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Asthma-COPD Overlap Syndrome

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 COPD MONOGRAPH 33

06. Asthma – COPD Overlap Syndrome

Dr. Ashok Mahashur1, Dr. Radhika Banka2

Introduction usually associated with COPD. ACOS is therefore

identified in clinical practice by the features that it
In respiratory medicine, the term overlap syndrome shares with both asthma and COPD.2 Just as asthma
has been applied both to the association between and COPD are heterogeneous diseases, each with a
obstructive sleep apnea and chronic obstructive range of underlying mechanisms, ACOS also does
pulmonary disease (COPD)1 and to patients with not represent a single disease. Mechanisms
features of both asthma and COPD (asthma–COPD underlying ACOS are largely unknown and hence a
overlap syndrome – ACOS). formal definition of ACOS cannot be provided at the
moment. It is acknowledged that various phenotypes
Asthma and COPD are major public health of ACOS exist that will be identified in due course by
problems.Asthma and COPD are typically more detailed characterization on the basis of
characterized as different diseases with unique clinical, pathophysiological and genetic
epidemiologicalfeatures as well as identifiers4,5,6.
pathophysiological mechanisms. Asthma is a
Why is there a need to classify ACOS?
heterogeneous disease, usually characterized by
chronic airway inflammation. It is defined by the Significant proportions of patients who present with
history of respiratory symptoms such as wheeze, chronic respiratory symptoms, particularly older
shortness of breath, chest tightness and cough that patients have diagnoses and/or features of both
vary over time and in intensity, together with variable asthma and COPD, and are found to have chronic
expiratory airflow limitation.2 airflow limitation (i.e. that is not completely
reversible after bronchodilatation). Although defining
COPD is defined as a common preventable and these individuals as ‘overlap syndrome’ is difficult,
treatable disease, characterized by persistent airflow there is broad agreement that patients with features of
limitation that is usually progressive and associated both asthma and COPD experience frequent
with enhanced chronic inflammatory responses in the exacerbations, have poor quality of life, a more rapid
airways and the lungs to noxious particles or gases. decline in lung function and high mortality, and
Exacerbations and comorbidities contribute to the consume a disproportionate amount of healthcare
overall severity in individual patients.2 resources than asthma or COPD alone and hence
there is a critical need to better define the
These definitions allow asthma and COPD to be management and treatment of this syndrome7,8.
recognized as distinct disease entities. However, this
concept needs to be re-evaluated as many Epidemiology of ACOS
epidemiological studies have shown that asthma and
COPD may coexist, or at least one condition may In epidemiological studies, reported prevalence rates
evolve into the other creating a condition commonly for ACOS have ranged between 15 and 55%, with
described as Asthma COPD Overlap Syndrome. It is variation by gender and age; the wide range reflects
a syndrome in which older adults with a significant the different criteria that have been used by different
smoking history have features of asthma in addition investigators for diagnosing asthma and COPD.7,9
to their COPD or non-smoking asthmatics have A recent meta-analysis by Alshabanat et al10 showed
persistent airflow obstruction3. However, the exact that pooled prevalence of overlap syndrome was 27%
definition of this syndrome remains ambiguous as it and 28% in population and hospital based studies
characterized by a functional and pathological respectively. Subjects with ACOS represent a large
overlap between asthma and COPD. proportion of COPD patients (~27%), and they form
a distinct clinical phenotype with unique
According to GINA 2016, ACOS is characterized by characteristics in comparison to patients with only
persistent airflow limitation with several features COPD. These subjects are more likely to be younger,
usually associated with asthma and several features have less smoking history and with a higher BMI.
1MD, FRCP | Consultant and Head of Department, Department of Pulmonary Medicine P.D Hinduja National Hospital & Medical
Research Centre | [email protected]
2DNB Trainee | Department of Pulmonary Medicine, P.D Hinduja National Hospital & Medical Research Centre |
[email protected]
 COPD MONOGRAPH 34

Pathophysiology lung elastic recoil leading to hyperinflation and

centrilobular emphysema has been proposed.
However, the mechanism(s) responsible for loss of
ACOS is characterized by TH2-mediated
lung elastic recoil and persistent expiratory airflow
eosinophilic inflammation, bronchodilator
limitation in non-smokers with chronic asthma
reversibility, and corticosteroid responsiveness in a
consistent with ACOS remain unknown in the
COPD subset, even in the absence of a clinical
absence of structure-function studies.12
history of asthma11. A subset of treated non-smokers
Both asthma and COPD are heterogenous diseases
with moderate to severe asthma has persistent
and comprise various phenotypes. Several
expiratory airflow limitation, despite partial
phenotypes of ACOS have been suggested which is
reversibility. This is attributed to large and especially
summarized in Figure 1.
small airway remodeling and recently theory of
reversible loss of

Figure 1:- Relation between asthma, COPD, and ACOS and possible phenotypes of these disorders that might be identified
by comprehensive phenotyping. ACOS “n” are hypothesized additional phenotypes of ACOS that might be identified in the
future. Dotted arrow represents that ACOS “n” is not a single phenotype but consists of an unknown number of
phenotypes.

Figure 1

Clinical features13  Frequently a history of doctor-diagnosed asthma

(existing or previous), allergies, a family history
Clinical description of patients with ACOS of asthma, or a history of noxious exposures—
includes13: or any of these features.
 Symptoms are partly but substantially reduced
 Age 40 years or older (usually). by treatment.
 Airflow limitation persistent and not fully  Exacerbations can be more common than in
reversible, but often with existing or historical COPD but are reduced by treatment.
variability or airway hyper-reactivity, or both.  Symptoms worsen over time.
 Respiratory symptoms, including exertional  Treatment needs are high.
dyspnea, are persistent but variability can be  Comorbidities can contribute to impairment.
prominent.  Chest radiograph—as for COPD (eg,
 Might have had symptoms in childhood or early hyperinflation or bullae might be seen).
adulthood.  Increase in eosinophils or neutrophils, or both,
in sputum.
 COPD MONOGRAPH 35

Differentiating factors between asthma, COPD and ACOS are summarized in Table 1.
Table 1:- Clinical features of Asthma, COPD and ACOS

Features Asthma COPD ACOS

Usually age ≥40 years, but
Usually childhood onset but can may have had symptoms in
Age of onset Usually > 40 years of age
commence at any age. childhood or early
adulthood.
Symptoms may vary over time (day to
Pattern of Chronic usually continuous Respiratory symptoms
day, or over longer periods), often
respiratory symptoms, particularly during including exertional dyspnea
limiting activity. Often triggered by
symptoms exercise, with ‘better’ and are persistent but variability
exercise, emotions including laughter,
‘worse’ days may be prominent
dust or exposure to allergens
Airflow limitation not fully
FEV1 may be improved by
Current and/or historical variable airflow reversible, but often with
Lung function therapy, but post-BD FEV1/FVC
limitation, e.g. BD reversibility, AHR current or historical
< 0.7 persists
variability
Lung function
between May be normal between symptoms Persistent airflow limitation Persistent airflow limitation
symptoms
Frequently a history of
doctor diagnosed
Many patients have
History of exposure to asthma (current or
Past history allergies and a personal
noxious particles and gases previous), allergies and a
or family history of asthma in
(mainly tobacco smoking and family history of asthma,
history childhood, and/or family history of
biomass fuels) and/or a history of noxious
asthma
exposures

Symptoms are partly but

Often improves significantly reduced by
Generally, slowly progressive
spontaneously or with treatment. Progression is
Time course over years
treatment, but may result in fixed usual
despite treatment
airflow limitation and treatment needs are
high
Severe hyperinflation & other
Chest X-ray Usually normal Similar to COPD
changes of COPD
Exacerbations may be more
Exacerbations can be reduced
Exacerbations occur, but the risk of common than in COPD but
by treatment. If
Exacerbations exacerbations can be considerably are reduced by treatment.
present, comorbidities
reduced by treatment Comorbidities can
contribute to impairment
contribute to impairment
Neutrophils ± eosinophils in
Eosinophils and/or
Airway Eosinophils and/or sputum, lymphocytes in
neutrophils
inflammation neutrophils airways, may have systemic
in sputum
inflammation

Diagnosis asthma and COPD, a history or evidence of atopy

(e.g., hay fever or raised total IgE concentrations), a
Until the past few years, clinical practice guidelines smoking history of more than 10 pack years, and a
have been relatively silent on how to diagnose and fixed airway obstruction. Minor criteria included an
manage patients with features of both asthma and increase in baseline FEV1 after bronchodilator of
COPD (ie, ACOS), except to advise that the two 15% or more, or of 12% or more, and 200 mL or
disorders might coexist. In 2013, Louie and more, from the baseline value. A Spanish consensus
colleagues14 suggested the diagnosis of ACOS be statement15 proposed that patients with COPD should
applied to patients with a doctor diagnosis of both be deemed to have “overlap phenotype COPD–
 COPD MONOGRAPH 36

asthma” if they satisfied two major criteria (increase responsiveness), with incomplete reversibility, with
in FEV1 of 15% or more and 400 mL or more, or without emphysema on CT scans or reduced
sputum eosinophilia, or a personal history of asthma), carbon monoxide diffusion capacity; or secondly,
or one major and two minor criteria (high total IgE, COPD with emphysema accompanied by reversible
personal history of atopy, or an increase in FEV1 of or partly reversible airflow limitation, with or without
12% or more and 200 mL or more on two or more an allergic syndrome or reduced carbon monoxide
occasions). diffusing capacity.
Some authors have included use of specialised tests Although ACOS is associated with persistent airflow
for defining ACOS. For example, Zeki and obstruction, significant post bronchodilator
colleagues16 described ACOS in two ways: first, reversibility (> 15% and 400 ml) is compatible with
patients with allergic disease consistent with asthma ACOS. Spiro metric findings in asthma, COPD and
(i.e., variable airflow limitation or airway hyper- ACOS have been summarized in Table 2.2

Table 2:- Spirometry findings in Asthma, COPD and ACOS

Spirometric Variable Asthma COPD ACOS

Not compatible unless
Normal FEV1/FVC Not compatible with
Compatible with diagnosis other evidence of chronic
pre- or post BD diagnosis
airflow limitation
Indicates airflow limitation
but may improve Required for diagnosis
Post-BD FEV1/FVC <0.7 Usually present
spontaneously or on (GOLD)
treatment
FEV1 ≥80% predicted Compatible with diagnosis Compatible with GOLD
(good asthma control or classification of mild airflow Compatible with diagnosis
interval between limitation (categories A or B) of mild ACOS
symptoms) if post-BD FEV1/FVC <0.7
An indicator of severity of
An indicator of severity of
Compatible with diagnosis. airflow limitation and risk
airflow limitation and risk of
FEV1 <80% predicted Risk factor for asthma of future events (e.g.
future events (e.g. mortality
exacerbations mortality and
and COPD exacerbations)
exacerbations)
Usual at some time in
Post-BD increase in FEV1
course of asthma, but may
>12% and 200 ml from Common and more likely Common and more likely
not be present when well-
baseline (reversible when FEV1 is low when FEV1 is low
controlled
airflow limitation).
or on controllers
Post-BD increase in FEV1
>12% and 400ml from Unusual in COPD. Consider Compatible with diagnosis
High probability of asthma
baseline (marked ACOS of ACOS
reversibility)

Treatment lung function and a reduction in rescue medication

were observed with tiotropium17. However, the main
There is little information about the response of interest in differentiating ACOS from COPD lies in
ACOS patients to most of the current the different response to inhaled corticosteroids
pharmacological therapies as they have been (ICS). Some studies demonstrate that patients with
systematically excluded from both COPD and asthma COPD and eosinophilic inflammation treated with
pharmacological trials. The only clinical trial ICS present a significant improvement in bronchial
performed to date in patients with ACOS studied the inflammation together with clinical and spirometric
effects of tiotropium in 472 individuals with improvement18,19. Two small, randomised trials have
concomitant COPD and asthma. Improvements in demonstrated that prescribing corticosteroids (oral or
 COPD MONOGRAPH 37

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At present, the only phenotype-directed treatment for High hospital burden in overlap syndrome of asthma and COPD.
COPD is the phosphodiesterase 4-inhibitor ClinRespir J 2013; 7:342-6.
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