Background: Chronic obstructive pulmonary disease (COPD) exacerbation (ECOPD) alters the natural course of the disease. To date, only C-reactive protein has been used as a biomarker in ECOPD, but it has important limitations. The mitochondria release peptides (Humanin (HN), FGF-21, GDF-15, MOTS-c and Romo1) under certain metabolic conditions. Here, we aimed to evaluate the pathophysiologic, diagnostic and prognostic value of measuring serum mitochondrial peptides at hospital admission in patients with ECOPD. Methods: A total of 51 consecutive patients admitted to our hospital for ECOPD were included and followed for 1 year; in addition, 160 participants with stable COPD from our out-patient clinic were recruited as controls. Results: Serum FGF-21 ( p < .001), MOTS-c ( p < .001) and Romo1 ( p = .002) levels were lower, and GDF-15 ( p < .001) levels were higher, in patients with ECOPD than stable COPD, but no differences were found in HN. In receiver operating characteristic analysis, MOTS-c (AUC 0.744, 95% CI 0.679–0.802, p < .001) and GDF-15 (AUC 0.735, 95% CI 0.670–0.793, p < .001) had the best diagnostic power for ECOPD, with a diagnostic accuracy similar to that of C-RP (AUC 0.796 95% IC 0.735–0.848, p < .001). FGF-21 (AUC 0.700, 95% CI 0.633–0.761, p < .001) and Romo1 (AUC 0.645 95% CI 0.573–0.712, p = .001) had lower diagnostic accuracy. HN levels did not differentiate patients with ECOPD versus stable COPD ( p = .557). In Cox regression analysis, HN (HR 2.661, CI95% 1.009–7.016, p = .048) and MOTS-c (HR 3.441, CI95% 1.252–9.297, p = .016) levels exceeding mean levels were independent risk factors for re-admission. Conclusions: Most mitochondrial peptides are altered in ECOPD, as compared with stable COPD. MOTS-c and GDF15 levels have a diagnostic accuracy similar to C-RP for ECOPD. HN and MOTS-c independently predict future re-hospitalization.

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.