**3. Prevalence of ACOS**

**1. Introduction**

204 Asthma - From Childhood Asthma to ACOS Phenotypes

**2. Definition of ACOS**

differential treatment.

all of them might be present in individual patients.

Although different studies recognize the presence of asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), the detection, diagnosis, and treatment of these patients in clinical practice are not always simple and are subject to different interpretations and controversies. These patients are of special interest, because they are usually excluded from clinical trials with new medications for asthma and also represent a clinically very important and quite prevalent population, apparently with particular characteristics: more respiratory symptoms, frequent exacerbations, and worse health-related quality of life [1–5]. They are also characterized by an increase in comorbidity and a greater consumption of health care resources compared to patients with only asthma or COPD alone. There are currently no universally accepted, validated criteria for the diagnosis of ACOS. Also, clinical trials are

ACOS is the coexistence of two distinct diseases in the same individual: asthma and COPD. Whether this concept is clinically relevant or not depends on its capacity to describe an entity with differentiated pathogenic mechanisms, prognostic particularities, and potentially specific treatment options. The recently updated Spanish COPD guidelines [6] acknowledge the existence of a syndrome that overlaps characteristics of COPD and asthma, and it proposes a

When considering how to define this entity, existing definitions of asthma and COPD should be taken into account. The new definition of COPD according to GOLD 2014 includes subtle changes regarding the previous definitions, integrating the findings of recent evidence [7]. For instance, there is no longer mention of reversibility, and it emphasizes the role of exacerbations and comorbidities. Thus, COPD is a common, preventable and treatable disorder, defined by persistent airflow obstruction that is mostly progressive, characterized by a chronic inflam‐ matory response in the airways and lungs to noxious particles and gases; exacerbations and comorbidities generally contribute to the severity of the disease in individual patients.

On the other hand, in 2014, GINA [8] defined asthma as "a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation". The similarities between asthma and COPD definitions are obvious, but none of their features are pathognomonic, and

For operative purposes, in 2014, GINA and GOLD published a joint document on ACOS [9]. ACOS was defined as the presence of persistent airflow limitation with several features usually associated with asthma and others usually associated with COPD. The document presents the characteristics of asthma and COPD listed separately and suggests that ACOS may be the

necessary to verify the response to treatments of this group of patients.

The exact prevalence of ACOS is unknown. In general, the literature on ACOS has been mostly retrospective and observational, and the studies focused on asthma or COPD populations. It is well known that studies on asthma are usually performed in populations of children or young adults, where the prevalence of COPD is negligible, whereas studies on COPD are usually performed in elderly populations, where the prevalence of asthma is low. The COPDGene study found a prevalence of 13% of ACOS [2]. These patients may have a different clinical natural history, with more frequent and severe exacerbations (odds ratio [OR] 3.55), and different treatment response, which led to recommend early introduction of inhaled corticosteroids (ICS) in these patients. These figures are similar to those reported in the PLATINO study [11]: 12% prevalence for the ACOS phenotype and more risk of exacerbations in these patients (OR 3.01). The inconsistencies and discrepancies that exist upon reported data on prevalence can be in part explained by the absence of a consistent definition and diagnostic standards. In comparison to previous studies that have considered selected groups of patients, such as COPD patients, the study published by de Marco et al [12] assessed the prevalence of ACOS in the general population. They found that this prevalence ranged from a minimum of 1.6% (95% confidence interval (CI): 1.3%–2.0%) in the 20–44 years old age group to 4.5% (95% CI: 3.2%–5.9) in the 60–84 years old age group.

### **4. Pathogenic mechanisms**

Several potential pathways might lead to the presentation of ACOS in adults. One such pathway begins in early-onset asthma. Smoking habit later in life might lead to development of fixed airflow limitation and COPD in many of these patients. A second potential pathway recognizes patients with a lifetime smoking history, subsequent COPD, and late-onset features of asthma (adult-onset eosinophilic asthma and aspirin-exacerbated respiratory disease) (see also Figure 1).

**Figure 1.** Pathogenic pathways leading to ACOS development.

Although no previous studies have addressed the underlying mechanisms of inflammation in ACOS, there is convincing evidence that eosinophils play a pivotal role, similar to what it is found in asthma with a Th2-high profile. Different studies have demonstrated that the presence of significant eosinophilia in an induced sputum sample predicts a good response to ICS, both in patients with COPD and ACOS [13–15]. On the other hand, the presence of more number of neutrophils in sputum has been recently associated with a worse prognosis in asthmatics [16]. Since both asthma and COPD are inflammatory diseases that affect the bronchial tree, it is to be expected to find, in patients with ACOS, some evidence of the Th-1 pattern (charac‐ teristic of COPD) and some evidence of Th-2 pattern (characteristic of asthma). The current search for reliable biomarkers of Th1 and Th2 inflammation hopefully will provide additional information in the upcoming years.

Previous studies defined two new asthma molecular phenotypes, namely Th2 high and Th2 low [17]. The Th2–high gene signature includes chloride channel accessory protein 1 (CLCA1), SERPINB2, and periostin (encoded by POSTN), a secreted 90-kDa extracellular matrix protein that is induced by interleukin (IL)-4 and IL-13 in airway epithelial cells and lung fibroblasts. All three genes are induced in bronchial epithelial cells by recombinant IL-13 treatment in vitro, and the expression of these genes correlates with IL-13 and IL-5 expression in the bronchial mucosa, airway and peripheral eosinophilia, airway remodeling, and clinical responsiveness to ICS treatment, but not with atopy. Even more so, periostin seems to become an emerging noninvasive biomarker associated with eosinophilic inflammation, Th2-high molecular phenotype, and airway remodeling, and has potential utility in patient selection for emerging asthma therapeutics targeting Th2 inflammation. A study by Jia et al. [18] identified serum periostin as a systemic biomarker of airway eosinophilia in severe, uncontrolled asthmatics belonging to the BOBCAT cohort (Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma). In a logistic regression model, serum periostin was the single best predictor of sputum and tissue eosinophilia, showing superiority to blood eosinophils, IgE, and FeNO. Mean periostin levels were significantly higher in "eosinophil-high" when compared with "eosinophil-low" patients, as defined by sputum or tissue eosinophil measurements. Using 25 ng/mL serum periostin as an arbitrary cutoff, eosinophil-low and eosinophil-high patients from the BOBCAT study were effectively differentiated, with a positive predictive value of 93% [18]. Moreover, in 62 patients diagnosed with severe asthma, Bobolea et al. [19] found that periostin levels were higher in patients with fixed airflow limitation than in patients with variable airflow limitation (69.76 vs 43.84 ng/ml, p < 0.05) and in patients with eosinophilic phenotype than in patients with mixed granulocytic phenotype (61.58 vs 37.31 ng/ml, P < 0.05). However, in a cohort of patients with a broad spectrum of asthma severities, Wagener et al. [20] found that blood eosinophils had the highest accuracy in the identification of sputum eosinophilia. In this study, serum periostin was not able to distinguish eosinophilic from noneosinophilic airway inflammation. Therefore, in view of the differing positions, the exact role of periostin in the diagnosis of Th2 bronchial inflam‐ mation remains to be determined.
