Alexis, Neil E.

Abstract Rationale: Adverse social determinants of health (SDOH) are common in COPD and associated with increased mortality. However, cause-specific mortality is understudied. We evaluated associations of neighborhood-level SDOH with all-cause and cause-specific mortality among individuals with or at-risk for COPD. Methods: SPIROMICS is an ongoing, multi-center, longitudinal observational study of individuals across the US with current or former personal smoking histories (≥20 pack-years), with or without spirometrically-defined COPD. We established geocoded neighborhood-level SDOH at baseline using 2010 census tract data, including specifically, area deprivation index (ADI) (range 0-100, 100 = most disadvantaged), poverty level (percentage of households below the poverty line), poor food access (>1/3 of residents with no access to fresh food stores within 1 mile in urban areas and 10 miles in rural areas), and food desert (low income plus poor food access). We ascertained all-cause and cause-specific mortality through 12/31/2021 using the National Death Index. Using Cox proportional hazards models, we evaluated the risk of all-cause mortality for each SDOH. We utilized competing-risk regression models to evaluate the risk of cardiovascular, respiratory, COPD (a subset of respiratory), and neoplastic causes of death individually with each SDOH. Models were adjusted for demographics, smoking status, pack-years, BMI categories, coronary heart disease, FEV1% predicted and study site. Effect modification by lung function was assessed using multiplicative interactions between SDOH and FEV1% predicted. Results: Among 2977 participants, mean ADI was 40.1±27.8. Within a participant's neighborhood, on average 10.4±10.4% of households were below the poverty line, 933 (31.3%) had poor food access, and 220 (7.4%) resided in a food desert. During a median follow-up of 7.8 years (IQR 5.6-9.2), 744 (25.0%) participants died, most commonly from respiratory causes including COPD. Neither ADI nor neighborhood poverty level were associated with all-cause mortality or any specific cause of death (Table). Despite lack of associations between food access and mortality (Table), individuals residing in a food desert had elevated risks of all-cause (HR: 1.36 [95%CI: 1.03-1.79]) and cardiovascular (HR: 2.62 [95%CI: 1.5-4.35]) deaths. There was no significant effect modification by lung function. Conclusions: In a large cohort of individuals with personal smoking histories, with or without COPD, living in a food desert was associated with increased all-cause and cardiovascular mortality. However, neighborhood poverty level and food access, the two components of food desert, were not independently associated with mortality, suggesting the association of multimodal SDOH variables with mortality in this population.

Nicotine from cigarette smoke is a biologically active molecule that has pleiotropic effects in the airway, which could play a role in smoking-induced lung disease. However, whether nicotine and its metabolites reach sustained, physiologically relevant concentrations on airway surfaces of smokers is not well defined. To address these issues, concentrations of nicotine, cotinine, and hydroxycotinine were measured by mass spectrometry (MS) in supernatants of induced sputum obtained from participants in the subpopulations and intermediate outcome measures in COPD study (SPIROMICS), an ongoing observational study that included never smokers, former smokers, and current smokers with and without chronic obstructive pulmonary disease (COPD). A total of 980 sputum supernatants were analyzed from 77 healthy never smokers, 494 former smokers (233 with COPD), and 396 active smokers (151 with COPD). Sputum nicotine, cotinine, and hydroxycotinine concentrations corresponded to self-reported smoking status and were strongly correlated to urine measures. A cutoff of ∼8–10 ng/mL of sputum cotinine distinguished never smokers from active smokers. Accounting for sample dilution during processing, active smokers had airway nicotine concentrations in the 70–850 ng/mL (∼0.5–5 µM) range, and concentrations remained elevated even in current smokers who had not smoked within 24 h. This study demonstrates that airway nicotine and its metabolites are readily measured in sputum supernatants and can serve as biological markers of smoke exposure. In current smokers, nicotine is present at physiologically relevant concentrations for prolonged periods, supporting a contribution to cigarette-induced airway disease.