronchial challenge is approximately
25-50% more robust in moderate to severe COPD than
in mild COPD. This might suggest that this later stage
development may simply be geometric in nature, as the
resistance of the airway is inversely proportional to the
radius to the fourth power (and therefore may merely
For personal use only 7 of 14
represent advanced airflow obstruction regardless of the
underlying airways disease).127 128 Airway wall thicken‑
ing, airway smooth muscle (ASM) proliferation, and the
obliteration of the terminal bronchioles develop over time
in COPD and, along with mucous secretions, contribute
to this airway narrowing.129‑131 The degree of airway
hyper-responsiveness depends on the balance between
ASM shortening and the opposite recoil force of the sur‑
rounding tissue, which in COPD may be compromised
by the development of emphysema and the destruction
of elastic fibres.132 As the airway wall thickens and as
ASM area increases, a larger ASM contraction against a
weaker opposing elastic load allows for a larger degree
of airway narrowing. Whether we can easily equate the
process of airway hyper-responsiveness in COPD with
that in asthma is not clear, however. The contribution
of changes in the extracellular matrix to airway hyper-
responsiveness is much larger in COPD than in asthma,
whereas the airway hyper-responsiveness in asthma is
driven primarily by ASM hypertrophy and hyperplasia.133
Therefore, although these processes may look similar on
provocation testing, treatments targeting airway hyper-
responsiveness in asthma may not necessarily translate to
COPD patients who develop airway hyper-responsiveness
and evolve to ACOS.
Airway inflammation
Conventional understanding of COPD places emphasis
on a neutrophilic, type 1 (Th1) inflammatory airway
response,134 135 but a subset of COPD patients who do
not cleanly fit this paradigm clearly exist. For instance,
peripheral blood eosinophil concentrations persistently
above 2% over a three year period were found in just
under 40% of participants in the ECLIPSE (Evaluation
of COPD Longitudinally to Identify Predictive Surrogate
End-points) cohort.136 Recently, Christensen et al applied
a 100 gene signature corresponding to high Th2 inflam‑
mation to airway epithelial cells from COPD patients.137
Approximately 5% of smokers with COPD showed a high
Th2 gene expression signature, which was associated
with increased serum and tissue eosinophil counts,
increased bronchodilator responsiveness, and greater
improvement in hyperinflation after treatment with
inhaled corticosteroids. This signature also notably cor‑
related with the gene expression of mast cell marker CPA3
and eosinophil chemotactic molecule CCL26. Whether
this signature has identified a unique endotype of COPD
or has isolated an important ACOS airway epithelial gene
signature is unclear; the authors recommend that the sig‑
nature be studied in cohorts better phenotyped for both
these conditions.
Despite the concerns about the quality of phenotyping
in Christensen et al’s cohorts, other authors investigating
sputum cytokine clusters would concur with their hypoth‑
esis that an overlap phenotype of eosinophilic COPD can
be readily recognised.138 In a cohort of patients with
severe asthma and COPD, three clusters were identified
on the basis of sputum cytokine measurements: asthma
with high Th2 and eosinophilic inflammation, asthma
and COPD with sputum neutrophil predominance, and
COPD with predominantly eosinophilic inflammation.
 STAT E O F T H E A RT R E V I E W
This latter group, corresponding to the high Th2 COPD
group in Christenson et al’s study, featured increased con‑
centrations of important Th2 cytokines and chemokines—
namely, IL-6, CCL2, CCL13, and CCL17. Although these
studies have been instrumental in exposing the sig‑
nificance of Th2 responses in COPD, why certain COPD
patients are driven towards this response compared with
others who remain in the Th1, neutrophilic realm is still
unclear.
Is ACOS its own disease?
Finally, in accordance with the British hypothesis, we
consider a third scenario in which ACOS has a unique
origin unrelated to either asthma or COPD. Some of the
strongest evidence against the Dutch hypothesis has been
the striking lack of a unifying genetic cause of asthma
and COPD despite many genome-wide association stud‑
ies (GWAS).139 Whether ACOS will follow this pattern and
show its own genetic determinants separate from those
of asthma or COPD has yet to be definitively answered.
One GWAS comparing patients with COPD and ACOS in
the COPDGene Study did not find any single nucleotide
polymorphisms (SNPs) associated with ACOS that met the
pre-determined genome-wide significance threshold of
5×10−8, although the authors noted that the study was
probably underpowered to detect this degree of differ‑
ence.16 SNPs that approached genome-wide significance
included those on the genes CSMD1 and GPR65, the for‑
mer a tumour suppressor gene previously implicated in
emphysema and the latter a mediator of eosinophil acti‑
vation in asthma.140 141 Clearly, genetic work on ACOS
remains preliminary and larger studies are needed to
better establish its genetic determinants.
If asthma and COPD are not in fact prerequisite stages
to be passed through before developing ACOS, it is con‑
ceivable that events or insults in early childhood might
trigger the shift towards asthma, COPD, or ACOS, each
having its own distinct trajectory. In support of this
hypothesis, the Tasmanian Longitudinal Health Study
analysed lung function collected at age 7 and then at age
45, determining whether childhood spirometry could
predict the development of ACOS in adulthood (defined
as a self report of asthma in conjunction with a post-bron‑
chodilator FEV1/FVC below the lower limit of normal).46
Those in the lowest quarters of FEV1/FVC and FEV1 per
cent predicted at age 7 had a 16.3 and 2.93 greater odds,
respectively, of developing ACOS by age 45. This associa‑
tion, which persisted even after accounting for smoking,
was far greater than that between childhood lung func‑
tion and COPD, whereas no association with asthma was
noted. Whether due to in utero and/or childhood expo‑
sure to smoke or childhood respiratory infections, the
inability to reach maximum lung function during child‑
hood, already discernible by age 7, seems to have lasting
implications for future airways disease.
Possibilities for therapeutic intervention
The myriad ways in which a particular person can poten‑
tially develop ACOS poses considerable challenges for
treatment. The very heterogeneity of ACOS, the untoward
by-product of a lack of consensus surrounding its patho‑
For personal use only 8 of 14
physiology and even its definition, implies that no single
class of treatment is likely to help all patients. Impor‑
tantly, we and others have advocated that the field move
towards deeper phenotyping of these patients to guide
treatment. In particular, as proposed by Barnes, three
phenotypes of ACOS have been described that are impor‑
tant to establish before starting treatment: eosinophilic
COPD (high Th2 inflammation), neutrophilic asthma
(low Th2 inflammation), and paucigranulocytic ACOS.142
Needless to say, improved access to and standardisation
of sputum cytology measurements is needed before such
a strategy can be implemented. Even so, this framework
provides a useful algorithm for targeting treatment of
ACOS, one rooted in the presumed pathophysiology of
the disease. In this section, we present the evidence for
therapeutic options based on these three phenotypes,
with the caveat that few trials have specifically investi‑
gated patients with ACOS. Extrapolations from asthma
and COPD trials are thus also presented.
Eosinophilic COPD
Inhaled corticosteroids
Targeted against eosinophilic pathology, inhaled corti‑
costeroids and combinations with long acting β agonists
(LABA) have naturally featured prominently in treat‑
ment recommendations for ACOS given the emphasis
many groups have placed on eosinophilia as a diagnos‑
tic criterion.143 144 In addition, inhaled corticosteroid/
LABA combinations are recommended in both asthma
and COPD, making their use in ACOS appealing. The
strength of evidence for these recommendations is mixed,
however. Trials evaluating inhaled corticosteroids alone
and in combination with LABA have been small in size
and mostly retrospective and observational in nature.
Moreover, results have been conflicting. A 12 year obser‑
vational retrospective cohort study in which 90 patients
with ACOS treated with inhaled corticosteroids were com‑
pared with 35 ACOS patients not treated with inhaled
corticosteroids found no difference in decline in FEV1,
exacerbation rates, or overall mortality.145 On the other
hand, a prospective study found that 127 ACOS patients
who received inhaled budesonide had improved spirom‑
etry and measures of hyperinflation, sputum eosinophils,
serum IgE, and FeNO after treatment.146 The lack of a true
placebo group in this trial, however, limits the generalis‑
ability of these results. Compared with COPD patients,
those with ACOS may show better FEV1 response to
inhaled corticosteroid/LABA treatments, but again, these
trials featured no more than 45 ACOS patients.52 147 The
possibility that inhaled corticosteroids with or without
LABA may provide benefit for eosinophilic ACOS patients
cannot be either discounted or definitively proven given
the amount and quality of data at hand.
Anti-IgE therapies
Severe, persistent asthma that remains uncontrolled
despite inhaled corticosteroids and inhaled corticoster‑
oid/LABA combinations now prompts consideration of
anti-IgE treatments, including recombinant humanised
monoclonal antibodies such as omalizumab. The binding
of IgE to the IgE receptor FcεR1 on basophils and mast
 STAT E O F T H E A RT R E V I E W
cells triggers cytokine mediated eosinophilic inflam‑
mation; blockage of this linkage by compounds such as
omalizumab helps to attenuate this cascade, which ulti‑
mately has been shown to reduce exacerbations, hospital
admissions, emergency department visits, and inhaled
corticosteroid and rescue inhaler use in patients with
advanced asthma.148 Recently, the efficacy of omalizumab
was assessed in patients with severe allergic asthma
enrolled in the Australian Xolair Registry who also had
a diagnosis of COPD, whether by physician assessment
(n=17) or by fixed airflow obstruction on spirometry
(n=55).149 Regardless of the definition of COPD, these
ACOS patients showed significantly improved asthma
control and health related quality of life scores (exceed‑
ing the minimally clinically important difference) follow‑
ing treatment with omalizumab despite no significant
improvements in their FEV1. These incremental gains
were equivalent to those observed in patients with asthma
alone. Smaller case series of three and 10 ACOS patients
treated with omalizumab each echoed these improve‑
ments in asthma symptom control.150 151
Anti-IL-5/IL-5Rα therapies
IL-5 plays a key role in eosinophil differentiation and
maturation in the bone marrow, as well as migration
from the blood to tissue sites.152 Three new anti-IL-5
and anti-IL-5Rα monoclonal antibodies (mepolizumab,
benralizumab, and reslizumab) have now been studied
in eosinophilic asthma with impressive improvements
in exacerbation rates, asthma control scores, and ster‑
oid usage.153‑156 These compounds have yet to be tested
in cohorts of ACOS patients, but a randomised, double
blind, placebo controlled study evaluating benralizumab
in COPD patients with sputum eosinophil counts above
3% was far from promising.157 Benralizumab failed to
reduce the exacerbation rate, the primary endpoint,
although improvements in spirometry seemed to occur.
For the subgroup of patients with baseline blood eosino‑
phil counts above 200 cells/μL, numerical but non-sig‑
nificant improvements in exacerbation rates, FEV1, and
St George’s Respiratory and Chronic Respiratory Disease
Questionnaire scores occurred, but until further large
randomised controlled trials are conducted, the role
for anti-IL-5 and anti-IL-5Rα monoclonal antibodies in
eosinophilic COPD is unclear.
Anti-IL-13/IL-4Rα therapies
IL-13 and IL-4 are important Th2 cytokines that contrib‑
ute to several asthma related pathologies including the
regulation of eosinophils, mucus production, goblet cell
hyperplasia, ASM contraction, and airway remodelling.148
Anti-IL-13 antibodies such as lebrikizumab and traloki‑
numab target IL-13, whereas anti-IL-4Rα antibodies such
as dupilumab target both IL-13 and IL-4. In patients with
severe, persistent asthma, these monoclonal antibodies
have shown improvements in lung function and exacer‑
bation rates.158‑162 The efficacy of these agents seems to be
enhanced in patients with high serum concentrations of
periostin, an extracellular matrix protein deposited in the
basement membrane of asthmatic airways that reflects
Th2 inflammation.163 Although the IL-4Rα antagonists
For personal use only 9 of 14
seem to show greater efficacy against asthma than do the
IL-13 agents, both have yet to be tested in eosinophilic
COPD, so extrapolation to ACOS is merely speculative at
this time.
Neutrophilic asthma—macrolides
The pleiotropic properties of macrolides, functioning
at once as antibacterial, immunomodulatory, and anti-
inflammatory drugs, have resulted in their wide appli‑
cation in several neutrophilic respiratory disorders such
as cystic fibrosis and non-cystic fibrosis bronchiectasis.
Macrolides seem to dampen IL-8 and CXCL1, leading to
neutrophil apoptosis and decreased oxidative stress.164
Importantly, azithromycin has become a therapeutic
option in COPD, in which its long term use was shown to
reduce the frequency of exacerbations,165 and whether
these effects could translate to neutrophilic forms of
asthma has been the subject of several studies. To date,
the results have been modest at best. Although the larger
randomised controlled trials focusing on patients with
non-eosinophilic asthma have shown a reduction in exac‑
erbation rates and duration of acute events with long term
macrolide use,166 167 other trials have shown no significant
benefit on either these outcomes or asthma symptom con‑
trol and lung function.168‑174 The 2015 Cochrane review
of macrolides in chronic asthma concluded that, on the
basis of very low quality evidence, macrolides had no dis‑
cernible benefit in reducing exacerbations or in improv‑
ing asthma control, quality of life, and rescue medication
use.175 A small positive effect on lung function could be
observed, suggesting that there may still be some clinical
benefit to certain asthma patients; however, large effect
sizes for clinically important endpoints in asthma are
unlikely to be achieved with macrolides.
Paucigranulocytic ACOS—long acting muscarinic
antagonists
For those ACOS patients without a distinct cellular inflam‑
matory response, we return to bronchodilators, the stal‑
wart of airways disease treatment. Ideally, for the patient
with ACOS, bronchodilators should reduce ASM tone and
dynamic hyperinflation. We have described the role of
inhaled corticosteroid/LABA combinations in ACOS
above; here we discuss whether long acting muscarinic
antagonists (LAMA) widely used in COPD have any benefit
in asthma and, by extension, ACOS. Studies assessing the
efficacy of LAMA therapy in asthma have largely evalu‑
ated tiotropium, an M1 and M3 receptor antagonist with
a proven benefit in COPD. Several large, high quality ran‑
domised controlled trials (one of which enrolled asthma
patients with persistent post-bronchodilator airflow limi‑
tation176) have consistently shown improvements in FEV1
in patients with asthma, both in children and in adults,
when tiotropium is added to inhaled corticosteroid and
inhaled corticosteroid/LABA therapies.176‑182 Several stud‑
ies have also shown a reduction in exacerbation risk,179 183
as well as asthma symptom control.179‑182 Whether LAMA
compounds other than tiotropium have similar positive
effects is yet to be tested, but the clinical improvements
observed in both COPD and asthma patients suggest that
LAMA therapies may be an option for patients with ACOS.
 STAT E O F T H E A RT R E V I E W
GLOSSARY OF ABBREVIATIONS
ACOS—asthma-COPD overlap syndrome
ASM—airway smooth muscle
COPD—chronic obstructive pulmonary disease
FeNO—fractional exhaled nitric oxide
FEV1—forced expiratory volume in 1 s
FVC—forced vital capacity
GINA—Global Initiative for Asthma
GOLD—Global Initiative for Chronic Obstructive Lung
Disease
GWAS—genome-wide association studies
IgE—immunoglobulin E
IL—interleukin
LABA—long acting β agonist
LAMA—long acting muscarinic antagonist
MMP—matrix metalloprotease
SNPs—single nucleotide polymorphism
Emerging treatments
Although several ongoing studies are aiming to charac‑
terise ACOS further, no clinical trials are being conducted
to assess the utility of either novel or known treatments
in ACOS patients. Furthermore, attempts to apply avail‑
able asthma therapies to COPD patients with an eosino‑
philic phenotype have garnered mixed results. One phase
III trial evaluating mepolizumab in eosinophilic COPD
showed a statistically significant reduction in moderate
to severe exacerbations compared with placebo, whereas
another failed to show any difference.184 Whether future
trials will be performed to resolve these conflicting results
has yet to be announced.
Guidelines
To date, no guideline statements grading the quality of
evidence surrounding ACOS have been issued. Expert
panel consensus statements (fig 1), however, have been
published with general agreement about two principles:
that ACOS should be considered in any patient over the
age of 40 with persistent airflow obstruction and a history
of asthma or evidence of bronchodilator reversibility and
that the treatment of ACOS should include inhaled corti‑
costeroids. However, these statements acknowledge the
need for additional evidence for these recommendations.
Conclusions
ACOS may represent a distinct clinical phenotype of
asthma and COPD and, importantly for clinicians, is
marked by worse respiratory symptoms and rates of
exacerbation and hospital admission. For these rea‑
sons, the diagnosis of ACOS should be considered in all
patients over the age of 40 years with persistent airflow
obstruction, a history of cigarette smoking or exposure to
biomass fuel, and a history of asthma or strong broncho‑
dilator reversibility on spirometry. Although the pathway
to ACOS has yet to be elucidated in its entirety, one can
speculate that several ways exist in which a patient with
asthma can develop a neutrophilic “COPD-like” airway
and a COPD patient can develop an eosinophilic, reac‑
tive “asthma-like” airway. Basing therapeutic choices on
these inflammatory distinctions may help to guide the
For personal use only 10 of 14
QUESTIONS FOR FUTURE RESEARCH
• Do unique genetic, molecular, and histological patterns
exist that distinguish asthma-COPD overlap syndrome
(ACOS) from asthma or chronic obstructive pulmonary
disease (COPD) alone?
• What are the long term clinical outcomes for patients with
ACOS, and how might these outcomes vary depending on
the definition used for ACOS?
• Should first line treatment for patients with ACOS include
inhalers containing inhaled corticosteroid?
• Do patients with ACOS benefit from standard treatments
for asthma and COPD, or are novel compounds needed
specifically tailored to the ACOS phenotype?
clinician in an otherwise data-free zone. Greater empha‑
sis on the ACOS population in future research is recom‑
mended.
We thank Cheng Wei Tony Yang and Chloe Chih Ya Huang for their
contribution to the figures.
Contributors: Both authors were involved in the conception, writing, and
editing of the manuscript. Both are guarantors.
Competing interests: We have read and understood BMJ policy on
declaration of interests and declare the following interests: DDS has
received honorariums for speaking engagements with AstraZeneca and
Boehringer Ingelheim and for participating in COPD advisory boards of
Sanofi, Regeneron, AstraZeneca, Boehringer Ingelheim, Novartis, and
Merck and has received research funding for investigator initiated COPD
studies from Merck, AstraZeneca, and Boehringer Ingelheim. DDS is
supported by a Tier 1 Canada research chair award in COPD.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient involvement: No patients were involved in the creation of this article.
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