Project Summary Chronic obstructive pulmonary disease (COPD) affects approximately 10% of adults above the age of 40 and is the third leading cause of mortality worldwide. Comorbid diseases commonly accompany COPD and are important determinants of COPD outcomes. In addition, exercise capacity and physical activity are strong independent predictors of all-cause mortality in COPD patients. The two important determinants of exercise capacity are hemoglobin level, the limiting factor for oxygen carrying capacity, and iron level, which dictates tissue oxidative capacity. Thus, while iron deficiency and anemia are related, they are distinct conditions with differing mechanisms of pathophysiology. Currently, compared to anemia, less is known regarding the association between iron deficiency and COPD morbidity. In limited observational and retrospective clinical studies, iron deficiency has been shown to be associated with self-reported exacerbations, worse exercise tolerance, and increased severity of chronic lung disease-associated pulmonary hypertension. Regarding treatment, there have been proof-of-concept studies showing improvement in exercise capacity with IV iron repletion in small cohorts of COPD patients. However, given the small scale of the studies thus far, it remains unknown whether all COPD patients are affected similarly by iron deficiency and whether iron repletion will provide equal benefit. The main object of this proposal is to understand the association between iron profile and COPD morbidity through two novel aims. First, to determine the association between iron profile, specifically ferritin and transferrin saturation, and COPD-related hospitalization by conducting a retrospective secondary analysis of a large COPD patient data registry with approximately 85,000 individuals. Second, to prospectively determine the association between iron profile and 2a) hospital readmission rate and 2b) functional status by physical activity level, in a cohort of patients recently hospitalized for COPD exacerbations. The second aim will be nested in an observational cohort study of patients recently hospitalized for COPD exacerbations that is enriched for exacerbation events. We will obtain iron profiles at 1-week post-index hospitalization and the cohort will be followed for 12 months with regular interval in-person or telephone assessments for exacerbations and validated respiratory symptom measures. Physical activity level will be acquired through step count and heart rate monitoring. This proposal provides an excellent training vehicle for patient-oriented clinical research through hands on experience following a cohort from enrollment to final analysis. I will also develop expertise in basic large data management and physical activity data acquisition and analysis. If we find that iron deficiency is associated with COPD morbidity, future investigation of treatment with iron repletion and assessment of benefit versus harm would be warranted,...