Asthma and COPD are chronic lung diseases which are highly prevalent and have significant socio-economic impact.1,2 Data from a recent nationwide study indicate that the current asthma prevalence in the Portuguese population is 6.8%.3 The national prevalence for COPD was estimated in 9.0% and 5.3% in 2 previous studies – in selected age groups (≥40 years old in one study and between 35 and 69 years old in the other); there is also another study carried out in the Lisbon area that showed a prevalence of 14.2% (in patients of 40 years old or more).4,5 Both asthma and COPD affect the airways and are characterized by the presence of bronchial obstruction.1,2 Even though these pathologies are heterogeneous, they usually present quite characteristic clinical symptoms, functional changes and underlying physiopathology, which enables a straightforward diagnosis in a majority of patients.1,2,6 However, there is a growing consensus that typical asthma and COPD characteristics can both exist simultaneously in one patient, especially in those who are older and have a history of smoking.6–8 Data from the INAsma study clearly show that, in Portugal, asthmatic patients smoke in the same proportion as the non-asthmatic and that the passive exposure is even higher in the first group.9 In reality, there are patients with severe asthma, that has evolved over a long period and frequently with smoking habits, that eventually develop fixed airway obstruction, a pattern usually seen in COPD.10,11 On the other hand, a positive bronchodilator test, as seen in many asthma patients, can be found in a significant proportion of COPD patients, although not of same magnitude.12,13 In this context, the concept of ACOS (asthma-COPD overlap syndrome) has been used to describe this set of patients that present concomitant asthma and COPD characteristics. It is important to highlight that in this group of patients, although they show a broad clinical heterogeneity, there are essentially two types of patients: the asthmatic patient that develops ACOS and the COPD patient that presents clinical characteristics of ACOS. It is, thus, important to be aware that in these cases there is an initial distinct physiological base that culminates in an overlap of symptoms, which can have implications for diagnosis and therapy.

The way these patients are characterized by the several entities analysing this issue is very heterogeneous, which makes it difficult to apply the concept of ACOS to the clinical situation in Portugal. In this context, there is a need for a first step towards clarification of concepts applied to the national context, in order to develop, in the near future, a broader ACOS medical consensus. This paper is an indexed literature revision on the subject, complemented by a series of critical reflexions regarding diagnostic criteria, patient identification, therapeutic approaches and guidelines for future clinical investigation.

A literature review was carried out via the PubMed database by searching for MeSH Terms (“asthma”, “chronic obstructive lung disease”, “overlap syndrome”). Articles between 2006 and 2016 were selected as relevant if they had epidemiological data, diagnostic criteria, clinical symptoms and impact and therapeutic approaches. In a second phase, a working meeting was held with medical experts from the chronic lung diseases field (Pulmonology, Immunoallergology, Family Medicine) where the several topics presented in this paper were discussed and proposals for recommendations on ACOS adapted to the Portuguese context drawn up.

The differentiation in terms of respiratory symptoms between asthma and COPD is, in many cases, quite difficult, because there are several areas where they can overlap, making the distinction more complicated. For example, the presence of chronic productive cough is more associated with COPD but can also be present in an asthmatic patient, which leads to a worse prognosis in terms of pulmonary function decline.14 On the other hand, it is also common to have the presence of asthmatic symptoms (occasional dyspnoea, sibilance) in COPD patients.15 In terms of bronchodilator response, the reversibility seen, although typical in asthma, is not exclusive to it, as it is also observed in up to 50% of COPD patients.16 Furthermore, the bronchial hyperresponsiveness, which is present in almost all asthma patients, can also be seen in a significant percentage of COPD cases.17

This clinical diversity leads to the overlap between these two obstructive respiratory diseases. It is possible, however, to isolate characteristics that enable the recognition of a new entity (ACOS) which aggregates features from both (asthma and COPD).

Several studies have analyzed the clinical differences between ACOS, COPD and asthma, showing a higher prevalence of respiratory symptoms in patients with ACOS compared to the other two alone.18,19 In the ACOS group, studies show a more significant exertional dyspnoea (assessed by the mMRC score),20 a higher percentage of sibilance when compared with COPD patients,21 less physical capacity, more exacerbations and lower quality of life.22 In the population-based study (EPI-SCAN21) the authors compared the prevalence of symptoms between COPD, asthma and ACOS patients, observing a higher percentage of dyspnoea in the ACOS group, more sibilance in the ACOS group when compared to the COPD group, and an equal percentage of productive cough in COPD and ACOS. Two other studies (GEIRD and PLATINO18,22) revealed, however, a higher percentage of productive cough in ACOS patients, even when compared to isolated cases of COPD.

On the other hand, the exercise capacity shown by ACOS patients was prospectively analyzed by Fu et al. in a 4-year follow-up study which concluded that the functional decrease in terms of 6-min walk test (6MWT) was lower in these patients compared to the COPD group.23

There is no consensus on the results concerning lung function, although many studies show lower values of FEV1, FVC and FEV1/FVC in patients with ACOS compared to COPD and asthma.18,24 Other studies reveal that there are no significant differences between these groups in this area.23,25,26

In relation to radiological differences between ACOS and COPD, there seems to be a slightly less emphysema expression in the first group as well as a predilection for the upper lung lobes.27

There is a higher degree of consensus between the studies over exacerbations, with a higher rate in ACOS patients.18,19,21 There is also a higher percentage of severe exacerbations and a higher rate of hospitalizations. In a study performed by Brzostek and Kokot a significant rate of recent exacerbations (69% in the last year) was observed.28

In terms of comorbidities, studies point towards a high prevalence in ACOS, especially cardiovascular ones. Some authors have referred to a higher incidence in ACOS patients compared to COPD and asthma but that is not applicable to the whole literature.20,24,28 Miravittles et al. have used the Charlson Comorbidity Index as a mortality prognostic indicator, showing a significantly higher value in ACOS patients.21

Chronic obstructive pulmonary diseases, due to its prevalence and health-resource consumption needs, have a higher economic burden associated with them. Within these, COPD has clearly more burdensome than asthma.29 However, a cost comparative analysis between ACOS and COPD, clearly shows a higher value for the former, mainly because of the higher rate of hospital admission.30

The ACOS-associated mortality rate was addressed in a recent analysis of a multicentric Italian study (SARA study),31 showing no significant differences compared to COPD but much higher than asthma.

Several study groups have published highly diverse proposals for definitions and diagnostic criteria for ACOS, most of these recommendations originating from expert opinion consensus.47,60–62 The description proposed by the joint project of GOLD and GINA characterizes ACOS as the presence of persistent airflow limitation with several characteristics usually associated with asthma and several characteristics usually associated with COPD.6 This definition is vague and the diagnosis is based on the balance of attributes taken from a checklist with typical asthma and COPD aspects.

In fact, ACOS is still poorly characterized, both in terms of general risk factors and pathophysiology, and in terms of clinical symptoms, treatment response and prognosis. This is largely due to the fact that patients who meet criteria compatible with a possible diagnosis of ACOS are usually excluded from clinical trials targeting COPD or asthma.

Table 1 summarizes the main definitions and diagnostic criteria proposed by several authors.

Therefore, although there is no agreed, established and validated definition for ACOS, this entity is widely recognized in clinical practice as an individualized phenotype demarcated from the spectrum of chronic obstructive airways disease.67 In addition, the identification/recognition of this phenotype of chronic obstructive respiratory disease may influence the prognostic and therapeutic approach. Thus, it is really necessary to establish a consensus, based on a review of the available literature and professional experience, to standardize the diagnosis of ACOS and outline an approach strategy for this group of patients, for whom randomized controlled clinical trials (RCTs) are still missing.

Proposed recommendation: the diagnosis of ACOS should be considered in the concomitant presence of:

• 1)

  simultaneous clinical manifestations characteristic of both asthma and COPD

• 2)

  persistent airway obstruction, defined as post-bronchodilator FEV1/FVC<0.7, evaluated in a period of clinical stability

• 3)

  positive response in bronchodilator test, defined by an increase in the value of FEV1 of ≥200mL and ≥12% from baseline

• 4)

  current or past history of smoking or exposure to biomass combustion

As aspects that are usually present in this group of patients and that can be taken into account in the diagnostic consideration, we highlight peripheral eosinophilia (>300eosinophils/¿L or >5% of leukocytes) and previous history of atopy. In annex 1, a representation of the proposed algorithm is presented.

Views on the prevalence of ACOS vary greatly among the published studies, reflecting the different diagnostic criteria applied in each, as well as the different populations analyzed.68–76

In asthmatic patients, prevalence of ACOS has been reported as ranging between 13 and 30%.22,77–79 However, when broader criteria are used and subpopulations of older patients are analyzed, the prevalence recorded is higher; for example, in a subgroup of asthmatic patients older than 65 years, a prevalence of 61% was found.22

Within the group of patients with COPD, the estimated prevalence of ACOS is also varies greatly across studies, with values ranging between 9% and 55%.18,65,77,80–82

In the population-based study PLATINUM, the prevalence of ACOS was 2%, and the prevalence of asthma and COPD was 2% and 12%, respectively.18 In other similar studies, a prevalence of ACOS in the general population ranging between 2 and 5% was found, with increasing prevalence associated with an increase of the age group being analyzed.22,83

Due to lack of studies to date, ACOS prevalence data relating to Portugal are not known

This document sets forward the heterogeneity of diagnosis that still exists in this area, which underlines its importance as a first stage in the examination of this field. It seems clear there is a group of patients who share characteristics that cross the COPD and asthma spectrum, it is therefore crucial to achieve a more accurate identification of these patients, enabling a more effective therapeutic approach. In the future this characterization of ACOS patients will provide for the development of national prevalence studies and the evaluation of the impact of different pharmacological and non-pharmacological therapies, which will complement our knowledge of this entity and optimize treatment strategies.

This document constitutes a first step towards what might become a nationwide Portuguese consensus in relation to ACOS, which would strengthen the medical community's vision on this subject.

The authors have no conflicts of interest to declare.