Update on Asthma–COPD Overlap (ACO): A Narrative Review

Figures & data

Table 1 Criteria for Diagnosis of Asthma–Chronic Obstructive Pulmonary Disease Overlap Syndrome

Major

1. Persistent airflow limitation [post-bronchodilator FEV1/FVC <0.70 or LLN] in individuals 40 years of age or older; LLN is preferred. 2. At least 10 pack-years of tobacco smoking OR equivalent indoor or outdoor air pollution exposure [eg biomass] 3. Documented history of asthma before 40 years of age OR BDR of >400 mL in FEV1

Minor

1. Documented history of atopy or allergic rhinitis 2. BDR of FEV1 ≥200 mL and 12% from baseline values on 2 or more visits 3. Peripheral blood eosinophil count of ≥ 300 cells/μL

Notes: The committee recommends the presence of all three major criteria and at least one minor criterion for asthma-chronic obstructive pulmonary disease overlap syndrome. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; BDR, bronchodilator response using 400 mg of albuterol/salbutamol [or equivalent]; LLN, Lower limit of normal. Reproduced with permission of the © ERS 2021: European Respiratory Journal 48 (3) 664–673; DOI: 10.1183/13993003.00436-2016 Published 31 August 2016. Reproduced from: Sin DD, Miravitlles M, Mannino DM, et al. What is asthma-COPD overlap syndrome (ACOS)? Towards a consensus definition from a roundtable discussion. Eur Respir J. 2016;48: 664–673.¹⁵ Copyright © ERS 2016.

Table 2 Definition of ACO from Japanese Respiratory Society

Basic Characteristics

Post-bronchodilator FEV1/FVC < 70% in individuals 40 years of age or older

Features of COPD

(1 item out of 1–3)

1. Smoking history (> 10 pack-year) or similar air pollution exposure

2. Presence of low attenuation area showing emphysematous lesions on CT

3. Impaired pulmonary diffusion (DLCO and/or DLCO/VA <0.8)

Features of asthma

(2 items out of 1–3 or 1 item out of 1–3 and 2 items out of 4)

1. Variable (diurnal, day to day, seasonal) or paroxysmal respiratory symptoms (cough, sputum, dyspnea)

2. Asthma diagnosis history under 40 years

3. Exhaled nitric oxide > 35ppb

4-1) Complication of allergic rhinitis

2) Bronchodilator response of FEV1≥200 mL and 12% from baseline

3) Peripheral blood eosinophil count> 5% or 300 cells/μL

4) High IgE (for total or inhaled antigens)

Notes: If basic characteristics, features of asthma and features of COPD are satisfied, diagnose as ACO. Reproduced from Yanagisawa S, Ichinose M. Definition and diagnosis of asthma-COPD overlap (ACO). Allergol Int. 2018;67(2):172–178.²⁰ Copyright © 2018 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved. Creative Commons (CC BY-NC-ND 4.0; https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode).

Table 3 Prevalence of ACO in Patients with COPD

	Country	No. of ACO	Prevalence of ACO in Patients with COPD	ACO Definition
Population studies
Marsh et al (2008)^Citation125	New Zealand	53	55.2%	Post BD FEV1/FVC <0.7 AND BDR ≥15% or peak flow variability ≥20% or physician diagnosis with current symptoms or inhaler use
de Marco et al (2013)^Citation25	Italy		Age 20–44: 32.7%	Self-reported physician diagnosis of asthma and COPD
			Age 45–64: 26.9%
			Age 65–84: 25.3%
Miravitlles et al (2013)^Citation24	Spain	67	17.4%	Post BD FEV1/FVC <0.7 AND Self-reported physician diagnosis of asthma
Rhee et al (2014)^Citation22	South Korea	101,004	54.6%	ICD-10 code of asthma and COPD AND Use of asthma and COPD medication
van Boven et al (2016)^Citation69	Spain	5093	18.3%	Physician confirmed diagnosis (ICD-9 code) of asthma and COPD
Krishnan et al (2019)^Citation23	UK	335	Patients with physician diagnosis of COPD only: 20.5% Patients with physician diagnosis of both asthma and COPD: 32.1%	Age ≥40 years AND Current or former smoking AND Post BD FEV1/FVC <0.7 AND BDR ≥12% and 200 mL
Morgan et al (2019)^Citation126	Low- and middle-income countries	450	Peru: 13.6%, Argentina: 29.3%, Chile: 32.5%, Uruguay: 35.1%, Bangladesh: 34.9%, Uganda: 21.3%	COPD: post BD FEV1/FVC <LLN AND Asthma: fulfilling 1 of 3 criteria - (1) Self-report of wheezing in 1 year, (2) Self-report of medication use for asthma in 1 year, (3) Self-report of a physician diagnosis of asthma
COPD cohort studies
Jo et al (2020)^Citation26	South Korea	264	Specialists’ diagnosis: 24.8%	Post BD FEV1/FVC <0.7 AND Pulmonologist/allergist diagnosis of asthma
		32	ATS roundtable criteria: 3.0%	All 3 major and at least 1 minor Major: (1) Post BD FEV1/FVC <0.7 and age ≥40, (2) Smoking ≥10 p-y or exposure to air pollution ≥10 year, (3) History of asthma before age 40 or BDR >400 mL in FEV1 Minor: (1) History of atopy or allergic rhinitis, (2) Separate BDR ≥12% and 200 mL, (3) Blood eosinophil count ≥300 cells/μL
		138	GINA/GOLD document: 12.9%	Patients who met at least 3 items in both the asthma and COPD categories
		171	Modified Spanish criteria: 16.0%	Post BD FEV1/FVC <0.7 AND at least 1 major or 2 minor Major: (1) Previous history of asthma, (2) BDR >15% and 400 mL Minor: (1) IgE >100 IU or history of atopy, (2) BDR >12% and 200 mL, (3) Blood eosinophil >5%
		138	Updated Spanish criteria: 12.9%	((1) and (2)) OR ((1) and (3)) (1) Age ≥35, smoking ≥10 pyrs, and post BD FEV1/FVC <0.7 (2) Current diagnosis of asthma (3) BDR ≥15% and 400 mL, and/or blood eosinophil ≥300 cells/μL
Barrecheguren et al (2020)^Citation10	Canada	264	Any ACO: 50.6%	Post BD FEV1/FVC <0.7 AND One of the following asthma features
		105	Reversibility: 20.1%	Post BD FEV1/FVC <0.7 AND BDR ≥12% and 200 mL
		31	Large reversibility: 5.9%	Post BD FEV1/FVC <0.7 AND BDR ≥15% and 400 mL
		124	Atopy: 23.8%	Post BD FEV1/FVC <0.7 AND Self-reported presence of respiratory allergies or hay fever
		162	Physician diagnosis: 31.0%	Post BD FEV1/FVC <0.7 AND Self-reported physician diagnosis of asthma
		27	Reversibility + atopy: 5.2%
		80	Atopy + physician diagnosis: 15.3%
		20	Reversibility + atopy + physician diagnosis: 3.8%

Abbreviations: No., number; ACO, asthma COPD overlap; BD, bronchodilator; ICD, international classification of diseases; LLN, lower limit of normal; ATS, American Thoracic Society; p-y, pack-years; BDR, bronchodilator response; GINA, Global Initiative for Asthma; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IgE, immunoglobulin E.

Table 4 Different Single Nucleotide Polymorphisms (SNPs) Identified in Patients with ACO

How the “Asthmatic” Phenotype was Defined in the Study	Study	Promising SNPs, Nearest Gene and p-value	Replication in an External Cohort
Physician-diagnosis before age 40 yrs^Citation41	COPDGene (non-Hispanic whites)	rs11779254, CSMD1 (10^−6)	No
		rs59569785, SOX5 (10^−6)
		rs10860172, RMST (10^−6)
		rs72812713, SEMA6A (10^−6)
		rs4298581, ZDHHC21 (10^−6)
Physician-diagnosis before age 40 yrs^Citation41	COPDGene (African-Americans)	rs2686829, PKD1L1 (10^−7)	No
		rs9577395, ATP11A (10^−6)
		rs3864801, REEP3 (10^−6)
		rs12681559, NRG1 (10^−6)
		rs28895885, AGA (10^−6)
		rs115905118, KCNK1 (10^−6)
Airway hyper-reactivity^Citation49	Lung Health Study (non-Hispanic whites)	rs10491678, LINGO2 (10^−6)	No
		rs9486594, PDSS2 (10^−6)
		rs7618314, RETNLB (10^−6)
		rs2642660, SGCD (10^−4)
Inhaled steroid response (FEV1 decline)^Citation50	Lung Health Study (non-Hispanic whites)	rs111720447, gene unknown (10^−5)	Yes
		rs10057473, NR3C1 (10^−2)

Figure 1 Proposed biomarkers for differentiating ACO from asthma and COPD.

Figure 2 Treatment algorithm for ACO.

Notes: *Due to risk in asthmatics with LABA monotherapy, ICS is the preferred therapy in ACO. **For patients with a chronic bronchitis phenotype and a FEV1 < 50%. ***For ex-smokers and infective exacerbations.

Abbreviations: ACO, asthma COPD overlap; FeNO, exhaled nitric oxide; ICS, inhaled corticosteroids; IgE, immunoglobulin E; IL, interleukin; LABA, long-acting beta agonist; LAMA, long-acting muscarinic antagonist.

Sin DD, Miravitlles M, Mannino DM, et al. What is asthma-COPD overlap syndrome (ACOS)? Towards a consensus definition from a roundtable discussion. Eur Respir J. 2016;48:664–673. doi:10.1183/13993003.00436-2016

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