[ Editorial ]
ACO is now recognized in several national and
Asthma-COPD Overlap
Peter J. Barnes, Master FCCP
London, England
Most clinicians can easily distinguish asthma and
COPD. Asthma usually has an early onset with
intermittent symptoms, a good response to inhaled
therapy, and is often associated with other allergic
diseases, whereas COPD is of late onset, slowly
progressive symptoms, poor response to inhaled
therapy, and is usually associated with long-term
smoking. However, patients can sometimes have
features of both diseases, and this condition has been
termed asthma-COPD overlap syndrome (ACOS).1
Some overlap may be predicted because asthma and
COPD are both common, and there is no evidence that
one disease protects against the other. To call this
overlap a syndrome is misleading, however; it includes
different phenotypes, such as patients with COPD
and eosinophilic inflammation, patients with asthma
and severe disease or who smoke in whom there is
predominantly neutrophilic inflammation, and patients
with asthma who have largely irreversible airway
obstruction due to structural changes. Thus, it may be
better to refer to asthma-COPD overlap (ACO), rather
than ACOS.2 Indeed, the patients who receive a primary
diagnosis of asthma who have some features of COPD
are better considered as phenotypes of asthma. The
“Dutch hypothesis,” first proposed in the 1960s,
suggested that there was a common genetic background
to airway obstruction with a spectrum of clinical disease
from asthma to COPD. Although the validity of the
Dutch hypothesis has been fiercely debated, recent
genetic studies indicate that there is very little, if any,
common genetic background of asthma and COPD.3
AFFILIATIONS: From the National Heart and Lung Institute,
Imperial College London.
FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.
CORRESPONDENCE TO: Peter J. Barnes, Master FCCP, National
Heart and Lung Institute, Dovehouse St, London SW3 6LY, England;
e-mail: p.j.barnes@imperial.ac.uk
Copyright Ó 2016 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: http://dx.doi.org/10.1016/j.chest.2015.08.017
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international guidelines.1
It is important to recognise whether a patient has ACO
because this determination may influence the clinical
course, long-term outlook, and response to therapy.
There is uncertainty about the prevalence of ACO; it
depends on the populations that are studied and tends
to be higher in patients referred to specialists because
they may be more difficult to manage. There is general
agreement from several studies that 10% to 20% of
patients with COPD have features of asthma.2 In the
study published in this issue of CHEST (see page 45),4
ACO was found in approximately 15% of a Spanish
cohort of > 800 patients with COPD, in good agreement
with the 13% of 3,500 patients with ACO in the COPD
Gene consortium.5 Among a population of patients with
asthma, a higher proportion are likely to have ACO
because many will be current smokers, about 5% will
have severe asthma, and a higher proportion will have
irreversible airway obstruction. Patients with ACO
identified among those who receive a primary diagnosis
of asthma or COPD will likely be of different
phenotypes.
Most studies have reported that patients with COPD
who have features of asthma have a worse prognosis,
in terms of more frequent and severe exacerbations,
more frequent symptoms, worse quality of life, more
comorbidities, and less emphysema as noted on CT
scans.2,5,6 A greater degree of airway reversibility in
response to bronchodilators has been used as a criterion
of ACOS; it is therefore not surprising that this factor
is more frequently found in these patients. Surprisingly,
in the study by Cosio et al,4 there were no significant
clinical differences apart from reversibility and the fact
that patients with ACOS had a better survival, at least
after 1 year of study. However, because of a lack of
longitudinal studies, it is unknown whether patients
with COPD and features of asthma have a more rapid
progression of disease.
The patterns of airway inflammation in asthma and
COPD are markedly different, with mast cell activation,
infiltration of eosinophils driven by activation of
T-helper type 2 cells and type 2 innate lymphoid cells
in asthma; in COPD, there is typically no mast cell
activation (which accounts for the lack of reversibility),
7
 infiltration of neutrophils and macrophages, and driven
by T-helper types 1 and 17 cells, and CD8þ T cells.7
COPD patients with asthma may have infiltration of
eosinophils in the airways, and this may be driven by
type 2 innate lymphoid cells, which secrete IL-5 but
are not activated by allergens.8 There is an increased
concentration of IL-5 in the sputum of patients with
COPD who have increased eosinophils, and both are
reduced by oral prednisolone.9 By contrast, patients with
asthma and features of COPD may have predominantly
neutrophilic inflammation or no increase in inflammatory
cells.
An important reason for identifying ACO is to select
the most appropriate therapy. There is scant
information on the therapy of overlap because these
patients are often excluded from large clinical trials of
asthma and COPD. Although most patients with COPD
exhibit little or no therapeutic response to even high
doses of inhaled corticosteroids, patients with COPD
and increased sputum eosinophil counts display a
greater improvement in FEV1.10 Increasing the dose of
inhaled corticosteroids when sputum eosinophil counts
increase > 3% significantly reduces exacerbations.11
A recent post hoc analysis of a COPD trial showed that
an inhaled corticosteroid was more effective in reducing
exacerbations in those with blood eosinophil counts
> 2%, particularly in those with > 6% eosinophils.12
These studies suggest that patients with COPD and
increased eosinophil counts may benefit from triple
therapy with the addition of an inhaled corticosteroid
to long-acting b2-agonist and anticholinergic inhalers.
Similarly, asthmatic patients with COPD features may
benefit from the addition of a long-acting anticholinergic
agent to an inhaled corticosteroid/long-acting b2-agonist
combination.13 Several new treatments are in development
that may be suitable for the future management of
patients with ACO, including anti-eosinophil-directed
monoclonal antibodies and kinase inhibitors.14 However,
benralizumab, an antibody that blocks the IL-5 receptor,
was ineffective in patients with COPD and eosinophilia.15
To manage patients with overlap effectively, it is
necessary to make the diagnosis. This is currently
done by clinical assessment, including history, exposure,
and bronchodilator reversibility, which are imprecise.1
Airway eosinophilia may be measured by using sputum
eosinophil counts or fractional exhaled nitric oxide, but
these tests are usually not available in routine clinical
practice. Blood eosinophil counts are easy to perform
8 Editorial
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and may reflect airway eosinophilia and predict
corticosteroid responsiveness.12 Sputum neutrophilia is
not reflected by circulating neutrophils and can only be
detected by examination of induced sputum, however.
A formal trial of oral corticosteroids (prednisolone or
prednisone 30 mg daily for 2 weeks) may be useful for
identifying an asthmatic component in patients with
COPD (with improvement in FEV1 > 15% or 200 mL).
ACO is a clinical reality and is important to identify,
but more research is needed to define these overlap
phenotypes, to identify them in the clinic, and to
understand the best way of managing these patients.
References
1. Global Initiative for Asthma. Asthma, COPD and asthma-COPD
overlap syndrome (ACOS). Global Initiative for Asthma website.
http://www.ginasthma.org/local/uploads/files/ACOS_2015.pdf.
Accessed October 2, 2015.
2. Gibson PG, McDonald VM. Asthma-COPD overlap 2015: now we
are six. Thorax. 2015;70(7):683-691.
3. Smolonska J, Koppelman GH, Wijmenga C, et al. Common genes
underlying asthma and COPD? Genome-wide analysis on the Dutch
hypothesis. Eur Respir J. 2014;44(4):860-872.
4. Cosio BG, Soriano JB, López-Campos JL, et al. Defining the asthma-
COPD overlap syndrome in a COPD cohort. Chest. 2016;149(1):
45-52.
5. Hardin M, Cho M, McDonald ML, et al. The clinical and genetic
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7. Barnes PJ. Immunology of asthma and chronic obstructive
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8. Hammad H, Lambrecht BN. Barrier epithelial cells and the control
of type 2 immunity. Immunity. 2015;43(1):29-40.
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and the short term response to inhaled mometasone in chronic
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12. Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. Blood
eosinophil counts, exacerbations, and response to the addition of inhaled
fluticasone furoate to vilanterol in patients with chronic obstructive
pulmonary disease: a secondary analysis of data from two parallel
randomised controlled trials. Lancet Respir Med. 2015;3(6):435-442.
13. Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly
controlled with standard combination therapy. N Engl J Med. 2012;
367(13):1198-1207.
14. Barnes PJ. Therapeutic approaches to asthma-chronic obstructive
pulmonary disease overlap syndromes. J Allergy Clin Immunol.
2015;136(3):531-545.
15. Brightling CE, Bleecker ER, Panettieri RA Jr, et al. Benralizumab for
chronic obstructive pulmonary disease and sputum eosinophilia: a
randomised, double-blind, placebo-controlled, phase 2a study.
Lancet Resp Med. 2014;2(11):891-901.
[ 149#1 CHEST JANUARY 2016 ]