Abstract
Background
Little is known about iron deficiency (ID) and anemia in Chronic Obstructive Pulmonary Disease (COPD). The purposes of this study were: (i) To study the prevalence and treatment of anemia and ID in patients hospitalized with an exacerbation of COPD. (ii) to study the hematological responses and degree of dyspnea before and after correction of anemia with subcutaneous Erythropoiesis Stimulating Agents (ESAs) and intravenous (IV) iron therapy, in ambulatory anemic patients with both COPD and chronic kidney disease.
Methods
(i) We examined the hospital records of all patients with an acute exacerbation of COPD (AECOPD) to assess the investigation, prevalence, and treatment of anemia and ID. (ii) We treated 12 anemic COPD outpatients with the combination of ESAs and IV-iron, given once weekly for 5 weeks. One week later we measured the hematological response and the severity of dyspnea by Visual Analogue Scale (VAS).
Results
(i) Anemia and iron deficiency in hospitalized COPD patients: Of 107 consecutive patients hospitalized with an AECOPD, 47 (43.9%) were found to be anemic on admission. Two (3.3%) of the 60 non-anemic patients and 18 (38.3%) of the 47 anemic patients had serum iron, percent transferrin saturation (%Tsat) and serum ferritin measured. All 18 (100%) anemic patients had ID, yet none had oral or IV iron subscribed before or during hospitalization, or at discharge. (ii) Intervention outpatient study: ID was found in 11 (91.7%) of the 12 anemic ambulatory patients. Hemoglobin (Hb), Hematocrit (Hct) and the VAS scale scores increased significantly with the ESAs and IV-iron treatment. There was a highly significant correlation between the ∆Hb and ∆VAS; rs = 0.71 p = 0.009 and between the ∆Hct and ∆VAS; rs = 0.8 p = 0.0014.
Conclusions
ID is common in COPD patients but is rarely looked for or treated. Yet correction of the ID in COPD patients with ESAs and IV iron can improve the anemia, the ID, and may improve the dyspnea.
Similar content being viewed by others
Background
Anemia is seen in 10-30% of Chronic Obstructive Pulmonary Disease (COPD) patients [1–15]. The anemia is associated with increased mortality and morbidity including increased hospitalization and increased health care costs [1–15]. The anemia in COPD has been associated with a negative effect on dyspnea and walking distance [5], on circulatory efficiency (as compared to non-anemic COPD patients) as judged by lower peak oxygen uptake and lower peak work rate [16] and with the need for home oxygen therapy and lower mean peripheral oxygen values both at rest and during exercise [9] Although there are many contributors to the anemia it is probably caused mainly by the inflammatory nature of COPD [12], with the increased cytokine production causing anemia and iron deficiency (ID) [17, 18].
Little information exists on the role of iron deficiency (ID) in COPD although serum iron and %TSat levels were found in a US population-based cross sectional study to be directly related to one second Forced Expiratory Volume (FEV 1) levels [19]. In addition iron intake in COPD patients has been found to be about half that of normal controls [20].
Surprisingly, not a single study has, to our knowledge, been reported using either of these two agents, Erythropoiesis Stimulating Agents (ESAs) or intravenous (IV) iron, in the treatment of the anemia and/or iron deficiency of COPD.
Our hypothesis was that functional ID may be a prevalent condition in patients with COPD. To test this hypothesis, we reviewed retrospectively a series of 107 patients admitted for AECOPD.
In our medical clinic devoted to the treatment of anemia due to chronic kidney disease (CKD) and congestive heart failure (CHF) [21, 22], we found 12 patients that were also suffering from COPD. We evaluated the clinical effect of treating anemia and ID with ESAs and IV iron.
Methods
Approval of the study was granted by the Ethical Committee of the Tel-Aviv Medical Center.
Study 1
We examined the hospital records of all patients admitted with an AECOPD between January 1, 2012 to December 31 2012 to assess the prevalence, the investigation and treatment of anemia and ID in these patients. COPD diagnosis was based on information encoded in the administrative database.
Study 2
We identified 12 anemic (defined as Hb < 12 g/dl) patients with an established diagnosis of COPD who had been treated in our clinic. We analyzed the effects of the combination of subcutaneous ESAs and IV-iron on dyspnea in these patients. Patient characteristics that were examined at baseline included presence of CKD, CHF, hypertension, diabetes, dyslipidemia and the medications taken.
The anemia was corrected with the combination of ESAs and IV-iron given once weekly for 5 weeks and the final assessment was done one week after the last dose. IV iron (200 mg of elemental iron) was given as two 5 ml ampoules- each containing a total of 100 mg of elemental iron) of Venofer -Ferric Sucrose (Vifor Int, St. Galen, Switzerland). The doses were given one week apart (a total of 1000 mg elemental iron) for 5 weeks. ESAs were given weekly in the form of 10,000 International Units (IU) of subcutaneous (sc) Recormon (Roche, Basel, Switzerland) for five weeks at the same time that the IV iron was given. Weight, height, and blood pressure were measured on every weekly visit. Blood work, done initially, at every visit and one week after the fifth treatment, included: Hemoglobin (Hb), Hematocrit (Hct), Red Blood Cells (RBCs) and RBC indices, Red Cell Distribution Width (RDW), platelets, serum iron, Transferrin, percent transferrin saturation (%Tsat) defined as serum iron divided by serum transferrin multiplied by 100%, serum ferritin, albumin, SGOT, SGPT, serum creatinine. Several definitions for ID were suggested [23] and here we defined ID by three different criteria: (i) serum ferritin of <100 ng/ml, (ii) %TSat <20%, or (iii) either a serum ferritin of <100 ng/ml or the combination of serum ferritin of 100-300 ng/ml and %TSat of <20%. Estimated glomerular filtration rate (eGFR) was calculated by the MDRD equation [24].
Pulmonary function was performed by spirometry which was performed in accordance with the recommendations of the American Thoracic Society [25]. The one second Forced Expiratory Volume (FEV 1), Forced Vital Capacity (FVC) and the FEV1/FVC, all assessed as percent of predicted values, were measured before but not after the EPO-IV iron therapy.
Health perception was assessed at baseline and one week after the fifth injection of EPO and IV iron. We used a Visual Analog Scale (VAS) making a line 10 cm in length, in which a score of 0 at one end corresponds to extremely severe dyspnea on walking a short distance or at rest and a score of 10 at the other end corresponds to no dyspnea on walking or at rest. The patient placed an X on what they considered their current status before and 1 week after the last dose of the combination treatment.
Statistical analysis
All results of Study 2 are reported as median and interquartile range [IQR]. All variables did not follow a normal distribution and were therefore analyzed by the Wilcoxon signed rank sum test to evaluate the changes in them after treatment. The Spearman correlation coefficients were calculated between pre- and post values of all parameters to examine the relationships between the two measurements. A two-tailed value of p < 0.05 was considered to be significant.
Statistical analysis was performed by SAS for windows version 9.2.
Results
Study 1- Prevalence of anemia and iron deficiency in patients hospitalized with AECOPD
Of 107 consecutive hospital records examined of patients admitted with AECOPD, 47 patients (43.9%) were found to be anemic on admission (Hb < 12 g/dl) and 60 (56.1%) not anemic (Table 1). Only two (3.3%) of the 60 non-anemic patients were investigated for ID (serum iron, %TSat and serum ferritin) as compared to18 (38.3%) of the 47 anemic patients. All 18 (100%) of the anemic patients had ID by our criteria, yet none had oral or IV iron subscribed either before admission, during hospitalization, or at the time of discharge. In the 18 anemic patients, if ID was only defined as a serum ferritin of <100 ng/ml it was found in 11/18 (61.1%). If ID was defined only as %TSat <20%, in 18/18 (100%). If defined as either a serum ferritin of <100 ng/ml or the combination of serum ferritin of 100-300 ng/ml and%TSat of <20% it was found in 18/18 (100%). By whatever definition used, ID was very common. In the two non anemic patients, in which the iron status was measured, one had a %TSat of 40% and a serum ferritin of 200 ng/ml and was not iron deficient while the other had a %TSat of 14% and a serum ferritin of 160 ng/ml and was iron deficient.
Study 2- Outpatients intervention study
Baseline assessment
The anthropological and clinical characteristics of the 12 patients (Table 2) showed a median age of 74.0 years [66.5-79.5]. A past medical history of hypertension, CKD, CHF, diabetes and dyslipidemia and a past or present history of smoking were very common; indeed all had CKD. Angiotensin Converting Enzyme Inhibitors (ACEIs) and/or Angiotensin II Receptor Blockers (ARBs), beta blockers and statins were being used frequently. All were on bronchodilators.
The baseline FEV1 was 46.5% [40–55] of predicted values and the baseline FEV1/FVC was 65.5% [49–68] of predicted values. The median basal oxygen saturation measured by pulse oximetry was 94.5% [92–96].
Red cell indices
The anemia was normocytic and normochromic in all, with normal mean values for MCH, MCV and MCHC. The mean RDW was increased.
Prevalence of iron deficiency
If defined as only a serum ferritin of <100 ng/ml it was found in 6/12 (50%). If defined only as %TSat <20%, in 9/12 (75%). If defined as the combination of serum ferritin of <300 ng/ml and %TSat of <20% it was found in 9/12 (75%). If defined (as we defined it) as either a serum ferritin of < 100 ng/ml or the combination of serum ferritin of 100-300 ng/ml and %TSat of <20%, it was found in 11/12 (91.6%) of the cases. By whatever definition used, iron deficiency was very common in these ambulatory anemic COPD patients.
Results of treatment
Hemoglobin and red cell indices
The Hb rose from an initial median of 9.9 g/dl [9.2-10.6] to 12.35 g/dl [11.6-13.0] (p = 0.0005) by one week after the last injection. The Hct similarly increased from 29.9% [28.0-31.5] to 38.1% [35.0-39.4] (p = 0.0005). The median RBC count increased from 3.3 cells/mcL [3.2-3.7] to 3.9 cells/mcL [3.6-4.3] (p = 0.01).
Iron indices
The serum ferritin and %TSat increased significantly by one week after the last dose versus baseline. Serum ferritin from 99 ng/ml [48.6-127.4] to 330.6 ng/ml [243.4-615.2] (p = 0.005) and %TSat from 12.8% [11–19.1] to 24.0% [18.5-27.9] (p = 0.005).
Other blood parameters
The changes in the RDW, WBC, lymphocytes and platelets were not significant (Table 3).
Hemoglobin and Hematocrit correction and improvement of dyspnea
The VAS scale increased from an initial 2.5 [2–3] to 8.5 [7–10] (p = 0.0005).
There was no significant correlation between baseline Hb and VAS or baseline Hct and VAS. There was a highly significant correlation between the ∆Hb and ∆VAS; rs = 0.71 p = 0.009 and between the ∆Hct and ∆VAS; rs = 0.8 p = 0.0014 (Figure 1).
Other effects
As seen in Table 3 the mean SBP and DBP, weight, BMI, serum albumin, cholesterol, SGOT, and SGPT remained unchanged. Neither the serum creatinine nor the eGFR changed significantly.
Clinical follow-up
The median follow-up period after termination of ESAs and IV-iron treatment was 1.9 years (range 0.4-4.5 years). Four patients died after follow-up of 0.4 to 3.8 years. Of these four patients, two reached end-stage renal disease with the need for hemodialysis. Only one of the four deaths was directly attributed to respiratory disease. Six patients continued treatment in our clinic with ESAs and/or IV iron therapy as needed and another two patients were lost during follow-up.
AECOPD episodes, in the first year after anemia treatment, were documented in seven of the nine patients that were followed for more than a year. The median time from termination of anemia therapy to first exacerbation in these seven patients was 131 days (range 23–307 days).
Discussion
We have shown that anemia and ID are very common in hospitalized AECOPD patients but ID is neither sought for or, if found, is not treated. Patients hospitalized for AECOPD have relatively severe COPD. It was suggested that the prevalence of anemia is likely higher in this group compared to the general COPD population [26–28]. Surprisingly, there are scarce data about ID in COPD. Recently, Comeche Casanova et al. have shown in a cohort of 130 patients with stable COPD that serum iron was significantly lower in anemic patients than in those without anemia [29].
We have also shown in a small retrospective study in anemic outpatients with moderate to severe COPD that treatment with ESA and IV-iron significantly improved the anemia and ID, and that this was associated with a significant improvement in self-assessed shortness of breath. The improvement in the VAS dyspnea score was directly related to the increase in Hb and Hct. The hematological improvement of the anemia in this group of patients with COPD was similar to the effect that we have previously shown when ESAs and IV-iron were used in renal failure and heart failure, even without COPD [21, 22].
These results are consistent with the findings of others who treated anemia in COPD with either anabolic steroids [30] or blood transfusions [30, 31]. The study involving the use of anabolic steroids in COPD [30] showed that the improvement in the Hb that was found was associated with an improvement in pulmonary function as judged by maximal inspiratory mouth pressure and peak workload. In another study, transfusion of a mean of 2.2 units of packed cells in 10 anemic COPD patients in an intensive care unit was shown to lead to a significant reduction of both minute ventilation and work of breathing [31]. In a second study by the same group [32], blood transfusions allowed five anemic COPD patients, in whom trials of weaning from a respirator before the transfusions had been unsuccessful, to be successfully weaned after the transfusions. All these studies, in addition to the present study, suggest that correction of the anemia in COPD may improve pulmonary functions and respiratory symptoms.
Anemia in patients with COPD is likely due to a combination of several factors [26, 29, 33]: (i) Elevated cytokines levels, especially Tumor Necrosis Factor alpha (TNF α) and interleukin-6 (IL-6) [1, 12, 17, 18, 34, 35]. Moreover, persistent inflammation may be associated with poor clinical outcome for COPD patients [36]. The elevation of cytokines can lead to reduced production of erythropoietin (EPO), reduced erythropoietic response of the bone marrow to EPO (i.e. resistance to EPO), hepcidin-induced failure of iron absorption from the gut, and hepcidin-induced trapping of iron in iron stores in the macrophages and hepatocytes [33]. (ii) Concomitant CKD with reduced production EPO [37]. (iii) Use of Angiotensin Converting Enzyme Inhibitors (ACE-I) and Angiotensin Receptor Blockers (ARBs) that can cause reduced activity of EPO in the bone marrow [38]. (iv) Concomitant Diabetes Mellitus [39] and (v) Gastrointestinal causes, especially with use of steroids [32].
There have been several studies suggesting that ID may contribute to pulmonary dysfunction. In a recent US Third National Health and Nutrition Examination survey (NHANES) [20] there was a direct correlation between pulmonary function as judged by the one second forced expiratory volume (FEV1) and the iron status as judged by the %TSat and ferritin, suggesting that reduced pulmonary function may be commonly associated with ID. In addition ID is common in cystic fibrosis [40] and pulmonary tuberculosis [41]. Pulmonary hypertension of different causes is often associated with iron deficiency and indeed treatment of iron deficiency can improve pulmonary hypertension [42–45].
In CHF, the correction of the anemia with ESAs and oral or IV iron or even with IV iron alone has been shown in many studies to improve cardiac and patient function and cardiac structure [33, 46–49], and more than 20% of COPD patients have also CHF [50]. However,
a recent large long-term double blind study with the ESA, Darbepoetin alpha, did not meet its primary endpoint of reducing the composite endpoint of time to death from any cause or first hospital admission for worsening heart failure in patients with systolic CHF [51, 52]. Thus the role of ESAs alone in CHF is still uncertain. There are concerns about complications related to ESAs therapy, since its use in renal failure has been associated with an increase in cardiovascular and thromboembolic phenomena, especially when given in high doses [53–57]. Correction of ID with or without anemia in CHF may improve symptoms, functional capacity, and quality of life [58]. However, some concerns have also been raised about the safety of IV iron with its possible worsening of oxidative stress and reduced immunological function with possible increased tendency to infections [59, 60].
Our study has limitations as it is a non-randomized, retrospective observation in a single medical center. In the intervention study (study 2), the patients had a very high rate of comorbidities including CKD, CHF, diabetes and hypertension- a higher rate than is seen with the usual COPD patients. In fact, all 12 patients had CKD and it is possible that CKD predominated over their other comorbidities. However the doses of CKD and CHF medications were unchanged during the study. Unfortunately we did not study pulmonary function at the termination of the treatment period in any of these 12 patients and are therefore unable to assess the effect of anemia correction on lung function. Another limitation is that the VAS scale for dyspnea was used since it is the common practice in our clinic. For patients with COPD it is preferred to use the Modified Medical Research Council Dyspnea Scale (mMRC) [61]. Nevertheless, our results here suggest that correction of anemia with ESAs or iron may benefit COPD patients, similarly to the benefits seen in CHF.
Any studies of anemia in COPD using ESAs, IV Iron or the combination of these agents, should be adequately powered, double-blind placebo-controlled, and of sufficient duration to assess the advantages and disadvantages of the therapy. But such an effort would seem to us worthwhile in these anemic and frequently iron deficient COPD patients in view of the possible improvement in cardiac and pulmonary function, hospitalization and mortality, exercise capacity and Quality of Life that might occur with correction of the their anemia and/or iron deficiency.
Conclusions
These studies suggest that ID is common in hospitalized COPD but generally not sought after and, if found, generally not treated. Our small retrospective intervention outpatient study also suggested that correction of anemia and ID in COPD patients may improve dyspnea. If further studies confirm our preliminary observations, evaluation and treatment of ID could become standard practice in COPD as is currently the case for CKD [62] and CHF [63].
Consent
Written informed consent was obtained from the patient for the publication of this report and any accompanying images.
References
John M, Hoernig S, Doehner W, Okonko DD, Witt C, Anker SD: Anemia and inflammation in COPD. Chest. 2005, 127: 825-829. 10.1378/chest.127.3.825.
Ershler WB, Chen K, Reyes EB, Dubois R: Economic burden of patients with anemia in selected diseases. Value Health. 2005, 8: 629-638. 10.1111/j.1524-4733.2005.00058.x.
Chambellan A, Chailleux E, Similowski T, ANTADIR Observatory Group: Prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy. Chest. 2005, 185: 1201-1208.
Krishnan G, Grant BJ, Muti PC, Mishra A, Ochs-Balcom HM, Freudenheim JL, Trevisan M, Schünemann HJ: Association between anemia and quality of life in a population sample of individuals with chronic obstructive pulmonary disease. BMC Pulm Med. 2006, 5 (6): 23-
Cote C, Zilberberg MD, Mody SH, Dordelly LJ, Celli B: Hemoglobin level and its clinical impact in a cohort of patients with COPD. Eur Respir J. 2007, 29: 923-929. 10.1183/09031936.00137106.
Halpern MT, Zilberberg MD, Schmier JK, Lau EC, Schorr AF: Anemia, costs and mortality in chronic obstructive pulmonary disease. Cost eff Resour Alloc. 2006, 4: 17-24. 10.1186/1478-7547-4-17.
John M, Lange A, Hoernig S, Witt C, Anker SD: Prevalence of anemia in chronic obstructive pulmonary disease: comparison to other chronic diseases. Int J Cardiol. 2006, 111: 365-370. 10.1016/j.ijcard.2005.07.043.
Martinez FJ, Foster G, Curtis JL, Criner G, Weinmann G, Fishman A, DeCamp MM, Benditt J, Sciurba F, Make B, Mohsenifar Z, Diaz P, Hoffman E, Wise R, NETT Research Group: Predictors of mortality in patients with emphysema and severe airflow obstruction. Am J Resp Crit Care Med. 2006, 173: 1326-1334. 10.1164/rccm.200510-1677OC.
Copur AS, Fulambarker A, Molnar J, Nadeem R, McCormack C, Ganesh A, Kheir F, Hamon S: Role of anemia in home oxygen therapy in chronic obstructive pulmonary disease patients. Am J Ther. 2013, Apr 5. (Epub ahead of print]
Shorr AF, Doyle J, Stern L, Dolgister M, Zilberberg MD: Anemia in chronic pulmonary disease: epidemiology and economic implications. Curr Med Res Opin. 2008, 24: 1123-1130. 10.1185/030079908X280699.
Barnes PJ, Celli BR: Systemic manifestations and comorbidities of COPD. Eur Resp J. 2009, 33: 1165-1185. 10.1183/09031936.00128008.
Cosio MG, Saetta M, Agusti A: Immunologic aspects of chronic obstructive pulmonary disease. NEJM. 2009, 360: 2445-2454. 10.1056/NEJMra0804752.
Kollert F, Müller C, Tippelt A, Jörres RA, Heidinger D, Probst C, Pfeifer M, Budweiser S: Anaemia in chronic respiratory failure. Int J Clin Pract. 2011, 65: 479-486. 10.1111/j.1742-1241.2011.02631.x.
Kollert F, Tippelt A, Müller C, Jörres RA, Porzelius C, Pfeifer M, Budweiser S: Hemoglobin levels above anemia thresholds are maximally predictive for long-term survival in COPD with chronic respiratory failure. Respir Care. 2012, Dec 4. [Epub ahead of print]
Boutou AK, Karrar S, Hopkinson NS, Polkey MI: Anemia and survival in chronic obstructive pulmonary disease: a dichotomous rather than a continuous predictor. Respiration. 2013, 85: 126-131. 10.1159/000338792.
Boutou AK, Stanopoulos I, Pitsiou GG, Kontakiotis T, Kyriazis G, Sichletidis L, Argyropoulou P: Anemia of chronic disease in chronic obstructive pulmonary disease: a case–control study of cardiopulmonary exercise responses. Respiration. 2011, 82: 237-245. 10.1159/000326899.
Nemeth E: Iron regulation and erythropoiesis. Curr Opin Hematol. 2008, 15: 169-175. 10.1097/MOH.0b013e3282f73335.
Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, Sonnweber T, Eberwein L, Witcher DR, Murphy AT, Wroblewski VJ, Wurz E, Datz C, Weiss G: Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood. 2009, 113: 5277-5286. 10.1182/blood-2008-12-195651.
McKeever TM, Lewis SA, Smit HA, Burney P, Cassano PA, Britton J: A multivariate analysis of serum nutrient levels and lung function. Respir Res. 2008, 9: 67-10.1186/1465-9921-9-67.
Obase Y, Mouri K, Shimizu H, Ohue Y, Kobashi Y, Kawahara K, Oka M: Nutritional deficits in elderly smokers with respiratory symptoms that do not fulfill the criteria for COPD. Int J Chron Obstruct Pulmon Dis. 2011, 6: 679-683.
Silverberg DS, Wexler D, Blum M, Keren G, Sheps D, Leibovitch E, Brosh D, Laniado S, Schwartz D, Yachnin T, Shapira I, Gavish D, Baruch R, Koifman B, Kaplan C, Steinbruch S, Iaina A: The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000, 35: 1737-1744. 10.1016/S0735-1097(00)00613-6.
Silverberg DS, Wexler D, Sheps D, Blum M, Keren G, Baruch R, Schwartz D, Yachnin T, Steinbruch S, Shapira I, Laniado S, Iaina A: The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol. 2001, 37: 1775-1780. 10.1016/S0735-1097(01)01248-7.
Jankowska EA, von Haehling S, Anker SD, Macdougall IC, Ponikowski P: Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J. 2013, 34: 816-829. 10.1093/eurheartj/ehs224.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med. 1999, 130: 461-470. 10.7326/0003-4819-130-6-199903160-00002.
American Thoracic Society: Standardization of spirometry, 1994 update. Am J Respir Crit Care Med. 1995, 152: 1107-1136.
Portillo K, Martinez-Rivera C, Ruiz-Manzano J: Anaemia in chronic obstructive pulmonary disease. Does it really matter?. Int J Clin Pract. 2013, 67: 558-565. 10.1111/ijcp.12125.
Portillo K, Belda J, Antón P, Casan P: High frequency of anemia in COPD patients admitted in a tertiary hospital. Rev Clin Esp. 2007, 207: 383-387. 10.1157/13108755.
Martinez-Rivera C, Portillo K, Muñoz-Ferrer A, Martínez-Ortiz ML, Molins E, Serra P, Ruiz-Manzano J, Morera J: Anemia is a mortality predictor in hospitalized patients for COPD exacerbation. COPD. 2012, 9: 243-250. 10.3109/15412555.2011.647131.
Comeche Casanova L, Echave-Sustaeta JM, García Luján R, Albarrán Lozano I, Alonso González P, Llorente Alonso MJ: Prevalence of anaemia associated with chronic obstructive pulmonary disease. Study of associated variables. Arch Bronconeumol. 2013, 49: 383-387.
Creutzberg EC, Wouters EF, Mostert R, Pluymers RJ, Schols AM: A role for anabolic steroids in the rehabilitation of patients with COPD? A double blind placebo controlled randomized trial. Chest. 2003, 134: 1733-1743.
Schonhofer B, Wenzel M, Geibel M, Kohler D: Blood transfusion and lung function in chronically anemic patients with severe chronic obstructive sleep pulmonary disease. Crit Care Med. 1998, 26: 1824-1828. 10.1097/00003246-199811000-00022.
Schonhofer B, Bohrer H, Kohler D: Blood transfusion facilitating difficulty meaning from ventilator. Anaesthesia. 1998, 53: 181-184. 10.1046/j.1365-2044.1998.00275.x.
Similowski T, Agustí A, MacNee W, Schönhofer B: The potential impact of anaemia of chronic disease in COPD. Eur Respir J. 2006, 27: 390-396. 10.1183/09031936.06.00143704.
Boutou AK, Pitsiou GG, Stanopoulos I, Kontakiotis T, Kyriazis G, Argyropoulou P: Levels of inflammatory mediators in chronic obstructive pulmonary disease patients with anemia of chronic disease: a case–control study. QJM. 2012, 105: 657-663. 10.1093/qjmed/hcs024.
Markoulaki D, Kostikas K, Papatheodorou G, Koutsokera A, Alchanatis M, Bakakos P, Gourgoulianis KI, Roussos C, Koulouris NG, Loukides S: Hemoglobin, erythropoietin and systemic inflammation in exacerbations of chronic obstructive pulmonary disease. Eur J Intern Med. 2011, 22: 103-107. 10.1016/j.ejim.2010.07.010.
Edwards LD, Rennard SI, MacNee W, Tal- Singer R, Miller BE, Vestbo J, Lomas DA, Calverley PM, Wouters E, Crim C, Yates JC, Silverman EK, Coxson HO, Bakke P, Mayer RJ, Celli B, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators: Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One. 2012, 7: e37483-10.1371/journal.pone.0037483.
Babitt JL, Lin HY: Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012, 23: 1631-1634. 10.1681/ASN.2011111078.
Leshem-Rubinow E, Steinvil A, Zeltser D, Berliner S, Rogowski O, Raz R, Chodick G, Shalev V: Association of angiotensin-converting enzyme inhibitor therapy initiation with a reduction in hemoglobin levels in patients without renal failure. Mayo Clin Proc. 2012, 87: 1189-1195. 10.1016/j.mayocp.2012.07.020.
Thomas MC: Anemia in diabetes: marker or mediator of microvascular disease?. Nat Clin Pract Nephrol. 2007, 3: 20-30.
Fischer R, Simmerlein R, Huber RM, Schiffl H, Lang SM: Lung disease severity, chronic inflammation, iron deficiency and transferrin response in adults with cystic fibrosis. Pediatr Pulmonol. 2007, 42: 1193-1197. 10.1002/ppul.20717.
Isanaka S, Aboud S, Mugusi F, Bosch RJ, Willett WC, Spiegelman D, Duggan C, Fawzi WW: Iron status predicts treatment failure and mortality in tuberculosis patients: a prospective cohort study from Dar es Salaam, Tanzania. PLoS One. 2012, 7: e37350-10.1371/journal.pone.0037350.
Smith TG, Talbot NP, Privat C, Rivera-Ch M, Nickol AH, Ratcliffe PJ, Dorrington KL, León-Velarde F, Robbins PA: Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials. JAMA. 2009, 302: 1444-1450. 10.1001/jama.2009.1404.
Rhodes CJ, Wharton J, Howard L, Gibbs JS, Vonk-Noordegraaf A, Wilkins MR: Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target. Eur Respir J. 2011, 38: 1453-1460. 10.1183/09031936.00037711.
Rhodes CJ, Howard LS, Busbridge M, Ashby D, Kondili E, Gibbs JS, Wharton J, Wilkins MR: Iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension: clinical prevalence, outcomes, and mechanistic insights. J Am Coll Cardiol. 2011, 58: 300-309. 10.1016/j.jacc.2011.02.057.
Ruiter G, Lankhorst S, Boonstra A, Postmus PE, Zweegman S, Westerhof N, van der Laarse WJ, Vonk-Noordegraaf A: Iron deficiency is common in idiopathic pulmonary arterial hypertension. Eur Respir J. 2011, 37: 1386-1391. 10.1183/09031936.00100510.
van der Meer P, Groenveld H, Januzzi JL, van Veldhuisen DJ: Erythropoietin treatment in patients with Chronic Heart Failure: a meta-analysis. Heart. 2009, 95: 1309-1314. 10.1136/hrt.2008.161091.
Ngo K, Kotecha D, Walters JA, Manzano L, Palazzuoli A, van Veldhuisen DJ, Flather M: Erythropoiesis-stimulating agents for anaemia in chronic heart failure patients. Cochrane Database Syst Rev. 2010, 20: CD007613-
Lawler PR, Filion KB, Eisenberg MJ: Correcting Anemia in Heart Failure: The Efficacy and Safety of Erythropoiesis-Stimulating Agents. J Cardiac Fail. 2010, 16: 649-658. 10.1016/j.cardfail.2010.03.013.
Silverberg DS: The role of erythropoiesis stimulating agents and intravenous (IV) iron in the cardio renal anemia syndrome. Heart Fail Rev. 2011, 16: 609-614. 10.1007/s10741-010-9194-2.
Zeng Q, Jiang S: Update in diagnosis and therapy of coexistent chronic obstructive pulmonary disease and chronic heart failure. J Thorac Dis. 2012, 4: 310-315.
McMurray JJ, Anand IS, Diaz R, Maggioni AP, O’Connor C, Pfeffer MA, Solomon SD, Tendera M, van Veldhuisen DJ, Albizem M, Cheng S, Scarlata D, Swedberg K, Young JB, RED-HF Committees Investigators: Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF). Eur J Heart Fail. 2013, 15: 334-341. 10.1093/eurjhf/hfs204.
Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJ, O’Connor C, Pfeffer MA, Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ, RED-HF Committees; RED-HF Investigators: Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013, 368: 1210-1219. 10.1056/NEJMoa1214865.
Unger EF, Thompson AM, Blank MJ, Temple R: Erythropoiesis-stimulating agents: time for a reevaluation. N Engl J Med. 2010, 362: 189-192. 10.1056/NEJMp0912328.
Goldsmith D: 2009: a requiem for rHuEPOs—but should we nail down the coffin in 2010?. Clin J Am Soc Nephrol. 2010, 5: 929-935. 10.2215/CJN.09131209.
Singh AK: Does TREAT give the boot to ESAs in the treatment of CKD anemia?. J Am Soc Nephrol. 2010, 21: 2-6. 10.1681/ASN.2009111127.
Besarab A, Hörl WH, Silverberg D: Iron metabolism, iron deficiency, thrombocytosis, and the cardiorenal anemia syndrome. Oncologist. 2009, 14 (Suppl 1): 22-33.
Vaziri ND, Zhou XJ: Potential mechanisms of adverse outcomes in trials of anemia correction with erythropoietin in chronic kidney disease. Nephrol Dial Transplant. 2009, 24: 1082-1088.
Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Lüscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P, FAIR-HF Trial Investigators: Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009, 361: 2436-2448. 10.1056/NEJMoa0908355.
Van Buren P, Velez RL, Vaziri ND, Zhou XJ: Iron overdose: a contributor to adverse outcomes in randomized trials of anemia correction in CKD. Int Urol Nephrol. 2012, 44: 499-507. 10.1007/s11255-011-0028-5.
Vaziri ND: Understanding iron: promoting its safe use in patients with Chronic Kidney Failure Treated by Hemodialysis. Am J Kidney Dis. 2013, EPub ahead of print
Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Update 2013 [accessed 28.9.2013]. Available from: http://www.goldcopd.org
Locatelli F, Bárány P, Covic A, De Francisco A, Del Vecchio L, Goldsmith D, Hörl W, London G, Vanholder R, Van Biesen W, on behalf of the ERA-EDTA ERBP Advisory Board: Kidney disease: improving global outcomes guidelines on anaemia management in chronic kidney disease: a European Renal Best Practice position statement. Nephrol Dial Transplant. 2013, Apr 12. [Epub ahead of print]
McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Køber L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Rønnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, Bax JJ, Baumgartner H, Ceconi C, Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology, et al: ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012, 14: 803-869.
Pre-publication history
The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/14/24/prepub
Author information
Authors and Affiliations
Corresponding author
Additional information
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
DSS- participated in the design and draft of manuscript (the major contributor). RM- participated in the acquisition and analyzing of clinical data and in the draft of manuscript. MTW,EB,DS,IFS- participated in the acquisition and analyzing of clinical data. GC- conceived of the study, and participated in its design and critically revisited the draft. All authors read and approved the final manuscript.
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
Rights and permissions
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
About this article
Cite this article
Silverberg, D.S., Mor, R., Weu, M.T. et al. Anemia and iron deficiency in COPD patients: prevalence and the effects of correction of the anemia with erythropoiesis stimulating agents and intravenous iron. BMC Pulm Med 14, 24 (2014). https://doi.org/10.1186/1471-2466-14-24
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/1471-2466-14-24