Causes of and Clinical Features Associated with Death in Tobacco Cigarette Users by Lung Function Impairment

Rationale: Cigarette smoking contributes to risk of death through different mechanisms. Objectives: To determine how causes of and clinical features associated with death vary in tobacco cigarette users by lung function impairment. Methods: We stratified current and former tobacco cigarette users enrolled in COPDGene into normal spirometry, Preserved Ratio Impaired Spirometry (PRISm), GOLD 1-2 and GOLD 3-4 COPD. Deaths were identified via longitudinal follow-up and Social Security Death Index search. Causes of death were adjudicated after review of death certificates, medical records and next-of-kin interviews. We tested associations between baseline clinical variables and all-cause mortality using multivariable Cox proportional-hazards models. Results: Over 10.1-year median follow-up, 2,200 deaths occurred among 10,132 participants (age 59.5±9.0 years; 46.6% women). Death from cardiovascular disease was most frequent in PRISm (31% of deaths). Lung cancer deaths were most frequent in GOLD 1-2 (18% of deaths vs 9-11% in other groups). Respiratory deaths outpaced competing causes of death in GOLD 3-4, particularly when BODE index ≥7. St. George's Respiratory Questionnaire score ≥25 was associated with higher mortality in all groups: HR 1.48 [1.20-1.84] normal spirometry; HR 1.40 [1.05-1.87] PRISm; HR 1.80 [1.49-2.17] GOLD 1-2; HR 1.65 [1.26-2.17] GOLD 3-4. History of respiratory exacerbations was associated with higher mortality in GOLD 1-2 and GOLD 3-4, quantitative emphysema in GOLD 1-2, and airway wall thickness in PRISm and GOLD 3-4. Conclusions: Leading causes of death vary by lung function impairment in tobacco cigarette users. Worse respiratory-related quality of life is associated with all-cause mortality regardless of lung function.