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Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone. A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 µg/day on budesonide/formoterol fumarate (BUD/FORM) 640/18 µg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization. A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55-83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in ( < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods. The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.

Overlap of asthma and COPD has attracted attention recently. We aimed to clarify physiological and morphological differences of the airways between COPD and asthma–COPD overlap (ACO). Respiratory resistance and reactance and three-dimensional computed tomography data were evaluated in 167 patients with COPD. Among them, 43 patients who fulfilled the diagnosis of asthma were defined as having ACO. Among 124 patients with COPD without ACO, 86 with a comparable smoking history and airflow limitation as those with ACO were selected using propensity score matching (matched COPD). The intraluminal area (Ai) and wall thickness (WT) of third- to sixth-generation bronchi were measured and adjusted by body surface area (BSA; Ai/BSA and WT/√BSA, respectively). Patients with ACO had higher respiratory resistance and reactance during tidal breathing, but a smaller gap between the inspiratory and expiratory phases, compared with matched patients with COPD. Patients with ACO had a greater WT/√BSA in third- to fourth-generation bronchi, smaller Ai/BSA in fifth- to sixth-generation bronchi, and less emphysematous changes than did matched patients with COPD. Even when patients with ACO and those with COPD have a comparable smoking history and fixed airflow limitation, they have different physiological and morphological features of the airways.

The primary objective of this study was to assess the prevalence of treatable traits (TTs) in patients with obstructive lung diseases in a primary care setting and how these TTs co-occur. The secondary objective was to assess the stability of TTs and the effect of management advice on changes in traits and health outcomes. Data from the Dutch asthma/COPD service (2007-2023) were studied retrospectively. Patients ≥18 years with asthma, COPD, or Asthma-COPD overlap (ACO) were included. The prevalence of eight TTs were assessed: 1) insufficient inhaler technique, 2) poor medication adherence, 3) blood eosinophilia, 4) smoking, 5) obesity, 6) physical inactivity, 7) reversible airflow limitation, and 8) anxiety and/or depression. The effect of management advice on TTs was evaluated for patients with a follow-up visit scheduled within 1-2 years. In total, 15246 patients (COPD n=4822; ACO n=1761, asthma n=8663) were included. The highest proportions of TTs were insufficient inhaler technique: 43.6% (95% CI: 42.9-44.4), followed by poor medication adherence: 40.3% (95% CI: 39.2-41.4) and blood eosinophilia: 36.9% (95% CI: 35.8-38.1). Overall, 83.3% of patients had ≥ 1 TTs, and 48.9% of patients ≥ 2 TTs. Among patients with blood eosinophilia, a significant reduction of the trait at follow-up (OR: 0.61, 95% CI: 0.39; 0.96) and improved health status were observed when the pulmonologist advised the general practitioner to initiate or increase the dose of ICS. No significant association was found between management advice and the exacerbation rate at follow-up. The TTs assessed in this study are common in primary care patients, with nearly half of the patients showing a combination of at least two TTs. These TTs coexist in many different combinations. A personalized approach targeting these traits may be effective in achieving better control of these heterogeneous diseases.

Asthma and chronic obstructive pulmonary disease overlap patients (ACO) have more exacerbations and a worse prognosis than pure asthma or COPD, and it is of great interest to identify differential biomarkers of ACO. We compared blood eosinophil counts, plasma IgE and protein levels among patients with asthma, ACO, COPD, and healthy subjects to identify those associated with ACO. 397 adults (age 40-90 years) were recruited from two Colombian cities: asthma (n=123), COPD (n=100), ACO (n=74) and healthy control (HC, n=100). Plasma protein levels were measured using the Proximity Extension Assay (Olink Proteomics). There were no differences in blood eosinophil counts between the patient groups. Total and specified IgE levels were higher in patients with ACO than in those with COPD. Ten plasma proteins showed significant differences between the patients with ACO and HC. In patients above 60 years old, CXCL9 discriminates ACO from asthma patients with AUC 0.73 (0.63-0.82, DeLong test p=0.007), and in patients below 60 years old, MCP-3 discriminates ACO from COPD patients with AUC 0.84 (0.62-1.0, DeLong test p=0.006). CUB domain-containing protein 1 (CDCP1) levels (OR, 0.47; p=0.008) and age > 60 years (OR, 0.25; p=0.001) were negatively associated with ACO. CXCL9 levels could be used to discriminate ACO from asthma patients and MCP-3 to discriminate ACO from COPD. Protein inflammatory signatures in plasma of ACO patients were similar to the COPD group. This study revealed novel biomarkers that may help characterize patients with ACO.

A woman in her forties with asthma and COPD was admitted to a general medical floor with respiratory symptoms, body aches, and anosmia. Reverse transcription polymerase chain reaction detected severe acute respiratory syndrome coronavirus-2. Admission labs, including biomarkers of the systemic immunological dysfunction seen in many cases of coronavirus disease 2019 (COVID-19), were within normal ranges. On the second day of admission, she developed neck and back pain that was constant, burning in quality, and exacerbated by light touch and heat. Wearing clothing caused pain and interfered with her sleep. The area was tender to light finger stroke. The patient was given acetaminophen, NSAIDs, and opioids with no relief of pain. However, gabapentin was effective. At follow-up 1 month later, her symptoms were improved and still relieved by gabapentin. Neuropathic pain was seen in over 2% of COVID-19 patients in one observational study. The pain seen in our case was bilateral, involved an area innervated by multiple levels of spinal nerves, and was limited to the back. While it is rare, a significant number of COVID-19 patients are afflicted by neuropathic pain, and our case illustrates that gabapentin may be effective.

Many older adults with a history of smoking and asthma develop clinical features of both asthma and COPD, an entity sometimes called asthma-COPD overlap (ACO). Patients with ACO may be at higher risk of poor health outcomes than those with asthma or COPD alone. However, understanding of ACO is limited in the primary care setting and more information is needed to better inform patient management. We aimed to compare the characteristics of patients with ACO or COPD in Australian general practices. Data were from the RADICALS (Review of Airway Dysfunction and Interdisciplinary Community-based care of Adult Long-term Smokers) trial, an intervention study of an interdisciplinary community-based model of care. Baseline demographic and clinical characteristics, pre- and post-bronchodilator spirometry, dyspnoea and St. George's Respiratory Questionnaire scores were compared between 60 ACO patients and 212 with COPD alone. Pre-bronchodilator Forced Expiratory Volume in 1 second (mean±SD 58.4±14.3 vs 67.5±20.1% predicted) and Forced Vital Capacity (mean 82.1±16.9 v 91.9±17.2% predicted) were significantly lower in the ACO group (p<0.001), but no difference was found in post-bronchodilator spirometry. Demographic and clinical characteristics, dyspnoea, quality of life, comorbidities and treatment prescribed did not differ significantly between groups. This is the first study describing the clinical characteristics of ACO patients in Australian general practices. Our finding of lower pre-bronchodilator lung function in the ACO group compared to those with COPD reinforces the importance of spirometry in primary care to inform management. Australian New Zealand Clinical Trials Registry ACTRN12614001155684.

Abstract Objective: The aim of this study was to determine the utility of dynamic-ventilatory digital radiography (DR) for pulmonary function assessment in patients with airflow limitation. Methods: One hundred and eighteen patients with airflow limitation (72 patients with lung cancer before surgery, 35 patients with chronic obstructive pulmonary disease [COPD], 6 patients with asthma, and 5 patients with asthma-COPD overlap syndrome) were assessed with dynamic-ventilatory DR. The patients were instructed to inhale and exhale slowly and maximally. Sequential chest X-ray images were captured in 15 frames per second using a dynamic flat-panel imaging system. The relationship between the lung area and the rate of change in the lung area due to respiratory motion with respect to pulmonary function was analyzed. Results: The rate of change in the lung area from maximum inspiration to maximum expiration (Rs ratio) was associated with the RV/TLC ratio (r = 0.48, p < 0.01) and the percentage of the predicted FEV1 (r = –0.33, p < 0.01) in patients with airflow limitations. The Rs ratio also decreased in an FEV1-dependent manner. Conclusion: The rate of change in the lung area due to respiratory motion evaluated with dynamic DR reflects air trapping. Dynamic DR is a potential tool for the comprehensive assessment of pulmonary function in patients with COPD.

Asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO) is a term used to describe a patient with coexisting clinical features of asthma and COPD. We have previously reported that epithelial to mesenchymal transition (EMT) is active in the lungs of patients with COPD however, EMT in ACO remains an unexplored area. We hypothesize that EMT is an active process in ACO. In this cross-sectional study, large airway endobronchial biopsy (EBB) tissues from patients with asthma (14), COPD (22), current (CS) and ex-smokers (ES), and ACO (12) were immunohistochemically stained for EMT markers (E and N cadherin, vimentin, S100A4, and Collagen IV) and compared with 12 current smokers with normal lung function (NLFS) and 10 non-smoking healthy control (HC) subjects. In addition, air-liquid interface (ALI) cell cultures were performed and cells from patients with ACO and HC were treated with TGF-β, IL-13 and cigarette smoke extract (CSE). Later cells from ALI cultures were lysed for Immunoblotting. Immunostained tissues were enumerated for percent expression of E and N-Cadherin in the epithelium, vimentin and S100A4 positive cells both in the epithelium and reticular basement membrane (RBM). Additionally, the degree of RBM fragmentation was evaluated, a key tissue structural marker of EMT. Compared to healthy controls and asthmatics, ACO had the greatest fragmentation of RBM (P < 0.01). ACO also had substantially decreased percentage expression of E-cadherin (P <0.01), increase percentage of N-cadherin expression, and higher vimentin and S100A4 positive basal cells, in comparison to healthy controls. In the RBM of ACO, S100A4 positive cells (P <0.05) and Vimentin-positive cells were markedly higher in comparison to HC. Similar changes were observed with western blots in response to Th-2 cytokine IL-13, CSE and EMT activator TGF-β. These data are suggestive of active EMT in ACO. Additionally, 50% of the patients with ACO were on 800 mcg/day inhaled corticosteroid (ICS) treatment which may have abrogated some EMT activity; however, it suggests protective effects of ICS as we previously reported in COPD. Studies with larger cohorts are needed to further confirm ICS effects in ACO.

The Advanced Lung Cancer Inflammation Index (ALI) is widely recognized as an emerging metric for assessing both inflammation and nutritional levels. However, it is unclear whether there is a correlation between ALI and Asthma-Chronic Obstructive Pulmonary Disease Overlap (ACO), Chronic Obstructive Pulmonary Disease (COPD), and asthma. ALI was considered as a continuous and categorical variable (Q1, Q2, Q3, Q4), respectively, and the categories of its categorical variables were based on the quartiles of ALI. Logistic regression models were then developed to analyze the correlation between ALI and ACO, COPD, and asthma. Finally, correlations were further analyzed by propensity score matching (PSM) methods. In addition, we calculated the area under the curve (AUC) of the ROC curve to assess the predictive performance of the ALI. Results with ALI as a continuous variable: ALI was negatively associated with both ACO and COPD (ACO: OR=0.70; 95% CI: 0.58-0.86; <0.001; COPD: OR=0.72; 95% CI: 0.65-0.79; <0.001), whereas there was no association between ALI and asthma (OR=1.08; 95% CI: 0.97-1.20; =0.140). Results of ALI as a categorical variable: the negative ALI-ACO association persisted in Q4 groups (Q4: OR=0.66; 95% CI: 0.49-0.88; =0.006); the negative ALI-COPD association was maintained in all groups. After PSM, ALI remained negatively associated with ACO and COPD (ACO: OR=0.61; 95% CI: 0.45-0.83; =0.002; COPD: OR=0.56; 95% CI: 0.48-0.64; <0.001). The AUC was 0.69 for ALI-ACO and 0.73 for ALI-COPD. High levels of ALI may be associated with a reduced risk of ACO and COPD.

IntroductionAsthma-chronic obstructive pulmonary disease (COPD) overlap, termed as ACO, is a complex heterogeneous disease without any clear diagnostic or therapeutic guidelines. The pathophysiology of the disease, its characteristic features, and existence as a unique disease entity remains unclear. Individuals with ACO have a faster lung function decline, more frequent exacerbations, and worse quality of life than those with COPD or asthma alone.ObjectivesThe present study aims to determine whether ACO has a distinct metabolic profile in comparison to asthma and COPD.MethodsTwo different groups of patients were recruited as discovery (D) and validation (V) cohorts. Serum samples obtained from moderate and severe asthma patients diagnosed as per GINA guidelines [n = 34(D); n = 32(V)], moderate and severe COPD cases identified by GOLD guidelines [n = 30(D); 32(V)], ACO patients diagnosed by joint GOLD and GINA guidelines [n = 35(D); 40(V)] and healthy controls [n = 33(D)] were characterized using nuclear magnetic resonance (NMR) spectrometry.ResultsMultivariate and univariate analysis indicated that 12 metabolites [lipid, isoleucine, N-acetylglycoproteins (NAG), valine, glutamate, citric acid, glucose, l-leucine, lysine, asparagine, phenylalanine and histidine] were dysregulated in ACO patients when compared with both asthma and COPD. These metabolites were further validated in a fresh cohort of patients, which again exhibited a similar expression pattern.ConclusionsOur findings suggest that ACO has an enhanced energy and metabolic burden associated with it as compared to asthma and COPD. It is anticipated that our results will stimulate researchers to further explore ACO and unravel the pathophysiological complexities associated with the disease.