Exploring health consequences of Asthma-COPD overlap syndrome in a national study.

Asthma-COPD overlap syndrome (ACOS) represents a clinically significant yet under characterized respiratory phenotype. Comprehensive population-based assessments of ACOS-attributable burden, smoking dose-response relationships, phenotypic subtypes, and mechanistic pathways remain limited. Using 2023-2024 Behavioral Risk Factor Surveillance System data, we conducted 1:1 propensity score matching of 675 ACOS patients with controls without respiratory disease, balanced on 15 covariates including demographics, smoking exposure, BMI, and adverse childhood experiences. Outcomes encompassed health-related quality of life, functional disabilities, healthcare access, and health behaviors. Restricted cubic splines characterized smoking dose-response relationships. Latent class analysis identified ACOS phenotypes. Structural equation modeling with bootstrapping (5,000 resamples) quantified mediation pathways. Despite rigorous matching, ACOS conferred 4.6 additional physically unhealthy days monthly (Cohen's d=0.37), 41% increased activity limitation risk (RR=1.41), and 19% elevated functional disability prevalence (RR=1.19). Smoking exhibited significant nonlinear dose-response (χ2=286.4, P<0.001); even 5 pack-years increased ACOS odds 42% (OR=1.42), with population attributable fraction reaching 85.3% at 60 pack-years. Three distinct phenotypes emerged: "Mild" (36%, younger with preserved function), "Metabolic-Predominant" (35%, 72.6% obesity, 48.2% diabetes), and "Severe Multimorbid" (29%, 95.8% functional disability, Charlson Index 4.8). Depression, BMI, and physical inactivity mediated 37.5% of smoking's total ACOS effect (18.0%, 14.1%, and 5.3%, respectively). ACOS imposes substantial excess morbidity independent of measured confounders, with no safe smoking threshold. Depression and metabolic pathways substantially mediate smoking's impact. Three clinically distinct phenotypes warrant tailored interventions, supporting precision medicine approaches for this high-burden respiratory syndrome.