Asthma-COPD overlap presents a severe and complex respiratory phenotype characterized by mixed inflammatory responses and extensive airway remodeling, according to a recent study.
Published in eBioMedicine, the study included more than 2,400 smokers aged 45 to 80 years from the COPDGene cohort, stratifying them into asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) categories based on Global Initiative for Chronic Obstructive Pulmonary Disease criteria. Researchers performed comprehensive assessments, including pulmonary function tests, blood analyses, bulk RNA sequencing, and quantitative computed tomography imaging.
Patients with ACO experienced the greatest symptom burden of the three categories, with significantly elevated COPD Assessment Test scores (18.32, 95% confidence interval [CI] = 17.02–19.63, P < .0001) and Modified Medical Research Council dyspnea scores (2.14, 95% CI = 1.92–2.35, P < .0001) compared to patients with COPD or asthma alone.
The study also reported notable impairments in lung function among patients with ACO. Forced expiratory volume in 1 second (FEV1) was 52.5% of predicted values for patients with ACO (95% CI = 50.08%–54.93%, P < .0001), with a FEV1/forced vital capacity ratio of 0.55 (95% CI = 0.5471–0.5546, P < .0001). These values were significantly worse than those observed in patients with only asthma, and closely mirrored those seen in patients with COPD.
Structurally, ACO presented with airway remodeling (Pi10 = 2.87, 95% CI = 2.83–2.91, P < .0001), intermediate levels of emphysema (5.66%, 95% CI = 4.72%–6.60%, P < .0001), and moderate small airway disease (PRMfSAD = 22.94%, 95% CI = 21.53%–24.34%, P < .0001). These findings indicated a blend of features typically associated with both asthma and COPD.
"At a molecular level, differential expression analysis revealed enrichment of the hypoxia-inducible factor 1 (HIF-1) pathway in ACO, highlighting unique hypoxia-driven metabolic adaptations, while COPD was associated with neutrophil extracellular trap formation and necroptosis," wrote lead study author Vrushali D. Fangal, of the Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, and colleagues.
Inflammatory profiles further distinguished the phenotypes. Patients with ACO exhibited elevated neutrophil counts (4.57 K/μL, 95% CI = 4.28–4.86, P < .0001) and eosinophil levels (0.22 K/μL, 95% CI = 0.20–0.25, P < .01), reflecting a mixed inflammatory response. This contrasted with the predominantly neutrophilic inflammation observed in COPD and the absence of systemic inflammation in asthma.
"Our analysis aimed to delineate the extent and variability of clinical features among disease phenotypes to guide targeted therapeutic strategies," the researchers wrote.
The authors also emphasized that understanding the unique physiological, inflammatory, and molecular characteristics of ACO could inform more targeted clinical approaches and novel treatments for this patient population.
This research was funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health. The authors declared no conflicts of interest.
