# ASO (Asthma-COPD Overlap) Is Independent from COPD, a Case in Favor: A Systematic Review
## 1 Introduction  
### Background of Asthma and Chronic Obstructive Pulmonary Disease  
The global burdens of asthma and chronic obstructive pulmonary disease (COPD) are increasing, each of which was estimated to affect respectively approximate 339 million and 251 million people worldwide in 2016 [1]. It has been widely accepted that asthma and COPD are strikingly different airway disorders [2; 3]. Although the \"Dutch hypothesis\" suggested a common genetic background underlying airway obstruction with a spectrum of clinical entities from asthma to COPD, recent genetic research indicated that it was unlikely that genetic factors are shared by asthma and COPD [4]. Asthma is a heterogenous and inflammatory disease affecting large and small respiratory tracts but not the lung parenchyma, and contains clusters of demographical, clinical and pathophysiological characteristics underpinned by different pathophysiological processes [5]. This heterogeneity may be explained by the complexity of dysregulated innate and adaptive inflammatory responses to exogenous allergens and proteases leading to the spectrum of abnormal tissue remodeling, where type 2 cytokines such as interleukin (IL)-4, IL-13 and IL-5 primarily promote airway eosinophil infiltration, mucus hypersecretion, bronchial hyperresponsiveness and mast cell activation [6]. Major subpopulations of asthmatics have molecular signatures of T helper 2 (Th2)--inflammation and airway obstruction that markedly respond to inhaled corticosteroid (ICS) [7]. In line with this translational study, accumulated evidence from randomized control trials have revealed the importance of ICS usage from the early steps of asthma treatment because clinical studies have shown that ICS robustly reduced the risk of symptoms, exacerbations, hospitalization and mortality from asthma [8; 9; 10]. COPD is defined as a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases and influenced by host factors including abnormal lung development [11]. In addition to cigarette smoking, known as the most common COPD risk factor [12], the susceptibility could be influenced by genetic factors [13; 14] and abnormal lung growth [15]. Unlike asthma, CD4\({}^{+}\) T helper 1 (Th1) cells, CD8\({}^{+}\) cytotoxic T (Tc) cells, neutrophils and macrophages predominantly affect the small airways and the lung parenchyma leading to mucus hypersecretion, alveolar wall destruction (emphysema) and small airway fibrosis in COPD [2; 16]. These pro-inflammatory cell-types are functionally altered by oxidative stress and intracellular signaling pathways including activation of the proinflammatory transcription factor nuclear factor xB (NF-kB) [17], and alveolar macrophages are defective in bacterial phagocytosis, possibly via several phagocytic receptors and mitochondrial molecules related to oxidative stress [18; 19; 20; 21]. The small airway narrowing induced by pro-inflammatory cell infiltration, luminal exudates, wall thickening, and the loss of small airways associated with emphysema increases airway obstruction [22; 23]. In the wall thickening, hyperplasia of basal cells, known as airway epithelial stem cells, could be formed through several molecules such as Axl receptor tyrosine kinase [24] and Yap-Wnt7b [25]. The airflow limitation progressively leads to gas-trapping in peripheral lungs during expiration on exercise, resulting in dynamic hyperinflation which is postulated to be the main mechanism of exertional dyspnea [26; 27]. Thus bronchodilators, long-acting muscarinic antagonists (LAMA) and long acting beta\({}_{2}\)-agonists (LABA), are commonly used as the pharmacological therapy for COPD and are known to reduce lung hyperinflation, dyspnea and exercise endurance [28; 29] leading to improvement of the quality of life and a reduction in the frequency of exacerbations [30].