International Journal of COPD Dovepress open access to scientific and medical research Open Access Full Text Article S h o r t R e po r t Is iron deficiency modulating physical activity in COPD? This article was published in the following Dove Medical Press journal: International Journal of COPD Clara Martín-Ontiyuelo 1 Abstract: There is evidence that iron plays a key role in the adequate functioning of skeletal Anna Rodó-Pin 1 muscle. While it has been demonstrated that nonanemic iron deficiency (NAID) affects exercise Antonio Sancho-Muñoz 1 tolerance and response to exercise training in patients with COPD, the impact on daily physical Juana María activities (DPAs) remains unknown. Eighteen COPD patients with NAID (ferritin ,100 ng/mL Martinez-Llorens 1 or ferritin 100–299 ng/mL with a transferrin saturation ,20%) and 18 COPD patients without this abnormality, matched for age, gender, and the degree of airflow limitation (control group), were Mireia Admetlló 1 enrolled to the study. The primary outcome was the level of DPA assessed by accelerometers. Lluis Molina 2 Patients were (mean [SD]) 66 (7) years and were mostly male (70%) and former smokers (52%). Joaquim Gea 1 Their forced expiratory volume at 1 second was 41 (16)% predicted, carbon monoxide diffusing Esther Barreiro 1 capacity was 47 (14)% predicted and oxygen arterial pressure reached 70 (11) mmHg. DPA and Diego A Rodríguez the number of steps per day were lower in NAID COPD patients compared with controls (physi- Chiaradía 1 cal activity level 1.39 vs 1.59, P,0.05; and 4,402 vs 6,975 steps/day, P,0.05, respectively). 1 Pulmonology Department, Hospital The percentage of patients with increased time spent sitting per day (.6 hours) was higher in del Mar, Institut Hospital del Mar patients with NAID compared with controls (73% vs 37%, P,0.05). In addition, the percentage d’Investigacions Mèdiques (IMIM), Universitat Pompeu Fabra (UPF), of patients doing moderate to vigorous physical activity per day (.3 metabolic equivalents of CIBERES, (ISCiii), Barcelona, Spain; task, at least 30 minutes) was lower in this group (66% vs 100%, P,0.05). The presence of 2 Cardiology Department, Hospital iron deficiency was associated with reduced DPA in COPD patients. Further studies are needed del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), to evaluate iron reposition and their impact on the level of physical activity in these patients. Universitat Autónoma de Barcelona Keywords: COPD, comorbidities, physical activity, iron, nutrition, chronic disease (UAB), Barcelona, Spain Introduction Nonanemic iron deficiency (NAID) in the adult population remains an important public health problem worldwide.1 Moreover, NAID prevalence in chronic complex disease is very high, rising up to 40% in patients with COPD2 and 50% in patients with chronic heart failure.3 Particularly, COPD patients with NAID showed more dyspnea,4 higher values of pulmonary arterial pressure at rest,5 and lower exercise capacity with a reduced training-induced response than patients without iron deficiency.2 These functional alterations cannot be fully explained by hemodynamic deterioration. An impairment in oxygen utilization by the peripheral muscles may also account for the reported loss Correspondence: Diego A Rodríguez of muscle function and/or exercise tolerance in COPD.6 This factor can be especially Chiaradía relevant for those diseases in which the peripheral muscle involvement has an impact Pulmonology Department, Hospital del Mar, Institut Hospital del Mar on daily physical activity (DPA).7 In line with this, the effects of reduced physical d’Investigacions Mèdiques (IMIM), activity and disuse in COPD have been extensively investigated in several studies8,9 Universitat Pompeu Fabra (UPF), CIBERES, (ISCiii), Passeig Maritim 25, resulting in a vicious circle with reductions in DPA leading to deconditioning and a 08003 Barcelona, Spain further deterioration of skeletal muscle function. Despite the clinical relevance and Tel +34 93 248 3548 Fax +34 93 248 3425 research problem, to the best of our knowledge, no studies have examined so far the Email darodriguez@psmar.cat impact of NAID on DPA in patients with COPD. In this context, we sought to compare submit your manuscript | www.dovepress.com International Journal of COPD 2019:14 211–214 211 Dovepress © 2019 Martín-Ontiyuelo et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php http://dx.doi.org/10.2147/COPD.S182700 and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Martín-Ontiyuelo et al Dovepress the level of DPA in COPD patients with NAID and in those significantly greater in NAID group (Table 1). No significant COPD patients with an adequate iron status. correlations were observed between hematologic variables To address this question, we conducted a pilot study, and physical activity among all COPD patients. in which 18 patients with COPD10 and NAID (hemo- To the best of our knowledge, the current study is the globin .12 g/dL in females and .13 g/dL in males, first to explore the impact of NAID on physical activity ferritin ,100 ng/mL or ferritin 100–299 ng/mL with a in patients with COPD. Previously, some of us published transferrin saturation ,20%)2 were recruited along with original research on the negative effects of NAID on exer- 18 COPD patients with normal iron content. The latter cise capacity and the response to pulmonary rehabilitation,2 patients were age-matched and were controlled for disease indicating a potential therapeutic target to improve exercise severity (control group). DPA was measured using the tolerance. However, it is widely known that the relationship SenseWear Pro Armband (BodyMedia, Pittsburgh, PA, between physical activity and exercise capacity in COPD USA), an accelerometer already validated in patients with is weak16 because of their specific determinants.9 Although COPD.11 DPA was measured for 7 consecutive days. The the assessment of exercise capacity is a key point in the minute-by-minute output of the number of steps and meta- evaluation of pharmacological and nonpharmacological bolic equivalents of task (METs) was exported for further interventions, physical activity allows to monitor these analysis using a SenseWear Professional version. The vari- effects on daily-life activities of these patients.17 In this ables chosen for this analysis were the following: 1) total context, muscle dysfunction is one of the main mechanisms daily number of steps; 2) moderate physical activity, defined involved in the low physical activity with a prognosis as any activity $3 METs; 3) physical activity level (PAL);12 implication in these patients.8 It is clear that muscle dys- and 4) time spent sitting per day.13 Lung function (Easy function contributes to both exercise intolerance and low One, Switzerland; Jaeger Master Screen Body; CareFusion; physical activity,7 with pulmonary rehabilitation being the Germany) was measured according to European Respiratory only treatment widely accepted. However, other specific Society/American Thorax Society standards.14 The results interventions have already been implemented in clinical were expressed as predicted normal values.15 The study was settings in the last years.7–18 Recently, there has been great approved by the local research ethics committee (CEIm– interest in the effect of iron deficiency on skeletal muscle as Parc de Salut MAR) and complies with the Declaration of a potential contributor to muscle dysfunction in COPD and Helsinki. Informed written consent was obtained from all other chronic complex diseases.19 Despite that our results patients before enrollment. do not fully support this hypothesis; we can speculate that Results are presented as percentages or mean (SDs), iron deficiency in the skeletal muscle could be a likely cause unless otherwise stated. Parametric (Student’s t-test) and of muscle dysfunction that generates low physical activ- nonparametric tests (Wilcoxon test) were performed to assess ity and exercise intolerance. Therefore, over the last year, the statistical significance of differences between groups. we have carried out a randomized control trial to explore Pearson or Spearman correlation coefficient (r) was used the effects of iron reposition in COPD patients (EudraCT to correlate DPA with hematologic variables (hemoglobin, 2016-001238-89). Participants are currently being recruited transferrin saturation, and ferritin). A P-value #0.05 was for the trial. As of June 1, 2018, a total of 30 patients with considered significant. All analyses were performed using NAID and COPD have been recruited into the trial. Data the IBM SPSS Statistics for Windows, Version 20.0 (IBM collection is anticipated to be completed by the end of 2019. Corp., Armonk, NY, USA). Our current study has some limitations that should be The characteristics of the study population are indicated considered when interpreting the results. First, the sample in Table 1. As expected, the baseline clinical and functional size was small and included only patients with moderate variables of patients with COPD and NAID were not different and severe COPD; these findings may not be applicable to from control COPD patients. Compared with control patients, the wider population of patients with COPD. In contrast, NAID patients showed lower levels of the parameter steps per the adequate matched groups by airflow limitation, carbon day and PAL. Also, the percentage of patients with adequate monoxide diffusing capacity, or comorbidities may not occur daily levels of moderate physical activity (.30 minutes) in more conventional studies. was significantly lower in NAID COPD patients than in In conclusion, NAID in moderate to severe COPD the control COPD patients. Conversely, the percentage of patients could be a potential modulator of physical patients with prolonged time spent sitting ($6 hours/day) was activity. Research is needed to examine the physiological 212 submit your manuscript | www.dovepress.com International Journal of COPD 2019:14 Dovepress Dovepress Iron deficiency in COPD Table 1 Clinical and functional characteristics of COPD patients with and without nonanemic iron deficiency (NAID) Clinical and functional variables All patients (N=36) NAID COPD (N=18) Non-NAID COPD controls (N=18) Clinical characteristics Male/female, n 21/15 10/8 11/7 Age, years 66 (7) 67 (6) 64 (7) Current smokers, n (%) 19 (52) 9 (50) 10 (55) Body mass index, kg/m2 24 (4) 24 (3) 25 (4) Fat-free mass index, kg/m2 16 (2) 15 (1) 16 (1) CAT score 16 (8) 17 (9) 15 (7) AECOPD $2/year, n (%) 10 (27) 5 (27) 5 (27) Charlson index [median (P5–95)] 2 (2.1–2.6) 2 (2.1–2.6) 2 (2.2–2.5) Treatment, n LABD 36 18 18 ICS 8 4 4 Beta-blockers 3 1 2 Aspirin 3 1 2 Statins 4 2 2 Pulmonary function FEV1/FVC, % 43 (12) 44 (13) 43 (12) FEV1, % predicted 41 (16) 40 (16) 42 (22) DLco, % predicted 47 (14) 46 (14) 49 (15) PaO2, mmHg 70 (11) 67 (11) 72 (10) PaCO2, mmHg 42 (6) 42 (5) 42 (6) IC/TLC 0.28 (0.09) 0.28 (0.08) 0.29 (0.11) QMVC, kg 37 (13) 35 (11) 40 (15) Hematological characteristics Hemoglobin, g/dL 14.5 (1) 15.2 (1) MCV (fL) 90 (5) 92 (4) MCHC (g/dL) 32 (1) 33 (1) Transferrin saturation, % 20 (5) 40 (3)* Ferritin, ng/mL 70 (27) 235 (39)* C-reactive protein, mg/dL 0.6 (1) 0.7 (0.9) Daily physical activity Steps per day 5,726 (3,337) 4,402 (2,145) 6,975 (3,813)** Physical activity level 1.49 (0.2) 1.39 (0.1) 1.59 (0.2)*** Moderate physical activity, min/day 103 (80) 85 (80) 120 (78) Moderate activity per day, % of patients 83 66 100† Time spent sitting, min/day 397 (196) 448 (184) 342 (201) Prolonged time spent sitting, % of patients 55 73 37†† Notes: Data are presented as mean (SD) unless otherwise stated. Moderate physical activity per day: at least 30 minutes; prolonged time spent sitting per day: .6 hours. *P,0.001; **P=0.020; ***P=0.019; †P=0.010; ††P=0.048. Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; CAT, chronic obstructive pulmonary disease assessment test; DLco, carbon monoxide diffusing capacity; FEV1/FVC, forced expiratory volume at 1 second/forced vital capacity; ICS, inhaled corticosteroid; IC/TLC, inspiratory capacity/total lung capacity; LABD, long-acting bronchodilators; MCV, mean corpuscular volume; MCHC, mean corpuscular hemoglobin concentration; PaCO2, carbon dioxide arterial pressure; PaO2, oxygen arterial pressure; QMVC, quadriceps maximal strength during maximum voluntary contraction. mechanisms implicated and the potential role of therapeutic Society (SEPAR) 2016 and 2017 (409/2017), Catalan interventions. Foundation of Pulmonology (FUCAP) 2016 and 2017, Catalan Respiratory Society (SOCAP) 2017, Ministerio de Acknowledgments Economía y Competitividad (SAF2014-54371 [FEDER]), The authors would like to thank Ana Balañá, Concepción Menarini (2015–2018), and Vifor Pharma (2017–2018). Ballano, and Laura Gutiérrez for their assistance in collecting The abstract of this paper was presented at the 2017 the data for this study. They want to acknowledge the support European Respiratory Society Congress as a poster of the Instituto de Salud Carlos-III (FIS 14/00713 [FEDER], presentation. The poster’s abstract was published in “Poster FIS 18/00075 [FEDER], FIS 17/00649 [FEDER], and BA Abstracts” in European Respiratory Journal 2017:50: 17/00025), CIBERES (ESF02/2017), Spanish Respiratory PA3457: DOI: 10.1183/1393003.congress-2017.PA3457. International Journal of COPD 2019:14 submit your manuscript | www.dovepress.com 213 Dovepress Martín-Ontiyuelo et al Dovepress Disclosure 10. 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