**5. Diagnosis of ACOS**

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

206 Asthma - From Childhood Asthma to ACOS Phenotypes

information in the upcoming years.

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

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

The specific criteria for diagnosis of this special syndrome had never been established until 2012, when an expert panel meeting of Spanish key opinion leaders agreed unanimously to confirm the existence of this patient profile and to establish a set of criteria for its diagnosis [10], which has been posteriorly adapted within the Spanish COPD Guideline, although not yet validated. The initial definition of ACOS proposed by the Spanish consensus group is as follows: the diagnosis of ACOS is made when two major criteria or one major and two minor criteria are met. The major criteria include a very positive bronchodilator (BD) test (increase in forced expiratory volume in 1 second [FEV1] >15% and >400 mL), eosinophilia in sputum, and personal history of asthma. Minor criteria include high total IgE, personal history of atopy, and positive BD test (increase in FEV1 >12% and >200 mL) on two or more occasions.

The new Finnish guidelines for the treatment of COPD proposed the same criteria for the diagnosis of ACOS as the Spanish guidelines, with the addition of an elevated FeNO higher than 50 parts per billion as a major criterion and a peak flow follow-up typical for asthma as an additional minor criterion [21]. The latest Czech Republic guidelines, published in 2013, also include ACOS with its own diagnostic criteria, similar to the Spanish recommendations [22]. These are, however, quite restrictive criteria and represent a very conservative approach until more evidence about the characterization of ACOS becomes available from large clinical trials or prospective studies. In fact, two recent studies in Spain, using the previous criteria, identified that only between 5% and 6% of the patients fulfilled the criteria for ACOS, in patients with smoking-related COPD [23, 24]. This percentage is clearly below the expected number of individuals sharing the characteristics of asthma and COPD, according to epide‐ miological data.

In fact, in a Spanish survey performed among pulmonology specialists, selected as experts in asthma and COPD, aimed at collecting their opinions about ACOS and their attitudes in regard to some case scenarios of ACOS patients, only 34.6% of the specialists surveyed were in agreement with the Spanish criteria, and 30.8% were in an intermediate position between agreement and disagreement. The main aspect highlighted by 76.9% of the specialists was that these criteria had to be validated in prospective studies [25].

On the other hand, the GINA–GOLD approach to diagnosis of ACOS [9] is deliberately descriptive and perhaps not very suitable for clinical applications, but recognizes that this entity, just like asthma and COPD, comprises a heterogeneous group of disorders.

The characteristics that might support the diagnosis of ACOS according to GINA–GOLD are as follows:


Taking into consideration all these previously proposed criteria, the most recent Spanish guideline on the management of asthma (GEMA 2015) [26] proposes an algorithm designed to guide physicians in their routine clinical practice. The existence of patients who fulfill the criteria for COPD – adult smokers with respiratory symptoms and post-BD FEV1/FVC <0.7 – and who present characteristics of asthma, such as high reversibility of airflow, signs of bronchial and systemic eosinophilic inflammation, history of atopy, or even a previous diagnosis of asthma before the age of 40 years, has been definitely recognized. This approach also includes, as a novelty when compared with all the others, an oral corticosteroid test with prednisone to assess reversibility of the bronchial obstruction. If FEV1/FVC remains below 70% after a BD test, a methacholine test and the presence or absence of biomarkers of Th2 inflammatory response should help the clinician to distinguish between COPD and ACOS [17]. The algorithm is summarized in Figure 2.

Asthma-COPD Overlap Syndrome (ACOS): Current Understanding and Future Perspectives http://dx.doi.org/10.5772/62412 209

**Figure 2.** Diagnostic algorithm for ACOS according to GEMA 2015 [26].

*BD-test: bronchodilator test; eos: eosinophils.*

#### **6. Prognostic implications**

In fact, in a Spanish survey performed among pulmonology specialists, selected as experts in asthma and COPD, aimed at collecting their opinions about ACOS and their attitudes in regard to some case scenarios of ACOS patients, only 34.6% of the specialists surveyed were in agreement with the Spanish criteria, and 30.8% were in an intermediate position between agreement and disagreement. The main aspect highlighted by 76.9% of the specialists was that

On the other hand, the GINA–GOLD approach to diagnosis of ACOS [9] is deliberately descriptive and perhaps not very suitable for clinical applications, but recognizes that this

The characteristics that might support the diagnosis of ACOS according to GINA–GOLD are

**1.** – Usually age 40 years or older, but may report symptoms in childhood or early adulthood.

**2.** – Respiratory symptoms, including exertional dyspnea, are persistent, but variability may

**3.** – Airflow limitation that is not fully reversible, but often with evidence of significant

**5.** – Frequently, a history of doctor-diagnosed asthma (current or previous), allergies and a family history of asthma, and/or a history of noxious exposures, as seen in COPD.

**6.** – Symptoms are partly but significantly reduced by treatment. Progression is usual, and

Taking into consideration all these previously proposed criteria, the most recent Spanish guideline on the management of asthma (GEMA 2015) [26] proposes an algorithm designed to guide physicians in their routine clinical practice. The existence of patients who fulfill the criteria for COPD – adult smokers with respiratory symptoms and post-BD FEV1/FVC <0.7 – and who present characteristics of asthma, such as high reversibility of airflow, signs of bronchial and systemic eosinophilic inflammation, history of atopy, or even a previous diagnosis of asthma before the age of 40 years, has been definitely recognized. This approach also includes, as a novelty when compared with all the others, an oral corticosteroid test with prednisone to assess reversibility of the bronchial obstruction. If FEV1/FVC remains below 70% after a BD test, a methacholine test and the presence or absence of biomarkers of Th2 inflammatory response should help the clinician to distinguish between COPD and ACOS [17].

**7.** – Exacerbations may be more common than in COPD, but are reduced by treatment.

**8.** – Comorbidities can contribute to clinical and functional impairment.

**10.** – Typically eosinophilia (with or without associated neutrophilia) in sputum.

entity, just like asthma and COPD, comprises a heterogeneous group of disorders.

these criteria had to be validated in prospective studies [25].

as follows:

be prominent.

current or historical variability.

208 Asthma - From Childhood Asthma to ACOS Phenotypes

**4.** – Persistent airflow limitation.

treatment needs are high.

**9.** – COPD-like findings on the chest X-ray.

The algorithm is summarized in Figure 2.

It has been reported that patients with ACOS have more frequent exacerbations, are more likely to have a severe exacerbation requiring hospitalization, use more respiratory medications, and have the highest reported pulmonary symptoms. More importantly, patients with ACOS also report worse quality of life than those with either disease alone [27, 28].

However, other authors found that the ACOS phenotype was not clinically different at baseline, in other than the specific criteria used to define it, than patients with no criteria for ACOS. Interestingly, survival after 1 year of follow-up was significantly better in patients with ACOS [29]. To explain such a discrepancy, it should be mentioned that this population included 72% of patients with mild-to-moderate disease, which differs from previous publi‐ cations with more severe COPD, and of note, 63% of patients with ACOS were receiving ICS, which likely contributed to ameliorate the clinical differences, when compared to the non-ACOS group.

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, asthmatics, and individuals with both diseases.
