Asthma-COPD Overlap (ACO) PRO-CON Debate. ACO: Call Me by My Name

Some, including the author of this editorial, were surprised by the publication of the Global Strategy for Obstructive Lung Disease (GOLD) 2020 update stating that “We no longer refer to asthma-COPD overlap (ACO), instead we emphasize that asthma and COPD are different disorders, although they may share common traits and clinical features (e.g. eosinophilia, some degree of reversibility)” [1].This appears to be the end of a story initiated in 2014 with the publication of the Global Initiative for Asthma (GINA) – GOLD document that defined Asthma-COPD overlap syndrome (ACOS) “as characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD” [2]. The same document highlighted the importance of ACOS in clinical practice and indicated that their “consensus-based description of ACOS was intended to stimulate further study of the character and treatments for this common clinical problem” [2]. This initiative was very successful because the number of publications dedicated to ACO found in PubMed increased from 91 in 2014 up to 565 in June 2020.

The story of ACO, however, is a bit older. Indeed, already in 2007, the Canadian guidelines for COPD recognised that patients with COPD and an asthma component may require different treatment, and early introduction of inhaled corticosteroids (ICS) could be justified [3]. But it was not until two years later when an article by Gibson and Simpson [4] named this condition as an overlap of asthma and COPD and stimulated interest in these patients, who, until then had been systematically excluded from studies of asthma or COPD for not being “pure” patients of either of these diseases. Following these initial publications, other COPD guidelines, such as the Japanese [5], the Spanish [6], the Czech [7] and the Finnish [8] guidelines incorporated ACO in their management recommendations, and finally GOLD-GINA published their report on ACOS in 2014 [2]. However, it was really surprising that after the publication of the joint GOLD-GINA statement on ACO in 2014, the following updates of the GOLD document did not explicitly include the concept of ACO in their recommendations of management, despite the exponential increase in the knowledge and the interest in ACO, the inclusion of ACO in several national guidelines and the increasing number of consensus definitions and reviews on ACO [9–11]. Furthermore, some authors even postulated that the GOLD A-D classification should also include the E for eosinophilic COPD, recognising that patients with ACO characteristics were systematically neglected [12].

Initially named as ACOS, it was lately named ACO, because it was considered that it did not fulfil the characteristics of a syndrome, but rather ACO includes different phenotypes of patients [9]. In fact, there are individuals with smoking-related COPD with a genetic background of Th2 inflammation expressed as increased eosinophilia in sputum and peripheral blood, and/or increased reversibility of airflow to short-acting beta agonists [13]. These patients could be defined as a particular phenotype of COPD named ACO for their resemblance to asthma, or Th2 COPD or even eosinophilic COPD [14]. Other subjects suffering from asthma and with significant exposure to smoking led to the development of the characteristics of COPD, i.e. non fully reversible airflow obstruction, reduction of diffusion capacity and emphysema on computed tomography scans. These individuals could be considered as having both asthma and COPD or an overlap (ACO) [14–16].

The identification of different phenotypes under the umbrella term of ACO has been used as one of the main arguments to question its validity. However, both asthma and COPD are certainly much more heterogeneous than ACO but the use of both terms is not questioned. Nonetheless, the heterogeneity of individuals included in the definition of ACO led to the development of consensus definitions that basically included a non-fully reversible airflow obstruction, significant exposure to smoking or other agents, plus an asthmatic component defined as previous or current diagnosis of asthma, blood and/or sputum eosinophilia or some degree of airflow reversibility [11, 16, 17]. These consensus definitions included all patients with ACO irrespective of their specific phenotype [11, 17, 18]. This is particularly relevant because, irrespective of the phenotype, the concept of ACO identifies a group of patients that have some specific genetic [13, 19] and epigenetic background [20], differential sputum, serum and exhaled biomarkers [21–23] and metabolomics [24]. They also present specific symptoms, different outcomes compared to asthma and COPD and specific response to treatment; basically, they should receive long-acting bronchodilators and ICS [14, 19, 25]. In addition, they may be a target for the new biological treatments initially developed only for asthma [26].

It is surprising that despite rejecting the term ACO, the GOLD document states that “asthma and COPD may coexist in an individual patient” [2]. It would have been more understandable to declare that ACO is rejected because it does not really exist and instead suggest that these individuals have a particular disease, different from asthma and COPD, with a particular name, whatever it might be. However, GOLD recognises that coexistence (or overlap) exists, but the name is rejected. Is it just a problem with the name? If so, then how should it be called? If asthma and COPD can coexist, should we call it asthma- COPD coexistence (ACC) instead of ACO?

Eliminating the concept of ACO may create confusion among clinicians and scientists, because the scientific community will then use different terms or expressions to name what we now call ACO. As an example, the past issue of COPD included two studies on this type of patients, named as COPD with concurrent diagnosis of asthma in one article [23] and asthma-COPD overlap in another [27]. More importantly, GOLD committee members should be aware that they are leaving a significant number of patients (20% to 30% of COPD patients) orphan, without a name and as such they become unmentionable and perhaps even invisible, and this strategy may significantly reduce the interest in research on a disorder that is not recognised in the most important global strategic document on COPD. Interestingly, some recent clinical trials have been designed for patients with ACO [26], but we may have to return to the old days when we had to declare that no evidence-based recommendation for treatment of ACO could be established, because these patients were excluded form clinical trials in asthma or COPD. At the end of the day, ACO may become another example of a definition that appears and then suddenly disappears based on expert opinion rather than on scientific evidence.

Conflicts of interest

Marc Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols and Novartis, consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, Kamada, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, TEVA, Spin Therapeutics, pH Pharma, Novartis, Sanofi and Grifols and research grants from GlaxoSmithKline and Grifols.