Practical Guide to the Identification and Diagnosis of Asthma-COPD Overlap (ACO)

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality around the world. COPD is characterised by a heterogeneous clinical presentation and prognosis which may vary according to the clinical phenotype. One of the phenotypes of COPD most frequently studied is the asthma-COPD overlap (ACO), however, there are no universally accepted diagnostic criteria for ACO. It is recognised that the term ACO includes patients with clinical features of both asthma and COPD, such as more intense eosinophilic bronchial inflammation, more severe respiratory symptoms and more frequent exacerbations, but in contrast, it is associated with a better prognosis compared to COPD. More importantly, ACO patients show better response to inhaled corticosteroid treatment than other COPD phenotypes. The diagnosis of ACO can be difficult in clinical practice, and the identification of these patients can be a challenge for non-specialized physicians. We describe how to recognise and diagnose ACO based on a recently proposed Spanish algorithm and by the analysis of three clinical cases of patients with COPD. The diagnosis of ACO is based on the diagnosis of COPD (chronic airflow obstruction in an adult with significant smoking exposure), in addition to a current diagnosis of asthma and/or signficant eosinophilia.

Keywords:

• COPD
• asthma
• asthma-COPD overlap
• diagnosis
• guidelines

Introduction

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with a clinical presentation and prognosis which may vary according to the clinical phenotype (1). In the last years, one of the phenotypes of COPD, the so-called asthma-COPD overlap (ACO), has received increasing attention. The term ACO has been applied to patients who present clinical features of both asthma and COPD (2).

In contrast to other COPD phenotypes, patients with ACO more frequently present a greater degree of eosinophilic bronchial inflammation, which translates into a greater response to inhaled corticosteroid (ICS) treatment (3–5). This characteristic can be explained in a significant number of ACO patients by a history of asthma during youth, which, in turn, is an independent risk factor for the development of chronic airflow obstruction (i.e. COPD) in smokers (6). From a clinical point of view, patients with ACO are usually more symptomatic and have a worse quality of life and a higher risk of exacerbations than other COPD patients (7–9), but in contrast, they have a better survival (10, 11).

In the last years there have been attempts to define the diagnostic criteria of this phenotype, but no definitive consensus has yet been achieved. In Spain, a diagnostic consensus was initially proposed with very restrictive criteria, in which 2 major criteria or 1 major and 2 minor had to be fulfilled for a patient to be defined as ACO. The major criteria included a very positive bronchodilator test (BDT) (increase in forced expiratory volume in the first second (FEV₁) of ≥400 mL and 15% compared to baseline), eosinophilia in sputum and a personal history of asthma before the age of 40; while the minor criteria were an elevated total IgE, a history of atopy and a positive BDT (≥200 mL and 12% increase in FEV₁) on at least two occasions (12). These diagnostic criteria have been adopted with minimal modifications by other national COPD guidelines, such as the Finnish and the Czech (13, 14). Thereafter, a joint document between the Global Initiative for Asthma (GINA) and the Global initiative for Chronic Obstructive Lung Disease (GOLD) defined ACO as persistent airflow obstruction with characteristics of both asthma and COPD, but did not clearly specify how many criteria should be met to establish a diagnosis of ACO (15). Moreover, the committee weighed each criterion equally.

Later, in 2016, an international consensus was developed by a group of specialists in North America, Europe and Asia, who proposed 3 major criteria (persistent airflow obstruction in patients over 40 years of age, exposure to smoking of at least 10 pack-years or the equivalent in biomass smoke exposure, a documented history of asthma before age 40 or an increase after BDT > 400 mL in FEV₁ and 3 minor criteria (documented history of atopy or allergic rhinitis, BDT ≥200 mL and 12% increase in FEV₁ on at least 2 occasions and peripheral eosinophilia ≥300 eosinophils/µL). For a diagnosis of ACO, 3 major criteria and at least one of the minor criteria proposed had to be met​ (16).

More recently, the new consensus between the Spanish COPD guidelines (GesEPOC) and the Spanish guidelines for asthma (GEMA) has simplified the definition of ACO, and it is now defined as the presence of chronic persistent airflow obstruction in a smoker or ex-smoker [exposure factor (EF) ≥10 pack-years] older than 35 years with a concomitant diagnosis of asthma or with one of the following characteristics: very positive BDT (≥15% and ≥400 mL increase in FEV₁) and/or blood eosinophilia (≥300 eosinophils/µL). Thus, the ACO phenotype includes not only smoking asthmatics with persistent airflow obstruction, but also COPD patients with asthma-like features, such as increased reversibility and/or eosinophilic inflammation. To fulfil this definition, airflow obstruction must be persistent over time, current or past smoking should be the main risk factor, and the patient must present clinical, biological or functional characteristics of asthma (17). Of note, GesEPOC recommends the use of the lower limit of normal of the FEV₁/FVC to identify airflow obstruction in individuals younger than 50 and older than 70 years to avoid misdiagnosis. These different consensus criteria proposed are summarised in Table 1.

Table 1. The different criteria proposed for the diagnosis of ACO in different consensus and guidelines.

Consensus	Diagnostic criteria of ACO
Finnish guidelines (13)	ACO is confirmed by presenting two main criteria or one main criteria and two additional criteria: Main criteria: Very positive BDT FEV1 >15 % and >400 ml Sputum eosinophilia or elevated FENO (>50 ppb) Previous asthma symptoms (starting age at < 40 y) Additional criteria Elevated total IgE Atopy Repeated significant positive BDT (FEV1 >12 % and >200 ml) Peak expiratory flow follow-up typical of asthma
Czech guidelines (14)	ACO is confirmed by the presence of two major criteria or one major plus two minor criteria: Definitive diagnosis of COPD Major criteria: Very positive BDT FEV1 >15% and >400 mL FENO ≥45–50 ppb and/or sputum eosinophils ≥3% history of asthma Minor criteria: Positive BDT (FEV1 >12% and >200 mL) elevated total IgE, history of atopy
Sin et al. (16)	ACO is confirmed by the presence of three major and at least one minor criteria Major criteria Post BDT FEV1/FVC <0.70 in individuals>40 years of age At least 10 pack-years of tobacco smoking Documented history of asthma before 40 years of age. BDT of >400 mL in FEV1 Minor criteria Documented history of atopy or allergic rhinitis BDR of FEV1 ≥200 mL and 12% from baseline values on 2 or more visits Peripheral blood eosinophil count of ≥300 cells/uL
GesEPOC-GEMA algorithm (17)	Age ≥35 years old Tobacco exposure ≥10 pack-years Post BDT FEV1/FVC < 0.70 Diagnosis of asthma In absence of asthma diagnosis: very positive BDT(≥400 mL and 15% ) and/or blood eosinophilia ≥300 cells/µL

BDT: bronchodilator test; FENO: fractioned exhaled nitric oxide; ppb: parts per billion; FEV₁: forced expiratory volume in the first second; FVC: forced vital capacity.

Due to the lack of universally accepted diagnostic criteria, the diagnosis of ACO in clinical practice is a daily challenge for physicians (18). Here, we present three clinical cases in order to analyse their clinical presentations and the different criteria proposed by the Spanish consensus.

Clinical cases

History of asthma

This was a 50-year-old male, former smoker with tobacco exposure of 30 pack-years, intolerant to aspirin and pharmacologic allergy to penicillin. Diagnosed with asthma at the age of 18 after two episodes of bronchospasm. He received a long-acting beta agonist (LABA) bronchodilator and ICS treatment for two years that was discontinued afterwards. Posteriorly, at the age of 48 he was hospitalised for an asthma exacerbation that was treated with bronchodilators, ICS and oral corticosteroids (OCS). Following hospitalisation, he was referred to our centre to continue study and treatment. Lung function tests showed moderate airflow obstruction: FVC (forced vital capacity) 3.95 L (66.8%), FEV₁ 2.41L (52.8%), FEV₁/FVC 61% with a negative bronchodilator test and severely decreased diffusing lung capacity of carbon monoxide (DLCO of 31%). In addition, paraseptal emphysema was observed in the thoracic computerised tomography (CT), and a blood analysis showed 210 eosinophils/μL (2.2%). With this presentation, the patient was diagnosed with COPD with an ACO phenotype because of his well-documented history of asthma. Triple therapy (LABA, LAMA (long-acting muscarinic antagonist) and ICS) was initiated, and after three months of follow-up, the patient showed clinical improvement without exacerbations.

Bronchodilator responsiveness

This was a 58 year-old male, former heavy smoker with tobacco exposure of 54 pack-years. He had a history of atopy and allergic rhinitis since youth and was hospitalised at the age of 56 due to dyspnoea and wheezing. During hospitalisation, a thoracic CT scan was performed showing bilateral centrilobular emphysema predominantly in the upper lobes. In addition, a lung function test after discharge showed severe airflow obstruction: FVC 2.64 (59%), FEV₁ 1.39L (31%), FEV₁/FVC 52.6% with a positive BDT (increase of 410 mL and 41.8%). Blood analysis showed 500 eosinophils/μl (7.9%). He was then diagnosed with COPD with an ACO phenotype due to the very positive BDT, although he also fulfilled the criterion of blood eosinophils > 300 cells/μL. The patient initiated triple therapy (LABA/LAMA/ICS), showing clinical improvement.

High blood eosinophilia

This was a 73 year-old male, former smoker with tobacco exposure of 60 pack-years. Since the age of 67 years he referred having at least two exacerbations per year with audible wheezing requiring systemic corticosteroids and antibiotics. Lung function tests showed severe airflow obstruction (FVC 2.40L (59.6%), FEV₁ 1.13L (40%), FEV₁/FVC 47%) with a negative BDT. The blood test showed high eosinophils (340 cells/μL, 5.7%), and diffuse centrilobular emphysema was observed in the thoracic CT scan. The patient was diagnosed with COPD with an ACO phenotype due to the high blood eosinophil count, and triple therapy was initiated, presenting clinical improvement.

Discussion

The identification of ACO in COPD is relevant because these patients will benefit from the early introduction of treatment with ICS. Although COPD and asthma have unique and differential characteristics, some patients may share aspects of both diseases. The difficulties in the differential diagnosis of asthma and COPD may increase with the addition of this third group of patients with ACO (18–20). Different scientific societies and expert groups have proposed criteria for the diagnosis of ACO (Table 1), and large observational studies have used different criteria to diagnose ACO (Table 2). Here, three clinical cases are described to illustrate the application of the recent Spanish criteria included in the Spanish guidelines for the management of asthma or COPD (17).

Table 2. Different diagnostic criteria of ACO used in clinical observational studies.

Study	Diagnostic criteria of ACO	N (total)	ACO N (%)
Hardin et al.(7) COPDGene	Age: 45–80 years old Smoking history ≥10 pack-years Post BDT FEV1/FVC <0.70 History of asthma (defined as diagnosis reported by a physician before 40 years of age)	915	119 (13%)
Miravitlles et al. (8) EPI-SCAN	Age: 40–80 years old Post BDT FEV1/FVC <0.70 Previous diagnosis of asthma	385	67 (17.4%)
Menezes et al. (9) PLATINO	COPD diagnosis (post BDT FEV1/FVC <0.70) Concomitant diagnosis of asthma: wheezing in the last 12 months + post BDT increase in FEV1 or FVC of 200 ml and 12% or previous diagnosis of asthma	767	89 (11.6%)
Barrecheguren et al. (23) FyCEPOC	Age ≥40 years old Smoking history ≥10 pack-years Post BDT FEV1/FVC<0.70 ACOS 1: ACOS diagnostic criteria of the Spanish consensus 2012 (12): 1) Major criteria: very positive bronchodilator test (improvement in FEV1 400 mL and 15%); sputum eosinophilia or a previous diagnosis of asthma before the age of 40 years. 2) Minor criteria: increased total serum immunoglobulin (Ig)E; and previous history of atopy or a positive bronchodilator test (200 mL and 12% in FEV1) on at least two occasions. ACOS 2: Previous diagnosis of asthma before the age of 40 years	3125	158 (5.1%) 338 (10.8%)
Wurst et al. (24) ECLIPSE	COPD diagnosis (FEV1/FVC <0.70) Self-reported previous diagnosis of asthma	1483	493 (25%)
Pérez de Llano et al. (40) CHACOS	GESEPOC- GEMA algorithm (17): Age ≥35 years old Tobacco exposure ≥10 pack-years Post BDT FEV1/FVC <0.70 History of asthma and/or other features of asthma (atopy and/or respiratory symptoms: wheezing, cough, chest oppression) In absence of asthma diagnosis: very positive BDT (≥400 mL and 15%) and/or Blood eosinophilia ≥300 eosinophils/µL	292	87 (29.8%)

BDT: bronchodilator test; FEV₁: forced expiratory volume in the first second; FVC: forced vital capacity.

Previous history of asthma

The first step to diagnose ACO should be a confirmed diagnosis of COPD based on smoking (or equivalent noxious exposure), respiratory symptoms and non-fully reversible airflow obstruction. Subsequently, the diagnosis of asthma should be confirmed by a well-documented history of asthma and/or a current diagnosis of asthma according to guidelines (21). If the diagnosis of asthma cannot be established, the diagnosis of ACO can be confirmed by the presence of a very positive BDT (increase of ≥400 mL and 15% in FEV₁ compared to baseline) and/or the presence of blood eosinophilia (≥300 cells/µL) as a surrogate marker of airway eosinophilia (22).

In a recent study performed by Barrecheguren et al. (23), the authors observed that a previous history of asthma before the age of 40 used as a single criterion to diagnose ACO in a population of patients with COPD identified a group of individuals with similar characteristics to those identified as ACO using the more restrictive criteria of the first Spanish consensus of ACO (12). Moreover, in the ECLIPSE study, the addition of other asthma features, such as bronchodilator responsiveness, the presence of atopy or respiratory symptoms, to the previous history of asthma did not add value to the diagnosis of ACO in patients with COPD (24).

In the new Spanish COPD guidelines, a history of asthma in a patient with COPD constitutes, by itself, a diagnostic criterion of ACO (25); however, it is important to highlight that significant smoking exposure is necessary for the diagnosis of COPD, and therefore, of ACO. Otherwise, in the absence of significant smoking exposure, the patient should be diagnosed with chronic, irreversible asthma but not ACO. Differences between ACO and irreversible asthma were evaluated by Tommola et al. (26), and no differences were found in terms of the prevalence of rhinitis, atopy or allergy between patients with ACO and non-smoking asthmatics with irreversible airway obstruction. However, a worse diffusion capacity, higher blood neutrophil counts and higher interleukin (IL)-6 concentrations were found in patients with ACO compared with irreversible asthmatics. Therefore, significant smoking exposure is necessary to differentiate chronic irreversible asthma from ACO. In any case, this differentiation has no practical consequences since in both, ACO and chronic irreversible asthma, the treatment is the same and is based on the combination of long-acting bronchodilators and ICS, with triple therapy in the most severe cases.

In our case, the patient had a well-established COPD and a previous diagnosis of asthma, and the key feature to differentiate ACO from chronic irreversible asthma was tobacco exposure of 30 pack-years.

Very positive bronchodilator test

Increased reversibility is included as a criterion for ACO in most consensus statements based on some evidence that suggests that these individuals are a particular type of COPD patients with different clinical characteristics that simulate asthma (27) and have a better long term prognosis compared with irreversible COPD (28). However, as indicated by Pascoe et al. (3), having a positive BDT (i.e. increase in FEV₁ of at least 200 mL and 12%) is a very frequent finding in COPD and is not a valid marker for response to ICS in COPD. For example, in the UPLIFT study, performed in COPD patients without a previous diagnosis of asthma, up to 54% of the 5756 patients included had a positive BDT (29). In addition, a positive or negative status in BDT can quite often change, suggesting that a positive BDT may not be a stable phenotype (30). For all these reasons, a positive BDT should not be considered a criterion for ACO (31). However, a very positive BDT, defined as an increase in FEV₁ of at least 400 mL and 15% may identify a particular population of COPD patients with different characteristics (27, 28). This threshold of 400 mL in FEV₁ was defined by the National Institute for Care and Health Excellence (NICE) as being suggestive of asthma or an asthmatic component of COPD (32). In fact, in one of the first definitions of ACO, Gibson and Simpson included a 400 mL increase in FEV₁ as one of the diagnostic criteria (33). This is supported by the relationship found between highly increased reversibility to airflow in COPD and response to ICS in terms of lung function (34–36), probably related to the linear association between increased reversibility and eosinophilic inflammation in COPD (37, 38).

Despite the possible association of high reversibility and response to ICS and ACO, this criterion may not be useful in clinical practice, since very few patients with COPD show this increased reversibility. In the ECLIPSE study only 5% of patients had a reversibility > 400 mL (24) similarly to the results of the ISOLDE trial (30), and probably most highly reversible patients also have some degree of eosinophilic inflammation (37, 38, 39). More recently, in the study conducted by Pérez de Llano et al. (40), only 12 patients (13.8%) out of 87 with a diagnosis of ACO showed very positive bronchodilator response, and almost all fulfilled other criteria for ACO (Figure 1). Similarly, our patient also presented asthma-like symptoms and high blood eosinophils, which led to a definitive diagnosis of ACO, irrespective of (or in addition to) the very positive BDT.

Figure 1. Nonproportional Venn diagram showing the interrelationship of ACO criteria in a population of 292 patients with chronic obstructive airways disease. Asthma means “current diagnosis” of the disease; ++ means “very positive” bronchodilator test. Reproduced with permission from Sociedad Española de Neumología y Cirugía Torácica (SEPAR) from Pérez de Llano et al. (40)

High blood eosinophilia

Another criterion proposed by the Spanish consensus and many other documents is high blood eosinophilia (≥300 eosinophils/µL) (22). It has been shown that an increased eosinophil count in COPD patients is a reliable marker of an underlying Th2 type of inflammation. Christenson et al. (41), observed that an increased eosinophil count in COPD patients was a marker of the Th2 genetic signature and was associated with asthma-related characteristics, such as increased bronchodilator responsiveness, and more importantly, a favourable ICS response. Recently, Cosío et al. (42) conducted a study in a heterogeneous group of individuals with different types of chronic obstructive airways disease, using elevated blood eosinophilia as a marker of Th2 inflammation. They found that the classification based upon the inflammatory profile provided the best distinction of patients with chronic airways disease. However, the cut-off value for blood eosinophils to identify ACO is still controversial, although studies comparing eosinophilic inflammation in blood and sputum have suggested that a cut-off value of ≥300 eosinophils/µL in blood is a good predictor of eosinophilia in sputum (43), and therefore, different consensus recommend this cut-off in peripheral blood to identify ACO (16, 22).

It is increasingly recognised that the current definition of ACO may include different phenotypes, both Th2 and non-Th2, or in other words, patients with increased blood eosinophilia and a clinical history of asthma without marked eosinophilia (44). These two phenotypes may have clinical and biological differences but have good response to treatment with ICS in common (45), and therefore, from a clinical point of view, it is justified to group them together under the umbrella term of ACO.

In conclusion, diagnosing ACO is still a clinical challenge partly due to the lack of universally accepted diagnostic criteria. The new Spanish consensus that includes eosinophilic COPD and patients with COPD and a concomitant diagnosis of asthma should facilitate the recognition of ACO in the population of patients with COPD and help in the decision to use ICS in the context of the pharmacological management of COPD.

Declaration of interest

Marc Miravitlles has received speaker or consulting fees from AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Laboratorios Esteve, GebroPharma, GlaxoSmithKline, Grifols, Menarini, Mereo Biopharma, Novartis, pH Pharma, Rovi, TEVA, Verona Pharma and Zambon, and research grants from GlaxoSmithKline and Grifols, unrelated to this manuscript. Miriam Barrecheguren has received speaker fees from Grifols, Menarini, CSL Behring, GSK and consulting fees from GSK, Novartis and GebroPharma. Cristina Esquinas has received speaker fees from CSL Behring. The rest of the authors have no conflicts of interest to declare.