# ASO (Asthma-COPD Overlap) Is Independent from COPD, a Case in Favor: A Systematic Review
## 4 Discussion  
There are important problems yet to be addressed in clinical practice for ACO and COPD: Why should we have a diagnostic term of ACO? How can we distinguish between COPD and ACO? Since inappropriate use of ICS increases the risk of respiratory infection in COPD patients, we need to maximize the ability to identify the subset of favourable response to ICS. Our systematic review showed that FeNO was useful biomarker to identify asthmatic components in patients with COPD. In addition, a combination of biomarkers such as FeNO and IgE would be useful and provide promising diagnostic criteria for ACO, which could be validated by future studies. To define more precisely the pathophysiology of ACO, it would be essential to uncover the molecular mechanisms underlying inflammation, tissue damage/repair and oxidative/nitrosative stress that can differentiate ACO from COPD. In fact, several attempts have been done to clarify eosinophilic and neutrophil inflammation using blood, induced sputum and urine. Because there has been no global consensus on the diagnostic criteria of ACO, its prevalence considerably depends on how it is defined [129]. However, a recent meta-analysis of 27 studies from North America, Europe and Asia reported that the prevalence of ACO was estimated to be 2.0% (95% confidence interval (CI): 1.4-2.6%) in the general population, 26.5% (95% CI: 19.5-33.6%) among patients with asthma and 29.6% (95% CI: 19.3-33.9%) among patients with COPD [130]. In line with this meta-analysis, recent epidemiological studies confirm that ACO is a common disease in primary care [131; 132]. These epidemiological data highlight the clinical importance of evaluating whether patients with airflow limitation have the features of both COPD and asthma and if patients with COPD concurrently have components of asthma in primary care. Thus, further studies are required to detect the features of asthma among patients with COPD using novel biomarkers. One biological aspect which was not described here is genetics. Genome-wide association studies in non-Hispanic whites and African-American populations (n = 3120 in COPD; 450 in ACO) indicated that the most significant single nucleotide polymorphisms (SNPs) were in or near _GPR65_ on chromosome 14 [133]. _GPP65_ encodes the chief acid-sensing receptor, G protein-coupled receptor 65 (GPR65), which increased the cellular viability of eosinophils in allergic airway inflammatory settings in mice [134]. Interestingly, the GWAS study for ACO and COPD failed to identify known asthma-associated genetic loci such as _ORMDL3_, _ILTRL1_ and _ILTR_[135], indicating that ACO was not just an overlapping condition of asthma and COPD but was associated with a specific genetic background independent of asthma or COPD. Another aspect of ACO is associated with redox imbalance. Our group has recently reported a key role of oxidative and nitrosative stress in the pathogenesis of ACO. We reported that excessive nitrosative stress and lower antioxidant capability were observed in neutrophils and macrophages collected from the airways of patients with ACO [136]. This redox imbalance was associated with increases in IL-8, monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor (TNF)-\(\alpha\) in induced sputum and with a prospective clinical course of higher frequency of exacerbation and more rapid decline of FEV1 in ACO subjects compared to asthmatics [136]. These current data on the role of oxidative and nitrosative stress in ACO development may have clinical implications and provide novel insights for therapeutic strategies [137]. Future basic and translational research to define the molecular and cellular phenotypes of ACO differentiating from COPD are needed. There are several limitations in this review. First, the number of patients included in the selected studies was relatively small. Second, diagnosis of asthma was not unified over the selected studies. Third, the selected studies were not randomized control trials. Finally, we did not examine publication bias.