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A new phenotype with overlapping characteristics between asthma and chronic obstructive pulmonary disease (COPD) called asthma-COPD overlap syndrome (ACOS) is emerging among inflammation diseases. To date, there is no agreement on specific criteria to define this syndrome, and the current guidelines are insufficient to classify the analogy and differences between overlap and COPD or asthma phenotypes. It would be necessary to identify new biomarkers able to identify these diseases clearly. Thus, the aim of this study was to identify a serum and supernatant of sputum microRNA (miRNA) expression profile of miRNA-145 and miRNA-338 in patients with asthma (n=13), COPD (n=31), and ACOS (n=8) and controls (n=7). The expression was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). For statistical analysis, the ANOVA test, Kruskal-Wallis test, Mann-Whitney -test, and Spearman's rank correlation were used. The main finding of this work is that the expression of miRNA-338 is higher in the supernatant of different obstructive diseases than in peripheral blood, while miRNA-145 is higher only in the supernatant of asthma patients. The expression of both selected miRNAs is higher in the supernatant of asthma and COPD patients than in controls. Differences in sputum miRNA expression profile were observed between patients with ACOS and asthma or COPD, which underline the potential role of miRNA as a biomarker that is able to discriminate patients with ACOS, asthma, and COPD.

Asthma-chronic obstructive pulmonary (COPD) overlap (ACO) coexists with asthma and COPD syndrome characteristics, with more frequent exacerbations, heavier disease burden, higher medical utilization, and even lower quality of life. However, the ACO standard medications supported by evidence-based medicine have not yet appeared. By using an ACO mouse model established previously and LPS-stimulated RAW264.7 macrophages in vitro, a potential therapeutic candidate, EAPP-2, was screened from derivatives of 3-arylbenzofuran, and its effect and mechanism on ACO inflammation were evaluated. EAPP-2 significantly alleviated airway inflammation in ACO mice and also inhibited the inflammatory reactions in LPS-induced RAW264.7 macrophages in vitro. Furthermore, EAPP-2 significantly inhibited the expression and phosphorylation of spleen tyrosine kinase (Syk), a common target regulating both eosinophils and neutrophils inflammation. In addition to this, EAPP-2 significantly down-regulates the expression of NF-κB, p-NF-κB, and NLRP3 in vivo and in vitro. Moreover, by using specific inhibitors in vitro, it was validated that EAPP-2 targeted on Syk and then regulated its downstream NF-κB and NLRP3. EAPP-2 is shown to be a potentially useful therapeutic candidate for ACO, and its mechanism is at least partially achieved by targeting on Syk and then inhibiting NF-κB or NLRP3. Moreover, this study suggests that Syk may be a potentially effective target for ACO therapy.

In its 2021 strategy report, the Global Initiative for Chronic Obstructive Lung Disease states: \"we no longer refer to asthma-COPD overlap (ACO), instead we emphasize that asthma and COPD are different disorders, although they may [...] coexist in an individual patient. If a concurrent diagnosis of asthma is suspected, pharmacotherapy should primarily follow asthma guidelines, but pharmacological and non-pharmacological approaches may also be needed for their COPD.\" What does this mean for the treating physician? In this review, we explore the implications of this new guidance on treating patients with chronic obstructive pulmonary disease, arguing for a personalized approach to treatment. Keywords: COPD, asthma, asthma-COPD overlap, inhaled corticosteroid, bronchodilator

Although biologics have demonstrated to be effective in T2-high asthma patients, there is little experience with these drugs in asthma-COPD overlap (ACO). The aim of this study was to compare the effectiveness of biologics in these two conditions. We included 318 patients (24 ACO and 297 asthma) treated with monoclonal antibodies and followed for at least 12 months. Omalizumab was the most frequently employed biologic agent both in patients with ACO and asthma. Asthma control test (ACT) scores after at least 12 months of biologic therapy were not significantly different between groups. The percentage of patients with ≥1 exacerbation and ≥1 corticosteroid burst was significantly higher in ACO patients (70.8 vs 27.3 and 83.3% vs 37.5%, respectively), whereas the percentage of \"controlled\" patients (with no exacerbations, no need for corticosteroids and ACT ≥ 20) was significantly lower (16.7% vs 39.7%). In conclusion, this report suggests that patients with ACO treated with biologics reach worse outcomes than asthma patients.

Purpose: To evaluate the accuracy of inflammatory biomarkers in differentiating patients with asthma-COPD overlap (ACO) from those with COPD alone. Methods: Clinical data of 134 patients with COPD and 48 patients with ACO admitted to the First Affiliated Hospital of Xi'an Jiaotong University from January 2016 to June 2019 were retrospectively analyzed. Receiver operating characteristic (ROC) curve analysis was performed to determine the best cut-off values of fractional exhaled nitric oxide (FeNO), blood eosinophil counts (EOS), and neutrophil to lymphocyte ratio (NLR) for differentiating between ACO and COPD alone. Spearman correlation analysis was conducted to evaluate the relationships between these inflammatory biomarkers and the forced expiratory volume in one second/prediction ([FEV.sub.1]%pred). Results: FeNO and EOS in the ACO patients were significantly higher than those in the COPD patients (FeNO: median 37.50 vs 24.50 ppb, P < 0.001; EOS: median 0.20 vs 0.10 * [10.sup.9]/L, P = 0.004). FeNO was positively correlated with [FEV.sub.1]%pred (r = 0.314, P = 0.030), while NLR was negatively correlated with [FEV.sub.1]%pred (r = -0.372, P = 0.009) in patients with ACO. In addition, a positive correlation between FeNO and EOS was also found in ACO, especially in patients without history of inhaled corticosteroids (ICS) use (r = 0.682, P < 0.001). The optimal cut-off value of FeNO was 31.5 ppb (AUC = 0.758, 95% CI = 0.631-0.886) in patients with smoking history, with 70.0% sensitivity and 89.9% specificity for differentiating ACO from COPD. In patients without history of ICS use, the best cut-off value of FeNO was 39.5 ppb (AUC = 0.740, 95% CI = 0.610-0.870), with 58.3% sensitivity and 84.9% specificity. Among patients without history of ICS use and smoking, 27.5 ppb was optimal cut-off level for FeNO (AUC = 0.744, 95% CI = 0.579-0.908) to diagnose ACO, with 81.8% sensitivity and 60.7% specificity, and the sensitivity was improved to 91.7% when FeNO was combined with EOS. Conclusion: The inflammatory biomarkers FeNO and EOS can be used as indicators for differentiating between ACO and COPD alone. Keywords: fractional exhaled nitric oxide, blood eosinophil counts, neutrophil to lymphocyte ratio, chronic obstructive pulmonary disease, asthma-COPD overlap

Asthma‐ COPD overlap ( ACO ) carries greater symptom burden, frequent exacerbations and impaired quality of life compared with asthma or COPD alone. Evidence‐based advanced therapies are lacking, and management is typically extrapolated from existing guidelines. Tezepelumab, an anti‐thymic stromal lymphopoietin antibody, reduces exacerbations and improves lung function in severe asthma. Bronchoscopic lung volume reduction ( BLVR ) with endobronchial valves benefits selected patients with advanced emphysema and hyperinflation despite optimal therapy. A 71‐year‐old woman with severe ACO , frequent exacerbations and hyperinflation despite triple inhaled therapy was treated sequentially with tezepelumab and BLVR . Tezepelumab improved airway control and reduced exacerbations; BLVR subsequently addressed persistent hyperinflation. Over 2 years, the patient achieved sustained improvements in lung function, St. George's Respiratory Questionnaire score and annual exacerbation rate. This case highlights the potential benefit of a combined anti‐inflammatory and interventional approach in difficult‐to‐treat ACO , a population for whom evidence‐based advanced therapies remain limited.

Purpose: Asthma-COPD overlap (ACO) has been reported as an association with a lower quality of life, frequent exacerbations, and higher mortality than those with COPD alone. However, clinical characteristics and outcomes of ACO remain controversial. Patients and Methods: We conducted a prospective observational study analyzing data of patients with stable COPD enrolled from the Ishinomaki COPD Network Registry. Patients with features of asthma who had a history of respiratory symptoms that vary over time and intensity, together with documented variable expiratory airflow limitation, were identified, and then defined as having ACO. The characteristics, frequency of exacerbations, and mortality during the 3-year follow-up were compared between patients with ACO and patients with COPD alone. Results: Among 387 patients with COPD, 41 (10.6%) were identified as having ACO. Patients with ACO tended to be younger, have higher BMI, have a shorter smoking history, and use more respiratory medications, especially inhaled corticosteroids. Inflammatory biomarkers including fractional exhaled nitric oxide, blood eosinophil count, total immunoglobulin E (IgE) level, and presence of antigen-specific IgE were significantly higher in patients with ACO than in those with COPD alone. Lung function, mMRC score, CAT score, and comorbidity index were not different between the groups. The annual rate of all exacerbations and severe exacerbations required hospital admission were not different between ACO and COPD alone (0.20 vs 0.14, 0.12 vs 0.10, events per person, respectively). Mortality was significantly higher in patients with COPD alone compared with those with ACO during the study period (P=0.037). Conclusion: The results of our study indicate that ACO is not associated with poor clinical features nor outcomes in an outpatient COPD cohort receiving appropriate treatment. Keywords: asthma, asthma-COPD overlap, COPD, exacerbations, mortality

COPD is associated with significant morbidity and is one of the leading causes of death worldwide. Periods of exacerbation, the acute worsening of symptoms, are interspersed throughout the disease's natural history and can result in increased treatment burden and hospitalization for patients with COPD. The frequency of exacerbations varies between countries, with both epidemiological studies and randomized controlled trials (RCTs) showing significant differences in observed prevalence rates. Differences in study design and the healthcare setting are likely to contribute to differences in exacerbation frequency, however the perceived rate of exacerbations in Japan is currently lower then the rest of the world. This review identified nine cohort studies and five RCTs that reported COPD annual exacerbation rates in Japan in the ranges of 0.1-2.1 and 0.33-1.79, respectively. The difference in exacerbation rate between studies appeared greater than the difference between Japan and Western countries, likely because of disparities between settings, design, and inclusion criteria. Of these, only one (Understanding the Long-Term Impacts of Tiotropium) had uniform inclusion criteria across different regions. This study found that the annual rate of exacerbation events per patient in Japan was 0.61, compared with 0.85 worldwide in the placebo groups. This review summarizes the published rates of COPD exacerbations in Japan and the rest of the world and explores the hypotheses as to why rates in Japan might be lower than other countries. These include access to medical care, variance in the associated morbidity profile, environmental factors, diagnostic crossover with related diseases, and differences in study design (including the underreporting of COPD exacerbations in Japan). Understanding the reasons why COPD exacerbation rates appear lower in Japan could help clinicians to recognize and modify treatment behaviors, which may lead to improved patient outcomes in all populations.

In patients with COPD, acute exacerbation (AE) is not only an important determinant of prognosis, but also an important factor in choosing therapeutic agents. In this study, we evaluated the usefulness of COPD subtypes identified through cluster analysis to predict the first AE. Among COPD patients in the Korea COPD Subgroup Study (KOCOSS) cohort, 1,195 who had follow-up data for AE were included in our study. We selected seven variables for cluster analysis - age, body mass index, smoking status, history of asthma, COPD assessment test (CAT) score, post-bronchodilator (BD) FEV % predicted, and diffusing capacity of carbon monoxide % predicted. K-means clustering identified four clusters for COPD that we named putative asthma-COPD overlap (ACO), mild COPD, moderate COPD, and severe COPD subtypes. The ACO group (n=196) showed the second-best post-BD FEV (75.5% vs 80.9% [mild COPD, n=313] vs 52.4% [moderate COPD, n=345] vs 46.7% [severe COPD, n=341] predicted), the longest 6-min walking distance (424 m vs 405 m vs 389  m vs 365 m), and the lowest CAT score (12.2 vs 13.7 vs 15.6 vs 17.5) among the four groups. ACO group had greater risk for first AE compared to the mild COPD group (HR, 1.683; 95% CI, 1.175-2.410). The moderate COPD and severe COPD group HR values were 1.587 (95% CI, 1.145-2.200) and 1.664 (95% CI, 1.203-2.302), respectively. In addition, St. George's Respiratory Questionnaire score (HR: 1.019; 95% CI, 1.014-1.024) and gastroesophageal reflux disease were independent factors associated with the first AE (HR: 1.535; 95% CI, 1.116-2.112). Our cluster analysis revealed an exacerbator subtype of COPD independent of FEV . Since these patients are susceptible to AE, a more aggressive treatment strategy is needed in these patients.

Incidence and prognosis for severe asthma-COPD overlap is poorly characterized. We investigated incidence and long-term outcome for patients with asthma-COPD overlap compared to asthma and COPD alone. A total of 57,053 adults (aged 50-64 years) enrolled in the Danish Diet, Cancer, and Health cohort (1993-1997) were followed in the National Patients Registry for admissions for asthma (DJ45-46) and COPD (DJ40-44) and vital status. Asthma-COPD overlap was defined as at least one hospital admission for asthma and one for COPD (different time points), and incident asthma-COPD overlap as at least one of the diagnoses occurring after enrollment into the Diet, Cancer, and Health cohort. A total of 1,845 (3.2%) and 4,037 (7.1%) participants had admissions for asthma and COPD, respectively, with 662 (1.2%) participants with asthma-COPD overlap. Incidence rate of asthma-COPD overlap per 1,000 person-years was higher in women (0.73) than in men (0.54) ( <0.02). Mortality rate was higher in asthma-COPD overlap (25.9 per 1,000 person-years) compared with COPD (23.1, <0.05) and asthma (7.9, <0.001) alone. Compared to COPD alone, mortality was higher in women with asthma-COPD overlap (19.6 and 25.5, respectively; <0.01), and the excess mortality rate for asthma-COPD overlap patients was most prominent for younger age groups (12.9 compared to 7.2 and 4.6 for COPD and asthma alone, respectively; <0.01). This large population-based study revealed a higher incidence of severe asthma-COPD overlap in women compared to men, and furthermore that all-cause mortality is higher in women and younger subjects with asthma-COPD overlap compared with those with asthma or COPD alone.