Asthma-COPD Overlap and Chronic Airflow Obstruction: Definitions, Management, and Unanswered Questions

Journal Pre-proof Asthma-COPD overlap and chronic airflow obstruction: definitions, management, and unanswered questions Stephen Milne, MBBS PhD, David Mannino, MD, Don D. Sin, MD PII:

S2213-2198(19)30939-0

DOI:

https://doi.org/10.1016/j.jaip.2019.10.044

Reference:

JAIP 2543

To appear in:

The Journal of Allergy and Clinical Immunology: In Practice

Received Date: 12 July 2019 Revised Date:

3 October 2019

Accepted Date: 31 October 2019

Please cite this article as: Milne S, Mannino D, Sin DD, Asthma-COPD overlap and chronic airflow obstruction: definitions, management, and unanswered questions, The Journal of Allergy and Clinical Immunology: In Practice (2019), doi: https://doi.org/10.1016/j.jaip.2019.10.044. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology

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MANUSCRIPT ID: INPRACTICE-D-19-00748

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MANUSCRIPT TITLE:

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Asthma-COPD overlap and chronic airflow obstruction: definitions, management, and

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unanswered questions

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AUTHORS AND AFFILIATIONS:

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Stephen Milne, MBBS PhD (1), David Mannino, MD (2), Don D. Sin, MD (1)

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1. Centre for Heart Lung Innovation, St Paul’s Hospital and Division of Respiratory Medicine, University of British Columbia, Vancouver, BC, Canada 2. Department of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky College of Medicine, Lexington, KY, USA

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CORRESPONDING AUTHOR:

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Don D. Sin, MD

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Room 548, Burrard Building, St. Paul’s Hospital, Vancouver, BC, Canada, V6Z 1Y6

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Email: [email protected]

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DDS is a Tier 1 Canada Research Chair in COPD and holds the De Lazzari Family Chair at the

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Centre for Heart Lung Innovation.

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KEY WORDS:

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Asthma, COPD, Overlap, epidemiology, diagnosis

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DISCLOSURES:

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SM reports personal fees from Novartis, Boehringer Ingelheim and Menarini, outside the

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submitted work. DM is an employee and shareholder of GlaxoSmithKline. DDS reports

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grants from Merck, personal fees from Sanofi-Aventis, Regeneron and Novartis, and grants

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and personal fees from Boehringer Ingelheim and AstraZeneca, outside the submitted work.

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ABBREVIATIONS: ACO

Asthma-COPD overlap

AHR

Airway hyperresponsiveness

BDR

Bronchodilator response/responsiveness

COPD

Chronic obstructive pulmonary disease

FAO

Fixed airflow obstruction

FeNO

Fraction of exhaled nitric oxide

FEV1

Forced expiratory volume in 1 second

FVC

Forced vital capacity

GINA

Global Initiative for Asthma committee

GOLD

Global Obstructive Lung Disease committee

HR

Hazard ratio

ICS

Inhaled corticosteroid

IgE

Immunoglobulin E

IL-13

Interleukin-13

IL-4Rα

Interleukin-4 receptor-alpha

IL-5

Interleukin-5

LABA

Long-acting beta-adrenoreceptor agonist

LAMA

Long-acting muscarinic antagonist

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ABSTRACT:

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Asthma-COPD overlap (ACO) is a common clinical presentation of chronic airways disease in

32

which patients show some features usually associated with asthma, and some usually

33

associated with COPD. There is ongoing debate over whether ACO is a discrete clinical

34

entity, or if it is part of a continuum of airways disease. Furthermore, there is considerable

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variation among current definitions of ACO, which makes diagnosis potentially challenging

36

for clinicians. Treating ACO may be equally challenging since ACO is an under-studied

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population, and the evidence base for its management comes largely from asthma and

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COPD studies, the relevance of which deserves careful consideration. In this review, we

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synthesize the various approaches to ACO diagnosis, and evaluate the role of currently-

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available diagnostic tests. We describe the potential benefits of existing asthma and COPD

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therapies in treating ACO patients, and the value of a “treatable traits” approach to ACO

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management. Throughout the review, we highlight some of the pressing, unanswered

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questions surrounding ACO that are relevant to the clinical community. Ultimately,

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addressing these questions is necessary if we are to improve clinical outcomes for this

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complex and heterogenous patient population.

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MAIN TEXT:

47 48

Asthma and chronic obstructive pulmonary disease (COPD) together affect over 600 million

49

people worldwide.1, 2 Although the two conditions share some common clinical features

50

(cough, wheeze and breathlessness) and physiological abnormalities (airflow obstruction),

51

they are traditionally considered to be separate disease entities with distinct pathologies

52

and natural histories.3 However, more detailed phenotyping of patients with chronic

53

airways disease reveals that asthma and COPD rarely exist in their “pure” forms. Instead, it

54

is common for patients with obstructive airways disease to have features of both asthma

55

and COPD. The existence of this “asthma-COPD overlap (ACO)” presents a challenge for

56

clinicians not only for making a diagnosis, but also for developing a treatment plan.

57 58

Although ACO provides a useful framework within which clinicians and researchers can

59

operate, its relevance as a disease entity unto itself remains controversial. Furthermore,

60

increased attention to ACO has not yet translated into major changes in clinical practice.

61

This review aims to update our current understanding of ACO, with a focus on the principles

62

of diagnosis and management. We identify areas of uncertainty, highlighting the many

63

unanswered questions surrounding this complex clinical phenomenon.

64 65

Is ACO just asthma with fixed airflow obstruction?

66 67

People with asthma most often demonstrate reversible airflow obstruction on spirometry,

68

such that the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity

69

(FVC) can normalize following acute bronchodilator administration or when clinically stable.

6 70

However, it has long been recognized that airflow obstruction may not fully reverse in some

71

asthma patients.4 Up to one third of people with asthma have a persistently reduced

72

FEV1/FVC ratio despite adequate treatment, particularly in longstanding or severe disease.5,

73

6

74

in asthma complicates the differentiation of asthma from COPD, the latter being associated

75

with “irreversible airflow obstruction” by definition.7

This phenomenon is referred to as “fixed airflow obstruction (FAO)”. The presence of FAO

76 77

Compared to asthma with reversible airflow obstruction, asthma with FAO is associated

78

with greater airway wall smooth muscle mass,8 increased sputum cellularity,8 greater

79

peripheral blood eosinophil count,9 and higher serum immunoglobulin E (IgE) levels.10

80

Physiologically, FAO in asthma is probably due not only to airway remodeling,8 but also from

81

increased lung compliance11 and air-trapping.

82 83

The presence of FAO in asthma is associated with earlier age of onset and longer duration of

84

disease,12, 13 accelerated lung function decline,6, 14 increased comorbidity,5 worse asthma

85

control and quality of life scores, greater risk of intubation,10 and higher mortality15

86

compared to reversible airflow obstruction. Data on the effect of FAO on the frequency of

87

acute exacerbations are conflicting.5, 14, 16 Asthmatic patients with FAO may also respond

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differently to inhaled medications.17, 18 Multiple reports have shown that asthmatic patients

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with FAO are prescribed higher doses of inhaled corticosteroids and use reliever

90

medications more frequently;17-19 this may reflect greater steroid resistance, or the

91

prescribing habits of physicians attempting to normalize lung function by escalating steroid

92

doses.

93

7 94

The presence of FAO can therefore be considered a distinct phenotype of asthma, since it

95

categorically differentiates a subgroup of patients based on spirometry and is associated

96

with different clinical outcomes and treatment responses. Indeed, in severe asthma studies,

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patients with FAO are the most severe. However, it should not be conflated with ACO: the

98

asthma with FAO phenotype does not necessarily include other features normally

99

associated with COPD. Such features include significant smoking or environmental exposure

100

history, persistent/daily symptoms that are poorly responsive to treatment, and

101

characteristic imaging abnormalities. The remainder of this review will therefore focus on

102

ACO as a clinical presentation, of which FAO is but one component.

103 104

Is ACO a distinct clinical entity?

105 106

ACO is at the center of the decades-old debate over the nature of chronic airways disease.20

107

If asthma and COPD are to be considered as discrete disease entities, then it is conceivable

108

that ACO, too, is a discrete entity with its own genetic and environmental determinants. If,

109

however, asthma and COPD are considered as manifestations of a continuum of airways

110

disease (the so-called Dutch Hypothesis), ACO is simply the center point of the two

111

phenotypic extremes. It is also possible that ACO patients have some features associated

112

with asthma, and some features associated with COPD, as a function of two commonly

113

occurring diseases in the population (Figure 1).

114 115 116

Can ACO be adequately defined?

8 117

A review of the literature reveals a multitude of definitions of ACO used in various studies.

118

The majority of previous studies define the ACO population based on spirometric criteria,

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either as a history of asthma with FAO,21-23 or a history of smoking and COPD with a

120

significant bronchodilator response,24, 25 most commonly defined as 200 ml and 12%

121

increase in FEV1.26 Alternative definitions incorporate inflammatory markers usually

122

associated with asthma (eosinophilia, increased IgE level) in the presence of clinical COPD.27-

123

29

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standard definition underscores the problem of classifying ACO as a distinct disease entity –

125

the various historical definitions are more accurately described as phenotypes of asthma or

126

COPD. For this reason, ACO is generally no longer described as a “syndrome”, but rather as a

127

collection of several different clinical phenotypes with several different underlying

128

mechanisms.7, 30

The definition used often varies according to the population being studied. This lack of a

129 130

The Global Initiative for Asthma (GINA)30 and Global Initiative for Chronic Obstructive Lung

131

Disease (GOLD)7 committees describe ACO as being “characterized by persistent airflow

132

limitation with several features usually associated with asthma and several features usually

133

associated with COPD”. The consensus statements explicitly acknowledge that this is a

134

“description for clinical use”, not a definition. This deliberately open description allows the

135

clinician to decide, based on his/her assessment, if the clinical presentation is consistent

136

with ACO. However, such an open definition presents its own challenges when it comes to

137

epidemiological studies or clinical trials.

138 139 140

How common is ACO?

9 141

Unsurprisingly, the prevalence of ACO varies according to the definition used. Recently,

142

Barczyk et al31 conducted a prospective study in a mixed population of asthma and COPD

143

patients. They applied 5 different published definitions of ACO, including the GINA/GOLD

144

statement; 33 percent of patients met the diagnostic criteria of at least one ACO definition,

145

but only 0.12 percent of patients met all 5 definitions. This finding highlights the challenges

146

faced when trying to conduct epidemiological studies in the absence of a standardized

147

definition.

148 149

With this important qualifier in mind, multiple studies have attempted to quantify the

150

burden of ACO in the community. Estimates range from approximately two percent in

151

general population samples, to 55 percent in COPD cohorts (Table 1).21, 22, 25, 32-38 Despite the

152

heterogeneity of estimates, it can be concluded that ACO carries a significant population

153

burden.

154 155

Are patients with ACO different to those with asthma or COPD?

156 157

If the GINA/GOLD open description is to be adopted, then ACO must share features of both

158

asthma and COPD.7, 30 Importantly, ACO patients must have clinical and/or spirometric

159

features of obstructive airways disease. This includes symptoms such as breathlessness,

160

cough, sputum production, or wheeze. The presence of these features may not help to

161

distinguish ACO from the pure forms of asthma and COPD. Nevertheless, many studies have

162

shown that ACO patients have a greater symptom burden and poorer quality of life than

163

patients with asthma or COPD alone.22, 23, 32, 39

164

10 165

The frequency of acute exacerbations in ACO may be higher than in either disease alone.

166

Menezes et al25 reported a 5-fold increase in the number of exacerbations and a 4-fold

167

increased risk of hospitalization among ACO patients. In the COPDGene cohort, ACO

168

patients were more likely to be frequent exacerbators (defined as two or more

169

exacerbations in the year prior to study enrollment) and almost twice as likely to have a

170

history of severe exacerbation (hospital presentation in the year prior to study enrolment).22

171

Meanwhile, Bai et al24 found that ACO patients, compared to COPD patients, had a shorter

172

duration of hospitalization despite an increased rate of acute exacerbation. It is possible

173

that patients with frequent healthcare utilization have more opportunities to attract a

174

“dual” diagnosis and thus be labelled as ACO. Regardless, these findings suggest that

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exacerbation prevention should be a high-priority treatment goal in the management of

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patients with an ACO-like phenotype.

177 178

Data on the rate of lung function decline in ACO are limited. ACO patients have been shown

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to have FEV1 decline that is faster than that of asthma patients,14 but slower than that of

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COPD patients.40, 41 The rate of decline in ACO therefore may be intermediate between that

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of asthma and COPD, although longitudinal population data suggest that smoking and

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starting FEV1 may be more important modifiers of the rate of FEV1 decline than disease

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status.42 For now, a definitive conclusion on the rate of FEV1 decline in ACO cannot be

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reached in the absence of large-scale, longitudinal studies in a well-defined ACO cohort.

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The burden of comorbid medical conditions is higher in ACO than in asthma, and is possibly

187

higher than in COPD.43 A comprehensive population survey in the USA found that self-

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reported ACO patients were most likely to have at least one comorbidity, found in 90

11 189

percent of respondents (compared to 84 percent in COPD and 71 percent in asthma).34 Out

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of 8 comorbid conditions, including cardiovascular diseases, diabetes and depression, all

191

conditions were more prevalent in ACO than in asthma, and 6 of the 8 were more prevalent

192

in ACO than in COPD. In a Spanish COPD cohort, the self-reported but “physician-confirmed”

193

ACO subgroup had higher odds of anxiety, gastroesophageal reflux disease, osteoporosis,

194

and allergic rhinitis.44 After applying more stringent diagnostic criteria, only anxiety and

195

allergic rhinitis remained significantly higher in ACO compared to COPD alone.44 A similarly

196

high prevalence of allergic rhinitis was found in a Norwegian population survey, with ACO

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patients having a two-fold greater risk than COPD alone.33

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Finally, ACO may be associated with increased mortality compared to either asthma or

200

COPD. In the NHANES-III cohort, where obstructive airways disease was defined by

201

spirometry, Diaz-Guzman et al45 found that the hazard ratio (HR) for mortality in ACO was

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1.8, compared to 1.4 in COPD and 1.2 in asthma. The HR was attenuated, but still greatest

203

for ACO, following adjustment for baseline lung function. These findings are in contrast to

204

other studies where ACO did not carry an increased risk of mortality compared to asthma or

205

COPD.24, 46

206 207

Art versus science: can we confidently make a diagnosis of ACO?

208 209

Given the lack of a standardized, universally-accepted definition of ACO, differentiating ACO

210

from either asthma or COPD with any degree of certainty is challenging for the clinician.47

211

Various approaches to diagnosis are summarized in Figure 2. Some commentators have

212

argued that assigning a diagnosis of asthma, COPD, or ACO is outdated, and fails to

12 213

adequately recognize the clinical heterogeneity of patients with airways disease.39

214

Nevertheless, there is a natural instinct to “label” the constellation of symptoms and signs

215

before us using our clinical acumen and available diagnostic tools.

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Is spirometry necessary for ACO diagnosis?

218 219

Spirometry is essential to confirm that the patient has an obstructive airways disease, as

220

indicated by a FEV1/FVC ratio less than 0.7 or the lower limit of normal. As shown in Figure

221

2, airflow obstruction on spirometry is considered an essential or major criterion by all

222

diagnostic algorithms. After obstruction is confirmed, its persistence following

223

administration of an inhaled bronchodilator (usually 400 µg albuterol) suggests FAO, which

224

is a necessary feature of ACO. Care should be taken to ensure the test is performed while

225

the patient is in a stable state or, particularly if there are prominent asthmatic features,

226

after a trial of treatment. FAO can be inconsistent between assessments in up to one third

227

of asthma patients.48

228 229

Bronchodilator responsiveness

230 231

The diagnostic value of bronchodilator responsiveness (BDR) in ACO is unclear. A

232

“significant” BDR (most often considered to be a 12 percent and 200 mL improvement in

233

FEV1 or FVC following bronchodilator)26 does not reliably differentiate asthma from COPD.49

234

Furthermore, up to half of COPD patients can exhibit a significant BDR,50 with considerable

235

variability over time.51 According to the majority of current criteria, the presence of BDR is

236

supportive of, but not essential to, a diagnosis of ACO (Figure 2).

13 237 238

Airway hyperresponsiveness

239 240

Airway hyperresponsiveness (AHR) measured by bronchial challenge testing is traditionally

241

associated with a diagnosis of asthma,52 but is also common in people diagnosed with

242

COPD, particularly women.53 The presence of AHR may identify a subset of COPD patients at

243

risk of adverse outcomes including accelerated lung function decline and increased risk of

244

mortality.54 The use of bronchial challenge testing becomes problematic in patients with

245

significant airflow obstruction, with respect to both safety and interpretation. The European

246

Respiratory Society technical statement advises against challenge testing in patients with

247

FEV1 <60 percent predicted.55 Therefore, although AHR may be supportive of ACO, the

248

routine use of bronchial challenge tests to diagnose ACO is not recommended, and few

249

diagnostic algorithms take this feature into account (Figure 2).

250 251

Are there inflammatory biomarkers of ACO?

252 253

Eosinophils

254 255

Even though eosinophilia of the bronchial wall, lavage fluid, sputum and blood is a hallmark

256

of allergic asthma, eosinophilia is increasingly recognized in COPD.56 Higher blood

257

eosinophils in COPD patients is associated with increased exacerbation rate57 and a non-

258

infectious type of exacerbation,58 as well as a better response to inhaled corticosteroid (ICS)

259

therapy.59 Eosinophilia may therefore identify an ACO-like subpopulation of COPD patients,

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although the significant overlap between the blood eosinophil counts of ACO, asthma and

14 261

COPD patients60 may limit its discriminatory power. Eosinophilia as a treatment response

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biomarker may be more useful. An appropriate absolute or relative (percentage) threshold

263

to define “eosinophilia” is required, but there is currently no consensus on what this

264

threshold should be, or how it should be determined. The majority of clinical trials in COPD

265

that have undergone (predominantly post hoc) subanalysis by blood eosinophil count have

266

used a threshold of two percent to demonstrate a superior response to ICS.59, 61-63 The

267

recent IMPACT trial in COPD used a cut off of at least 150 cells/µL to show a greater

268

reduction in exacerbation rate with triple inhaled therapy compared to combination long-

269

acting beta-adrenoreceptor agonist (LABA)/long-acting muscarinic antagonist (LAMA)

270

therapy in patients with a history of exacerbations.64 Since ACO patients are, in general,

271

considered to be a steroid-responsive group (see section on “Management of ACO”), the

272

additional benefit of eosinophil count as a treatment response biomarker needs to be

273

determined.

274 275

Serum IgE

276 277

Elevated serum IgE, which is typically associated with allergic asthma, may help identify a

278

subgroup of COPD patients with asthma-like features. In a cluster analysis of pooled asthma

279

and COPD patients, a cluster resembling ACO was found to have the highest mean IgE level.

280

This was despite the absence of upregulated Th2-type transcription factors in peripheral

281

blood mononuclear cells.60 Antigen-specific IgE has also been found to be increased in ACO

282

patients,65 which suggests that at least some ACO patients are allergen-sensitized. However,

283

care should be taken to ensure these patients have other features of asthma before being

284

labelled as ACO, since allergen sensitization is common in the general population.66

15 285 286

Fraction of exhaled nitric oxide (FeNO)

287 288

High FeNO, which is measured by breath analysis, quantifies nitric oxide gas produced by

289

airway epithelial cells, and reflects type-2 airway inflammation, may also identify a

290

subgroup of COPD patients with asthma-like features. In one COPD cohort, a high-FeNO

291

threshold of >35 ppb was met by 16 percent of the cohort; this group was significantly more

292

likely to have a history of allergic rhinitis, but there were no significant differences in the

293

rates of other important clinical features such as exacerbations.67 Another study found that

294

a cut-off of >55 ppb adequately differentiated ACO patients from non-ACO patients, but this

295

very high threshold was met by only 6 percent of ACO patients.68 Meanwhile, Chen et al69

296

found that the optimal cut-off for differentiating ACO from COPD was much lower at >22.5

297

ppb, but this cut-off only achieved a sensitivity of 70 percent and a specificity of 75 percent.

298

It therefore seems that, although FeNO may be high in a subset of patients, the trade-off

299

between specificity and sensitivity may limit the usefulness of FeNO for diagnosing ACO.

300 301

Summary of biomarker profiles

302 303

Since each of these diagnostic tests suffers from low sensitivity and/or specificity, some

304

investigators have combined the tests to improve diagnostic accuracy for ACO.65 Whether

305

this improved accuracy translates into improved clinical outcomes is unknown. The utility of

306

these biomarkers may therefore be not as diagnostic tests per se, but rather as tools to

307

identify “features usually associated with asthma” as part of the patient assessment.

308

Indeed, some authors have advocated abandoning the ACO categorization and instead

16 309

classifying airways diseases by the presence or absence of a type-2 inflammatory signature,

310

and using this to guide therapy.27

311 312

Can current clinical guidelines help diagnose ACO?

313 314

There is considerable heterogeneity among the diagnostic criteria for ACO proposed by

315

different groups (Figure 2).7, 28-30, 70-72 Most diagnostic approaches set essential or “major”

316

criteria that are supported by the presence of one or more non-essential or “minor” criteria,

317

but there is inconsistency in these approaches. Several working groups have attempted to

318

better define ACO, recognizing the need for a robust diagnostic framework to inform clinical

319

practice as well as future research studies. However, these attempts are generally

320

accompanied by the caveat that ACO is difficult to define based on our current knowledge,

321

and that attempts at creating diagnostic criteria should only be seen as an interim measure

322

until more is known about this group of patients.73

323 324

In their joint statements, GINA30 and GOLD7 do not advocate a prescriptive diagnostic

325

framework, in keeping with their definition of ACO as sharing some features of both asthma

326

and COPD. They do, however, present an algorithm for a “syndromic approach” to

327

differentiating asthma, COPD and ACO, based on the presence or absence of these features

328

(Table 2). Features based on history (age of onset, family history, pattern of symptoms),

329

lung function (BDR), and laboratory workup (eosinophils, neutrophils) are tallied: patients

330

with three or more features usually associated with asthma, or usually associated with

331

COPD, are diagnosed as such; patients with more or less equal numbers of asthma and

332

COPD features are considered to have ACO. Spirometry is then used for confirmation, and

17 333

the presence of fixed airflow obstruction is considered essential to the diagnosis of ACO. It is

334

important to note that the tick-a-box classification is somewhat arbitrary and has not been

335

fully validated. Nevertheless, the GINA/GOLD algorithm is a useful framework for

336

differential diagnosis.

337 338

A feature common to most ACO diagnostic frameworks is a history of significant exposure to

339

noxious particles or gases, most commonly cigarette smoking (Figure 2). However, the

340

absence of a smoking history does not discount ACO since around one third of people with

341

COPD are non-smokers.74 Recent large-scale epidemiological studies have highlighted the

342

impact of air pollution on lung function and COPD risk.75 There is also evidence that

343

environmental (passive) tobacco smoke exposure increases the risk of both COPD76 and

344

adult-onset asthma.77. In the absence of a personal tobacco smoking history, a meticulous

345

inquiry into other possible exposures – including environmental and occupational exposures

346

– should be conducted in order to establish this feature of ACO.

347 348

Management of ACO: should we treat patients differently?

349 350

There is inadequate clinical trial data to make strong, evidence-based recommendations for

351

the treatment of ACO. This is due largely to the fact that ACO patients are traditionally

352

excluded from clinical trials: most COPD trials exclude patients with a history of asthma, and

353

most asthma trials exclude patients with a past diagnosis of COPD or a significant smoking

354

history29. The result is that ACO is an under-studied population, and most of the available

355

evidence is extrapolated from trials in asthma and/or COPD populations.

356

18 357

The syndromic approach: why not treat for both asthma and COPD?

358 359

One approach to treating ACO patients is to apply the current evidence for medications

360

used in asthma and COPD, with the expectation that patients with overlapping features of

361

these diseases will respond similarly to those with ‘pure’ disease.

362 363

Inhaled corticosteroid (ICS) and its combination with LABA

364 365

The initiation of ICS is a key difference in the step-wise management of asthma and COPD.

366

In asthma, ICS monotherapy is recommended in mild disease. In COPD, ICS therapy (in

367

combination with a long-acting bronchodilator, and never as a monotherapy) is reserved for

368

severe disease with frequent exacerbations (defined as two or more exacerbations per year

369

requiring antibiotics or systemic corticosteroids, or one or more hospitalization or

370

emergency visit per year). For ACO, GINA/GOLD advocate commencing ICS therapy, typically

371

in combination with a long-acting bronchodilator, in all cases.7, 30 This acknowledges the

372

important role of ICS in reducing the risk of exacerbations and deaths from asthma.78

373 374

There are very few studies of ICS therapy in ACO patients. A 12-week, open-label trial of ICS

375

monotherapy in symptomatic but steroid-naïve subjects showed that people in an ACO-like

376

cluster had significant improvements in symptoms and reduced peak flow variability.79 In a

377

3-month trial of ICS/LABA combination therapy, ACO patients of mild-moderate severity

378

showed a greater improvement in FEV1 than COPD patients.80 Regarding exacerbation rates,

379

a health insurance database study of ACO patients found that ICS/LABA combination

380

therapy was associated with a reduction in exacerbation risk compared to monotherapy

19 381

with either ICS or LABA.81 Data on the effects of ICS on lung function decline and mortality

382

are lacking: one retrospective analysis in a small number of ACO patients found no

383

difference in the rate of FEV1 decline or death between those treated with or without ICS

384

over a 12-year period,82 but the generalizability of this small study is limited.

385 386

Two important safety concerns with ICS and LABA therapy warrant a mention. The first is

387

that LABA monotherapy may not be appropriate in ACO if data from asthma, which shows

388

an increased risk of death with LABA monotherapy,83 is to be extrapolated. At least one

389

observational study suggests the risk of LABA monotherapy may also apply to ACO

390

patients.84 However, LABA in combination with ICS appears to be safe in both asthma and

391

ACO patients. The second concern is that ICS usage, particularly at high doses, is associated

392

with an increased risk of pneumonia in patients with COPD.85 This effect is not observed in

393

asthma patients,86 and the risk in ACO patients is not known. Baseline pneumonia risk may

394

be modified by disease severity and/or eosinophilia,87, 88 irrespective of ICS use. Regardless,

395

the risk-benefit ratio of low-dose ICS, in combination with LABA, is likely to be acceptable in

396

the ACO population.

397 398

Inhaled LAMA therapy

399 400

There is a large body of evidence supporting the use of inhaled LAMA in COPD,89 and more

401

recent evidence that the addition of the LAMA tiotropium to ICS/LABA therapy in severe

402

asthma improves symptom control and reduces exacerbations.90 By extension, ACO patients

403

should derive a benefit from the inclusion of LAMA in their therapeutic regimen. However,

404

the evidence supporting the use of LAMA, either as monotherapy or in addition to ICS +/-

20 405

LABA, in ACO is limited.91 A recent trial of the addition of LAMA (umecledinium) to ICS/LABA

406

(fluticasone furoate/vilanterol) significantly improved FEV1 after 12 weeks of therapy.92

407

Interestingly, asthmatic patients with emphysema may have a greater physiological

408

response to the addition of LAMA to ICS than those without emphysema,93 which suggests

409

that ACO patients may be a particularly responsive group. Despite the limited data in ACO,

410

the use of LAMA, generally as part of a “triple therapy” regimen, is recommended due to its

411

benefits extrapolated from asthma and COPD studies. LAMA monotherapy in ACO is not

412

recommended.

413 414

Macrolide therapy

415 416

There are no data on the benefits (or harm) of long-term low-dose daily macrolide therapy

417

in ACO patients. However, it is now well established that in COPD patients with frequent

418

exacerbations despite “triple” inhaler therapy, the use of daily low dose (250 mg/day)

419

azithromycin therapy reduces the risk of exacerbation by approximately 25 percent.94 The

420

adverse effects are acceptable for most patients, but a minority of patients experience side

421

effects including hearing impairment and prolong QT interval on electrocardiogram, which

422

may preclude its use. At a population-level, prolonged use of azithromycin therapy may

423

promote antimicrobial drug resistance of respiratory pathogens such as Staphylococcus

424

aureus, which is a source of ongoing public health concern.95 In asthma, thrice weekly

425

regimen of azithromycin therapy (500 mg/day three times a week) also reduces the risk of

426

exacerbation in patients who continue to exacerbate despite ICS and long-acting

427

bronchodilator therapy by approximately 40 percent.96 Unlike the COPD patients, asthmatic

428

patients did not experience any significant hearing loss or prolonged QT interval in one

21 429

study.96 The reasons for these differences are unknown, although the asthmatic patients

430

were, on average, younger and had fewer comorbidities than the COPD patients.94, 96 By

431

extrapolation, it is likely that low-dose azithromycin therapy would be of benefit to ACO

432

patients who continue to exacerbate despite ICS/LABA/LAMA therapy. As the long-term

433

adverse effects in this population of patients are unknown, we recommend regular (yearly)

434

hearing acuity assessment and electrocardiogram.

435 436

Biological therapies

437 438

There is a range of other therapeutic options available for asthma and COPD, which may be

439

of benefit in selected ACO patients. Anti-IgE therapy, with the monoclonal antibody

440

omalizumab, has a proven track record in the treatment of severe allergic asthma.97 A small

441

case series of ACO patients with high serum IgE levels suggests omalizumab can improve

442

symptom control and exacerbation rate, but not necessarily lung function.98 This is

443

supported by data from the Australian Xolair Registry.99 Other biological therapies targeting

444

type-2 inflammation, including those targeting the interleukin-13 (IL-13)/interleukin-4

445

receptor-alpha (IL-4Rα) pathway (dupilumab) and the interleukin-5 (IL-5) pathway

446

(mepolizumab, benralizumab, reslizumab), have shown success in the treatment of severe

447

asthma.100-102 but this has not translated into consistent improvements in COPD.103, 104 Their

448

role in the treatment of ACO is therefore unknown, however it is possible that ACO patients

449

may represent a subgroup of COPD patients who would benefit from such therapies. This

450

needs to be tested in a clinical trial setting.

451 452

Can we adopt a “treatable traits” approach to ACO?

22 453 454

The clinical heterogeneity of chronic airways diseases has led some investigators to

455

advocate for the so-called “treatable traits” approach.105 This is a framework whereby

456

treatment is guided by the identification of certain phenotypes, endotypes, or

457

comorbidities, rather than a one-size-fits-all approach to treatment by disease label. Given

458

the difficulty in defining ACO as a discreet entity, a treatable traits approach may be

459

preferable for patients who present with overlapping features.

460 461

However, even this highly-pragmatic approach raises a number of questions. Firstly, is this a

462

trait that warrants treatment? The clinical feature or biomarker of interest needs to be

463

identifiable as a contributor to, or a surrogate for pathology related to, disease outcomes.

464

Secondly, is the trait genuinely treatable? There should be evidence that the underlying

465

pathology represented by the particular trait can be targeted by an existing therapy (drug or

466

other). Ideally, the trait itself would be modifiable, and could be measured to assess

467

treatment response. Thirdly, is treatment of the trait expected to lead to a clinically-

468

meaningful outcome? Examples include a reduction in exacerbation rates, or an

469

improvement in symptoms. Finally, does treatment of the trait carry an acceptable

470

risk:benefit ratio? This is particularly important in an older population where the risks of

471

side-effects and polypharmacy are not insignificant. The cost of therapy should also be

472

considered here.

473 474

The evidence for treatment of certain traits comes from the asthma and COPD literature

475

(Table 3).85, 94, 96, 98-104, 106-125 Whether the effects of treatment can be generalized to patients

476

with overlapping features is unclear. However, there is some evidence that comprehensively

23 477

assessing patients, identifying treatable traits, and developing a coordinated management

478

strategy can lead to meaningful clinical outcomes, regardless of the nature of the underlying

479

airways disease.126

480 481 482

Conclusion: where to from here for ACO?

483 484

Whether or not ACO is a distinct clinical entity will continue to be debated, but there is no

485

doubt that a significant number of patients with chronic airways disease do not fit the

486

classical definition of asthma or COPD. The lack of a standard definition of ACO makes

487

epidemiological studies and clinical trials problematic; the absence of a large evidence base

488

in ACO is a testament to the difficulty in defining such a complex clinical presentation.

489

Currently-available guidelines agree on at least two aspect of ACO diagnosis: spirometry is

490

an essential tool for confirming FAO; and a significant environmental exposure history is a

491

prerequisite. Patients presenting with symptoms of chronic airways disease, and these two

492

essential features, should be thoroughly assessed to determine if they are of an ACO

493

phenotype. For treatment, ICS in combination with a long-acting bronchodilator should be

494

considered as first-line therapy. Beyond this, we advocate a “treatable traits” approach to

495

managing these patients. Indeed, such an approach may allow the clinical community to

496

circumvent the lack of standardized definitions and ACO-specific clinical trial evidence.

497 498

Despite the ever-increasing interest in ACO, our current state of knowledge leaves many

499

pressing questions. Should we continue to standardize our definition of ACO, or should we

500

abandon this pigeon-holing and pursue a deep-phenotyping approach, right down to the

24 501

level of the genome? If deep phenotyping reveals new biomarkers, how do we translate

502

these into clinical practice – that is, how do new traits become treatable? Should we

503

continue to extrapolate evidence from asthma and COPD studies, or should we work

504

towards more label-free, real-world type trials in chronic airways patients? If so, what are

505

the most appropriate and clinically-meaningful outcome measures to assess?

506 507

Finally, ACO represents an opportunity for the clinician to ask: how can I better adopt a

508

personalized approach to the patient sitting before me?

509 510

ACKNOWLEDGEMENTS:

511

The authors are grateful to Dr Katrina O Tonga for her contribution to the literature search.

512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536

REFERENCES

1. Adeloye D, Chua S, Lee C, Basquill C, Papana A, Theodoratou E, et al. Global and regional estimates of COPD prevalence: Systematic review and meta-analysis. J Glob Health 2015;5(2):020415. 2. To T, Stanojevic S, Moores G, Gershon AS, Bateman ED, Cruz AA, et al. Global asthma prevalence in adults: findings from the cross-sectional world health survey. BMC Public Health 2012;12(1):204. 3. Barnes PJ. Mechanisms in COPD: differences from asthma. Chest 2000;117(2 Suppl):10S-14S. 4. Turner-Warwick M. On observing patterns of airflow obstruction in chronic asthma. Br J Dis Chest 1977;71(2):73-86. 5. Bennett GH, Carpenter L, Hao W, Song P, Steinberg J, Baptist AP. Risk factors and clinical outcomes associated with fixed airflow obstruction in older adults with asthma. Ann Allergy Asthma Immunol 2018;120(2):164-168 e161. 6. Ulrik CS, Backer V. Nonreversible airflow obstruction in life-long nonsmokers with moderate to severe asthma. Eur Respir J 1999;14(4):892-896. 7. Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary. Eur Respir J 2017;49(3).

25 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581

8. Kaminska M, Foley S, Maghni K, Storness-Bliss C, Coxson H, Ghezzo H, et al. Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction. J Allergy Clin Immunol 2009;124(1):45-51 e41-44. 9. Fabbri LM, Romagnoli M, Corbetta L, Casoni G, Busljetic K, Turato G, et al. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;167(3):418-424. 10. Lee JH, Haselkorn T, Borish L, Rasouliyan L, Chipps BE, Wenzel SE. Risk factors associated with persistent airflow limitation in severe or difficult-to-treat asthma: insights from the TENOR study. Chest 2007;132(6):1882-1889. 11. Gelb AF, Zamel N. Unsuspected pseudophysiologic emphysema in chronic persistent asthma. Am J Respir Crit Care Med 2000;162(5):1778-1782. 12. Bumbacea D, Campbell D, Nguyen L, Carr D, Barnes PJ, Robinson D, et al. Parameters associated with persistent airflow obstruction in chronic severe asthma. Eur Respir J 2004;24(1):122-128. 13. Connolly CK, Chan NS, Prescott RJ. The relationship between age and duration of asthma and the presence of persistent obstruction in asthma. Postgrad Med J 1988;64(752):422-425. 14. Contoli M, Baraldo S, Marku B, Casolari P, Marwick JA, Turato G, et al. Fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease: 5-year follow-up. J Allergy Clin Immunol 2010;125(4):830-837. 15. Panizza JA, James AL, Ryan G, de Klerk N, Finucane KE. Mortality and airflow obstruction in asthma: a 17-year follow-up study. Intern Med J 2006;36(12):773-780. 16. Vonk JM, Jongepier H, Panhuysen CI, Schouten JP, Bleecker ER, Postma DS. Risk factors associated with the presence of irreversible airflow limitation and reduced transfer coefficient in patients with asthma after 26 years of follow up. Thorax 2003;58(4):322-327. 17. Tashkin DP, Chipps BE, Trudo F, Zangrilli JG. Fixed airflow obstruction in asthma: a descriptive study of patient profiles and effect on treatment responses. J Asthma 2014;51(6):603-609. 18. Chang TS, Lemanske RF, Jr., Mauger DT, Fitzpatrick AM, Sorkness CA, Szefler SJ, et al. Childhood asthma clusters and response to therapy in clinical trials. J Allergy Clin Immunol 2014;133(2):363-369. 19. Fitzpatrick AM, Teague WG, Meyers DA, Peters SP, Li X, Li H, et al. Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. J Allergy Clin Immunol 2011;127(2):382-389 e381-313. 20. Postma DS, Weiss ST, van den Berge M, Kerstjens HA, Koppelman GH. Revisiting the Dutch hypothesis. J Allergy Clin Immunol 2015;136(3):521-529. 21. Barrecheguren M, Roman-Rodriguez M, Miravitlles M. Is a previous diagnosis of asthma a reliable criterion for asthma-COPD overlap syndrome in a patient with COPD? Int J Chron Obstruct Pulmon Dis 2015;10:1745-1752. 22. Hardin M, Silverman EK, Barr RG, Hansel NN, Schroeder JD, Make BJ, et al. The clinical features of the overlap between COPD and asthma. Respir Res 2011;12(1):127. 23. Miravitlles M, Soriano JB, Ancochea J, Munoz L, Duran-Tauleria E, Sanchez G, et al. Characterisation of the overlap COPD-asthma phenotype. Focus on physical activity and health status. Respir Med 2013;107(7):1053-1060.

26 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628

24. Bai JW, Mao B, Yang WL, Liang S, Lu HW, Xu JF. Asthma-COPD overlap syndrome showed more exacerbations however lower mortality than COPD. QJM 2017;110(7):431436. 25. Menezes AMB, Montes de Oca M, Perez-Padilla R, Nadeau G, Wehrmeister FC, Lopez-Varela MV, et al. Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma. Chest 2014;145(2):297-304. 26. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J 2005;26(5):948-968. 27. Cosio BG, Perez de Llano L, Lopez Vina A, Torrego A, Lopez-Campos JL, Soriano JB, et al. Th-2 signature in chronic airway diseases: towards the extinction of asthma-COPD overlap syndrome? Eur Respir J 2017;49(5):1602397. 28. Cosio BG, Soriano JB, Lopez-Campos JL, Calle-Rubio M, Soler-Cataluna JJ, de-Torres JP, et al. Defining the asthma-COPD overlap syndrome in a COPD cohort. Chest 2016;149(1):45-52. 29. Sin DD, Miravitlles M, Mannino DM, Soriano JB, Price D, Celli BR, et al. What is asthma-COPD overlap syndrome? Towards a consensus definition from a round table discussion. Eur Respir J 2016;48(3):664-673. 30. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2018. Available from: www.ginasthma.org. Last accessed 24 June 2019. 2018. 31. Barczyk A, Maskey-Warzechowska M, Gorska K, Barczyk M, Kuziemski K, Sliwinski P, et al. Asthma-COPD overlap-a discordance between patient populations defined by different diagnostic criteria. J Allergy Clin Immunol Pract 2019. 32. de Marco R, Pesce G, Marcon A, Accordini S, Antonicelli L, Bugiani M, et al. The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population. PLoS One 2013;8(5):e62985. 33. Henriksen AH, Langhammer A, Steinshamn S, Mai XM, Brumpton BM. The prevalence and symptom profile of asthma-COPD overlap: the HUNT study. COPD 2018;15(1):27-35. 34. Kumbhare S, Pleasants R, Ohar JA, Strange C. Characteristics and prevalence of asthma/chronic obstructive pulmonary disease overlap in the United States. Ann Am Thorac Soc 2016;13(6):803-810. 35. Marsh SE, Travers J, Weatherall M, Williams MV, Aldington S, Shirtcliffe PM, et al. Proportional classifications of COPD phenotypes. Thorax 2008;63(9):761-767. 36. Alshabanat A, Zafari Z, Albanyan O, Dairi M, FitzGerald JM. asthma and COPD overlap syndrome (ACOS): a systematic review and meta analysis. PLoS One 2015;10(9):e0136065. 37. Milanese M, Di Marco F, Corsico AG, Rolla G, Sposato B, Chieco-Bianchi F, et al. Asthma control in elderly asthmatics. An Italian observational study. Respir Med 2014;108(8):1091-1099. 38. Kiljander T, Helin T, Venho K, Jaakkola A, Lehtimaki L. Prevalence of asthma-COPD overlap syndrome among primary care asthmatics with a smoking history: a cross-sectional study. NPJ Prim Care Respir Med 2015;25:15047. 39. Cazzola M, Rogliani P. Do we really need asthma-chronic obstructive pulmonary disease overlap syndrome? J Allergy Clin Immunol 2016;138(4):977-983. 40. de Marco R, Marcon A, Rossi A, Anto JM, Cerveri I, Gislason T, et al. Asthma, COPD and overlap syndrome: a longitudinal study in young European adults. Eur Respir J 2015;46(3):671-679.

27 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674

41. Park HY, Lee SY, Kang D, Cho J, Lee H, Lim SY, et al. Favorable longitudinal change of lung function in patients with asthma-COPD overlap from a COPD cohort. Respir Res 2018;19(1):36. 42. James AL, Palmer LJ, Kicic E, Maxwell PS, Lagan SE, Ryan GF, et al. Decline in lung function in the Busselton Health Study: the effects of asthma and cigarette smoking. Am J Respir Crit Care Med 2005;171(2):109-114. 43. Pleasants RA, Ohar JA, Croft JB, Liu Y, Kraft M, Mannino DM, et al. Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment. COPD 2014;11(3):256-266. 44. van Boven JF, Roman-Rodriguez M, Palmer JF, Toledo-Pons N, Cosio BG, Soriano JB. Comorbidome, pattern, and impact of asthma-COPD overlap syndrome in real life. Chest 2016;149(4):1011-1020. 45. Diaz-Guzman E, Khosravi M, Mannino DM. Asthma, chronic obstructive pulmonary disease, and mortality in the U.S. population. COPD 2011;8(6):400-407. 46. Fu JJ, Gibson PG, Simpson JL, McDonald VM. Longitudinal changes in clinical outcomes in older patients with asthma, COPD and asthma-COPD overlap syndrome. Respiration 2014;87(1):63-74. 47. Jenkins C, FitzGerald JM, Martinez FJ, Postma DS, Rennard S, van der Molen T, et al. Diagnosis and management of asthma, COPD and asthma-COPD overlap among primary care physicians and respiratory/allergy specialists: A global survey. Clin Respir J 2019;13(6):355-367. 48. Tashkin DP, Moore GE, Trudo F, DePietro M, Chipps BE. Assessment of consistency of fixed airflow obstruction status during budesonide/formoterol treatment and its effects on treatment outcomes in patients with asthma. J Allergy Clin Immunol Pract 2016;4(4):705712. 49. Gjevre JA, Hurst TS, Taylor-Gjevre RM, Cockcroft DW. The American Thoracic Society's spirometric criteria alone is inadequate in asthma diagnosis. Can Respir J 2006;13(8):433-437. 50. Tashkin DP, Celli B, Decramer M, Liu D, Burkhart D, Cassino C, et al. Bronchodilator responsiveness in patients with COPD. Eur Respir J 2008;31(4):742-750. 51. Albert P, Agusti A, Edwards L, Tal-Singer R, Yates J, Bakke P, et al. Bronchodilator responsiveness as a phenotypic characteristic of established chronic obstructive pulmonary disease. Thorax 2012;67(8):701-708. 52. Nair P, Martin JG, Cockcroft DC, Dolovich M, Lemiere C, Boulet LP, et al. Airway hyperresponsiveness in asthma: measurement and clinical relevance. J Allergy Clin Immunol Pract 2017;5(3):649-659 e642. 53. Tashkin DP, Altose MD, Bleecker ER, Connett JE, Kanner RE, Lee WW, et al. The Lung Health Study: airway responsiveness to inhaled methacholine in smokers with mild to moderate airflow limitation. The Lung Health Study Research Group. Am Rev Respir Dis 1992;145(2 Pt 1):301-310. 54. Tkacova R, Dai DLY, Vonk JM, Leung JM, Hiemstra PS, van den Berge M, et al. Airway hyperresponsiveness in chronic obstructive pulmonary disease: a marker of asthma-chronic obstructive pulmonary disease overlap syndrome? J Allergy Clin Immunol 2016;138(6):15711579 e1510. 55. Coates AL, Wanger J, Cockcroft DW, Culver BH, Bronchoprovocation Testing Task Force: Kai-Hakon C, Diamant Z, et al. ERS technical standard on bronchial challenge testing:

28 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721

general considerations and performance of methacholine challenge tests. Eur Respir J 2017;49(5):1601526. 56. Bafadhel M, Pavord ID, Russell REK. Eosinophils in COPD: just another biomarker? Lancet Respir Med 2017;5(9):747-759. 57. Vedel-Krogh S, Nielsen SF, Lange P, Vestbo J, Nordestgaard BG. Blood eosinophils and exacerbations in chronic obstructive pulmonary disease. The Copenhagen General Population Study. Am J Respir Crit Care Med 2016;193(9):965-974. 58. MacDonald MI, Osadnik CR, Bulfin L, Hamza K, Leong P, Wong A, et al. Low and high blood eosinophil counts as biomarkers in hospitalized acute exacerbations of COPD. Chest 2019;156(1):92-100. 59. Barnes NC, Sharma R, Lettis S, Calverley PM. Blood eosinophils as a marker of response to inhaled corticosteroids in COPD. Eur Respir J 2016;47(5):1374-1382. 60. Hirai K, Shirai T, Suzuki M, Akamatsu T, Suzuki T, Hayashi I, et al. A clustering approach to identify and characterize the asthma and chronic obstructive pulmonary disease overlap phenotype. Clin Exp Allergy 2017;47(11):1374-1382. 61. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361(9356):449-456. 62. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008;177(1):19-26. 63. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, et al. Indacaterolglycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med 2016;374(23):22222234. 64. Lipson DA, Barnhart F, Brealey N, Brooks J, Criner GJ, Day NC, et al. Once-daily singleinhaler triple versus dual therapy in patients with COPD. N Engl J Med 2018;378(18):16711680. 65. Kobayashi S, Hanagama M, Yamanda S, Ishida M, Yanai M. Inflammatory biomarkers in asthma-COPD overlap syndrome. Int J Chron Obstruct Pulmon Dis 2016;11:2117-2123. 66. Bousquet PJ, Castelli C, Daures JP, Heinrich J, Hooper R, Sunyer J, et al. Assessment of allergen sensitization in a general population-based survey (European Community Respiratory Health Survey I). Ann Epidemiol 2010;20(11):797-803. 67. Tamada T, Sugiura H, Takahashi T, Matsunaga K, Kimura K, Katsumata U, et al. Biomarker-based detection of asthma-COPD overlap syndrome in COPD populations. Int J Chron Obstruct Pulmon Dis 2015;10:2169-2176. 68. Donohue JF, Herje N, Crater G, Rickard K. Characterization of airway inflammation in patients with COPD using fractional exhaled nitric oxide levels: a pilot study. Int J Chron Obstruct Pulmon Dis 2014;9:745-751. 69. Chen FJ, Huang XY, Liu YL, Lin GP, Xie CM. Importance of fractional exhaled nitric oxide in the differentiation of asthma-COPD overlap syndrome, asthma, and COPD. Int J Chron Obstruct Pulmon Dis 2016;11:2385-2390. 70. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax 2009;64(8):728-735. 71. Miravitlles M, Alvarez-Gutierrez FJ, Calle M, Casanova C, Cosio BG, Lopez-Vina A, et al. Algorithm for identification of asthma-COPD overlap: consensus between the Spanish COPD and asthma guidelines. Eur Respir J 2017;49(5):1700068.

29 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766

72. Koblizek V, Milenkovic B, Barczyk A, Tkacova R, Somfay A, Zykov K, et al. Phenotypes of COPD patients with a smoking history in Central and Eastern Europe: the POPE Study. Eur Respir J 2017;49(5):1601446. 73. Woodruff PG, van den Berge M, Boucher RC, Brightling C, Burchard EG, Christenson SA, et al. American Thoracic Society/National Heart, Lung, and Blood Institute AsthmaChronic Obstructive Pulmonary Disease Overlap Workshop report. Am J Respir Crit Care Med 2017;196(3):375-381. 74. Tan WC, Sin DD, Bourbeau J, Hernandez P, Chapman KR, Cowie R, et al. Characteristics of COPD in never-smokers and ever-smokers in the general population: results from the CanCOLD study. Thorax 2015;70(9):822-829. 75. Doiron D, de Hoogh K, Probst-Hensch N, Fortier I, Cai Y, De Matteis S, et al. Air pollution, lung function and COPD: results from the population-based UK Biobank study. European Respiratory Journal 2019;54(1):1802140. 76. Eisner MD, Balmes J, Katz PP, Trupin L, Yelin EH, Blanc PD. Lifetime environmental tobacco smoke exposure and the risk of chronic obstructive pulmonary disease. Environmental health : a global access science source 2005;4(1):7-7. 77. Jaakkola MS, Piipari R, Jaakkola N, Jaakkola JJK. Environmental Tobacco Smoke and Adult-Onset Asthma: A Population-Based Incident Case–Control Study. Am J Public Health 2003;93(12):2055-2060. 78. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000;343(5):332-336. 79. Fingleton J, Travers J, Williams M, Charles T, Bowles D, Strik R, et al. Treatment responsiveness of phenotypes of symptomatic airways obstruction in adults. J Allergy Clin Immunol 2015;136(3):601-609. 80. Lee SY, Park HY, Kim EK, Lim SY, Rhee CK, Hwang YI, et al. Combination therapy of inhaled steroids and long-acting beta2-agonists in asthma-COPD overlap syndrome. Int J Chron Obstruct Pulmon Dis 2016;11:2797-2803. 81. Su VY, Yang KY, Yang YH, Tsai YH, Perng DW, Su WJ, et al. Use of ICS/LABA combinations or LAMA is associated with a lower risk of acute exacerbation in patients with coexistent COPD and asthma. J Allergy Clin Immunol Pract 2018;6(6):1927-1935 e1923. 82. Lim HS, Choi SM, Lee J, Park YS, Lee SM, Yim JJ, et al. Responsiveness to inhaled corticosteroid treatment in patients with asthma-chronic obstructive pulmonary disease overlap syndrome. Ann Allergy Asthma Immunol 2014;113(6):652-657. 83. Chowdhury BA, Dal Pan G. The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med 2010;362(13):1169-1171. 84. Gershon AS, Campitelli MA, Croxford R, Stanbrook MB, To T, Upshur R, et al. Combination long-acting beta-agonists and inhaled corticosteroids compared with longacting beta-agonists alone in older adults with chronic obstructive pulmonary disease. JAMA 2014;312(11):1114-1121. 85. Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J 2009;34(3):641-647. 86. O'Byrne PM, Pedersen S, Carlsson LG, Radner F, Thoren A, Peterson S, et al. Risks of pneumonia in patients with asthma taking inhaled corticosteroids. Am J Respir Crit Care Med 2011;183(5):589-595.

30 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811

87. Vedel-Krogh S, Nordestgaard BG, Lange P, Vestbo J, Nielsen SF. Blood eosinophil count and risk of pneumonia hospitalisations in individuals with COPD. Eur Respir J 2018;51(5):1800120. 88. Pavord ID, Lettis S, Anzueto A, Barnes N. Blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis. Lancet Respir Med 2016;4(9):731-741. 89. Kew KM, Dias S, Cates CJ. Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis. Cochrane Database Syst Rev 2014(3):CD010844. 90. Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012;367(13):1198-1207. 91. Magnussen H, Bugnas B, van Noord J, Schmidt P, Gerken F, Kesten S. Improvements with tiotropium in COPD patients with concomitant asthma. Respir Med 2008;102(1):50-56. 92. Ishiura Y, Fujimura M, Ohkura N, Hara J, Kasahara K, Ishii N, et al. Effect of triple therapy in patients with asthma-COPD overlap. Int J Clin Pharmacol Ther 2019. 93. Yoshida M, Nakano T, Fukuyama S, Matsumoto T, Eguchi M, Moriwaki A, et al. Effects of tiotropium on lung function in severe asthmatics with or without emphysematous changes. Pulm Pharmacol Ther 2013;26(2):159-166. 94. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Jr., Criner GJ, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365(8):689-698. 95. Rahimi S. Urgent action on antimicrobial resistance. Lancet Respir Med 2019;7(3):208-209. 96. Gibson PG, Yang IA, Upham JW, Reynolds PN, Hodge S, James AL, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet 2017;390(10095):659-668. 97. Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev 2014(1):CD003559. 98. Tat TS, Cilli A. Omalizumab treatment in asthma-COPD overlap syndrome. J Asthma 2016;53(10):1048-1050. 99. Maltby S, Gibson PG, Powell H, McDonald VM. Omalizumab treatment response in a population with severe allergic asthma and overlapping COPD. Chest 2017;151(1):78-89. 100. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med 2018;378(26):2486-2496. 101. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014;371(13):1198-1207. 102. FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2016;388(10056):2128-2141. 103. Criner GJ, Celli BR, Brightling CE, Agusti A, Papi A, Singh D, et al. Benralizumab for the prevention of COPD exacerbations. N Engl J Med 2019.

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104. Pavord ID, Chanez P, Criner GJ, Kerstjens HAM, Korn S, Lugogo N, et al. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. N Engl J Med 2017;377(17):16131629. 105. Agusti A, Bel E, Thomas M, Vogelmeier C, Brusselle G, Holgate S, et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J 2016;47(2):410419. 106. Kitaguchi Y, Komatsu Y, Fujimoto K, Hanaoka M, Kubo K. Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma. Int J Chron Obstruct Pulmon Dis 2012;7:283-289. 107. Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348(21):2059-2073. 108. Davey C, Zoumot Z, Jordan S, McNulty WH, Carr DH, Hind MD, et al. Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi study): a randomised controlled trial. Lancet 2015;386(9998):1066-1073. 109. Mainardi AS, Castro M, Chupp G. Bronchial thermoplasty. Clin Chest Med 2019;40(1):193-207. 110. Burn J, Sims AJ, Patrick H, Heaney LG, Niven RM. Efficacy and safety of bronchial thermoplasty in clinical practice: a prospective, longitudinal, cohort study using evidence from the UK Severe Asthma Registry. BMJ Open 2019;9(6):e026742. 111. Doeing DC, Mahajan AK, White SR, Naureckas ET, Krishnan JA, Hogarth DK. Safety and feasibility of bronchial thermoplasty in asthma patients with very severe fixed airflow obstruction: a case series. J Asthma 2013;50(2):215-218. 112. Adams RJ, Fuhlbrigge AL, Finkelstein JA, Weiss ST. Intranasal steroids and the risk of emergency department visits for asthma. J Allergy Clin Immunol 2002;109(4):636-642. 113. Callebaut I, Hox V, Bobic S, Bullens DM, Janssens W, Dupont L, et al. Effect of nasal anti-inflammatory treatment in chronic obstructive pulmonary disease. Am J Rhinol Allergy 2013;27(4):273-277. 114. Georgalas C, Cornet M, Adriaensen G, Reinartz S, Holland C, Prokopakis E, et al. Evidence-based surgery for chronic rhinosinusitis with and without nasal polyps. Curr Allergy Asthma Rep 2014;14(4):427. 115. Dixon AE, Pratley RE, Forgione PM, Kaminsky DA, Whittaker-Leclair LA, Griffes LA, et al. Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J Allergy Clin Immunol 2011;128(3):508-515 e501-502. 116. Goto T, Tsugawa Y, Faridi MK, Camargo CA, Jr., Hasegawa K. Reduced risk of acute exacerbation of COPD after bariatric surgery: a self-controlled case series study. Chest 2018;153(3):611-617. 117. McCarthy B, Casey D, Devane D, Murphy K, Murphy E, Lacasse Y. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2015(2):CD003793. 118. Conemans L, Agterhuis D, Franssen F, Spruit M, Wouters E, Vanfleteren L. Effects of pulmonary rehabilitation in patients with asthma. Eur Respir J 2018;52(suppl 62):PA2043. 119. Chaudhuri R, Livingston E, McMahon AD, Lafferty J, Fraser I, Spears M, et al. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med 2006;174(2):127-133.

32 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882

120. Tonnesen P, Pisinger C, Hvidberg S, Wennike P, Bremann L, Westin A, et al. Effects of smoking cessation and reduction in asthmatics. Nicotine Tob Res 2005;7(1):139-148. 121. Godtfredsen NS, Lam TH, Hansel TT, Leon ME, Gray N, Dresler C, et al. COPD-related morbidity and mortality after smoking cessation: status of the evidence. Eur Respir J 2008;32(4):844-853. 122. Dalal AA, Shah M, Lunacsek O, Hanania NA. Clinical and economic burden of depression/anxiety in chronic obstructive pulmonary disease patients within a managed care population. COPD 2011;8(4):293-299. 123. Paz-Diaz H, Montes de Oca M, Lopez JM, Celli BR. Pulmonary rehabilitation improves depression, anxiety, dyspnea and health status in patients with COPD. Am J Phys Med Rehabil 2007;86(1):30-36. 124. Hynninen MJ, Nordhus IH. Non-pharmacological interventions to manage depression and anxiety associated with chronic respiratory diseases: cognitive behavioral therapy and others. In: Sharafkhaneh A, Yohannes AM, Hanania NA, Kunik ME, editors. Depression and Anxiety in Patients with Chronic Respiratory Diseases. New York, NY: Springer New York; 2017. p. 149-165. 125. Yohannes AM, Leroi I. Pharmacological therapy and anxiolytics in patients with respiratory diseases. In: Sharafkhaneh A, Yohannes AM, Hanania NA, Kunik ME, editors. Depression and anxiety in patients with chronic respiratory diseases. New York, NY: Springer New York; 2017. p. 167-182. 126. McDonald VM, Simpson JL, Higgins I, Gibson PG. Multidimensional assessment of older people with asthma and COPD: clinical management and health status. Age Ageing 2011;40(1):42-49.

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FIGURE LEGENDS: Figure 1: Asthma-COPD overlap and the chronic airways disease paradigms. Figure 2: The heterogeneity of diagnostic criteria for ACO. Selected guidelines, consensus statements and clinical studies defining ACO based on clinical, physiological and laboratory features. Features are designated as “major/essential” if considered an absolute requirement for diagnosis. “Minor/non-essential” features are taken into consideration but not specified as an absolute requirement for diagnosis. Threshold values for each feature are included if stated in the publication. Note that GINA/GOLD considers only fixed airflow obstruction on spirometry to be an essential criterion; all other features are considered as part of a syndromic diagnosis of asthma, COPD or ACO (see Table 2). ACO, asthma-COPD overlap; FAO, fixed airflow obstruction; BDR, bronchodilator response; AHR, airway hyperresponsiveness; IgE, immunoglobulin E; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; %pred, percent of predicted value; PD15, provocative dose causing a 15 percent fall in FEV1.

34 900 901

TABLES: Population/ Population studied Reference General population Menezes et al25 PLATINO Latin American spirometry study de Marco et al32 GEIRD Italian general population survey

Definition

Prevalence

Diagnosis of COPD with FEV1/FVC <0.7, plus both history of wheeze in past 12 months and significant BDR Self-reported doctor diagnosis of both COPD and asthma

1.8%

Henriksen et al33 HUNT Norwegian FEV1/FVC <0.7, plus self-reported doctor population survey diagnosis of asthma 34 Kumbhare et al USA population telephone Self-reported doctor diagnosis of both survey COPD and past (but not current) asthma COPD cohorts Hardin et al22 COPDGene non-Hispanic Diagnosis of COPD with FEV1/FVC <0.7 and white and African FEV1 <80% predicted, plus self-reported American cohort with doctor diagnosis of asthma before age 40 moderate to severe COPD 35 Marsh et al COPD subjects from the Post-BD FEV1/FVC <0.7, plus asthma Wellington Respiratory defined as BDR ≥15% in FEV1 OR peak flow Survey variability ≥20% over 1 week OR doctor diagnosis of asthma with current symptoms or inhaler use Alshabanat et Meta-analysis of COPD defined by post-BD spirometry only, al36 published studies of COPD plus asthma defined as either doctor/selfpatients reported diagnosis OR BDR ≥15% in FEV1 OR peak flow variability ≥20% OR AHR

Barrecheguren et Spanish COPD cohort al21 Asthma cohorts Milanese et al37 Italian older asthma cohort Kiljander et al38 Primary care sample of asthma patients

902 903 904 905 906 907 908 909

Diagnosis of COPD with FEV1/FVC <0.7, plus self-reported doctor diagnosis of asthma before age 40

1.6% (ages 20-44) 4.5% (ages 65-84) 2% 3.2%

13%

55%

27% (communitybased) 28% (hospitalbased) 15.9%

Aged >65 years with diagnosis of asthma 29% by GINA 2012 criteria, plus either chronic bronchitis symptoms or impaired DLCO Doctor diagnosis of asthma with current or 27.4% ex-smoking history, plus FEV1/FVC <0.7

Table 1: Prevalence of ACO in selected observational studies. FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; BDR, bronchodilator response; AHR, airway hyperresponsiveness; GINA, Global Initiative for Asthma committee.

35 910 Feature Age of onset Pattern of respiratory symptoms

Lung function

Asthma Usually in childhood

COPD

Asthma-COPD overlap

Usually >40 years but may have had earlier symptoms May vary over time, often Chronic, usually continuous, Symptoms persistent by may
Variable over identifiable triggers particularly during exercise show variability minutes/hours/days
Worse in night/morning
Triggered by exercise, emotions, dust, allergens Current or historical variable Post-BD FEV1/FVC ratio <0.7 Obstruction not fully
Record of variable airflow airflow obstruction persists reversible, but often obstruction historical variability May be normal Persistent airflow Persistent airflow
Lung function normal between obstruction obstruction symptoms

Lung function between symptoms Past history or Often history of allergies family history and/or family history of asthma

Usually >40 years

More likely to be asthma if several of:
Onset before 20 years

History of exposure to noxious particles/gases (mainly tobacco smoke)

Frequently personal and family history of asthma and allergies, and history of noxious exposures


Previous doctor diagnosis of asthma
Family history of asthma, other allergic conditions
No worsening of symptoms over time
Spontaneous improvement or immediate response to BD or to ICS over weeks
Normal

Time course

Often improves spontaneously or with treatment

Slowly progressive over years despite treatment

Symptoms partly but significantly reduced by treatment

Chest X-ray

Usually normal

Similar to COPD

Exacerbations

Risk reduced by treatment

Airway inflammation

Eosinophils +/- neutrophils

Severe hyperinflation and other changes Risk may be reduced by treatment; comorbidities may contribute Neutrophils +/- eosinophils in sputum, may have systemic inflammation

More likely to be COPD if several of:
Onset after 40 years
Persistence despite treatment
Good and bad days but always present during exercise
Chronic cough/sputum preceded onset of dyspnea
Record of persistent airflow obstruction
Lung function abnormal between symptoms
Previous doctor diagnosis of COPD, chronic bronchitis, emphysema
Heavy exposure to a risk factor (eg tobacco smoke)
Symptoms slowly worsening over time
Rapid-acting BD provides limited relief
Severe hyperinflation

May be more common than Diagnosis is made based on the predominance of features usually in COPD but responsive to associated with the disease. In the presence of balanced features of treatment both asthma and COPD, a diagnosis of asthma-COPD overlap is Eosinophils +/- neutrophils in considered sputum

36 911 912 913

Table 2: Clinical features and diagnostic rubric for asthma, COPD, and asthma-COPD overlap. Adapted from Global Initiative for Asthma report 2018.30 FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; BD, bronchodilator; ICS, inhaled corticosteroid

37 Trait

Is treatment warranted?

Airflow obstruction Correlates with symptoms and risk of exacerbation

Exacerbations with Sign of eosinophilic airway eosinophilia inflammation and steroid responsiveness

Is it treatable?

Is there an expected outcome? Improvements in lung function, reduced exacerbation rate

Is the risk:benefit Selected acceptable? references ICS + long-acting LABA monotherapy Crim et al85 bronchodilators contraindicated. ICS has good safety profile; pneumonia risk at high doses ICS beneficial in both asthma Reduction in exacerbations Minimal side-effects in Kitaguchi et al106 and COPD clinical trials

Reduction in exacerbations, Reasonable safety profile; Castro et al100 improved lung function in high cost of therapy needs to asthma; minimal evidence be considered for efficacy in COPD Anti-IL-5 therapy May reduce exacerbations; Good safety profile; consider Criner et al103 good evidence for efficacy in high cost of therapy Pavord et al104 asthma, but inconsistent in Ortega et al101 COPD Fitzgerald et al102 Exacerbations with Associated with frequent Omalizumab Improves exacerbation rate Rare risk of anaphylaxis, Tat, Cilli98 high serum IgE exacerbations, symptoms in people already on otherwise good safety Maltby et al99 ICS/LABA/LAMA therapy profile Neutrophilic Associated with frequent Macrolides Improved exacerbation rate Risk of hearing impairment Albert et al94 inflammation exacerbations and heart arrhythmia in Gibson et al96 selected patients, requires monitoring Emphysema with Reduces inspiratory capacity, Lung volume reduction Improved exercise capacity Risk assessment for surgery Fishman et al107 severe gas trapping associated with significant surgery and mortality in selected should be undertaken disability patients Endobronchial lung volume Improved symptoms and May be suitable for patients Davey et al108 reduction - valves, coils etc. exercise capacity in selected unfit for surgery; risk patients assessment should be undertaken Exacerbations Patients often dependent on Bronchial thermoplasty Reduced exacerbations, Small case series suggest Mainardi et al109 refractory to oral corticosteroids improved QOL safe even in severe disease Burn et al110 Anti-IL-4/IL-13 therapy

38 medical treatment Allergic Associated with poor rhinosinusitis symptom control and exacerbations

Nasal steroids

Surgery Obesity

Bariatric surgery

Physical inactivity Associated with increased and deconditioning symptoms, poor QOL, mortality

Pulmonary rehabilitation and exercise training

Smoking

Behavioural interventions +/- pharmacotherapy

Anxiety and depression

Worse symptom control, increased exacerbations, hospitalizations, mortality; reduced responsiveness to steroid treatment Associated with poor QOL, increased rate of exacerbations

Pulmonary rehabilitation

Improved symptoms in both asthma and COPD, reduced exacerbation rate in asthma May improve symptoms limited evidence base Improves asthma control and AHR, reduced COPD exacerbations Asthma and COPD patients shown to benefit. Improved exercise capacity, QOL, symptoms, reduced anxiety. Effect on exacerbations and mortality uncertain. Improvement in lung function decline, improved symptoms, reduced exacerbation

Good safety profile

Improved anxiety and depression scores, QOL

Doeing et al111 Adams et al112 Callebaut et al113

Risk assessment for surgery Georgalas et al114 should be undertaken Risk assessment for surgery Dixon et al115 should be undertaken Goto et al116 Risk acceptable in even severe COPD with recent hospitalization

McCarthy et al117 Conemans et al118

Good safety profile; risk assessment before commencing pharmacotherapy

Chaudhuri et al119 Tønnesen et al120 Godtfredsen et al121

Non-exercise component carries negligible risk

Dalal et al122 Paz-Díaz et al123

Psychological interventions CBT may improve anxiety Negligible risk and depression as well as respiratory symptoms Pharmacotherapy Evidence for effectiveness of Risk assessment for drug anti-depressants is lacking interactions is necessary

Hynninen et al124

Yohannes et al125

Table 3: Selected treatable traits for asthma, COPD, and ACO. IgE, immunoglobulin E; QOL, quality of life; ICS, inhaled corticosteroid; LABA, long-acting beta agonist; LAMA, long-acting muscarinic antagonist; IL-4/-13/-5, interleukin-4, -13 and -5; CBT, cognitive behavioural therapy

ACO AS A DISCRETE CLINICAL ENTITY

ACO AS THE COINCIDENCE OF PREVALENT DISEASES

EARLY LIFE INFLUENCES GENETICS

ENVIRONMENT ACO EARLY LIFE INFLUENCES

ASTHMA

COPD

COPD

ACO ON A CONTINUUM OF AIRWAYS DISEASE ENVIRONMENT

GENETICS

IgE

Allergens Th2 cytokines

EARLY LIFE INFLUENCES Airway hyperresponsiveness Eosinophils

Mucus hypersecretion

Bronchodilator responsiveness

Smoke exposure

Neutrophils

Emphysema

Th1 cytokines

COPD PHENOTYPE

ASTHMA PHENOTYPE ACO PHENOTYPE

ENVIRONMENT

GENETICS

ASTHMA

Gibson & 70 Simpson 2019

Features

Fixed airflow obstruction

CHAIN study28

POPE study72

Sin et al 29

All criteria

1 major or 2 minor

All major + ≥1 minor

All major + ≥1 minor

All major + ≥1 minor

FEV1/FVC <0.7 + FEV1 <80 %pred

COPD confirmed by spirometry

Post-treatment FEV1/FVC <0.7 ≥10 pack-yr smoking

COPD confirmed by spirometry ≥10 pack-yr smoking

FEV1/FVC <0.7 or
Current asthma

Diagnosed age <40

Diagnosed age <40 + BDR >400 mL

>15% and 400 mL >12% / 200 mL (x 2)

>15% and 400 mL

In past year

>12% / 200 mL (x 2)

>5%

≥300/µL

Age

≥35 years

Diagnosis of asthma BDR PD15 <12 mL

Pattern of symptoms History of atopy/allergy Blood eosinophil count Serum IgE Family history Chest imaging

GINA/GOLD7,30

Combination of criteria required for a diagnosis of ACO:

Exposure history

AHR

GEMA/GesEPOC 71 consensus

>100 IU

≥300/µL

Essential / major consideration Non-essential / minor consideration

Features of both asthma + COPD Confirm FAO

Not considered / not specified