# ASO (Asthma-COPD Overlap) Is Independent from COPD, a Case in Favor: A Systematic Review
## 1 Introduction
### Needs for Considering Patients with Clinical Features of Both Asthma and COPD  
From the early 2000s onwards, the differential diagnosis of patients with respiratory symptoms who are more than forty years of age has been recognized to be more problematic. This is because COPD becomes more common in older adults and discriminating asthma with persistent airflow obstruction from COPD is often challenging [37; 38]. In fact, in 2007, the _Canadian Thoracic Society Recommendations for Management of Chronic Obstructive Pulmonary Disease--2007 Update_ described the concept of \"combined COPD and asthma\" to highlight the finding that early introduction of ICS could be justified if the COPD patients had prominent features of asthma [39]. In 2009, [PERSON] and [PERSON] introduced the word of \"the overlap syndrome of asthma and COPD\" and noted that, since these patients had been largely excluded from pivotal therapeutic trials for both asthma and COPD, its diagnosis and treatment were poorly defined and lacking firm evidence [40]. Despite a growing controversy over clinical and prognostic features of ACO, retrospective studies have provided the plausible premise showing that patients with both asthma and COPD have more respiratory symptoms [41], high frequency of exacerbations [41; 42] and accelerated decline in lung function [43]. Thereafter, articles regarding asthma-COPD overlap syndrome (ACOS) have been widely reviewed [44; 45; 46]. Following these early reviews, in 2014, the Global Strategy for Asthma Management and Prevention (GINA) and the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) jointly issued their consensus-based document on ACOS so that clinicians were able to distinguish asthma from COPD and make a diagnosis of ACOS in patients with chronic airflow limitation [47]. GINA then suggested the descriptive term asthma-COPD overlap (ACO) rather than ACOS, which had been often interpreted as implying a single disease [48].  
In 2016, based on the urgent requirement of an operational definition of ACO, a global expert panel from North America, Western Europe and Asia proposed criteria for its diagnosis, which consisted of age, smoking history, the presence of persistent airflow limitation defined by spirometry, history of asthma and allergic rhinitis, bronchodilator response in FEV\({}_{1}\) and peripheral blood eosinophil counts [49]. Following this attempt, some guidelines, such as Spanish [50] and Japanese [51] guidelines, published diagnostic algorithms that employed objective evaluations of eosinophil and allergic airway inflammation by quantifying the levels of fractional exhaled nitric oxide (FeNO) and serum immunoglobulin E (IgE). However, the GOLD 2020 update has stated that it no longer mentions ACO [11]. This was because asthma and COPD were different disorders, although they might share common traits and clinical features. In addition, it further documented that \"if a concurrent diagnosis of asthma is suspected, pharmacotherapy should primarily follow asthma guidelines, but pharmacological and non-pharmacological approaches may be needed for their COPD\". This has given rise to pro and con arguments for experts in obstructive lung diseases [52; 53]. As patients with ACO have been certainly excluded from clinical studies of asthma and COPD [49], molecular mechanisms of the disease and evidence of appropriate therapies are less well understood. Considering the pro-con discussion, we still have a large, unresolved question concerning why we should have a diagnostic term of ACO and how we can distinguish between COPD and ACO. The rationale of this systematic review is to describe how ACO differs in clinical features and pathogenesis from COPD. Thus, we aimed to elaborate clinical features and diagnostic markers that enable to discriminate ACO from COPD.