Non-Anemic Iron Deficiency Predicts COPD Exacerbations and Hospitalizations: Results from a Prospective Cohort

Background: Non-anemic iron deficiency (NAID) has been increasingly recognized as a potential factor affecting chronic obstructive pulmonary disease (COPD) outcomes. However, its prognostic role in COPD exacerbations and hospitalizations remains poorly understood. This study aimed to evaluate the prevalence of NAID in COPD patients, its impact on functional parameters, and its predictive value for exacerbations and hospitalizations. Methods: This prospective observational study included 238 patients with stable COPD and 60 age- and sex-matched smokers without COPD as a control group. NAID was defined as serum ferritin < 100 ng/mL or serum ferritin between 100 and 299 ng/mL with transferrin saturation < 20%. Clinical assessments included pulmonary function tests, 6 min walk distance (6MWD), handgrip strength, and fat-free mass index (FFMI). Patients were followed for 12 months to record moderate and severe COPD exacerbations. Cox regression analysis was used to determine the predictive value of NAID for exacerbations and hospitalizations. Results: NAID was present in 68.9% of COPD patients compared to 46.7% of smokers without COPD (p = 0.001). COPD patients with NAID had lower 6MWD (430 (330-500) m vs. 462 (390-510) m, p = 0.029), reduced FFMI (17.9 (15.5-20.2) kg/m² vs. 20.6 (17.6-22.6) kg/m², p < 0.001), and weaker handgrip strength (26 (22-33) kg vs. 34 (27-40) kg, p < 0.001) compared to non-NAID COPD patients. During the 12-month follow-up period, 140 patients developed moderate COPD exacerbations (107 in the NAID group), and 43 patients were hospitalized due to severe exacerbations (36 in the NAID group). Cox regression analysis showed that NAID was an independent predictor of moderate COPD exacerbations (HR 1.846, 95% CI 1.249-2.729, p = 0.002) and hospitalization (HR 2.537, 95% CI 1.129-5.703, p = 0.024) after adjusting for age, sex, lung function, and comorbidities. Conclusions: NAID is highly prevalent in COPD and is associated with worse exercise capacity, lower muscle mass, and increased exacerbation risk independently of sex and age. These findings suggest that NAID could be a valuable biomarker for risk stratification in COPD patients, warranting further research on potential therapeutic interventions targeting iron metabolism.