# ASO (Asthma-COPD Overlap) Is Independent from COPD, a Case in Favor: A Systematic Review
## 3 Results
### Characteristics of Selected Studies and Risk of Bias
#### 3.2.4 Combination of Type 2 Inflammation-Related Biomarkers to Define ACO  
In order to maximize the benefits of ICS for COPD patients while preventing them from having pulmonary infectious diseases including pneumonia and TB caused by its inappropriate use, a combination of biomarkers may be promising for precisely defining an ICS-responsive subset. Based on this concept, our group attempted to determine whether the combination of FeNO and serum IgE had the ability to discern asthmatic, ICS-responsive features among patients with COPD. We found that the sensitivity was 1.0 and the specificity was 0.56 for the subjects who had reversibility of airway obstruction by 12-week-inhalation therapy of fluticasone propionate (FP)/Salmeterol (SAL) when FeNO > 35 parts per billion (ppb) and/or a positive result for specific IgE (atopy+) were combined [78]. Especially, all of the patients with both FeNO > 35 ppb and atopy+ responded to the additional FP/SAL therapy [78]. In addition, no patients with both less than 35 ppb of FeNO and a negative result of specific IgE responded to FP/SAL. We further reported that the prevalence of expected high ICS responders (i.e., FeNO > 35 ppb and atopy+) was 7.8 % of Japanese COPD subjects, whereas that of patients who were not likely given the benefits of ICS (i.e., FeNO \(\leq\) 35 ppb and atopy\(-\)) was 54.8% [87]. Another Japanese cohort confirmed this result [88]. These clinical proof-of-concept studies may illustrate that a combination of biomarkers related to type 2 inflammation could be useful for a more precise definition of ACO. Given this concept, in 2018 the Japanese Respiratory Society (JRS) issued guidelines for new definitions and diagnostic criteria of ACO (Table 2) [51,110]. It is noteworthy that these two biomarkers (FeNO and IgE) were included in the criteria to identify the features of asthma among COPD subjects. Two recent reports used the criteria to better characterize the clinical features of ACO in the Japanese population. A retrospective study investigating 170 subjects with persistent airflow limitation indicated that the prevalence of ACO among COPD patients was 31.5% [111]. However, one of the limitations in the retrospective study was that the use of ICS was not controlled, and that the characterization of clinical phenotypes could be biased or masked by ICS. More recently, [PERSON], et al. investigated the prevalence of ACO among ICS-naive patients with COPD and compared the baseline characteristics between COPD and ACO [112]. 197 patients with COPD were included in this study and 38 (19.3%) met the ACO diagnostic criteria by the Japanese guidelines. Although they did not find statistical significance in the baseline clinical features (age, gender, pack  
\begin{table}
\begin{tabular}{l l l} \hline \multicolumn{2}{c}{**Fundamental Aspects: Over 40 Years of Age, Chronic Airway Obstruction Defined By \textless{} 70\% of Post-Bronchodilator FEV\textless{}/FVC**} \\ \hline \begin{tabular}{l} [Features of COPD] \\ At least one positive features of the followings (1, 2, 3) \\ \end{tabular}  & \begin{tabular}{l} (Features of asthma) \\ Two positive features of the following 1, 2, 3 items; or at least one \\ positive features of 1, 2, 3 plus two positive features of 4 \\ \end{tabular}  \\ \hline \begin{tabular}{l} 1. \\ \end{tabular}  & Smoking history \textgreater{} 10 pack-years or equivalent exposure to air pollution & 1. & Variable in diurnal, daily or seasonal symptoms, or paroxysmal respiratory symptoms (cough, sputum, dyspnea) \\ \hline \ \begin{tabular}{l} 2. \\ \end{tabular}  & Low attenuation area indicating emphysematous changes on HRCT & 2. & Past history of asthma before the age of 40 years \\ \hline \begin{tabular}{l} 3. \\ \end{tabular}  & Attenuated diffusion capacity (\%D\textless{} 80\% or \%D\textless{  
years of smoking and pulmonary function) between ACO and COPD, symptoms and dyspnea evaluated by COPD assessment test (CAT) and modified MRC (mMRC) scale were significantly worse in ACO compared to COPD [112].