Distinct physiological, transcriptomic, and imaging characteristics of asthma-COPD overlap compared to asthma and COPD in smokers.

Abstract

Background: The clinical and pathological features of asthma and chronic obstructive pulmonary disease (COPD) can converge in smokers and elderly individuals as asthma-COPD overlap (ACO). This overlap challenges the diagnosis and treatment of the distinct aetiologies underlying these conditions.

Methods: We analysed 2453 smokers (≥10 pack-years), aged 45-80 years, from the Genetic Epidemiology of COPD (COPDGene) Study, stratified as Control, Asthma, COPD, and ACO based on Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. A comprehensive assessment was performed, encompassing symptomatology, pulmonary function tests (PFTs), complete blood counts (CBCs), bulk RNA sequencing (RNA-seq), and high-resolution quantitative computed tomography (QCT) imaging to evaluate clinical impact, lung function, systemic inflammation, and structural alterations contributing to disease progression across respiratory phenotypes. Differential expression (DE) analysis was performed using whole blood RNA-seq (BH-corrected FDR < 0.01), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Group differences were assessed using the Mann-Whitney U-test (MWU) or Chi-squared test (χ²), with Bonferroni correction applied for multiple comparisons. Multivariate linear regression models were used to adjust the associations between disease status and specific clinical outcomes for confounders, with one-way ANOVA and Tukey's Honest Significant Difference (HSD) post-hoc test applied for pairwise comparisons. Our analysis aimed to delineate the extent and variability of clinical features among disease phenotypes to guide targeted therapeutic strategies.

Findings: Our study highlights distinct yet overlapping profiles across ACO, asthma, and COPD. We effectively isolated disease-specific mechanisms by comparing each phenotype to smoking controls (GOLD 0) while accounting for baseline smoking-related inflammation. ACO exhibited the most severe symptom burden, with significantly higher COPD Assessment Test (CAT) score (18.32, 95% CI: [17.02, 19.63], P < 0.0001) and Modified Medical Research Council (mMRC) Dyspnea score (2.14, 95% CI: [1.92, 2.35], P < 0.0001) compared to COPD and asthma. ACO also displayed reduced lung capacity (forced expiratory volume in 1 s [FEV₁]: 52.5%, 95% CI: [50.08, 54.93], P < 0.0001) and airflow limitation (FEV₁/forced vital capacity [FVC]: 0.55, 95% CI: [0.5471, 0.5546], P < 0.0001), closely resembling COPD but significantly worse than asthma. The inflammatory profile of ACO exhibited a mixed response, featuring elevated neutrophil counts (4.57 K/μL, 95% CI: [4.28, 4.86], P < 0.0001) and eosinophil levels (0.22 K/μL, 95% CI: [0.20, 0.25], P < 0.01), contrasting with the predominantly neutrophilic inflammation in COPD and the absence of systemic inflammation in asthma. Structurally, ACO demonstrated significant airway remodelling (Pi10: 2.87, 95% CI: [2.83, 2.91], P < 0.0001), intermediate emphysema (5.66%, 95% CI: [4.72, 6.60], P < 0.0001), and moderate small airway disease (parametric response mapping for functional small airway disease [PRM^fSAD]: 22.94%, 95% CI: [21.53, 24.34], P < 0.0001), reflecting features of both asthma and COPD. COPD was characterised by more extensive emphysema (8.9%, 95% CI: [8.34, 9.45], P < 0.0001), small airway disease (PRM^fSAD: 27.09%, 95% CI: [26.51, 27.66], P < 0.0001), and gas trapping (37.34%, 95% CI: [36.33, 38.35], P < 0.0001), alongside moderate airway remodelling. At a molecular level, DE 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 (NET) formation and necroptosis. In contrast, asthma exhibited significant airway remodelling (Pi10: 2.09, 95% CI: [2.05, 2.13], P < 0.0001), minimal parenchymal damage, and no systemic gene expression changes.

Interpretation: Collectively, our findings underscore the lung function impairments, systemic inflammation, molecular mechanisms, and structural correlates distinguishing ACO from COPD and asthma, emphasising the need for precise clinical management and the potential for novel therapeutic interventions.

Funding: This work was supported by National Heart, Lung, and Blood Institute (NHLBI) grants U01 HL089897 and U01 HL089856, as well as by National Institutes of Health (NIH) contract 75N92023D00011. Additional support was provided by grants R01 HL166231 (C.P.H.) and K01 HL157613 (A.S.).