**7. Treatment of ACOS**

The present approach to pharmacotherapy for ACOS includes trial and error and extrapolation from results of investigations, in particular subpopulations of asthma or COPD patients. The first option recommended by the Spanish consensus guideline for patients with overlap phenotype COPD-asthma is to add ICS to the treatment for COPD [10], as it is also indicated in the Finnish and Czech guidelines [21, 22]. The GINA–GOLD document also indicates that the default position in the case of ACOS should be to start treatment accordingly for asthma, and recommends the LABA/ICS combination, with special attention to avoid the use of LABAs in monotherapy. In the Spanish survey among expert pulmonologists mentioned before [25], 88.5% of the participants agreed that ACOS requires a different treatment compared to COPD, starting with LABA/ICS and stepping up to triple therapy (LABA/ICS+LAMA) in severe cases.

However, these and other recommendations are not based on high-quality data, because patients with ACOS have been classically excluded from pharmacological clinical trials both in asthma and in COPD. As a consequence, there is no clear information about the response of these patients to most of the current pharmacological therapies. The only clinical trial performed to date in patients with ACOS studied the spirometric effects of tiotropium in individuals with concomitant COPD and asthma. Improvement in lung function and a reduction in rescue medication were observed with tiotropium [30].

However, the main interest in differentiating ACOS from COPD lies in the different response to ICS.

Kitaguchi et al. [15], in a retrospective study with a small sample size, found that COPD patients with asthmatic symptoms had high peripheral and sputum eosinophil counts and better reversibility response to treatment with ICS. These findings reproduce those of other studies, in which COPD patients with a positive BD test, or with a positive hyperreactivity test, or with sputum eosinophilia, have been shown to be more responsive to ICS than those without these features [31–36]. Therefore, it seems logical to consider ICSs as the cornerstone of treatment in ACOS with the addition of long-acting β-agonists in those patients who remain symptomatic or suffer recurrent exacerbations.

In addition to the only clinical trial of Magnussen et al., more recent literature has demonstrated the efficacy of long-acting muscarinic antagonists (LAMA), such as tiotropium, in people with asthma with persistent bronchial obstruction [37, 38]. With all these recent data in mind, the Spanish guideline GEMA 2015 recommends the combination of an ICS with a long-acting βagonist as the first therapeutic choice in patients with ACOS, leaving open the option to add a LAMA if the patients remain uncontrolled [26].

Biological treatments that target Th2-related pathways (omalizumab, anti–IL-5, and perhaps anti–IL-4/-13) might also be effective in ACOS, and they warrant further investigation. This is also the case for drugs that target predominantly neutrophil-driven mechanisms, such as roflumilast.

The prognostic significance of having a diagnosis of ACOS must be further assessed in the light of a prospective cohort study, designed to compare the outcomes of COPD patients,

The present approach to pharmacotherapy for ACOS includes trial and error and extrapolation from results of investigations, in particular subpopulations of asthma or COPD patients. The first option recommended by the Spanish consensus guideline for patients with overlap phenotype COPD-asthma is to add ICS to the treatment for COPD [10], as it is also indicated in the Finnish and Czech guidelines [21, 22]. The GINA–GOLD document also indicates that the default position in the case of ACOS should be to start treatment accordingly for asthma, and recommends the LABA/ICS combination, with special attention to avoid the use of LABAs in monotherapy. In the Spanish survey among expert pulmonologists mentioned before [25], 88.5% of the participants agreed that ACOS requires a different treatment compared to COPD, starting with LABA/ICS and stepping up to triple therapy (LABA/ICS+LAMA) in severe cases.

However, these and other recommendations are not based on high-quality data, because patients with ACOS have been classically excluded from pharmacological clinical trials both in asthma and in COPD. As a consequence, there is no clear information about the response of these patients to most of the current pharmacological therapies. The only clinical trial performed to date in patients with ACOS studied the spirometric effects of tiotropium in individuals with concomitant COPD and asthma. Improvement in lung function and a

However, the main interest in differentiating ACOS from COPD lies in the different response

Kitaguchi et al. [15], in a retrospective study with a small sample size, found that COPD patients with asthmatic symptoms had high peripheral and sputum eosinophil counts and better reversibility response to treatment with ICS. These findings reproduce those of other studies, in which COPD patients with a positive BD test, or with a positive hyperreactivity test, or with sputum eosinophilia, have been shown to be more responsive to ICS than those without these features [31–36]. Therefore, it seems logical to consider ICSs as the cornerstone of treatment in ACOS with the addition of long-acting β-agonists in those patients who remain

In addition to the only clinical trial of Magnussen et al., more recent literature has demonstrated the efficacy of long-acting muscarinic antagonists (LAMA), such as tiotropium, in people with asthma with persistent bronchial obstruction [37, 38]. With all these recent data in mind, the Spanish guideline GEMA 2015 recommends the combination of an ICS with a long-acting βagonist as the first therapeutic choice in patients with ACOS, leaving open the option to add

reduction in rescue medication were observed with tiotropium [30].

symptomatic or suffer recurrent exacerbations.

a LAMA if the patients remain uncontrolled [26].

asthmatics, and individuals with both diseases.

210 Asthma - From Childhood Asthma to ACOS Phenotypes

**7. Treatment of ACOS**

to ICS.
