Imperial College London



Anemia in Chronic Obstructive Pulmonary Disease: an insight into its prevalence and pathophysiologyAfroditi K. Boutou, Nicholas S. Hopkinson, Michael I. PolkeyNIHR Respiratory Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UKShort title: Anemia in Chronic Obstructive Pulmonary DiseaseCorresponding authorAfroditi K BoutouStratigou Sarafi 9-13, 55132, Thessaloniki, GreeceEmail: afboutou@Telephone number: 00306946611433Keywords: Anemia;Chronic Obstructive Pulmonary Disease;Epidemiology;Systemic Inflammation;AetiologyAbstractChronic Obstructive Pulmonary Disease (COPD) is a major health problem, with increasing morbidity and mortality. There is a growing literature regarding the extra-pulmonary manifestations of COPD, which can have a significant impact on symptom burden and disease progression. Anemia is one of the more recently identified co-morbidities, with a prevalence that varies between 4.9% to 38% depending on patient characteristics and the diagnostic criteria used. Systemic inflammation seems to be an important factor for its establishment and repeated bursts of inflammatory mediators during COPD exacerbations could further inhibit erythropoiesis. However, renal impairment, malnutrition, low testosterone levels, growth hormone level abnormalities, oxygen supplementation, theophylline treatment, inhibition of angiotensin converting enzyme and aging itself are additional factors that could be associated with the development of anemia. This review evaluates the published literature on the prevalence and significance of anemia in COPD. Moreover, it attempts to elucidate the reasons for the high variability reported and investigates the complex pathophysiology underlying the development of anemia in these patients. The prevalence of anemia in COPDThere is a huge variation of anemia prevalence in the published literature, most likely reflecting the different cohorts which have been studied. A systematic search in the electronic database of PubMed using the search terms Chronic Obstructive Pulmonary Disease (COPD) and an(a)emia, h(a)ematocrit, h(a)emoglobin, iron deficiency or red blood cells, identified 24 studies which were conducted in humans and published as full-text articles in English between 2005 and 2013. These studies reported the prevalence of anemia in COPD, using either percentages or absolute patient numbers and explored its potential association with the disease or its impact on several disease outcomes (Table 1). In these reports anemia frequency varied widely from 4.9% to 38%. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rlyDNYAh","properties":{"formattedCitation":"(1)","plainCitation":"(1)"},"citationItems":[{"id":260,"uris":[""],"uri":[""],"itemData":{"id":260,"type":"article-journal","title":"[The impact of comorbidities on the length of hospital treatment in patients with chronic obstructive pulmonary disease]","container-title":"Pneumonologia i alergologia polska","page":"388-396","volume":"79","issue":"6","source":"NCBI PubMed","abstract":"INTRODUCTION: The aim of this study was to assess relationships of chronic obstructive pulmonary disease (COPD) comorbidities number, with the duration of hospital stay due to acute AE COPD in longitudinal prospective study.\nMATERIAL AND METHODS: We evaluated the number of re-hospitalizations, length of stay and number of comorbidities in 464 consecutive COPD patients admitted to the tertiary respiratory hospital due to AE COPD enrolled in longitudinal prospective study from 2005 to 2009 year.\nRESULTS: GOLD II stage COPD patients had 4.1 ± 1.2 comorbidities (p = 0.002), stage III 3.4 ± 1.3 and stage IV had 3.6 ± 1.2 comorbidities. Duration of hospital stay (medians) was longer in more severe patients. Duration of hospitalization correlated with urea level (r = 0.19 p 〈 0.001), pCO(2) (r = 0.193, p = 0.0003), HCO(3) (r = 0.25, p 〈 0.0001), haemoglobin (r = -0.18, p 〈 0.001), and hematocrit (r = -0.13, p = 0.008). The patients with the risk of readmission had more severe GOLD stage and were hypercapnic (pCO(2) = 47.6 mmHg v. 43.9 mmHg in those without hospitalization).\nCONCLUSIONS: The haemoglobin level, hypercapnia and renal function are predictors of prolonged hospitalization. Patients with more severe airflow limitation and higher pCO(2) have increased risk for readmission to the hospital. More severe disease stage, clinical diagnosis of cor pulmonale or bronchiectasis was related to longer hospital stay.","ISSN":"0867-7077","note":"PMID: 22028117","journalAbbreviation":"Pneumonol Alergol Pol","language":"pol","author":[{"family":"Nowiński","given":"Adam"},{"family":"Kamiński","given":"Dariusz"},{"family":"Korzybski","given":"Damian"},{"family":"Stok?osa","given":"Anna"},{"family":"Górecka","given":"Dorota"}],"issued":{"date-parts":[["2011"]]},"PMID":"22028117"}}],"schema":""} (1) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"g2iAlURe","properties":{"formattedCitation":"(2)","plainCitation":"(2)"},"citationItems":[{"id":162,"uris":[""],"uri":[""],"itemData":{"id":162,"type":"article-journal","title":"Role of Anemia in Home Oxygen Therapy in Chronic Obstructive Pulmonary Disease Patients","container-title":"American journal of therapeutics","source":"NCBI PubMed","abstract":"Anemia is a known comorbidity found in chronic obstructive pulmonary disease (COPD) patients. Hypoxemia is common and basically due to ventilation/perfusion (V/Q) mismatch in COPD. Anemia, by decreasing arterial oxygen content, may be a contributing factor for decreased delivery of oxygen to tissues. The objective of this study is to determine if anemia is a factor in qualifying COPD patients for home oxygen therapy. The study was designed as a retrospective, cross-sectional, observational chart review. Patients who were referred for home oxygen therapy evaluation were selected from the computerized patient record system. Demographic data, oxygen saturation at rest and during exercise, pulmonary function test results, hemoglobin level, medications, reason for anemia, comorbid diseases, and smoking status were recorded. The χ tests, independent sample t tests, and logistic regression were used for statistical analysis. Only 356 of total 478 patient referrals had a diagnosis of COPD over a 2-year period. Although 39 of them were excluded, 317 patients were included in the study. The overall rate of anemia was 38% in all COPD patients. Anemia was found significantly more frequent in COPD patients on home oxygen therapy (46%) than those not on home oxygen therapy (18.5%) (P < 0.0001). Mean saturation of peripheral oxygen values were significantly lower in anemic COPD patients both at rest and during exercise (P < 0.0001). Also, in COPD patients, age, Global Initiative for Chronic Obstructive Lung Disease class, smoking status, hemoglobin level, hematocrit, percent of forced expiratory volume in first second, forced expiratory volume in first second/forced vital capacity, residual volume/total lung volume, percent of carbon monoxide diffusion capacity were significantly different between home oxygen therapy and those not on home oxygen therapy (P < 0.05). Multivariate logistic regression showed that anemia remained a strong predictor for long-term oxygen therapy use in COPD patients after adjusting for other significant parameters. Anemic COPD patients are more hypoxic especially during exercise than those who are not anemic. We conclude that anemia is a contributing factor in qualifying COPD patients for home oxygen therapy.","DOI":"10.1097/MJT.0b013e3182785f7c","ISSN":"1536-3686","note":"PMID: 23567789","journalAbbreviation":"Am J Ther","language":"ENG","author":[{"family":"Copur","given":"Ahmet Sinan"},{"family":"Fulambarker","given":"Ashok"},{"family":"Molnar","given":"Janos"},{"family":"Nadeem","given":"Rashid"},{"family":"McCormack","given":"Charles"},{"family":"Ganesh","given":"Aarthi"},{"family":"Kheir","given":"Fayez"},{"family":"Hamon","given":"Sara"}],"issued":{"date-parts":[["2013",4,5]]},"PMID":"23567789"}}],"schema":""} (2) In contrast to expectations, polycythemia was less common than anemia, its prevalence ranging from 6-18.1%. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lzZQ2x3S","properties":{"formattedCitation":"(3)","plainCitation":"(3)"},"citationItems":[{"id":232,"uris":[""],"uri":[""],"itemData":{"id":232,"type":"article-journal","title":"Prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy","container-title":"Chest","page":"1201-1208","volume":"128","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Although traditionally associated with polycythemia, COPD has a systemic inflammatory component that could interfere with erythropoiesis. This study describes the distribution and prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy (LTOT).\nMETHODS: A total of 2,524 patients with COPD, FEV1/vital capacity (VC) < 70%, FEV1 < 80% of predicted, and Pa(O2) < 7.3 kPa in whom a hematocrit was available at entry was identified between 1980 and 1999 in the French Association Nationale pour le Traitement à Domicile de l'Insuffisance Respiratoire chronic respiratory insufficiency and home-care database (male/female ratio, 5/1; mean +/- SD age, 68 +/- 10 years for men, and 70 +/- 10 years for women). Correlations between hematocrit, demographic data, and pulmonary function data were examined. A multivariate Cox proportional hazard regression was performed to identify prognostic factors.\nRESULTS: Mean hematocrit was 45.9 +/- 7.0% in men and 43.9 +/- 6.0% in women (< 39% in 12.6% of men, and < 36% in 8.2% of women) according to the World Health Organization definition of anemia. Hematocrit was negatively correlated with age (r = - 0.245) and FEV1/VC (r = - 0.068) and was positively correlated with Pa(CO2) (r = 0.161) and body mass index (r = 0.127). Multivariate analysis found hematocrit to be an independent predictor of survival, hospital admission rate, and cumulative duration of hospitalization. The 3-year survival was 24% (95% confidence interval, 16 to 33%) when the hematocrit was < 35%, and 70% (63 to 76%) when the hematocrit was > or = 55%.\nCONCLUSIONS: A low hematocrit is not uncommon in LTOT/COPD patients. Hematocrit is negatively associated with mortality and morbidity. Whether the association is causative or not and whether or not corrective measures are warranted remain to be determined.","DOI":"10.1378/chest.128.3.1201","ISSN":"0012-3692","note":"PMID: 16162707","journalAbbreviation":"Chest","language":"eng","author":[{"family":"Chambellan","given":"Arnaud"},{"family":"Chailleux","given":"Edmond"},{"family":"Similowski","given":"Thomas"},{"family":"ANTADIR Observatory Group","given":""}],"issued":{"date-parts":[["2005",9]]},"PMID":"16162707"}}],"schema":""} (3) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"iCmOhtoW","properties":{"formattedCitation":"(4)","plainCitation":"(4)"},"citationItems":[{"id":256,"uris":[""],"uri":[""],"itemData":{"id":256,"type":"article-journal","title":"Haemoglobin level and its clinical impact in a cohort of patients with COPD","container-title":"The European respiratory journal","page":"923-929","volume":"29","issue":"5","source":"NCBI PubMed","abstract":"Haemoglobin (Hb) abnormalities in chronic obstructive pulmonary disease (COPD) are not well characterised. The present authors investigated the prevalence and association of abnormal Hb with clinical outcomes. Analysis of a prospective cohort of stable COPD outpatients (n = 683) in a USA Veterans Administration pulmonary clinic was undertaken. Patients were classified as anaemic (Hb <13 g.dL(-1)), polycythemic (Hb > or =17 g.dL(-1) and > or =15 g.dL(-1) for males and females, respectively) or normal. Demographic characteristics and physiological/functional outcomes were compared between groups. Regression models adjusting for confounders examined the independent association of anaemia with clinical outcomes. Anaemia was present in 116 (17%) patients and polycythemia in 40 (6%). While the only values that differed between polycythemic and nonpolycythemic patients were mean body mass index and Hb, anaemic patients showed a significantly higher modified Medical Research Council dyspnoea scale score (2.8 versus 2.6), lower 6-min walk distance (265 versus 325 m) and shorter median survival (49 versus 74 months) than nonanaemic patients. In regression models, anaemia independently predicted dyspnoea and reduced exercise capacity. Anaemia in chronic obstructive pulmonary disease was an independent risk factor for reduced functional capacity. Polycythemia prevalence was low and had no association with worsened outcomes. Further work is required to evaluate the effect of anaemia correction on outcomes in chronic obstructive pulmonary disease.","DOI":"10.1183/09031936.00137106","ISSN":"0903-1936","note":"PMID: 17251227","journalAbbreviation":"Eur. Respir. J.","language":"eng","author":[{"family":"Cote","given":"C"},{"family":"Zilberberg","given":"M D"},{"family":"Mody","given":"S H"},{"family":"Dordelly","given":"L J"},{"family":"Celli","given":"B"}],"issued":{"date-parts":[["2007",5]]},"PMID":"17251227"}}],"schema":""} (4) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4hFL7Kx0","properties":{"formattedCitation":"(5)","plainCitation":"(5)"},"citationItems":[{"id":174,"uris":[""],"uri":[""],"itemData":{"id":174,"type":"article-journal","title":"Hemoglobin Levels Above Anemia Thresholds Are Maximally Predictive for Long-Term Survival in COPD With Chronic Respiratory Failure","container-title":"Respiratory care","page":"1204-1212","volume":"58","issue":"7","source":"NCBI PubMed","abstract":"BACKGROUND: In patients with COPD, chronic anemia is known as an unfavorable prognostic factor. Whether the association between hemoglobin (Hb) levels and long-term survival is restricted to anemia or extends to higher Hb levels has not yet been systematically assessed.\nMETHODS: We determined Hb levels in 309 subjects with COPD and chronic respiratory failure prior to initiation of noninvasive ventilation, accounting for confounders that might affect Hb. Subjects were categorized as anemic (Hb < 12 g/dL in females, Hb < 13 g/dL in males), polycythemic (Hb ≥ 15 g/dL in females, Hb ≥ 17 g/dL in males), or normocythemic. In addition, percentiles of Hb values were analyzed with regard to mortality from any cause.\nRESULTS: Two-hundred seven subjects (67.0%) showed normal Hb levels, 46 (14.9%) had anemia, and 56 (18.1%) had polycythemia. Polycythemic subjects showed a higher survival rate than anemic (P = .01) and normocythemic subjects (P = .043). In a univariate Cox hazards model, Hb was associated with long-term survival (hazard ratio 0.855; 95% CI 0.783-0.934, P < .001). The 58th percentiles of Hb (14.3 g/dL in females, 15.1 g/dL in males) yielded the highest discriminative value for predicting survival (hazard ratio 0.463, 95% CI 0.324-0.660, P < .001). In the multivariate analysis this cutoff was an independent predictor for survival (hazard ratio 0.627, 95% CI 0.414-0.949, P = .03), in addition to age and body mass index.\nCONCLUSIONS: In subjects with COPD and chronic respiratory failure undergoing treatment with noninvasive ventilation and LTOT, high Hb levels are associated with better long-term survival. The optimal cutoff level for prediction was above the established threshold defining anemia. Thus, predicting survival only on the basis of anemia does not fully utilize the prognostic potential of Hb values in COPD.","DOI":"10.4187/respcare.01961","ISSN":"1943-3654","note":"PMID: 23232736","journalAbbreviation":"Respir Care","language":"eng","author":[{"family":"Kollert","given":"Florian"},{"family":"Tippelt","given":"Andrea"},{"family":"Müller","given":"Carolin"},{"family":"J?rres","given":"Rudolf A"},{"family":"Porzelius","given":"Christine"},{"family":"Pfeifer","given":"Michael"},{"family":"Budweiser","given":"Stephan"}],"issued":{"date-parts":[["2013",7]]},"PMID":"23232736"}}],"schema":""} (5), perhaps reflecting more widespread use of domiciliary oxygen and other forms of respiratory support. Several reasons can be proposed for this discrepancy in anemia prevalence, and the varying characteristics of the populations studied is one of them, as anemia prevalence has been investigated in stable COPD outpatients, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"K9oAfpx5","properties":{"formattedCitation":"(6)","plainCitation":"(6)"},"citationItems":[{"id":218,"uris":[""],"uri":[""],"itemData":{"id":218,"type":"article-journal","title":"Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: a cross-sectional study","container-title":"American journal of respiratory and critical care medicine","page":"743-751","volume":"177","issue":"7","source":"NCBI PubMed","abstract":"RATIONALE: Physical activity is reduced in patients with chronic obstructive pulmonary disease (COPD). COPD has a systemic component that includes significant extrapulmonary effects that may contribute to its severity in individual patients.\nOBJECTIVES: To investigate the association of extrapulmonary effects of the disease and its comorbidities with reduced physical activity in patients with COPD.\nMETHODS: In a cross-sectional study, 170 outpatients with COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages I-IV; BODE [body mass index, airway obstruction, dyspnea, and exercise capacity] score 0-10) underwent a series of tests. Physical activity was assessed over 5 to 6 consecutive days by using a multisensor accelerometer armband that records steps per day and the physical activity level (total daily energy expenditure divided by whole-night sleeping energy expenditure). Cardiovascular status was assessed by echocardiography, vascular Doppler sonography, and levels of N-terminal pro-B-type natriuretic peptide. Mental status, metabolic/muscular status, systemic inflammation, and anemia were assessed by Beck Depression Inventory, bioelectrical impedance analysis, handgrip strength, high-sensitivity C-reactive protein/fibrinogen, and hemoglobin, respectively.\nMEASUREMENTS AND MAIN RESULTS: In a multivariate linear regression analysis using either steps per day or physical activity level as a dependent variable, the extrapulmonary parameters that were associated with reduced physical activity in patients with COPD independently of GOLD stages or BODE score were N-terminal pro-B-type natriuretic peptide levels, echocardiographically measured left ventricular diastolic function, and systemic inflammation.\nCONCLUSIONS: Higher values of systemic inflammation and left cardiac dysfunction are associated with reduced physical activity in patients with COPD.","DOI":"10.1164/rccm.200707-1011OC","ISSN":"1535-4970","note":"PMID: 18048807","shortTitle":"Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","language":"eng","author":[{"family":"Watz","given":"Henrik"},{"family":"Waschki","given":"Benjamin"},{"family":"Boehme","given":"Corinna"},{"family":"Claussen","given":"Martin"},{"family":"Meyer","given":"Thorsten"},{"family":"Magnussen","given":"Helgo"}],"issued":{"date-parts":[["2008",4,1]]},"PMID":"18048807"}}],"schema":""} (6) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"33hUzgTB","properties":{"formattedCitation":"(4)","plainCitation":"(4)"},"citationItems":[{"id":256,"uris":[""],"uri":[""],"itemData":{"id":256,"type":"article-journal","title":"Haemoglobin level and its clinical impact in a cohort of patients with COPD","container-title":"The European respiratory journal","page":"923-929","volume":"29","issue":"5","source":"NCBI PubMed","abstract":"Haemoglobin (Hb) abnormalities in chronic obstructive pulmonary disease (COPD) are not well characterised. The present authors investigated the prevalence and association of abnormal Hb with clinical outcomes. Analysis of a prospective cohort of stable COPD outpatients (n = 683) in a USA Veterans Administration pulmonary clinic was undertaken. Patients were classified as anaemic (Hb <13 g.dL(-1)), polycythemic (Hb > or =17 g.dL(-1) and > or =15 g.dL(-1) for males and females, respectively) or normal. Demographic characteristics and physiological/functional outcomes were compared between groups. Regression models adjusting for confounders examined the independent association of anaemia with clinical outcomes. Anaemia was present in 116 (17%) patients and polycythemia in 40 (6%). While the only values that differed between polycythemic and nonpolycythemic patients were mean body mass index and Hb, anaemic patients showed a significantly higher modified Medical Research Council dyspnoea scale score (2.8 versus 2.6), lower 6-min walk distance (265 versus 325 m) and shorter median survival (49 versus 74 months) than nonanaemic patients. In regression models, anaemia independently predicted dyspnoea and reduced exercise capacity. Anaemia in chronic obstructive pulmonary disease was an independent risk factor for reduced functional capacity. Polycythemia prevalence was low and had no association with worsened outcomes. Further work is required to evaluate the effect of anaemia correction on outcomes in chronic obstructive pulmonary disease.","DOI":"10.1183/09031936.00137106","ISSN":"0903-1936","note":"PMID: 17251227","journalAbbreviation":"Eur. Respir. J.","language":"eng","author":[{"family":"Cote","given":"C"},{"family":"Zilberberg","given":"M D"},{"family":"Mody","given":"S H"},{"family":"Dordelly","given":"L J"},{"family":"Celli","given":"B"}],"issued":{"date-parts":[["2007",5]]},"PMID":"17251227"}}],"schema":""} (4) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"x6LvMaWG","properties":{"formattedCitation":"(7)","plainCitation":"(7)"},"citationItems":[{"id":180,"uris":[""],"uri":[""],"itemData":{"id":180,"type":"article-journal","title":"Anemia and survival in chronic obstructive pulmonary disease: a dichotomous rather than a continuous predictor","container-title":"Respiration; international review of thoracic diseases","page":"126-131","volume":"85","issue":"2","source":"NCBI PubMed","abstract":"BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disorder characterized by high mortality. Hemoglobin (Hb) concentration has a prognostic impact on COPD patients receiving long-term oxygen treatment, but its value as an independent predictor of survival among stable COPD outpatients has not been fully clarified by previous studies.\nOBJECTIVES: To investigate the potential association between anemia and survival in a cohort of stable COPD outpatients.\nMETHODS: A cohort of stable COPD patients, who had had their first spirometry, blood count and serum chemistry profile done between October 1999 and November 2010 were retrospectively analyzed. Patients with heart failure, renal impairment, malignancy, recent hemorrhage and other causes of anemia were excluded. Variables that were found to be univariately associated with survival entered a multivariate stepwise Cox regression analysis model, to allow independent predictors of survival to be identified.\nRESULTS: Of 294 patients (67.9 ± 9.8 years old, 64.6% male) 15.6% were anemic (Hb <13 g/dl). The median survival differed significantly between anemic [68.7 (18.1-91.5) months] and nonanemic [79.8 (57.5-98.4) months, p = 0.035] individuals. Independent predictors of mortality in the total population were anemia [hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.06-3.29], age (HR 1.08, 95% CI 1.04-1.12) and forced expiratory volume in 1 s (FEV(1)) % predicted (HR 0.94, 95% CI 0.92-0.97); the Hb concentration was neither univariately nor multivariately associated with mortality.\nCONCLUSION: This is the first study to indicate that anemia (but not the Hb value) is independently associated with survival in stable COPD outpatients. It would be better to treat this as a categorical variable in future scoring systems.","DOI":"10.1159/000338792","ISSN":"1423-0356","note":"PMID: 22759351","shortTitle":"Anemia and survival in chronic obstructive pulmonary disease","journalAbbreviation":"Respiration","language":"eng","author":[{"family":"Boutou","given":"Afroditi K"},{"family":"Karrar","given":"Sarah"},{"family":"Hopkinson","given":"Nicholas S"},{"family":"Polkey","given":"Michael I"}],"issued":{"date-parts":[["2013"]]},"PMID":"22759351"}}],"schema":""} (7) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ux5voDGk","properties":{"formattedCitation":"(8)","plainCitation":"(8)"},"citationItems":[{"id":198,"uris":[""],"uri":[""],"itemData":{"id":198,"type":"article-journal","title":"Anemia of chronic disease in chronic obstructive pulmonary disease: a case-control study of cardiopulmonary exercise responses","container-title":"Respiration; international review of thoracic diseases","page":"237-245","volume":"82","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia may be present in patients with chronic obstructive pulmonary disease (COPD) and further impair their functional capacity.\nOBJECTIVES: This study investigated the prevalence of anemia of chronic disease (ACD) in COPD patients and its impact on dyspnea and exercise capacity, utilizing cardiopulmonary exercise testing (CPET).\nMETHODS: ACD prevalence was assessed in 283 consecutive patients with stable COPD (263 males, 60 females; age 60.31 ± 5.34 years; percent forced expiratory volume in 1 s 46.94 ± 6.12). ACD diagnosis was based on a combination of clinical and laboratory parameters [hemoglobin (Hb) <13 g/dl for males, <12 g/dl for females; ferritin >30 ng/ml; total iron-binding capacity <250 μg/dl, and transferrin saturation rate between 15 and 50%]. Twenty-seven patients who were identified with ACD (cases) and 27 matched nonanemic patients (controls) completed maximal CPET, and data were compared between the groups.\nRESULTS: ACD was diagnosed in 29 patients, which represents a prevalence of 10.24%; the severity of anemia was generally mild (mean Hb: 12.19 ± 0.66 g/dl). Patients with ACD had a higher Medical Research Council dyspnea score compared to controls (2.78 ± 0.44 vs. 2.07 ± 0.55; p <0.001) and lower peak O(2) uptake (VO(2)) (59.54 ± 17.17 vs. 71.26 ± 11.85% predicted; p <0.05), peak work rate (54.94 ± 21.42 vs. 68.72 ± 20.81% predicted; p <0.05) and peak VO(2)/heart rate (69.07 ± 17.26 vs. 82.04 ± 18.22% predicted; p <0.05). There was also a trend for a lower anaerobic threshold (48.48 ± 15.16 vs. 55.42 ± 9.99% predicted; p = 0.062). No exercise parameter indicative of respiratory limitation differed between the groups.\nCONCLUSIONS: ACD occurs in approximately 10% of stable COPD patients and has a negative impact on dyspnea and circulatory efficiency during exercise.","DOI":"10.1159/000326899","ISSN":"1423-0356","note":"PMID: 21576921","shortTitle":"Anemia of chronic disease in chronic obstructive pulmonary disease","journalAbbreviation":"Respiration","language":"eng","author":[{"family":"Boutou","given":"Afroditi K"},{"family":"Stanopoulos","given":"Ioannis"},{"family":"Pitsiou","given":"Georgia G"},{"family":"Kontakiotis","given":"Theodoros"},{"family":"Kyriazis","given":"George"},{"family":"Sichletidis","given":"Lazaros"},{"family":"Argyropoulou","given":"Paraskevi"}],"issued":{"date-parts":[["2011"]]},"PMID":"21576921"}}],"schema":""} (8) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tuO7ERnb","properties":{"formattedCitation":"(9)","plainCitation":"(9)"},"citationItems":[{"id":234,"uris":[""],"uri":[""],"itemData":{"id":234,"type":"article-journal","title":"Anemia and inflammation in COPD","container-title":"Chest","page":"825-829","volume":"127","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia in patients with COPD and its pathophysiology is an understudied issue.\nMETHODS: In a group of 101 COPD patients (FEV(1) percentage of predicted, 37 +/- 2% [mean +/- SEM]; mean age, 61 +/- 1 years; 35% female gender), the prevalence of anemia and its relationship to body mass and weight loss, inflammatory parameters, and erythropoietin levels was determined. Data were compared to a control group (healthy persons with matched age) in order to identify potential factors that may influence the development of anemia in patients with COPD.\nRESULTS: Anemia was diagnosed in 13 patients (hemoglobin levels < 13.5 mg/dL in male patients and < 12.0 mg/dL in female patients), which represents a prevalence of 13%. Anemic COPD patients showed elevated erythropoietin levels (41.8 +/- 25.4 U/L vs 16.3 +/- 2.9 U/L) and an increased inflammatory response compared to nonanemic patients. A significant inverse correlation of hemoglobin vs erythropoietin (r = - 0.84, p < 0.01) was observed in anemic COPD patients, but not in the nonanemic group.\nCONCLUSION: Anemic COPD patients show high erythropoietin levels, which may indicate presence of erythropoietin resistance. The latter may be mediated through inflammatory mechanisms, which is typical for anemia of chronic illness.","DOI":"10.1378/chest.127.3.825","ISSN":"0012-3692","note":"PMID: 15764763","journalAbbreviation":"Chest","language":"eng","author":[{"family":"John","given":"Matthias"},{"family":"Hoernig","given":"Soeren"},{"family":"Doehner","given":"Wolfram"},{"family":"Okonko","given":"Darlington D"},{"family":"Witt","given":"Christian"},{"family":"Anker","given":"Stefan D"}],"issued":{"date-parts":[["2005",3]]},"PMID":"15764763"}}],"schema":""} (9) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lhfh8wLr","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":178,"uris":[""],"uri":[""],"itemData":{"id":178,"type":"article-journal","title":"Comorbidities of chronic obstructive pulmonary disease in Koreans: a population-based study","container-title":"Journal of Korean medical science","page":"901-906","volume":"27","issue":"8","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) includes pulmonary components with increased comorbidity rates, as well as being a systemic disease. Comorbidities may frequently occur in COPD patients over 40 yr old. We report the comorbidities of patients with COPD, diagnosed by spirometry, in a population-based epidemiologic survey in Korea. Data were derived from the fourth Korean Health and Nutrition Examination Survey in 2008, a stratified multistage clustered probability design survey of a sample representing the entire population of Korea. Results of spirometry and various health-related questionnaires were analyzed in 2,177 subjects aged ≥ 40 yr. The prevalence of COPD (FEV(1)/FVC < 0.7) in subjects ≥ 40 yr of age was 14.1%. Multivariate analysis showed that underweight (odds ratio [OR] 3.07, 95% confidence interval [CI] 1.05-8.98), coronary heart disease (OR, 0.43; 95% CI, 0.20-0.93) and dyslipidemia (OR, 0.61; 95% CI, 0.45-0.82) were significantly associated with COPD, whereas allergic rhinitis, anemia, arthritis, chronic renal failure, depression, diabetes mellitus, hypertension, gastrointestinal ulcer, and osteoporosis were not. Underweight might be more prevalent but coronary heart disease and dyslipidemia are less prevalent in Koreans with than without COPD in population setting.","DOI":"10.3346/jkms.2012.27.8.901","ISSN":"1598-6357","note":"PMID: 22876057","shortTitle":"Comorbidities of chronic obstructive pulmonary disease in Koreans","journalAbbreviation":"J. Korean Med. Sci.","language":"eng","author":[{"family":"Joo","given":"Hyejin"},{"family":"Park","given":"Jinkyeong"},{"family":"Lee","given":"Sang Do"},{"family":"Oh","given":"Yeon-Mok"}],"issued":{"date-parts":[["2012",8]]},"PMID":"22876057"}}],"schema":""} (10) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"yiMOjTU3","properties":{"formattedCitation":"(11)","plainCitation":"(11)"},"citationItems":[{"id":226,"uris":[""],"uri":[""],"itemData":{"id":226,"type":"article-journal","title":"Association between anemia and quality of life in a population sample of individuals with chronic obstructive pulmonary disease","container-title":"BMC pulmonary medicine","page":"23","volume":"6","source":"NCBI PubMed","abstract":"BACKGROUND: Several studies investigated the association of anemia with health related quality of life (HRQL) in patients with chronic disease. However, there is little evidence regarding the association of anemia with HRQL in patients with chronic obstructive pulmonary disease (COPD).\nMETHODS: This is a post-hoc analysis of a study which enrolled a population of adults aged 35-79 randomly selected from residents of Erie and Niagara Counties, NY, between 1996 and 2000. In addition to demographic information and physical measurements, we obtained spirometry data and hemoglobin levels. We used modified Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria to define COPD, and World Health Organization (WHO) criteria to define anemia. To assess HRQL we used the Short Form-36 (SF-36) to assess physical functioning (PF), physical component summary (PCS) measures and mental component summary (MCS) measures.\nRESULTS: In the entire study population (n = 2704), respondents with anemia had lower scores on the physical functioning domain [45.4 (SD10.9) vs. 49.2 (SD 9.1); p < 0.0001]. Among patients with COPD (n = 495) the PF scores (39.9 vs. 45.4) and the PCS (41.9 vs. 45.9) were significantly lower in individuals with anemia compared to those without. In multiple regression analysis, the association between hemoglobin and PCS was positive (regression coefficient 0.02, p = 0.003). There was no significant association of hemoglobin with PF scores or the mental component summary measure after adjusting for covariates in patients with COPD.\nCONCLUSION: In patients with moderate to very severe COPD anemia may be associated with worse HRQL. However, co-morbidities may explain part or all of this association in these patients.","DOI":"10.1186/1471-2466-6-23","ISSN":"1471-2466","note":"PMID: 16953872","journalAbbreviation":"BMC Pulm Med","language":"eng","author":[{"family":"Krishnan","given":"Gokul"},{"family":"Grant","given":"Brydon J"},{"family":"Muti","given":"Paola C"},{"family":"Mishra","given":"Archana"},{"family":"Ochs-Balcom","given":"Heather M"},{"family":"Freudenheim","given":"Jo L"},{"family":"Trevisan","given":"Maurizio"},{"family":"Schünemann","given":"Holger J"}],"issued":{"date-parts":[["2006"]]},"PMID":"16953872"}}],"schema":""} (11) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"DYSYCG26","properties":{"formattedCitation":"(12)","plainCitation":"(12)"},"citationItems":[{"id":908,"uris":[""],"uri":[""],"itemData":{"id":908,"type":"article-journal","title":"Association between Anemia and COPD in Iranian Population","container-title":"International Journal of Hematology-Oncology and Stem Cell Research","page":"6-10","volume":"7","issue":"2","source":"PubMed Central","abstract":"Background and Aim\nChronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality in adults. Anemia is known as comorbidity in many chronic diseases that can increase morbidity and mortality of COPD. Recent studies have shown that anemia may be more prevalent than expected in COPD patients and can increase disabilities of COPD. In this study we have evaluated the correlation between anemia and the severity of COPD in patients referred to teaching hospitals of the Tehran University of Medical Sciences (TUMS), Tehran, Iran.\n\nMaterials and Methods\nIn this cross-sectional study the severity of COPD in 760 patients with dyspnea who referred to teaching hospitals of Tehran University of Medical Sciences and 96 stable COPD patients were categorize using a GOLD criteria from mild to moderate, severe and very severe. Anemia was determined as hemoglobin <13 g/dL in men and <12 g/dL in women, respectively. Demographic characteristics, spirometry parameters and laboratory findings were compared between anemic and non-anemic groups using Student t-test and regression tests (SPSS v.18 software).\n\nResults\nThe Mean age of patients was 65 ± 13.07 years (59.4% male). Overall prevalence of anemia was 27% and there was no correlation between severity of COPD and anemia. Anemic patients were significantly older than non-anemic patients (71.1 ± 8.5 years vs. 65.4± 12.8 years; p = 0.030). RBC count of anemic patients were significantly lower than non-anemic group (4.3 ± 0.5 vs. 5.02± 0.8 ×106/?L; p < 0.001). Erythropoietin levels in anemic group was significantly higher than non-anemic group (16.33±2.43 vs. 10.22 ± 2.67 mu/ml; p < 0.001) and there was a significant inverse correlation of hemoglobin vs erythropoietin (r= ?0.8).\n\nConclusion\nThere was a high prevalence of anemia in COPD patients. Anemia can increase disabilities of COPD. Thus, treatment of anemia may improve quality of life in these patients. Further comprehensive studies are needed for determination of exact prevalence of anemia and its physiologic effects in COPD.","ISSN":"2008-3009","note":"PMID: 24505521\nPMCID: PMC3913136","journalAbbreviation":"Int J Hematol Oncol Stem Cell Res","author":[{"family":"Zavarreh","given":"Roshanak Hasheminasab"},{"family":"Zahmatkesh","given":"Mohammad-Mehdi"},{"family":"Vakili","given":"Masood"},{"family":"Shahriari-Ahmadi","given":"Ali"},{"family":"Zohal","given":"Mohammad Ali"},{"family":"Arabi","given":"Mohsen"},{"family":"Mahmoudian","given":"Alireza"},{"family":"Gheisuri","given":"Abbas"},{"family":"Kian","given":"Abdolhamed"},{"family":"Fahimi","given":"Ali"}],"issued":{"date-parts":[["2013"]]},"accessed":{"date-parts":[["2014",3,25]]},"PMID":"24505521","PMCID":"PMC3913136"}}],"schema":""} (12) hospitalized patients for an acute exacerbation of COPD (AECOPD), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"d2BLL6Cc","properties":{"formattedCitation":"(13)","plainCitation":"(13)"},"citationItems":[{"id":188,"uris":[""],"uri":[""],"itemData":{"id":188,"type":"article-journal","title":"Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor","container-title":"Current medical research and opinion","page":"617-622","volume":"28","issue":"4","source":"NCBI PubMed","abstract":"OBJECTIVE: The prevalence of comorbid anemia in patients with COPD ranges from 7.5% to 34%. The aim of this study is to determine if anemia is a risk factor for readmission in COPD patients.\nMETHODS: This study analyzed the hospital data of 289,077 adults with acute exacerbations of COPD admitted to the hospital at any public center in Spain, in 2006 and 2007. We calculated the prevalence of anemia and compared readmissions between COPD patients with and without anemia. Multiple regression analyses were carried out with the aim of determining the risk of readmission attributable to anemia, after the correction of possible confounding variables.\nRESULTS: Of the patients with COPD, 9.8% (n?=?26,899) had a diagnosis of anemia. Anemic patients were older, more likely to be female and had a greater comorbidity burden than non-anemic individuals. Multiple regression modeling revealed that multiple independent factors were associated with an increased risk of readmission in persons with COPD. Anemia was one of the greatest risks: anemic patients had a 25% higher risk of readmission than non-anemic patients (odds ratio [OR], 1.25; 95% confidence interval [CI] 1.21-1.29).\nCONCLUSION: Utilizing an administrative database the authors found that anemia correlates independently with readmission in COPD patients.\nLIMITATIONS: This is a retrospective cohort study and thus subject to multiple forms of bias. Although spirometric evidence of COPD was not available, our case identification methods have been previously validated and found to be accurate in recognizing COPD.","DOI":"10.1185/03007995.2012.675318","ISSN":"1473-4877","note":"PMID: 22409165","shortTitle":"Anemia in chronic obstructive pulmonary disease","journalAbbreviation":"Curr Med Res Opin","language":"eng","author":[{"family":"Barba","given":"Raquel"},{"family":"de Casasola","given":"Gonzalo García"},{"family":"Marco","given":"Javier"},{"family":"Emilio Losa","given":"Juan"},{"family":"Plaza","given":"Susana"},{"family":"Canora","given":"Jesús"},{"family":"Zapatero","given":"Antonio"}],"issued":{"date-parts":[["2012",4]]},"PMID":"22409165"}}],"schema":""} (13) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dASdYNpJ","properties":{"formattedCitation":"(14)","plainCitation":"(14)"},"citationItems":[{"id":168,"uris":[""],"uri":[""],"itemData":{"id":168,"type":"article-journal","title":"Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de medicina interna (ESMI) study","container-title":"Chest","page":"1126-1133","volume":"142","issue":"5","source":"NCBI PubMed","abstract":"BACKGROUND: Comorbidities are frequent in patients hospitalized for COPD exacerbation, but little is known about their relation with short-term mortality and hospital readmissions. Our hypothesis is that the frequency and type of comorbidities impair the prognosis within 12 weeks after discharge.\nMETHODS: A longitudinal, observational, multicenter study of patients hospitalized for a COPD exacerbation with spirometric confirmation was performed. Comorbidity information was collected using the Charlson index and a questionnaire that included other common conditions not included in this index. Dyspnea, functional status, and previous hospitalization for COPD or other reasons among other variables were investigated. Information on mortality and readmissions for COPD or other causes was collected up to 3 months after discharge.\nRESULTS: We studied 606 patients, 594 men (89.9%), with a mean (SD) age of 72.6 (9.9) years and a postbronchodilator FEV1 of 43.2% (21.2). The mean Charlson index score was 3.1 (2.0). On admission, 63.4% of patients had arterial hypertension, 35.8% diabetes mellitus, 32.8% chronic heart failure, 20.8% ischemic heart disease, 19.3% anemia, and 34% dyslipemia. Twenty-seven patients (4.5%) died within 3 months. The Charlson index was an independent predictor of mortality (P &lt; .003; OR,1.23; 95% CI, 1.07-1.40), even after adjustment for age, FEV1, and functional status measured with the Katz index. Comorbidity was also related with the need for hospitalization from the ED, length of stay, and hospital readmissions for COPD or other causes.\nCONCLUSIONS: Comorbidities are common in patients hospitalized for a COPD exacerbation, and they are related to short-term prognosis.","DOI":"10.1378/chest.11-2413","ISSN":"1931-3543","note":"PMID: 23303399","shortTitle":"Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD","journalAbbreviation":"Chest","language":"eng","author":[{"family":"Almagro","given":"Pedro"},{"family":"Cabrera","given":"Francisco Javier"},{"family":"Diez","given":"Jesus"},{"family":"Boixeda","given":"Ramon"},{"family":"Alonso Ortiz","given":"M Belen"},{"family":"Murio","given":"Cristina"},{"family":"Soriano","given":"Joan B"},{"family":"Working Group on COPD , Spanish Society of Internal Medicine","given":""}],"issued":{"date-parts":[["2012",11]]},"PMID":"23303399"}}],"schema":""} (14) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zURhRX9k","properties":{"formattedCitation":"(15)","plainCitation":"(15)"},"citationItems":[{"id":208,"uris":[""],"uri":[""],"itemData":{"id":208,"type":"article-journal","title":"Modification of COPD presentation during the last 25 years","container-title":"COPD","page":"345-351","volume":"7","issue":"5","source":"NCBI PubMed","abstract":"During the last decades progress has been made in the treatment of Chronic Obstructive Pulmonary Disease (COPD). We compared a random sample of patients admitted for an exacerbation in the period 2001-2005 (n = 101), with a random sample of patients hospitalized for the same reason in the period 1980-1984 (n = 51). Patients of the 2001-2005 cohort had a lower FEV1 (48 ± 3 vs. 41 ± 2% predicted, p = 0.01) for similar mean age, gender and body- mass index when compared to the historical sample. Co-morbidities, according to the Charlson's index, were more prevalent in the 2001-2005 cohort compared to the 1980-1984 cohort, with a reduction of hemoglobin (13.9 ± 0.2 gr/dl vs. 14.9 ± 0.2, p < 0.01) and higher prevalence of anemia in the most recent cohort. We found an increase in the use of cardiovascular drugs and respiratory medications over time with exception for the long-term use of oxygen. Despite lower FEV1 and more prevalent co-morbidities, no difference in length of hospitalization (13.6 ± 1.4 days vs. 12.7 ± 0.7 days, p = 0.52) and 30 months survival post-exacerbation was noted (66.6% vs. 69.3%, p = 0.85). Over the course of 20 years, the presentation of COPD patients admitted for an exacerbation seems to be changed towards a more severe phenotype with lower FEV1 and more co-morbidities. As the length of hospitalization and the overall survival were not different between the two samples, a currently improved management of COPD can be hypothesized.","DOI":"10.3109/15412555.2010.510546","ISSN":"1541-2563","note":"PMID: 20854049","journalAbbreviation":"COPD","language":"eng","author":[{"family":"Fremault","given":"Antoine"},{"family":"Janssens","given":"Wim"},{"family":"Beaucage","given":"Fran?ois"},{"family":"Celis","given":"Geert"},{"family":"Pérez-Bogerd","given":"Silvia"},{"family":"Decramer","given":"Marc"}],"issued":{"date-parts":[["2010",10]]},"PMID":"20854049"}}],"schema":""} (15) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"wcOncAWy","properties":{"formattedCitation":"(14)","plainCitation":"(14)","dontUpdate":true},"citationItems":[{"id":250,"uris":[""],"uri":[""],"itemData":{"id":250,"type":"article-journal","title":"Impact of mild anaemia on dyspnoea during exertion and exercise tolerance in patients with acute exacerbation of chronic obstructive pulmonary disease","container-title":"Pneumonologia i alergologia polska","page":"200-206","volume":"81","issue":"3","source":"NCBI PubMed","abstract":"INTRODUCTION: Dyspnoea and decreased exercise tolerance are symptoms of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Anaemia is a risk factor for reduced functional capacity and dyspnoea in stable COPD. There is limited information about the impact of anaemia on functional capacity and dyspnoea of patients during AECOPD. The aim of this study was to evaluate the impact of decreased blood haemoglobin concentration on the results of six-minute walking test (6MWT) in patients during AECOPD.\nMATERIAL AND METHODS: A post hoc analysis of data collected from prospective long-term studies on AECOPD. Haemoglobin concentration from the first obtainable hospital measurement were included in the assessment. 6MWT was performed after clinical improvement of the patient. Dyspnoea at baseline and after exercise and oxygen saturation (SpO(2)) during exercise was measured.\nRESULTS: (presented as means ± SD): 402 patients with exacerbation of COPD (COPD stage 3.5 ± 0.6) were examined. Patients with anaemia (26% of those studied, age 74.5 ± 8.2 years) achieved 258.1 ± 125.1 m during 6MWT, with exertional desaturation of 2.9 ± 2.6%. Patients without anaemia (74% of those studied, age 70.2 ± 8.7 years) achieved 271 ± 136.0 m during 6MWT with exertional desaturation of 3.8 ± 3.7%. The haemoglobin concentration did not correlate with 6MWT, dyspnoea during 6MWT, or exercise oxygenation and blood desaturation during exercise.\nCONCLUSION: Mildly decreased blood haemoglobin concentration did not influence the results of 6MWT in patients with AECOPD.","ISSN":"0867-7077","note":"PMID: 23609426","journalAbbreviation":"Pneumonol Alergol Pol","language":"eng","author":[{"family":"Nowiński","given":"Adam"},{"family":"Kamiński","given":"Dariusz"},{"family":"Kram","given":"Marek"},{"family":"Korzybski","given":"Damian"},{"family":"Stok?osa","given":"Anna"},{"family":"Górecka","given":"Dorota"}],"issued":{"date-parts":[["2013"]]},"PMID":"23609426"}}],"schema":""} (15) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"o4jkl57g","properties":{"formattedCitation":"(17)","plainCitation":"(17)"},"citationItems":[{"id":182,"uris":[""],"uri":[""],"itemData":{"id":182,"type":"article-journal","title":"Clinical factors affecting the direct cost of patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease","container-title":"International journal of medical sciences","page":"285-290","volume":"9","issue":"4","source":"NCBI PubMed","abstract":"BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disease of increasing significance in terms of economic and social burden due to its increasing prevalence and high costs. Direct costs of COPD are mostly associated with hospitalization expenditures. In this study, our objective was to investigate the costs of hospitalization and factors affecting these costs in patients hospitalized due to acute exacerbation of COPD (AECOPD).\nMETHODS: A total of 284 patients hospitalized AECOPD were included in the study. Data were examined retrospectively using the electronic hospital charts.\nRESULTS: Mean duration of hospitalization was 11.38 ± 6.94 days among study patients. Rates of admission to the intensive care unit, initiation of non-invasive mechanical ventilation (NIMV) and invasive mechanical ventilation (MIV) were 37.3% (n=106), 44.4% (n=126) and 18.3% (n=52) respectively. The rate of mortality was 14.8% (n=42). Mean cost of a single patient hospitalized for an AECOPD was calculated as $1765 ± 2139. Mean cost of admission was $889 ± 533 in standard ward, and $2508 ± 2857 in intensive care unit (ICU). The duration of hospitalization, a FEV1% predicted value below 30%, having smoked 40 package-years or more, the number of co-morbidities, NIMV, IMV, ICU, exitus and the number of hospitalizations in the past year were among the factors that increased costs significantly. Hospital acquired pneumonia, chronic renal failure and anemia also increased the costs of COPD significantly.\nCONCLUSION: The costs of treatment increase with the severity of COPD or with progression to a higher stage. Efforts and expenditures aimed at preventing COPD exacerbations might decrease the costs in COPD.","DOI":"10.7150/ijms.4039","ISSN":"1449-1907","note":"PMID: 22701335","journalAbbreviation":"Int J Med Sci","language":"eng","author":[{"family":"Ornek","given":"Tacettin"},{"family":"Tor","given":"Meltem"},{"family":"Alt?n","given":"Remzi"},{"family":"Atalay","given":"Figen"},{"family":"Geredeli","given":"Elif"},{"family":"Soylu","given":"Omer"},{"family":"Erboy","given":"Fatma"}],"issued":{"date-parts":[["2012"]]},"PMID":"22701335"}}],"schema":""} (17) intubated patients in the intensive care unit ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"L8s6OsSF","properties":{"formattedCitation":"(18)","plainCitation":"(18)"},"citationItems":[{"id":200,"uris":[""],"uri":[""],"itemData":{"id":200,"type":"article-journal","title":"Anemia and 90-day mortality in COPD patients requiring invasive mechanical ventilation","container-title":"Clinical epidemiology","page":"1-5","volume":"3","source":"NCBI PubMed","abstract":"BACKGROUND: There are data to suggest that anemia is associated with increased mortality in patients with chronic obstructive pulmonary disease (COPD). In contrast, critically ill patients with low hemoglobin levels (4.3-5.5 mmol/L, 7.0-9.0 g/dL) in general do not appear to have a worsened clinical outcome. The effects of anemia in critically ill patients with COPD remain to be clarified. We examined the association between anemia (hemoglobin <7.4 mmol/L, <12.0 g/dL) and 90-day mortality in COPD patients with acute respiratory failure treated with invasive mechanical ventilation in a single-institution follow-up study.\nMETHOD: We identified all COPD patients at our institution (n = 222) admitted for the first time to the intensive care unit (ICU) requiring invasive mechanical ventilation in 1994-2004. Data on patient characteristics (eg, hemoglobin, pH, blood transfusions, and Charlson Comorbidity Index), and mortality were obtained from population-based clinical and administrative registries and medical records. We used Cox's regression analysis to estimate mortality rate ratios (MRR) in COPD patients with and without anemia.\nRESULTS: A total of 42 (18%) COPD patients were anemic at time of initiating invasive mechanical ventilation. The overall 90-day mortality among anemic COPD patients was 57.1% versus 25% in nonanemic patients. The corresponding adjusted 90-day MRR was 2.6 (95% confidence interval 1.5-4.5). Restricting analyses to patients not treated with blood transfusions during their intensive care unit stay did not materially change the MRR.\nCONCLUSION: We found anemia to be associated with increased mortality among COPD patients with acute respiratory failure requiring invasive mechanical ventilation.","DOI":"10.2147/CLEP.S12885","ISSN":"1179-1349","note":"PMID: 21326654","journalAbbreviation":"Clin Epidemiol","language":"eng","author":[{"family":"Rasmussen","given":"Lone"},{"family":"Christensen","given":"Steffen"},{"family":"Lenler-Petersen","given":"Poul"},{"family":"Johnsen","given":"S?ren P"}],"issued":{"date-parts":[["2011"]]},"PMID":"21326654"}}],"schema":""} (18), COPD patients from the general population ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"JhDjCLNy","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":178,"uris":[""],"uri":[""],"itemData":{"id":178,"type":"article-journal","title":"Comorbidities of chronic obstructive pulmonary disease in Koreans: a population-based study","container-title":"Journal of Korean medical science","page":"901-906","volume":"27","issue":"8","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) includes pulmonary components with increased comorbidity rates, as well as being a systemic disease. Comorbidities may frequently occur in COPD patients over 40 yr old. We report the comorbidities of patients with COPD, diagnosed by spirometry, in a population-based epidemiologic survey in Korea. Data were derived from the fourth Korean Health and Nutrition Examination Survey in 2008, a stratified multistage clustered probability design survey of a sample representing the entire population of Korea. Results of spirometry and various health-related questionnaires were analyzed in 2,177 subjects aged ≥ 40 yr. The prevalence of COPD (FEV(1)/FVC < 0.7) in subjects ≥ 40 yr of age was 14.1%. Multivariate analysis showed that underweight (odds ratio [OR] 3.07, 95% confidence interval [CI] 1.05-8.98), coronary heart disease (OR, 0.43; 95% CI, 0.20-0.93) and dyslipidemia (OR, 0.61; 95% CI, 0.45-0.82) were significantly associated with COPD, whereas allergic rhinitis, anemia, arthritis, chronic renal failure, depression, diabetes mellitus, hypertension, gastrointestinal ulcer, and osteoporosis were not. Underweight might be more prevalent but coronary heart disease and dyslipidemia are less prevalent in Koreans with than without COPD in population setting.","DOI":"10.3346/jkms.2012.27.8.901","ISSN":"1598-6357","note":"PMID: 22876057","shortTitle":"Comorbidities of chronic obstructive pulmonary disease in Koreans","journalAbbreviation":"J. Korean Med. Sci.","language":"eng","author":[{"family":"Joo","given":"Hyejin"},{"family":"Park","given":"Jinkyeong"},{"family":"Lee","given":"Sang Do"},{"family":"Oh","given":"Yeon-Mok"}],"issued":{"date-parts":[["2012",8]]},"PMID":"22876057"}}],"schema":""} (10) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8d5fvQEK","properties":{"formattedCitation":"(11)","plainCitation":"(11)"},"citationItems":[{"id":226,"uris":[""],"uri":[""],"itemData":{"id":226,"type":"article-journal","title":"Association between anemia and quality of life in a population sample of individuals with chronic obstructive pulmonary disease","container-title":"BMC pulmonary medicine","page":"23","volume":"6","source":"NCBI PubMed","abstract":"BACKGROUND: Several studies investigated the association of anemia with health related quality of life (HRQL) in patients with chronic disease. However, there is little evidence regarding the association of anemia with HRQL in patients with chronic obstructive pulmonary disease (COPD).\nMETHODS: This is a post-hoc analysis of a study which enrolled a population of adults aged 35-79 randomly selected from residents of Erie and Niagara Counties, NY, between 1996 and 2000. In addition to demographic information and physical measurements, we obtained spirometry data and hemoglobin levels. We used modified Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria to define COPD, and World Health Organization (WHO) criteria to define anemia. To assess HRQL we used the Short Form-36 (SF-36) to assess physical functioning (PF), physical component summary (PCS) measures and mental component summary (MCS) measures.\nRESULTS: In the entire study population (n = 2704), respondents with anemia had lower scores on the physical functioning domain [45.4 (SD10.9) vs. 49.2 (SD 9.1); p < 0.0001]. Among patients with COPD (n = 495) the PF scores (39.9 vs. 45.4) and the PCS (41.9 vs. 45.9) were significantly lower in individuals with anemia compared to those without. In multiple regression analysis, the association between hemoglobin and PCS was positive (regression coefficient 0.02, p = 0.003). There was no significant association of hemoglobin with PF scores or the mental component summary measure after adjusting for covariates in patients with COPD.\nCONCLUSION: In patients with moderate to very severe COPD anemia may be associated with worse HRQL. However, co-morbidities may explain part or all of this association in these patients.","DOI":"10.1186/1471-2466-6-23","ISSN":"1471-2466","note":"PMID: 16953872","journalAbbreviation":"BMC Pulm Med","language":"eng","author":[{"family":"Krishnan","given":"Gokul"},{"family":"Grant","given":"Brydon J"},{"family":"Muti","given":"Paola C"},{"family":"Mishra","given":"Archana"},{"family":"Ochs-Balcom","given":"Heather M"},{"family":"Freudenheim","given":"Jo L"},{"family":"Trevisan","given":"Maurizio"},{"family":"Schünemann","given":"Holger J"}],"issued":{"date-parts":[["2006"]]},"PMID":"16953872"}}],"schema":""} (11) and COPD patients using long-term oxygen treatment (LTOT) or non-invasive ventilation (NIV). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"HTiRZzxW","properties":{"formattedCitation":"(3)","plainCitation":"(3)"},"citationItems":[{"id":232,"uris":[""],"uri":[""],"itemData":{"id":232,"type":"article-journal","title":"Prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy","container-title":"Chest","page":"1201-1208","volume":"128","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Although traditionally associated with polycythemia, COPD has a systemic inflammatory component that could interfere with erythropoiesis. This study describes the distribution and prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy (LTOT).\nMETHODS: A total of 2,524 patients with COPD, FEV1/vital capacity (VC) < 70%, FEV1 < 80% of predicted, and Pa(O2) < 7.3 kPa in whom a hematocrit was available at entry was identified between 1980 and 1999 in the French Association Nationale pour le Traitement à Domicile de l'Insuffisance Respiratoire chronic respiratory insufficiency and home-care database (male/female ratio, 5/1; mean +/- SD age, 68 +/- 10 years for men, and 70 +/- 10 years for women). Correlations between hematocrit, demographic data, and pulmonary function data were examined. A multivariate Cox proportional hazard regression was performed to identify prognostic factors.\nRESULTS: Mean hematocrit was 45.9 +/- 7.0% in men and 43.9 +/- 6.0% in women (< 39% in 12.6% of men, and < 36% in 8.2% of women) according to the World Health Organization definition of anemia. Hematocrit was negatively correlated with age (r = - 0.245) and FEV1/VC (r = - 0.068) and was positively correlated with Pa(CO2) (r = 0.161) and body mass index (r = 0.127). Multivariate analysis found hematocrit to be an independent predictor of survival, hospital admission rate, and cumulative duration of hospitalization. The 3-year survival was 24% (95% confidence interval, 16 to 33%) when the hematocrit was < 35%, and 70% (63 to 76%) when the hematocrit was > or = 55%.\nCONCLUSIONS: A low hematocrit is not uncommon in LTOT/COPD patients. Hematocrit is negatively associated with mortality and morbidity. Whether the association is causative or not and whether or not corrective measures are warranted remain to be determined.","DOI":"10.1378/chest.128.3.1201","ISSN":"0012-3692","note":"PMID: 16162707","journalAbbreviation":"Chest","language":"eng","author":[{"family":"Chambellan","given":"Arnaud"},{"family":"Chailleux","given":"Edmond"},{"family":"Similowski","given":"Thomas"},{"family":"ANTADIR Observatory Group","given":""}],"issued":{"date-parts":[["2005",9]]},"PMID":"16162707"}}],"schema":""} (3) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rJNHWGIQ","properties":{"formattedCitation":"(5)","plainCitation":"(5)"},"citationItems":[{"id":174,"uris":[""],"uri":[""],"itemData":{"id":174,"type":"article-journal","title":"Hemoglobin Levels Above Anemia Thresholds Are Maximally Predictive for Long-Term Survival in COPD With Chronic Respiratory Failure","container-title":"Respiratory care","page":"1204-1212","volume":"58","issue":"7","source":"NCBI PubMed","abstract":"BACKGROUND: In patients with COPD, chronic anemia is known as an unfavorable prognostic factor. Whether the association between hemoglobin (Hb) levels and long-term survival is restricted to anemia or extends to higher Hb levels has not yet been systematically assessed.\nMETHODS: We determined Hb levels in 309 subjects with COPD and chronic respiratory failure prior to initiation of noninvasive ventilation, accounting for confounders that might affect Hb. Subjects were categorized as anemic (Hb < 12 g/dL in females, Hb < 13 g/dL in males), polycythemic (Hb ≥ 15 g/dL in females, Hb ≥ 17 g/dL in males), or normocythemic. In addition, percentiles of Hb values were analyzed with regard to mortality from any cause.\nRESULTS: Two-hundred seven subjects (67.0%) showed normal Hb levels, 46 (14.9%) had anemia, and 56 (18.1%) had polycythemia. Polycythemic subjects showed a higher survival rate than anemic (P = .01) and normocythemic subjects (P = .043). In a univariate Cox hazards model, Hb was associated with long-term survival (hazard ratio 0.855; 95% CI 0.783-0.934, P < .001). The 58th percentiles of Hb (14.3 g/dL in females, 15.1 g/dL in males) yielded the highest discriminative value for predicting survival (hazard ratio 0.463, 95% CI 0.324-0.660, P < .001). In the multivariate analysis this cutoff was an independent predictor for survival (hazard ratio 0.627, 95% CI 0.414-0.949, P = .03), in addition to age and body mass index.\nCONCLUSIONS: In subjects with COPD and chronic respiratory failure undergoing treatment with noninvasive ventilation and LTOT, high Hb levels are associated with better long-term survival. The optimal cutoff level for prediction was above the established threshold defining anemia. Thus, predicting survival only on the basis of anemia does not fully utilize the prognostic potential of Hb values in COPD.","DOI":"10.4187/respcare.01961","ISSN":"1943-3654","note":"PMID: 23232736","journalAbbreviation":"Respir Care","language":"eng","author":[{"family":"Kollert","given":"Florian"},{"family":"Tippelt","given":"Andrea"},{"family":"Müller","given":"Carolin"},{"family":"J?rres","given":"Rudolf A"},{"family":"Porzelius","given":"Christine"},{"family":"Pfeifer","given":"Michael"},{"family":"Budweiser","given":"Stephan"}],"issued":{"date-parts":[["2013",7]]},"PMID":"23232736"}}],"schema":""} (5) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"kA5Hb175","properties":{"formattedCitation":"(19)","plainCitation":"(19)"},"citationItems":[{"id":176,"uris":[""],"uri":[""],"itemData":{"id":176,"type":"article-journal","title":"Changes in blood hemoglobin and blood gases PaO2 and PaCO2 in severe COPD overa three-year telemonitored program of long-term oxygen treatment","container-title":"Multidisciplinary respiratory medicine","page":"15","volume":"7","issue":"1","source":"NCBI PubMed","abstract":"BACKGROUND: Information on the effects of long-term oxygen treatment (LTOT) on blood hemoglobin (Hb) in severe COPD are limited. The aim was to assess blood Hb values in severe COPD, and investigate the time-course of both Hb and blood gas changes during a 3-year telemetric LTOT.\nMETHODS: A cohort of 132 severe COPD patients (94 males; 71.4?years?±?8.8?sd), newly admitted to the tele-LTOT program, was investigated. Subjects were divided according to their original blood Hb: group A: <13?g/dL; group B: ≥13?<?15?g/dL; group C: ≥ 5?<?16?g/dL; group D: ≥16?g/dL. Blood Hb (g/dL), PaO2 and PaCO2 (mmHg), SaO2 (%), and BMI were measured at LTOT admission (t0), and at least quarterly over three years (t1-t3). Wilcoxon test was used to compare t0 vs. t1 values; linear regression to assess a possible Hb-BMI relationship; ANOVA to compare changes in Hb time-courses over the 3?years.\nRESULTS: LTOT induced a systematic increase of PaO2, and changes were significant since the first year (from 52.1?mmHg?±?6.6sd to 65.1?mmHg?±?8.7?sd, p?<?0.001). Changes in SaO2 were quite similar. Comparable and equally significant trends were seen in all subgroups (p?<?0.001). PaCO2 dropped within the first year of LTOT (from 49.4?mmHg?±?9.1sd to 45.9?mmHg ±7.5?sd, p?<?0.001): the t0-t1 comparison proved significant (p?<?0.01) only in subgroups with the highest basal Hb, who showed a further PaCO2 decline over the remaining two years (p?<?0.001). Hb tended to normalization during LTOT only in subgroups with basal Hb?>?15?g/dl (ANOVA p?<?0.001); anemic subjects (Hb?<?13?g/dl) ameliorated not significantly in the same period (ANOVA?=?0.5). Survival was independent of the original blood Hb. Anemia and polyglobulia are differently prevalent in COPD, the latter being the most represented in our cohort. LTOT affected both conditions, but to a different extent and according to different time-courses. The most striking Hb improvement was in polyglobulic patients in whom also PaO2, PaCO2 and SaO2 dramatically improved. In anemic subjects effects were smaller and slower, oxygenation being equally ameliorated by LTOT.\nCONCLUSIONS: LTOT effects on Hb and PaCO2 are regulated by an Hb-dependent gradient which seems independent of the original impairment of blood gases and of effects on oxygenation.","DOI":"10.1186/2049-6958-7-15","ISSN":"2049-6958","note":"PMID: 22958465","journalAbbreviation":"Multidiscip Respir Med","language":"eng","author":[{"family":"Dal Negro","given":"Roberto W"},{"family":"Tognella","given":"Silvia"},{"family":"Bonadiman","given":"Luca"},{"family":"Turco","given":"Paola"}],"issued":{"date-parts":[["2012"]]},"PMID":"22958465"}}],"schema":""} (19) These patients not only presented with a different COPD severity, but have a dissimilar health status overall, together with varying burden of concomitant disorders that could cause anemia, so results are not easily comparable.COPD diagnosis, according to ERS/ATS guidelines, should be based on specific spirometric criteria. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6igTc5rA","properties":{"formattedCitation":"(20)","plainCitation":"(20)"},"citationItems":[{"id":822,"uris":[""],"uri":[""],"itemData":{"id":822,"type":"article-journal","title":"Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary","container-title":"American journal of respiratory and critical care medicine","page":"347-365","volume":"187","issue":"4","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) is a global health problem, and since 2001, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published its strategy document for the diagnosis and management of COPD. This executive summary presents the main contents of the second 5-year revision of the GOLD document that has implemented some of the vast knowledge about COPD accumulated over the last years. Today, GOLD recommends that spirometry is required for the clinical diagnosis of COPD to avoid misdiagnosis and to ensure proper evaluation of severity of airflow limitation. The document highlights that the assessment of the patient with COPD should always include assessment of (1) symptoms, (2) severity of airflow limitation, (3) history of exacerbations, and (4) comorbidities. The first three points can be used to evaluate level of symptoms and risk of future exacerbations, and this is done in a way that splits patients with COPD into four categories-A, B, C, and D. Nonpharmacologic and pharmacologic management of COPD match this assessment in an evidence-based attempt to relieve symptoms and reduce risk of exacerbations. Identification and treatment of comorbidities must have high priority, and a separate section in the document addresses management of comorbidities as well as COPD in the presence of comorbidities. The revised document also contains a new section on exacerbations of COPD. The GOLD initiative will continue to bring COPD to the attention of all relevant shareholders and will hopefully inspire future national and local guidelines on the management of COPD.","DOI":"10.1164/rccm.201204-0596PP","ISSN":"1535-4970","note":"PMID: 22878278","shortTitle":"Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","language":"eng","author":[{"family":"Vestbo","given":"J?rgen"},{"family":"Hurd","given":"Suzanne S"},{"family":"Agustí","given":"Alvar G"},{"family":"Jones","given":"Paul W"},{"family":"Vogelmeier","given":"Claus"},{"family":"Anzueto","given":"Antonio"},{"family":"Barnes","given":"Peter J"},{"family":"Fabbri","given":"Leonardo M"},{"family":"Martinez","given":"Fernando J"},{"family":"Nishimura","given":"Masaharu"},{"family":"Stockley","given":"Robert A"},{"family":"Sin","given":"Don D"},{"family":"Rodriguez-Roisin","given":"Roberto"}],"issued":{"date-parts":[["2013",2,15]]},"PMID":"22878278"}}],"schema":""} (20) Nevertheless, this is not the case for every published study which has investigated anemia prevalence in COPD patients. Although most authors have used the post-bronchodilator Forced Expiratory Volume in 1 second/Forced Vital Capacity (FEV1/FVC)<0.7, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"S4SudE3d","properties":{"formattedCitation":"(4)","plainCitation":"(4)"},"citationItems":[{"id":256,"uris":[""],"uri":[""],"itemData":{"id":256,"type":"article-journal","title":"Haemoglobin level and its clinical impact in a cohort of patients with COPD","container-title":"The European respiratory journal","page":"923-929","volume":"29","issue":"5","source":"NCBI PubMed","abstract":"Haemoglobin (Hb) abnormalities in chronic obstructive pulmonary disease (COPD) are not well characterised. The present authors investigated the prevalence and association of abnormal Hb with clinical outcomes. Analysis of a prospective cohort of stable COPD outpatients (n = 683) in a USA Veterans Administration pulmonary clinic was undertaken. Patients were classified as anaemic (Hb <13 g.dL(-1)), polycythemic (Hb > or =17 g.dL(-1) and > or =15 g.dL(-1) for males and females, respectively) or normal. Demographic characteristics and physiological/functional outcomes were compared between groups. Regression models adjusting for confounders examined the independent association of anaemia with clinical outcomes. Anaemia was present in 116 (17%) patients and polycythemia in 40 (6%). While the only values that differed between polycythemic and nonpolycythemic patients were mean body mass index and Hb, anaemic patients showed a significantly higher modified Medical Research Council dyspnoea scale score (2.8 versus 2.6), lower 6-min walk distance (265 versus 325 m) and shorter median survival (49 versus 74 months) than nonanaemic patients. In regression models, anaemia independently predicted dyspnoea and reduced exercise capacity. Anaemia in chronic obstructive pulmonary disease was an independent risk factor for reduced functional capacity. Polycythemia prevalence was low and had no association with worsened outcomes. Further work is required to evaluate the effect of anaemia correction on outcomes in chronic obstructive pulmonary disease.","DOI":"10.1183/09031936.00137106","ISSN":"0903-1936","note":"PMID: 17251227","journalAbbreviation":"Eur. Respir. J.","language":"eng","author":[{"family":"Cote","given":"C"},{"family":"Zilberberg","given":"M D"},{"family":"Mody","given":"S H"},{"family":"Dordelly","given":"L J"},{"family":"Celli","given":"B"}],"issued":{"date-parts":[["2007",5]]},"PMID":"17251227"}}],"schema":""} (4) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Yg8QCthJ","properties":{"formattedCitation":"(7)","plainCitation":"(7)"},"citationItems":[{"id":180,"uris":[""],"uri":[""],"itemData":{"id":180,"type":"article-journal","title":"Anemia and survival in chronic obstructive pulmonary disease: a dichotomous rather than a continuous predictor","container-title":"Respiration; international review of thoracic diseases","page":"126-131","volume":"85","issue":"2","source":"NCBI PubMed","abstract":"BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disorder characterized by high mortality. Hemoglobin (Hb) concentration has a prognostic impact on COPD patients receiving long-term oxygen treatment, but its value as an independent predictor of survival among stable COPD outpatients has not been fully clarified by previous studies.\nOBJECTIVES: To investigate the potential association between anemia and survival in a cohort of stable COPD outpatients.\nMETHODS: A cohort of stable COPD patients, who had had their first spirometry, blood count and serum chemistry profile done between October 1999 and November 2010 were retrospectively analyzed. Patients with heart failure, renal impairment, malignancy, recent hemorrhage and other causes of anemia were excluded. Variables that were found to be univariately associated with survival entered a multivariate stepwise Cox regression analysis model, to allow independent predictors of survival to be identified.\nRESULTS: Of 294 patients (67.9 ± 9.8 years old, 64.6% male) 15.6% were anemic (Hb <13 g/dl). The median survival differed significantly between anemic [68.7 (18.1-91.5) months] and nonanemic [79.8 (57.5-98.4) months, p = 0.035] individuals. Independent predictors of mortality in the total population were anemia [hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.06-3.29], age (HR 1.08, 95% CI 1.04-1.12) and forced expiratory volume in 1 s (FEV(1)) % predicted (HR 0.94, 95% CI 0.92-0.97); the Hb concentration was neither univariately nor multivariately associated with mortality.\nCONCLUSION: This is the first study to indicate that anemia (but not the Hb value) is independently associated with survival in stable COPD outpatients. It would be better to treat this as a categorical variable in future scoring systems.","DOI":"10.1159/000338792","ISSN":"1423-0356","note":"PMID: 22759351","shortTitle":"Anemia and survival in chronic obstructive pulmonary disease","journalAbbreviation":"Respiration","language":"eng","author":[{"family":"Boutou","given":"Afroditi K"},{"family":"Karrar","given":"Sarah"},{"family":"Hopkinson","given":"Nicholas S"},{"family":"Polkey","given":"Michael I"}],"issued":{"date-parts":[["2013"]]},"PMID":"22759351"}}],"schema":""} (7) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6JcnUPt0","properties":{"formattedCitation":"(8)","plainCitation":"(8)"},"citationItems":[{"id":198,"uris":[""],"uri":[""],"itemData":{"id":198,"type":"article-journal","title":"Anemia of chronic disease in chronic obstructive pulmonary disease: a case-control study of cardiopulmonary exercise responses","container-title":"Respiration; international review of thoracic diseases","page":"237-245","volume":"82","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia may be present in patients with chronic obstructive pulmonary disease (COPD) and further impair their functional capacity.\nOBJECTIVES: This study investigated the prevalence of anemia of chronic disease (ACD) in COPD patients and its impact on dyspnea and exercise capacity, utilizing cardiopulmonary exercise testing (CPET).\nMETHODS: ACD prevalence was assessed in 283 consecutive patients with stable COPD (263 males, 60 females; age 60.31 ± 5.34 years; percent forced expiratory volume in 1 s 46.94 ± 6.12). ACD diagnosis was based on a combination of clinical and laboratory parameters [hemoglobin (Hb) <13 g/dl for males, <12 g/dl for females; ferritin >30 ng/ml; total iron-binding capacity <250 μg/dl, and transferrin saturation rate between 15 and 50%]. Twenty-seven patients who were identified with ACD (cases) and 27 matched nonanemic patients (controls) completed maximal CPET, and data were compared between the groups.\nRESULTS: ACD was diagnosed in 29 patients, which represents a prevalence of 10.24%; the severity of anemia was generally mild (mean Hb: 12.19 ± 0.66 g/dl). Patients with ACD had a higher Medical Research Council dyspnea score compared to controls (2.78 ± 0.44 vs. 2.07 ± 0.55; p <0.001) and lower peak O(2) uptake (VO(2)) (59.54 ± 17.17 vs. 71.26 ± 11.85% predicted; p <0.05), peak work rate (54.94 ± 21.42 vs. 68.72 ± 20.81% predicted; p <0.05) and peak VO(2)/heart rate (69.07 ± 17.26 vs. 82.04 ± 18.22% predicted; p <0.05). There was also a trend for a lower anaerobic threshold (48.48 ± 15.16 vs. 55.42 ± 9.99% predicted; p = 0.062). No exercise parameter indicative of respiratory limitation differed between the groups.\nCONCLUSIONS: ACD occurs in approximately 10% of stable COPD patients and has a negative impact on dyspnea and circulatory efficiency during exercise.","DOI":"10.1159/000326899","ISSN":"1423-0356","note":"PMID: 21576921","shortTitle":"Anemia of chronic disease in chronic obstructive pulmonary disease","journalAbbreviation":"Respiration","language":"eng","author":[{"family":"Boutou","given":"Afroditi K"},{"family":"Stanopoulos","given":"Ioannis"},{"family":"Pitsiou","given":"Georgia G"},{"family":"Kontakiotis","given":"Theodoros"},{"family":"Kyriazis","given":"George"},{"family":"Sichletidis","given":"Lazaros"},{"family":"Argyropoulou","given":"Paraskevi"}],"issued":{"date-parts":[["2011"]]},"PMID":"21576921"}}],"schema":""} (8) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"PCPB70Qu","properties":{"formattedCitation":"(9)","plainCitation":"(9)"},"citationItems":[{"id":234,"uris":[""],"uri":[""],"itemData":{"id":234,"type":"article-journal","title":"Anemia and inflammation in COPD","container-title":"Chest","page":"825-829","volume":"127","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia in patients with COPD and its pathophysiology is an understudied issue.\nMETHODS: In a group of 101 COPD patients (FEV(1) percentage of predicted, 37 +/- 2% [mean +/- SEM]; mean age, 61 +/- 1 years; 35% female gender), the prevalence of anemia and its relationship to body mass and weight loss, inflammatory parameters, and erythropoietin levels was determined. Data were compared to a control group (healthy persons with matched age) in order to identify potential factors that may influence the development of anemia in patients with COPD.\nRESULTS: Anemia was diagnosed in 13 patients (hemoglobin levels < 13.5 mg/dL in male patients and < 12.0 mg/dL in female patients), which represents a prevalence of 13%. Anemic COPD patients showed elevated erythropoietin levels (41.8 +/- 25.4 U/L vs 16.3 +/- 2.9 U/L) and an increased inflammatory response compared to nonanemic patients. A significant inverse correlation of hemoglobin vs erythropoietin (r = - 0.84, p < 0.01) was observed in anemic COPD patients, but not in the nonanemic group.\nCONCLUSION: Anemic COPD patients show high erythropoietin levels, which may indicate presence of erythropoietin resistance. The latter may be mediated through inflammatory mechanisms, which is typical for anemia of chronic illness.","DOI":"10.1378/chest.127.3.825","ISSN":"0012-3692","note":"PMID: 15764763","journalAbbreviation":"Chest","language":"eng","author":[{"family":"John","given":"Matthias"},{"family":"Hoernig","given":"Soeren"},{"family":"Doehner","given":"Wolfram"},{"family":"Okonko","given":"Darlington D"},{"family":"Witt","given":"Christian"},{"family":"Anker","given":"Stefan D"}],"issued":{"date-parts":[["2005",3]]},"PMID":"15764763"}}],"schema":""} (9) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"iTHbap5g","properties":{"formattedCitation":"(14)","plainCitation":"(14)"},"citationItems":[{"id":168,"uris":[""],"uri":[""],"itemData":{"id":168,"type":"article-journal","title":"Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de medicina interna (ESMI) study","container-title":"Chest","page":"1126-1133","volume":"142","issue":"5","source":"NCBI PubMed","abstract":"BACKGROUND: Comorbidities are frequent in patients hospitalized for COPD exacerbation, but little is known about their relation with short-term mortality and hospital readmissions. Our hypothesis is that the frequency and type of comorbidities impair the prognosis within 12 weeks after discharge.\nMETHODS: A longitudinal, observational, multicenter study of patients hospitalized for a COPD exacerbation with spirometric confirmation was performed. Comorbidity information was collected using the Charlson index and a questionnaire that included other common conditions not included in this index. Dyspnea, functional status, and previous hospitalization for COPD or other reasons among other variables were investigated. Information on mortality and readmissions for COPD or other causes was collected up to 3 months after discharge.\nRESULTS: We studied 606 patients, 594 men (89.9%), with a mean (SD) age of 72.6 (9.9) years and a postbronchodilator FEV1 of 43.2% (21.2). The mean Charlson index score was 3.1 (2.0). On admission, 63.4% of patients had arterial hypertension, 35.8% diabetes mellitus, 32.8% chronic heart failure, 20.8% ischemic heart disease, 19.3% anemia, and 34% dyslipemia. Twenty-seven patients (4.5%) died within 3 months. The Charlson index was an independent predictor of mortality (P &lt; .003; OR,1.23; 95% CI, 1.07-1.40), even after adjustment for age, FEV1, and functional status measured with the Katz index. Comorbidity was also related with the need for hospitalization from the ED, length of stay, and hospital readmissions for COPD or other causes.\nCONCLUSIONS: Comorbidities are common in patients hospitalized for a COPD exacerbation, and they are related to short-term prognosis.","DOI":"10.1378/chest.11-2413","ISSN":"1931-3543","note":"PMID: 23303399","shortTitle":"Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD","journalAbbreviation":"Chest","language":"eng","author":[{"family":"Almagro","given":"Pedro"},{"family":"Cabrera","given":"Francisco Javier"},{"family":"Diez","given":"Jesus"},{"family":"Boixeda","given":"Ramon"},{"family":"Alonso Ortiz","given":"M Belen"},{"family":"Murio","given":"Cristina"},{"family":"Soriano","given":"Joan B"},{"family":"Working Group on COPD , Spanish Society of Internal Medicine","given":""}],"issued":{"date-parts":[["2012",11]]},"PMID":"23303399"}}],"schema":""} (14) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vCJG7Avs","properties":{"formattedCitation":"(2)","plainCitation":"(2)"},"citationItems":[{"id":162,"uris":[""],"uri":[""],"itemData":{"id":162,"type":"article-journal","title":"Role of Anemia in Home Oxygen Therapy in Chronic Obstructive Pulmonary Disease Patients","container-title":"American journal of therapeutics","source":"NCBI PubMed","abstract":"Anemia is a known comorbidity found in chronic obstructive pulmonary disease (COPD) patients. Hypoxemia is common and basically due to ventilation/perfusion (V/Q) mismatch in COPD. Anemia, by decreasing arterial oxygen content, may be a contributing factor for decreased delivery of oxygen to tissues. The objective of this study is to determine if anemia is a factor in qualifying COPD patients for home oxygen therapy. The study was designed as a retrospective, cross-sectional, observational chart review. Patients who were referred for home oxygen therapy evaluation were selected from the computerized patient record system. Demographic data, oxygen saturation at rest and during exercise, pulmonary function test results, hemoglobin level, medications, reason for anemia, comorbid diseases, and smoking status were recorded. The χ tests, independent sample t tests, and logistic regression were used for statistical analysis. Only 356 of total 478 patient referrals had a diagnosis of COPD over a 2-year period. Although 39 of them were excluded, 317 patients were included in the study. The overall rate of anemia was 38% in all COPD patients. Anemia was found significantly more frequent in COPD patients on home oxygen therapy (46%) than those not on home oxygen therapy (18.5%) (P < 0.0001). Mean saturation of peripheral oxygen values were significantly lower in anemic COPD patients both at rest and during exercise (P < 0.0001). Also, in COPD patients, age, Global Initiative for Chronic Obstructive Lung Disease class, smoking status, hemoglobin level, hematocrit, percent of forced expiratory volume in first second, forced expiratory volume in first second/forced vital capacity, residual volume/total lung volume, percent of carbon monoxide diffusion capacity were significantly different between home oxygen therapy and those not on home oxygen therapy (P < 0.05). Multivariate logistic regression showed that anemia remained a strong predictor for long-term oxygen therapy use in COPD patients after adjusting for other significant parameters. Anemic COPD patients are more hypoxic especially during exercise than those who are not anemic. We conclude that anemia is a contributing factor in qualifying COPD patients for home oxygen therapy.","DOI":"10.1097/MJT.0b013e3182785f7c","ISSN":"1536-3686","note":"PMID: 23567789","journalAbbreviation":"Am J Ther","language":"ENG","author":[{"family":"Copur","given":"Ahmet Sinan"},{"family":"Fulambarker","given":"Ashok"},{"family":"Molnar","given":"Janos"},{"family":"Nadeem","given":"Rashid"},{"family":"McCormack","given":"Charles"},{"family":"Ganesh","given":"Aarthi"},{"family":"Kheir","given":"Fayez"},{"family":"Hamon","given":"Sara"}],"issued":{"date-parts":[["2013",4,5]]},"PMID":"23567789"}}],"schema":""} (2) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oVC6040o","properties":{"formattedCitation":"(21)","plainCitation":"(21)"},"citationItems":[{"id":170,"uris":[""],"uri":[""],"itemData":{"id":170,"type":"article-journal","title":"Anemia is associated with bone mineral density in chronic obstructive pulmonary disease","container-title":"COPD","page":"286-292","volume":"10","issue":"3","source":"NCBI PubMed","abstract":"OBJECTIVE: Patients with chronic obstructive pulmonary disease (COPD) often suffer from systemic co-morbidities, including anemia. However, anemia is related to multiple outcomes in COPD and in other chronic diseases, but it's impact is underestimated in COPD. The objective of the present study was to relate anemia in patients with COPD with disease-related outcomes, systemic inflammation and COPD related co-morbidities.\nMETHODS: Data of 321 patients with COPD admitted for pulmonary rehabilitation were analysed. Besides general characteristics, lung function, body composition, arterial gases and plasma haemoglobin concentration, disease-related outcomes (health-related quality of life by St. George's Respiratory Questionnaire, 6-minute walking distance, mMRC dyspnea scale, and BODE index), systemic inflammation (C-reactive protein (CRP)) and self-reported and objectified co-morbidities (low muscle mass, osteoporosis, renal failure, risk for undernutrition) were taken into account.\nRESULTS: First, 20% of the patients were anemic, and 8% was polycythemic. Polycythemic patients had a lower proportion of men and a lower proportion of low muscle mass compared to the other groups. Anemic patients had higher plasma CRP levels and lower total body bone mineral density compared to the other groups. There was no difference in disease-related outcomes or other co-morbidities in the patients with and without anemia. Even after adjustment for confounders, anemia was an independent determinant for higher CRP levels and lower bone mineral density.\nCONCLUSION: Anemia is frequently present in patients with COPD and there is evidence that it is associated with lower whole body bone mineral density.","DOI":"10.3109/15412555.2012.744390","ISSN":"1541-2563","note":"PMID: 23272661","journalAbbreviation":"COPD","language":"eng","author":[{"family":"Rutten","given":"Erica P A"},{"family":"Franssen","given":"Frits M E"},{"family":"Spruit","given":"Martijn A"},{"family":"Wouters","given":"Emiel F M"}],"issued":{"date-parts":[["2013",6]]},"PMID":"23272661"}}],"schema":""} (21) several have applied the ICD 9/10 codes ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"njzIwovE","properties":{"formattedCitation":"(13)","plainCitation":"(13)"},"citationItems":[{"id":188,"uris":[""],"uri":[""],"itemData":{"id":188,"type":"article-journal","title":"Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor","container-title":"Current medical research and opinion","page":"617-622","volume":"28","issue":"4","source":"NCBI PubMed","abstract":"OBJECTIVE: The prevalence of comorbid anemia in patients with COPD ranges from 7.5% to 34%. The aim of this study is to determine if anemia is a risk factor for readmission in COPD patients.\nMETHODS: This study analyzed the hospital data of 289,077 adults with acute exacerbations of COPD admitted to the hospital at any public center in Spain, in 2006 and 2007. We calculated the prevalence of anemia and compared readmissions between COPD patients with and without anemia. Multiple regression analyses were carried out with the aim of determining the risk of readmission attributable to anemia, after the correction of possible confounding variables.\nRESULTS: Of the patients with COPD, 9.8% (n?=?26,899) had a diagnosis of anemia. Anemic patients were older, more likely to be female and had a greater comorbidity burden than non-anemic individuals. Multiple regression modeling revealed that multiple independent factors were associated with an increased risk of readmission in persons with COPD. Anemia was one of the greatest risks: anemic patients had a 25% higher risk of readmission than non-anemic patients (odds ratio [OR], 1.25; 95% confidence interval [CI] 1.21-1.29).\nCONCLUSION: Utilizing an administrative database the authors found that anemia correlates independently with readmission in COPD patients.\nLIMITATIONS: This is a retrospective cohort study and thus subject to multiple forms of bias. Although spirometric evidence of COPD was not available, our case identification methods have been previously validated and found to be accurate in recognizing COPD.","DOI":"10.1185/03007995.2012.675318","ISSN":"1473-4877","note":"PMID: 22409165","shortTitle":"Anemia in chronic obstructive pulmonary disease","journalAbbreviation":"Curr Med Res Opin","language":"eng","author":[{"family":"Barba","given":"Raquel"},{"family":"de Casasola","given":"Gonzalo García"},{"family":"Marco","given":"Javier"},{"family":"Emilio Losa","given":"Juan"},{"family":"Plaza","given":"Susana"},{"family":"Canora","given":"Jesús"},{"family":"Zapatero","given":"Antonio"}],"issued":{"date-parts":[["2012",4]]},"PMID":"22409165"}}],"schema":""} (13) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"aiTNwfTR","properties":{"formattedCitation":"(22)","plainCitation":"(22)"},"citationItems":[{"id":222,"uris":[""],"uri":[""],"itemData":{"id":222,"type":"article-journal","title":"Anemia, costs and mortality in chronic obstructive pulmonary disease","container-title":"Cost effectiveness and resource allocation: C/E","page":"17","volume":"4","source":"NCBI PubMed","abstract":"BACKGROUND: Little is known about cost implications of anemia and its association with mortality in chronic obstructive pulmonary disease (COPD). This claims analysis addresses these questions.\nMETHODS: Using the the US Medicare claims database (1997-2001), this study identified Medicare enrollees with an ICD-9 diagnosis of COPD. Concomitant anemia was identified based on ICD-9 codes or receipt of transfusions. Persons with anemia secondary to another disease state, a nutritional deficiency or a hereditary disease were excluded. Medicare claims and payments, resource utilization and mortality were compared between COPD patients with and without anemia.\nRESULTS: Of the 132,424 enrollees with a COPD diagnosis, 21% (n = 27,932) had concomitant anemia. At baseline, anemic patients were older, had more co-morbidities and higher rates of health care resource use than non-anemic individuals with COPD. In a univariate analysis annual Medicare payments for persons with anemia were more than double for those without anemia ($1,466 vs. $649, p < 0.001), the direction maintained in all categories of payments. Adjusting for demographics, co-morbidities, and other markers of disease severity revealed that anemia was independently associated with $3,582 incremental increase per patient (95% CI: $3,299 to $3,865) in Medicare annual reimbursements. The mortality rate among COPD patients with anemia was 262 vs. 133 deaths per 1,000 person-years among those without anemia (p < 0.001).\nCONCLUSION: Anemia was present in 21% of COPD patients. Although more prevalent in more severely ill COPD patients, anemia significantly and independently contributes to the costs of care for COPD and is associated with increased mortality.","DOI":"10.1186/1478-7547-4-17","ISSN":"1478-7547","note":"PMID: 17042950","journalAbbreviation":"Cost Eff Resour Alloc","language":"eng","author":[{"family":"Halpern","given":"Michael T"},{"family":"Zilberberg","given":"Marya D"},{"family":"Schmier","given":"Jordana K"},{"family":"Lau","given":"Edmund C"},{"family":"Shorr","given":"Andrew F"}],"issued":{"date-parts":[["2006"]]},"PMID":"17042950"}}],"schema":""} (22) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"J4qanSDB","properties":{"formattedCitation":"(23)","plainCitation":"(23)"},"citationItems":[{"id":230,"uris":[""],"uri":[""],"itemData":{"id":230,"type":"article-journal","title":"Prevalence of anemia in chronic obstructive pulmonary disease: comparison to other chronic diseases","container-title":"International journal of cardiology","page":"365-370","volume":"111","issue":"3","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) is a multisystemic inflammatory disease characterized by pulmonary and extrapulmonary symptoms. The impaired lung function has long-term implications on metabolism and homeostasis of many organ systems such as the skeleton, heart, brain and skeletal muscle. The occurrence and prevalence of anemia in COPD has rarely been studied. Anemia is such a common and simple clinical finding that we may underestimate its physiological relevance in COPD. The aim of the study was to retrospectively investigate the prevalence of anemia in a large population of COPD patients and to compare it to patients with chronic heart failure, renal insufficiency, cancer and asthma. A population of 7337 patients that was treated in the University Hospital Charité, Berlin, Germany, from 1996 to 2003 was subsetted according to the ICD-9/10 code of the discharge diagnoses into the above-mentioned diagnoses groups. The overall prevalence of anemia in COPD patients was 23.1%. It was comparable to the prevalence of anemia we found in patients with chronic heart failure (23.3%). Patients with renal insufficiency and cancer presented the highest anemia frequencies. The high prevalence of anemia in hospitalised COPD patients that were treated mostly for exacerbations gives evidence that anemia is also a comorbidity in COPD and may contribute to exercise limitation and dyspnoea.","DOI":"10.1016/j.ijcard.2005.07.043","ISSN":"0167-5273","note":"PMID: 16242192","shortTitle":"Prevalence of anemia in chronic obstructive pulmonary disease","journalAbbreviation":"Int. J. Cardiol.","language":"eng","author":[{"family":"John","given":"Matthias"},{"family":"Lange","given":"Andre"},{"family":"Hoernig","given":"Soeren"},{"family":"Witt","given":"Christian"},{"family":"Anker","given":"Stefan D"}],"issued":{"date-parts":[["2006",8,28]]},"PMID":"16242192"}}],"schema":""} (23) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"U2ZUtfW9","properties":{"formattedCitation":"(24)","plainCitation":"(24)"},"citationItems":[{"id":216,"uris":[""],"uri":[""],"itemData":{"id":216,"type":"article-journal","title":"Anemia in chronic obstructive pulmonary disease: epidemiology and economic implications","container-title":"Current medical research and opinion","page":"1123-1130","volume":"24","issue":"4","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia in chronic illness is associated with increased healthcare resource utilization (HRU) and costs. In COPD, it occurs frequently and influences both clinical and economic outcomes. Because no data studies have been performed either in a single center or a subpopulation of COPD patients, anemia's influence on the outcomes is not fully understood.\nRESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study in a large healthcare database to quantify prevalence, HRU and costs of anemia in COPD. From 1997 to 2005, patients > or = 45 years of age with an ICD-9 diagnosis code for COPD and > 3.5 years of follow-up were included. Anemia was defined by the WHO criteria. Other disease states for which anemia is a known complication were excluded. We calculated the prevalence of anemia and compared annual HRU and costs between COPD patients with and without anemia. Multiple regression analysis adjusted for the effects of age, gender, race, length of enrollment, diagnosing physician specialty, co-morbidity burden, anemia and COPD severity.\nRESULTS: Of the 2404 patients with COPD, 33% (n = 788) had a diagnosis of anemia. Anemic patients were older, more likely to be male and non-Caucasian, and had a greater co-morbidity burden than non-anemic individuals. Annual costs for COPD patients with anemia were more than twice those for patients without anemia ($17,240 vs. 6492, p < 0.001, unadjusted). HRU was also significantly greater among anemic than non-anemic COPD patients (p < 0.0001). In a multiple regression analysis, anemia accounted for $7929 per patient (95% CI: $5572-10,599) of the total costs of care.\nLIMITATIONS: This is a retrospective cohort study and thus subject to multiple forms of bias. Although spirometric evidence of COPD was available only for a subgroup of patients, our case identification methods have been previously validated and found to be accurate in recognizing COPD.\nCONCLUSIONS: Anemia is a common co-morbidity in COPD. It is significantly associated with an increase in HRU and costs of care for COPD, independent of demographic and clinical patient characteristics.","DOI":"10.1185/030079908X280699","ISSN":"1473-4877","note":"PMID: 18331668","shortTitle":"Anemia in chronic obstructive pulmonary disease","journalAbbreviation":"Curr Med Res Opin","language":"eng","author":[{"family":"Shorr","given":"Andrew F"},{"family":"Doyle","given":"John"},{"family":"Stern","given":"Lee"},{"family":"Dolgitser","given":"Margarita"},{"family":"Zilberberg","given":"Marya D"}],"issued":{"date-parts":[["2008",4]]},"PMID":"18331668"}}],"schema":""} (24) or identified COPD patients from existing databases without describing the diagnostic criteria in detail. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"n76goXCF","properties":{"formattedCitation":"(19)","plainCitation":"(19)"},"citationItems":[{"id":176,"uris":[""],"uri":[""],"itemData":{"id":176,"type":"article-journal","title":"Changes in blood hemoglobin and blood gases PaO2 and PaCO2 in severe COPD overa three-year telemonitored program of long-term oxygen treatment","container-title":"Multidisciplinary respiratory medicine","page":"15","volume":"7","issue":"1","source":"NCBI PubMed","abstract":"BACKGROUND: Information on the effects of long-term oxygen treatment (LTOT) on blood hemoglobin (Hb) in severe COPD are limited. The aim was to assess blood Hb values in severe COPD, and investigate the time-course of both Hb and blood gas changes during a 3-year telemetric LTOT.\nMETHODS: A cohort of 132 severe COPD patients (94 males; 71.4?years?±?8.8?sd), newly admitted to the tele-LTOT program, was investigated. Subjects were divided according to their original blood Hb: group A: <13?g/dL; group B: ≥13?<?15?g/dL; group C: ≥ 5?<?16?g/dL; group D: ≥16?g/dL. Blood Hb (g/dL), PaO2 and PaCO2 (mmHg), SaO2 (%), and BMI were measured at LTOT admission (t0), and at least quarterly over three years (t1-t3). Wilcoxon test was used to compare t0 vs. t1 values; linear regression to assess a possible Hb-BMI relationship; ANOVA to compare changes in Hb time-courses over the 3?years.\nRESULTS: LTOT induced a systematic increase of PaO2, and changes were significant since the first year (from 52.1?mmHg?±?6.6sd to 65.1?mmHg?±?8.7?sd, p?<?0.001). Changes in SaO2 were quite similar. Comparable and equally significant trends were seen in all subgroups (p?<?0.001). PaCO2 dropped within the first year of LTOT (from 49.4?mmHg?±?9.1sd to 45.9?mmHg ±7.5?sd, p?<?0.001): the t0-t1 comparison proved significant (p?<?0.01) only in subgroups with the highest basal Hb, who showed a further PaCO2 decline over the remaining two years (p?<?0.001). Hb tended to normalization during LTOT only in subgroups with basal Hb?>?15?g/dl (ANOVA p?<?0.001); anemic subjects (Hb?<?13?g/dl) ameliorated not significantly in the same period (ANOVA?=?0.5). Survival was independent of the original blood Hb. Anemia and polyglobulia are differently prevalent in COPD, the latter being the most represented in our cohort. LTOT affected both conditions, but to a different extent and according to different time-courses. The most striking Hb improvement was in polyglobulic patients in whom also PaO2, PaCO2 and SaO2 dramatically improved. In anemic subjects effects were smaller and slower, oxygenation being equally ameliorated by LTOT.\nCONCLUSIONS: LTOT effects on Hb and PaCO2 are regulated by an Hb-dependent gradient which seems independent of the original impairment of blood gases and of effects on oxygenation.","DOI":"10.1186/2049-6958-7-15","ISSN":"2049-6958","note":"PMID: 22958465","journalAbbreviation":"Multidiscip Respir Med","language":"eng","author":[{"family":"Dal Negro","given":"Roberto W"},{"family":"Tognella","given":"Silvia"},{"family":"Bonadiman","given":"Luca"},{"family":"Turco","given":"Paola"}],"issued":{"date-parts":[["2012"]]},"PMID":"22958465"}}],"schema":""} (19) Thus it is possible that in these studies patients with respiratory symptoms of airflow obstruction without fulfilling spirometric criteria for COPD were misclassified, creating more variation regarding anemia prevalence.Furthermore, anemia definition has been variable in published studies. According to current World Health Organization, anemia in the general population is defined by hemoglobin (Hb) levels <13 g/dL in male and <12 g/dL in female ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"i2mskNpe","properties":{"formattedCitation":"(25)","plainCitation":"(25)"},"citationItems":[{"id":314,"uris":[""],"uri":[""],"itemData":{"id":314,"type":"article-journal","title":"Nutritional anaemias. Report of a WHO scientific group","container-title":"World Health Organization technical report series","page":"5-37","volume":"405","source":"NCBI PubMed","ISSN":"0512-3054","note":"PMID: 4975372","journalAbbreviation":"World Health Organ Tech Rep Ser","language":"eng","issued":{"date-parts":[["1968"]]},"PMID":"4975372"}}],"schema":""} (25) and these thresholds have been used by several authors in order to identify anemic COPD patients. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"nSS3xOAi","properties":{"formattedCitation":"(5)","plainCitation":"(5)"},"citationItems":[{"id":174,"uris":[""],"uri":[""],"itemData":{"id":174,"type":"article-journal","title":"Hemoglobin Levels Above Anemia Thresholds Are Maximally Predictive for Long-Term Survival in COPD With Chronic Respiratory Failure","container-title":"Respiratory care","page":"1204-1212","volume":"58","issue":"7","source":"NCBI PubMed","abstract":"BACKGROUND: In patients with COPD, chronic anemia is known as an unfavorable prognostic factor. Whether the association between hemoglobin (Hb) levels and long-term survival is restricted to anemia or extends to higher Hb levels has not yet been systematically assessed.\nMETHODS: We determined Hb levels in 309 subjects with COPD and chronic respiratory failure prior to initiation of noninvasive ventilation, accounting for confounders that might affect Hb. Subjects were categorized as anemic (Hb < 12 g/dL in females, Hb < 13 g/dL in males), polycythemic (Hb ≥ 15 g/dL in females, Hb ≥ 17 g/dL in males), or normocythemic. In addition, percentiles of Hb values were analyzed with regard to mortality from any cause.\nRESULTS: Two-hundred seven subjects (67.0%) showed normal Hb levels, 46 (14.9%) had anemia, and 56 (18.1%) had polycythemia. Polycythemic subjects showed a higher survival rate than anemic (P = .01) and normocythemic subjects (P = .043). In a univariate Cox hazards model, Hb was associated with long-term survival (hazard ratio 0.855; 95% CI 0.783-0.934, P < .001). The 58th percentiles of Hb (14.3 g/dL in females, 15.1 g/dL in males) yielded the highest discriminative value for predicting survival (hazard ratio 0.463, 95% CI 0.324-0.660, P < .001). In the multivariate analysis this cutoff was an independent predictor for survival (hazard ratio 0.627, 95% CI 0.414-0.949, P = .03), in addition to age and body mass index.\nCONCLUSIONS: In subjects with COPD and chronic respiratory failure undergoing treatment with noninvasive ventilation and LTOT, high Hb levels are associated with better long-term survival. The optimal cutoff level for prediction was above the established threshold defining anemia. Thus, predicting survival only on the basis of anemia does not fully utilize the prognostic potential of Hb values in COPD.","DOI":"10.4187/respcare.01961","ISSN":"1943-3654","note":"PMID: 23232736","journalAbbreviation":"Respir Care","language":"eng","author":[{"family":"Kollert","given":"Florian"},{"family":"Tippelt","given":"Andrea"},{"family":"Müller","given":"Carolin"},{"family":"J?rres","given":"Rudolf A"},{"family":"Porzelius","given":"Christine"},{"family":"Pfeifer","given":"Michael"},{"family":"Budweiser","given":"Stephan"}],"issued":{"date-parts":[["2013",7]]},"PMID":"23232736"}}],"schema":""} (5) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"93OFFQD7","properties":{"formattedCitation":"(8)","plainCitation":"(8)"},"citationItems":[{"id":198,"uris":[""],"uri":[""],"itemData":{"id":198,"type":"article-journal","title":"Anemia of chronic disease in chronic obstructive pulmonary disease: a case-control study of cardiopulmonary exercise responses","container-title":"Respiration; international review of thoracic diseases","page":"237-245","volume":"82","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia may be present in patients with chronic obstructive pulmonary disease (COPD) and further impair their functional capacity.\nOBJECTIVES: This study investigated the prevalence of anemia of chronic disease (ACD) in COPD patients and its impact on dyspnea and exercise capacity, utilizing cardiopulmonary exercise testing (CPET).\nMETHODS: ACD prevalence was assessed in 283 consecutive patients with stable COPD (263 males, 60 females; age 60.31 ± 5.34 years; percent forced expiratory volume in 1 s 46.94 ± 6.12). ACD diagnosis was based on a combination of clinical and laboratory parameters [hemoglobin (Hb) <13 g/dl for males, <12 g/dl for females; ferritin >30 ng/ml; total iron-binding capacity <250 μg/dl, and transferrin saturation rate between 15 and 50%]. Twenty-seven patients who were identified with ACD (cases) and 27 matched nonanemic patients (controls) completed maximal CPET, and data were compared between the groups.\nRESULTS: ACD was diagnosed in 29 patients, which represents a prevalence of 10.24%; the severity of anemia was generally mild (mean Hb: 12.19 ± 0.66 g/dl). Patients with ACD had a higher Medical Research Council dyspnea score compared to controls (2.78 ± 0.44 vs. 2.07 ± 0.55; p <0.001) and lower peak O(2) uptake (VO(2)) (59.54 ± 17.17 vs. 71.26 ± 11.85% predicted; p <0.05), peak work rate (54.94 ± 21.42 vs. 68.72 ± 20.81% predicted; p <0.05) and peak VO(2)/heart rate (69.07 ± 17.26 vs. 82.04 ± 18.22% predicted; p <0.05). There was also a trend for a lower anaerobic threshold (48.48 ± 15.16 vs. 55.42 ± 9.99% predicted; p = 0.062). No exercise parameter indicative of respiratory limitation differed between the groups.\nCONCLUSIONS: ACD occurs in approximately 10% of stable COPD patients and has a negative impact on dyspnea and circulatory efficiency during exercise.","DOI":"10.1159/000326899","ISSN":"1423-0356","note":"PMID: 21576921","shortTitle":"Anemia of chronic disease in chronic obstructive pulmonary disease","journalAbbreviation":"Respiration","language":"eng","author":[{"family":"Boutou","given":"Afroditi K"},{"family":"Stanopoulos","given":"Ioannis"},{"family":"Pitsiou","given":"Georgia G"},{"family":"Kontakiotis","given":"Theodoros"},{"family":"Kyriazis","given":"George"},{"family":"Sichletidis","given":"Lazaros"},{"family":"Argyropoulou","given":"Paraskevi"}],"issued":{"date-parts":[["2011"]]},"PMID":"21576921"}}],"schema":""} (8) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"GiEP9zGk","properties":{"formattedCitation":"(11)","plainCitation":"(11)"},"citationItems":[{"id":226,"uris":[""],"uri":[""],"itemData":{"id":226,"type":"article-journal","title":"Association between anemia and quality of life in a population sample of individuals with chronic obstructive pulmonary disease","container-title":"BMC pulmonary medicine","page":"23","volume":"6","source":"NCBI PubMed","abstract":"BACKGROUND: Several studies investigated the association of anemia with health related quality of life (HRQL) in patients with chronic disease. However, there is little evidence regarding the association of anemia with HRQL in patients with chronic obstructive pulmonary disease (COPD).\nMETHODS: This is a post-hoc analysis of a study which enrolled a population of adults aged 35-79 randomly selected from residents of Erie and Niagara Counties, NY, between 1996 and 2000. In addition to demographic information and physical measurements, we obtained spirometry data and hemoglobin levels. We used modified Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria to define COPD, and World Health Organization (WHO) criteria to define anemia. To assess HRQL we used the Short Form-36 (SF-36) to assess physical functioning (PF), physical component summary (PCS) measures and mental component summary (MCS) measures.\nRESULTS: In the entire study population (n = 2704), respondents with anemia had lower scores on the physical functioning domain [45.4 (SD10.9) vs. 49.2 (SD 9.1); p < 0.0001]. Among patients with COPD (n = 495) the PF scores (39.9 vs. 45.4) and the PCS (41.9 vs. 45.9) were significantly lower in individuals with anemia compared to those without. In multiple regression analysis, the association between hemoglobin and PCS was positive (regression coefficient 0.02, p = 0.003). There was no significant association of hemoglobin with PF scores or the mental component summary measure after adjusting for covariates in patients with COPD.\nCONCLUSION: In patients with moderate to very severe COPD anemia may be associated with worse HRQL. However, co-morbidities may explain part or all of this association in these patients.","DOI":"10.1186/1471-2466-6-23","ISSN":"1471-2466","note":"PMID: 16953872","journalAbbreviation":"BMC Pulm Med","language":"eng","author":[{"family":"Krishnan","given":"Gokul"},{"family":"Grant","given":"Brydon J"},{"family":"Muti","given":"Paola C"},{"family":"Mishra","given":"Archana"},{"family":"Ochs-Balcom","given":"Heather M"},{"family":"Freudenheim","given":"Jo L"},{"family":"Trevisan","given":"Maurizio"},{"family":"Schünemann","given":"Holger J"}],"issued":{"date-parts":[["2006"]]},"PMID":"16953872"}}],"schema":""} (11) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bEF33YHh","properties":{"formattedCitation":"(15)","plainCitation":"(15)"},"citationItems":[{"id":208,"uris":[""],"uri":[""],"itemData":{"id":208,"type":"article-journal","title":"Modification of COPD presentation during the last 25 years","container-title":"COPD","page":"345-351","volume":"7","issue":"5","source":"NCBI PubMed","abstract":"During the last decades progress has been made in the treatment of Chronic Obstructive Pulmonary Disease (COPD). We compared a random sample of patients admitted for an exacerbation in the period 2001-2005 (n = 101), with a random sample of patients hospitalized for the same reason in the period 1980-1984 (n = 51). Patients of the 2001-2005 cohort had a lower FEV1 (48 ± 3 vs. 41 ± 2% predicted, p = 0.01) for similar mean age, gender and body- mass index when compared to the historical sample. Co-morbidities, according to the Charlson's index, were more prevalent in the 2001-2005 cohort compared to the 1980-1984 cohort, with a reduction of hemoglobin (13.9 ± 0.2 gr/dl vs. 14.9 ± 0.2, p < 0.01) and higher prevalence of anemia in the most recent cohort. We found an increase in the use of cardiovascular drugs and respiratory medications over time with exception for the long-term use of oxygen. Despite lower FEV1 and more prevalent co-morbidities, no difference in length of hospitalization (13.6 ± 1.4 days vs. 12.7 ± 0.7 days, p = 0.52) and 30 months survival post-exacerbation was noted (66.6% vs. 69.3%, p = 0.85). Over the course of 20 years, the presentation of COPD patients admitted for an exacerbation seems to be changed towards a more severe phenotype with lower FEV1 and more co-morbidities. As the length of hospitalization and the overall survival were not different between the two samples, a currently improved management of COPD can be hypothesized.","DOI":"10.3109/15412555.2010.510546","ISSN":"1541-2563","note":"PMID: 20854049","journalAbbreviation":"COPD","language":"eng","author":[{"family":"Fremault","given":"Antoine"},{"family":"Janssens","given":"Wim"},{"family":"Beaucage","given":"Fran?ois"},{"family":"Celis","given":"Geert"},{"family":"Pérez-Bogerd","given":"Silvia"},{"family":"Decramer","given":"Marc"}],"issued":{"date-parts":[["2010",10]]},"PMID":"20854049"}}],"schema":""} (15) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"H6KsMXhQ","properties":{"formattedCitation":"(26)","plainCitation":"(26)"},"citationItems":[{"id":248,"uris":[""],"uri":[""],"itemData":{"id":248,"type":"article-journal","title":"Prevalence of Anaemia Associated With Chronic Obstructive Pulmonary Disease. Study of Associated Variables","container-title":"Archivos de bronconeumologia","source":"NCBI PubMed","abstract":"BACKGROUND: Anaemia is one of the extrapulmonary manifestations of chronic obstructive pulmonary disease (COPD). Its real prevalence, physiopathology and clinical repercussion are unknown. The objectives of our study were: to determine the prevalence of anaemia in patients with stable COPD not attributable to other causes and to establish the relationship of anaemia with clinical, prognostic and inflammatory markers with an important role in COPD.\nMETHODS: The study included stable COPD patients with no other known causes of anaemia. The following tests were carried out: respiratory function tests; serum determination of erythropoietin and inflammatory markers: high sensitivity C-reactive protein (hs-CRP), fibrinogen, interleukin 6 (IL-6), interleukin 8 (IL-8) and tumour necrosis factor α (TNF-α). Body mass index (BMI), Charlson and BODE indices, the number of exacerbations in the previous year, dyspnoea and quality of life were also calculated.\nRESULTS: One hundred and thirty patients were included. Anaemia prevalence was 6.2%. Mean haemoglobin value in anaemic patients was 11.9±0.95g/dL. Patients with anaemia had a lower BMI (P=.03), higher Charlson index (P=.002), more elevated erythropoietin levels (P=.016), a tendency to present a lower FEV1% value (P=.08) and significantly lower IL-6 values when compared to non-anaemic patients (P=.003).\nCONCLUSIONS: In our series, the anaemia associated with COPD was less prevalent than that published in the literature to date, and was related to certain clinical and inflammatory markers.","DOI":"10.1016/j.arbres.2013.04.007","ISSN":"1579-2129","note":"PMID: 23791383","journalAbbreviation":"Arch. Bronconeumol.","language":"ENG, SPA","author":[{"family":"Comeche Casanova","given":"Lorena"},{"family":"Echave-Sustaeta","given":"Jose María"},{"family":"García Luján","given":"Ricardo"},{"family":"Albarrán Lozano","given":"Irene"},{"family":"Alonso González","given":"Pablo"},{"family":"Llorente Alonso","given":"María Jesús"}],"issued":{"date-parts":[["2013",6,19]]},"PMID":"23791383"}}],"schema":""} (26) However, the use of a Hb <12 g/dL threshold to define anemia in postmenopausal women is currently under debate, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"q5Fe9iuU","properties":{"formattedCitation":"(27)","plainCitation":"(27)"},"citationItems":[{"id":316,"uris":[""],"uri":[""],"itemData":{"id":316,"type":"article-journal","title":"Anemia in the elderly: a public health crisis in hematology","container-title":"Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program","page":"528-532","source":"NCBI PubMed","abstract":"Over 3 million people in the United States aged 65 years and older are anemic. This condition is associated with significant functional impairment and, perhaps, increased mortality. In March 2004, the American Society of Hematology (in conjunction with the National Institute of Aging) convened a \"blue ribbon\" panel of twenty physicians who are experts on various aspects of this topic. This paper highlights important consensus concepts resulting from that meeting. In particular, four areas of thought are shared. First, the epidemiology of anemia in the elderly is reviewed, including its definition, its expression in different racial groups, and its wide-ranging manifestations. Second, the pathophysiology of anemia in the elderly is reviewed as pertains to three general etiological categories (nutritional, chronic diseases, and so-called \"unexplained\" anemias). Particular emphasis is given to pathophysiologic mechanisms of anemia that are potentially unique to this age group. Third, a practical approach to the diagnosis and management of anemia for this patient population for the practicing hematologist is provided. Finally, the public health implications of anemia in the elderly for key stakeholder constituencies will be discussed in the oral presentation.","DOI":"10.1182/asheducation-2005.1.528","ISSN":"1520-4383","note":"PMID: 16304431","shortTitle":"Anemia in the elderly","journalAbbreviation":"Hematology Am Soc Hematol Educ Program","language":"eng","author":[{"family":"Guralnik","given":"Jack M"},{"family":"Ershler","given":"William B"},{"family":"Schrier","given":"Stanley L"},{"family":"Picozzi","given":"Vincent J"}],"issued":{"date-parts":[["2005"]]},"PMID":"16304431"}}],"schema":""} (27) so the 13g/dL threshold for both male and female has also been applied. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zYHvQdJP","properties":{"formattedCitation":"(4)","plainCitation":"(4)"},"citationItems":[{"id":256,"uris":[""],"uri":[""],"itemData":{"id":256,"type":"article-journal","title":"Haemoglobin level and its clinical impact in a cohort of patients with COPD","container-title":"The European respiratory journal","page":"923-929","volume":"29","issue":"5","source":"NCBI PubMed","abstract":"Haemoglobin (Hb) abnormalities in chronic obstructive pulmonary disease (COPD) are not well characterised. The present authors investigated the prevalence and association of abnormal Hb with clinical outcomes. Analysis of a prospective cohort of stable COPD outpatients (n = 683) in a USA Veterans Administration pulmonary clinic was undertaken. Patients were classified as anaemic (Hb <13 g.dL(-1)), polycythemic (Hb > or =17 g.dL(-1) and > or =15 g.dL(-1) for males and females, respectively) or normal. Demographic characteristics and physiological/functional outcomes were compared between groups. Regression models adjusting for confounders examined the independent association of anaemia with clinical outcomes. Anaemia was present in 116 (17%) patients and polycythemia in 40 (6%). While the only values that differed between polycythemic and nonpolycythemic patients were mean body mass index and Hb, anaemic patients showed a significantly higher modified Medical Research Council dyspnoea scale score (2.8 versus 2.6), lower 6-min walk distance (265 versus 325 m) and shorter median survival (49 versus 74 months) than nonanaemic patients. In regression models, anaemia independently predicted dyspnoea and reduced exercise capacity. Anaemia in chronic obstructive pulmonary disease was an independent risk factor for reduced functional capacity. Polycythemia prevalence was low and had no association with worsened outcomes. Further work is required to evaluate the effect of anaemia correction on outcomes in chronic obstructive pulmonary disease.","DOI":"10.1183/09031936.00137106","ISSN":"0903-1936","note":"PMID: 17251227","journalAbbreviation":"Eur. Respir. J.","language":"eng","author":[{"family":"Cote","given":"C"},{"family":"Zilberberg","given":"M D"},{"family":"Mody","given":"S H"},{"family":"Dordelly","given":"L J"},{"family":"Celli","given":"B"}],"issued":{"date-parts":[["2007",5]]},"PMID":"17251227"}}],"schema":""} (4) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"A1RESmXd","properties":{"formattedCitation":"(7)","plainCitation":"(7)"},"citationItems":[{"id":180,"uris":[""],"uri":[""],"itemData":{"id":180,"type":"article-journal","title":"Anemia and survival in chronic obstructive pulmonary disease: a dichotomous rather than a continuous predictor","container-title":"Respiration; international review of thoracic diseases","page":"126-131","volume":"85","issue":"2","source":"NCBI PubMed","abstract":"BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disorder characterized by high mortality. Hemoglobin (Hb) concentration has a prognostic impact on COPD patients receiving long-term oxygen treatment, but its value as an independent predictor of survival among stable COPD outpatients has not been fully clarified by previous studies.\nOBJECTIVES: To investigate the potential association between anemia and survival in a cohort of stable COPD outpatients.\nMETHODS: A cohort of stable COPD patients, who had had their first spirometry, blood count and serum chemistry profile done between October 1999 and November 2010 were retrospectively analyzed. Patients with heart failure, renal impairment, malignancy, recent hemorrhage and other causes of anemia were excluded. Variables that were found to be univariately associated with survival entered a multivariate stepwise Cox regression analysis model, to allow independent predictors of survival to be identified.\nRESULTS: Of 294 patients (67.9 ± 9.8 years old, 64.6% male) 15.6% were anemic (Hb <13 g/dl). The median survival differed significantly between anemic [68.7 (18.1-91.5) months] and nonanemic [79.8 (57.5-98.4) months, p = 0.035] individuals. Independent predictors of mortality in the total population were anemia [hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.06-3.29], age (HR 1.08, 95% CI 1.04-1.12) and forced expiratory volume in 1 s (FEV(1)) % predicted (HR 0.94, 95% CI 0.92-0.97); the Hb concentration was neither univariately nor multivariately associated with mortality.\nCONCLUSION: This is the first study to indicate that anemia (but not the Hb value) is independently associated with survival in stable COPD outpatients. It would be better to treat this as a categorical variable in future scoring systems.","DOI":"10.1159/000338792","ISSN":"1423-0356","note":"PMID: 22759351","shortTitle":"Anemia and survival in chronic obstructive pulmonary disease","journalAbbreviation":"Respiration","language":"eng","author":[{"family":"Boutou","given":"Afroditi K"},{"family":"Karrar","given":"Sarah"},{"family":"Hopkinson","given":"Nicholas S"},{"family":"Polkey","given":"Michael I"}],"issued":{"date-parts":[["2013"]]},"PMID":"22759351"}}],"schema":""} (7) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gst2DCeC","properties":{"formattedCitation":"(2)","plainCitation":"(2)"},"citationItems":[{"id":162,"uris":[""],"uri":[""],"itemData":{"id":162,"type":"article-journal","title":"Role of Anemia in Home Oxygen Therapy in Chronic Obstructive Pulmonary Disease Patients","container-title":"American journal of therapeutics","source":"NCBI PubMed","abstract":"Anemia is a known comorbidity found in chronic obstructive pulmonary disease (COPD) patients. Hypoxemia is common and basically due to ventilation/perfusion (V/Q) mismatch in COPD. Anemia, by decreasing arterial oxygen content, may be a contributing factor for decreased delivery of oxygen to tissues. The objective of this study is to determine if anemia is a factor in qualifying COPD patients for home oxygen therapy. The study was designed as a retrospective, cross-sectional, observational chart review. Patients who were referred for home oxygen therapy evaluation were selected from the computerized patient record system. Demographic data, oxygen saturation at rest and during exercise, pulmonary function test results, hemoglobin level, medications, reason for anemia, comorbid diseases, and smoking status were recorded. The χ tests, independent sample t tests, and logistic regression were used for statistical analysis. Only 356 of total 478 patient referrals had a diagnosis of COPD over a 2-year period. Although 39 of them were excluded, 317 patients were included in the study. The overall rate of anemia was 38% in all COPD patients. Anemia was found significantly more frequent in COPD patients on home oxygen therapy (46%) than those not on home oxygen therapy (18.5%) (P < 0.0001). Mean saturation of peripheral oxygen values were significantly lower in anemic COPD patients both at rest and during exercise (P < 0.0001). Also, in COPD patients, age, Global Initiative for Chronic Obstructive Lung Disease class, smoking status, hemoglobin level, hematocrit, percent of forced expiratory volume in first second, forced expiratory volume in first second/forced vital capacity, residual volume/total lung volume, percent of carbon monoxide diffusion capacity were significantly different between home oxygen therapy and those not on home oxygen therapy (P < 0.05). Multivariate logistic regression showed that anemia remained a strong predictor for long-term oxygen therapy use in COPD patients after adjusting for other significant parameters. Anemic COPD patients are more hypoxic especially during exercise than those who are not anemic. We conclude that anemia is a contributing factor in qualifying COPD patients for home oxygen therapy.","DOI":"10.1097/MJT.0b013e3182785f7c","ISSN":"1536-3686","note":"PMID: 23567789","journalAbbreviation":"Am J Ther","language":"ENG","author":[{"family":"Copur","given":"Ahmet Sinan"},{"family":"Fulambarker","given":"Ashok"},{"family":"Molnar","given":"Janos"},{"family":"Nadeem","given":"Rashid"},{"family":"McCormack","given":"Charles"},{"family":"Ganesh","given":"Aarthi"},{"family":"Kheir","given":"Fayez"},{"family":"Hamon","given":"Sara"}],"issued":{"date-parts":[["2013",4,5]]},"PMID":"23567789"}}],"schema":""} (2) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7z1Gzu4N","properties":{"formattedCitation":"(19)","plainCitation":"(19)"},"citationItems":[{"id":176,"uris":[""],"uri":[""],"itemData":{"id":176,"type":"article-journal","title":"Changes in blood hemoglobin and blood gases PaO2 and PaCO2 in severe COPD overa three-year telemonitored program of long-term oxygen treatment","container-title":"Multidisciplinary respiratory medicine","page":"15","volume":"7","issue":"1","source":"NCBI PubMed","abstract":"BACKGROUND: Information on the effects of long-term oxygen treatment (LTOT) on blood hemoglobin (Hb) in severe COPD are limited. The aim was to assess blood Hb values in severe COPD, and investigate the time-course of both Hb and blood gas changes during a 3-year telemetric LTOT.\nMETHODS: A cohort of 132 severe COPD patients (94 males; 71.4?years?±?8.8?sd), newly admitted to the tele-LTOT program, was investigated. Subjects were divided according to their original blood Hb: group A: <13?g/dL; group B: ≥13?<?15?g/dL; group C: ≥ 5?<?16?g/dL; group D: ≥16?g/dL. Blood Hb (g/dL), PaO2 and PaCO2 (mmHg), SaO2 (%), and BMI were measured at LTOT admission (t0), and at least quarterly over three years (t1-t3). Wilcoxon test was used to compare t0 vs. t1 values; linear regression to assess a possible Hb-BMI relationship; ANOVA to compare changes in Hb time-courses over the 3?years.\nRESULTS: LTOT induced a systematic increase of PaO2, and changes were significant since the first year (from 52.1?mmHg?±?6.6sd to 65.1?mmHg?±?8.7?sd, p?<?0.001). Changes in SaO2 were quite similar. Comparable and equally significant trends were seen in all subgroups (p?<?0.001). PaCO2 dropped within the first year of LTOT (from 49.4?mmHg?±?9.1sd to 45.9?mmHg ±7.5?sd, p?<?0.001): the t0-t1 comparison proved significant (p?<?0.01) only in subgroups with the highest basal Hb, who showed a further PaCO2 decline over the remaining two years (p?<?0.001). Hb tended to normalization during LTOT only in subgroups with basal Hb?>?15?g/dl (ANOVA p?<?0.001); anemic subjects (Hb?<?13?g/dl) ameliorated not significantly in the same period (ANOVA?=?0.5). Survival was independent of the original blood Hb. Anemia and polyglobulia are differently prevalent in COPD, the latter being the most represented in our cohort. LTOT affected both conditions, but to a different extent and according to different time-courses. The most striking Hb improvement was in polyglobulic patients in whom also PaO2, PaCO2 and SaO2 dramatically improved. In anemic subjects effects were smaller and slower, oxygenation being equally ameliorated by LTOT.\nCONCLUSIONS: LTOT effects on Hb and PaCO2 are regulated by an Hb-dependent gradient which seems independent of the original impairment of blood gases and of effects on oxygenation.","DOI":"10.1186/2049-6958-7-15","ISSN":"2049-6958","note":"PMID: 22958465","journalAbbreviation":"Multidiscip Respir Med","language":"eng","author":[{"family":"Dal Negro","given":"Roberto W"},{"family":"Tognella","given":"Silvia"},{"family":"Bonadiman","given":"Luca"},{"family":"Turco","given":"Paola"}],"issued":{"date-parts":[["2012"]]},"PMID":"22958465"}}],"schema":""} (19) Controversy is even more evident regarding COPD patients admitted in the ICU, since there is as yet no accepted definition of abnormal hemoglobin values in the critically ill. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9myjDtex","properties":{"formattedCitation":"(18)","plainCitation":"(18)"},"citationItems":[{"id":200,"uris":[""],"uri":[""],"itemData":{"id":200,"type":"article-journal","title":"Anemia and 90-day mortality in COPD patients requiring invasive mechanical ventilation","container-title":"Clinical epidemiology","page":"1-5","volume":"3","source":"NCBI PubMed","abstract":"BACKGROUND: There are data to suggest that anemia is associated with increased mortality in patients with chronic obstructive pulmonary disease (COPD). In contrast, critically ill patients with low hemoglobin levels (4.3-5.5 mmol/L, 7.0-9.0 g/dL) in general do not appear to have a worsened clinical outcome. The effects of anemia in critically ill patients with COPD remain to be clarified. We examined the association between anemia (hemoglobin <7.4 mmol/L, <12.0 g/dL) and 90-day mortality in COPD patients with acute respiratory failure treated with invasive mechanical ventilation in a single-institution follow-up study.\nMETHOD: We identified all COPD patients at our institution (n = 222) admitted for the first time to the intensive care unit (ICU) requiring invasive mechanical ventilation in 1994-2004. Data on patient characteristics (eg, hemoglobin, pH, blood transfusions, and Charlson Comorbidity Index), and mortality were obtained from population-based clinical and administrative registries and medical records. We used Cox's regression analysis to estimate mortality rate ratios (MRR) in COPD patients with and without anemia.\nRESULTS: A total of 42 (18%) COPD patients were anemic at time of initiating invasive mechanical ventilation. The overall 90-day mortality among anemic COPD patients was 57.1% versus 25% in nonanemic patients. The corresponding adjusted 90-day MRR was 2.6 (95% confidence interval 1.5-4.5). Restricting analyses to patients not treated with blood transfusions during their intensive care unit stay did not materially change the MRR.\nCONCLUSION: We found anemia to be associated with increased mortality among COPD patients with acute respiratory failure requiring invasive mechanical ventilation.","DOI":"10.2147/CLEP.S12885","ISSN":"1179-1349","note":"PMID: 21326654","journalAbbreviation":"Clin Epidemiol","language":"eng","author":[{"family":"Rasmussen","given":"Lone"},{"family":"Christensen","given":"Steffen"},{"family":"Lenler-Petersen","given":"Poul"},{"family":"Johnsen","given":"S?ren P"}],"issued":{"date-parts":[["2011"]]},"PMID":"21326654"}}],"schema":""} (18) A final problem with many of the studies is that the prevalence of anemia was often not measured in an age and sex matched population with similar comorbidity burden (control population); ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ZYPDr0Yl","properties":{"formattedCitation":"(3)","plainCitation":"(3)"},"citationItems":[{"id":232,"uris":[""],"uri":[""],"itemData":{"id":232,"type":"article-journal","title":"Prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy","container-title":"Chest","page":"1201-1208","volume":"128","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Although traditionally associated with polycythemia, COPD has a systemic inflammatory component that could interfere with erythropoiesis. This study describes the distribution and prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy (LTOT).\nMETHODS: A total of 2,524 patients with COPD, FEV1/vital capacity (VC) < 70%, FEV1 < 80% of predicted, and Pa(O2) < 7.3 kPa in whom a hematocrit was available at entry was identified between 1980 and 1999 in the French Association Nationale pour le Traitement à Domicile de l'Insuffisance Respiratoire chronic respiratory insufficiency and home-care database (male/female ratio, 5/1; mean +/- SD age, 68 +/- 10 years for men, and 70 +/- 10 years for women). Correlations between hematocrit, demographic data, and pulmonary function data were examined. A multivariate Cox proportional hazard regression was performed to identify prognostic factors.\nRESULTS: Mean hematocrit was 45.9 +/- 7.0% in men and 43.9 +/- 6.0% in women (< 39% in 12.6% of men, and < 36% in 8.2% of women) according to the World Health Organization definition of anemia. Hematocrit was negatively correlated with age (r = - 0.245) and FEV1/VC (r = - 0.068) and was positively correlated with Pa(CO2) (r = 0.161) and body mass index (r = 0.127). Multivariate analysis found hematocrit to be an independent predictor of survival, hospital admission rate, and cumulative duration of hospitalization. The 3-year survival was 24% (95% confidence interval, 16 to 33%) when the hematocrit was < 35%, and 70% (63 to 76%) when the hematocrit was > or = 55%.\nCONCLUSIONS: A low hematocrit is not uncommon in LTOT/COPD patients. Hematocrit is negatively associated with mortality and morbidity. Whether the association is causative or not and whether or not corrective measures are warranted remain to be determined.","DOI":"10.1378/chest.128.3.1201","ISSN":"0012-3692","note":"PMID: 16162707","journalAbbreviation":"Chest","language":"eng","author":[{"family":"Chambellan","given":"Arnaud"},{"family":"Chailleux","given":"Edmond"},{"family":"Similowski","given":"Thomas"},{"family":"ANTADIR Observatory Group","given":""}],"issued":{"date-parts":[["2005",9]]},"PMID":"16162707"}}],"schema":""} (3) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"uX5cA6Sd","properties":{"formattedCitation":"(9)","plainCitation":"(9)"},"citationItems":[{"id":234,"uris":[""],"uri":[""],"itemData":{"id":234,"type":"article-journal","title":"Anemia and inflammation in COPD","container-title":"Chest","page":"825-829","volume":"127","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia in patients with COPD and its pathophysiology is an understudied issue.\nMETHODS: In a group of 101 COPD patients (FEV(1) percentage of predicted, 37 +/- 2% [mean +/- SEM]; mean age, 61 +/- 1 years; 35% female gender), the prevalence of anemia and its relationship to body mass and weight loss, inflammatory parameters, and erythropoietin levels was determined. Data were compared to a control group (healthy persons with matched age) in order to identify potential factors that may influence the development of anemia in patients with COPD.\nRESULTS: Anemia was diagnosed in 13 patients (hemoglobin levels < 13.5 mg/dL in male patients and < 12.0 mg/dL in female patients), which represents a prevalence of 13%. Anemic COPD patients showed elevated erythropoietin levels (41.8 +/- 25.4 U/L vs 16.3 +/- 2.9 U/L) and an increased inflammatory response compared to nonanemic patients. A significant inverse correlation of hemoglobin vs erythropoietin (r = - 0.84, p < 0.01) was observed in anemic COPD patients, but not in the nonanemic group.\nCONCLUSION: Anemic COPD patients show high erythropoietin levels, which may indicate presence of erythropoietin resistance. The latter may be mediated through inflammatory mechanisms, which is typical for anemia of chronic illness.","DOI":"10.1378/chest.127.3.825","ISSN":"0012-3692","note":"PMID: 15764763","journalAbbreviation":"Chest","language":"eng","author":[{"family":"John","given":"Matthias"},{"family":"Hoernig","given":"Soeren"},{"family":"Doehner","given":"Wolfram"},{"family":"Okonko","given":"Darlington D"},{"family":"Witt","given":"Christian"},{"family":"Anker","given":"Stefan D"}],"issued":{"date-parts":[["2005",3]]},"PMID":"15764763"}}],"schema":""} (9) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vrqqnYsb","properties":{"formattedCitation":"(14)","plainCitation":"(14)"},"citationItems":[{"id":168,"uris":[""],"uri":[""],"itemData":{"id":168,"type":"article-journal","title":"Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de medicina interna (ESMI) study","container-title":"Chest","page":"1126-1133","volume":"142","issue":"5","source":"NCBI PubMed","abstract":"BACKGROUND: Comorbidities are frequent in patients hospitalized for COPD exacerbation, but little is known about their relation with short-term mortality and hospital readmissions. Our hypothesis is that the frequency and type of comorbidities impair the prognosis within 12 weeks after discharge.\nMETHODS: A longitudinal, observational, multicenter study of patients hospitalized for a COPD exacerbation with spirometric confirmation was performed. Comorbidity information was collected using the Charlson index and a questionnaire that included other common conditions not included in this index. Dyspnea, functional status, and previous hospitalization for COPD or other reasons among other variables were investigated. Information on mortality and readmissions for COPD or other causes was collected up to 3 months after discharge.\nRESULTS: We studied 606 patients, 594 men (89.9%), with a mean (SD) age of 72.6 (9.9) years and a postbronchodilator FEV1 of 43.2% (21.2). The mean Charlson index score was 3.1 (2.0). On admission, 63.4% of patients had arterial hypertension, 35.8% diabetes mellitus, 32.8% chronic heart failure, 20.8% ischemic heart disease, 19.3% anemia, and 34% dyslipemia. Twenty-seven patients (4.5%) died within 3 months. The Charlson index was an independent predictor of mortality (P &lt; .003; OR,1.23; 95% CI, 1.07-1.40), even after adjustment for age, FEV1, and functional status measured with the Katz index. Comorbidity was also related with the need for hospitalization from the ED, length of stay, and hospital readmissions for COPD or other causes.\nCONCLUSIONS: Comorbidities are common in patients hospitalized for a COPD exacerbation, and they are related to short-term prognosis.","DOI":"10.1378/chest.11-2413","ISSN":"1931-3543","note":"PMID: 23303399","shortTitle":"Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD","journalAbbreviation":"Chest","language":"eng","author":[{"family":"Almagro","given":"Pedro"},{"family":"Cabrera","given":"Francisco Javier"},{"family":"Diez","given":"Jesus"},{"family":"Boixeda","given":"Ramon"},{"family":"Alonso Ortiz","given":"M Belen"},{"family":"Murio","given":"Cristina"},{"family":"Soriano","given":"Joan B"},{"family":"Working Group on COPD , Spanish Society of Internal Medicine","given":""}],"issued":{"date-parts":[["2012",11]]},"PMID":"23303399"}}],"schema":""} (14) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4BnZeh99","properties":{"formattedCitation":"(26)","plainCitation":"(26)"},"citationItems":[{"id":248,"uris":[""],"uri":[""],"itemData":{"id":248,"type":"article-journal","title":"Prevalence of Anaemia Associated With Chronic Obstructive Pulmonary Disease. Study of Associated Variables","container-title":"Archivos de bronconeumologia","source":"NCBI PubMed","abstract":"BACKGROUND: Anaemia is one of the extrapulmonary manifestations of chronic obstructive pulmonary disease (COPD). Its real prevalence, physiopathology and clinical repercussion are unknown. The objectives of our study were: to determine the prevalence of anaemia in patients with stable COPD not attributable to other causes and to establish the relationship of anaemia with clinical, prognostic and inflammatory markers with an important role in COPD.\nMETHODS: The study included stable COPD patients with no other known causes of anaemia. The following tests were carried out: respiratory function tests; serum determination of erythropoietin and inflammatory markers: high sensitivity C-reactive protein (hs-CRP), fibrinogen, interleukin 6 (IL-6), interleukin 8 (IL-8) and tumour necrosis factor α (TNF-α). Body mass index (BMI), Charlson and BODE indices, the number of exacerbations in the previous year, dyspnoea and quality of life were also calculated.\nRESULTS: One hundred and thirty patients were included. Anaemia prevalence was 6.2%. Mean haemoglobin value in anaemic patients was 11.9±0.95g/dL. Patients with anaemia had a lower BMI (P=.03), higher Charlson index (P=.002), more elevated erythropoietin levels (P=.016), a tendency to present a lower FEV1% value (P=.08) and significantly lower IL-6 values when compared to non-anaemic patients (P=.003).\nCONCLUSIONS: In our series, the anaemia associated with COPD was less prevalent than that published in the literature to date, and was related to certain clinical and inflammatory markers.","DOI":"10.1016/j.arbres.2013.04.007","ISSN":"1579-2129","note":"PMID: 23791383","journalAbbreviation":"Arch. Bronconeumol.","language":"ENG, SPA","author":[{"family":"Comeche Casanova","given":"Lorena"},{"family":"Echave-Sustaeta","given":"Jose María"},{"family":"García Luján","given":"Ricardo"},{"family":"Albarrán Lozano","given":"Irene"},{"family":"Alonso González","given":"Pablo"},{"family":"Llorente Alonso","given":"María Jesús"}],"issued":{"date-parts":[["2013",6,19]]},"PMID":"23791383"}}],"schema":""} (26) thus it is difficult to establish whether the prevalence of anemia is increased in COPD.In one of the first studies in the field, John et al studied 101 stable severe COPD outpatients; the prevalence of anemia was 13%. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sjyINt3b","properties":{"formattedCitation":"(9)","plainCitation":"(9)"},"citationItems":[{"id":234,"uris":[""],"uri":[""],"itemData":{"id":234,"type":"article-journal","title":"Anemia and inflammation in COPD","container-title":"Chest","page":"825-829","volume":"127","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia in patients with COPD and its pathophysiology is an understudied issue.\nMETHODS: In a group of 101 COPD patients (FEV(1) percentage of predicted, 37 +/- 2% [mean +/- SEM]; mean age, 61 +/- 1 years; 35% female gender), the prevalence of anemia and its relationship to body mass and weight loss, inflammatory parameters, and erythropoietin levels was determined. Data were compared to a control group (healthy persons with matched age) in order to identify potential factors that may influence the development of anemia in patients with COPD.\nRESULTS: Anemia was diagnosed in 13 patients (hemoglobin levels < 13.5 mg/dL in male patients and < 12.0 mg/dL in female patients), which represents a prevalence of 13%. Anemic COPD patients showed elevated erythropoietin levels (41.8 +/- 25.4 U/L vs 16.3 +/- 2.9 U/L) and an increased inflammatory response compared to nonanemic patients. A significant inverse correlation of hemoglobin vs erythropoietin (r = - 0.84, p < 0.01) was observed in anemic COPD patients, but not in the nonanemic group.\nCONCLUSION: Anemic COPD patients show high erythropoietin levels, which may indicate presence of erythropoietin resistance. The latter may be mediated through inflammatory mechanisms, which is typical for anemia of chronic illness.","DOI":"10.1378/chest.127.3.825","ISSN":"0012-3692","note":"PMID: 15764763","journalAbbreviation":"Chest","language":"eng","author":[{"family":"John","given":"Matthias"},{"family":"Hoernig","given":"Soeren"},{"family":"Doehner","given":"Wolfram"},{"family":"Okonko","given":"Darlington D"},{"family":"Witt","given":"Christian"},{"family":"Anker","given":"Stefan D"}],"issued":{"date-parts":[["2005",3]]},"PMID":"15764763"}}],"schema":""} (9) Although patients with disorders that could be accompanied by low Hb levels, such as heart failure, gastrointestinal bleeding and malignancy were excluded, renal function was not investigated. Results of two more studies conducted in COPD hospital outpatients of various severities were comparable, with anemia prevalence ranging between 15%-17.1%. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Mve25J9p","properties":{"formattedCitation":"(7)","plainCitation":"(7)"},"citationItems":[{"id":180,"uris":[""],"uri":[""],"itemData":{"id":180,"type":"article-journal","title":"Anemia and survival in chronic obstructive pulmonary disease: a dichotomous rather than a continuous predictor","container-title":"Respiration; international review of thoracic diseases","page":"126-131","volume":"85","issue":"2","source":"NCBI PubMed","abstract":"BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disorder characterized by high mortality. Hemoglobin (Hb) concentration has a prognostic impact on COPD patients receiving long-term oxygen treatment, but its value as an independent predictor of survival among stable COPD outpatients has not been fully clarified by previous studies.\nOBJECTIVES: To investigate the potential association between anemia and survival in a cohort of stable COPD outpatients.\nMETHODS: A cohort of stable COPD patients, who had had their first spirometry, blood count and serum chemistry profile done between October 1999 and November 2010 were retrospectively analyzed. Patients with heart failure, renal impairment, malignancy, recent hemorrhage and other causes of anemia were excluded. Variables that were found to be univariately associated with survival entered a multivariate stepwise Cox regression analysis model, to allow independent predictors of survival to be identified.\nRESULTS: Of 294 patients (67.9 ± 9.8 years old, 64.6% male) 15.6% were anemic (Hb <13 g/dl). The median survival differed significantly between anemic [68.7 (18.1-91.5) months] and nonanemic [79.8 (57.5-98.4) months, p = 0.035] individuals. Independent predictors of mortality in the total population were anemia [hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.06-3.29], age (HR 1.08, 95% CI 1.04-1.12) and forced expiratory volume in 1 s (FEV(1)) % predicted (HR 0.94, 95% CI 0.92-0.97); the Hb concentration was neither univariately nor multivariately associated with mortality.\nCONCLUSION: This is the first study to indicate that anemia (but not the Hb value) is independently associated with survival in stable COPD outpatients. It would be better to treat this as a categorical variable in future scoring systems.","DOI":"10.1159/000338792","ISSN":"1423-0356","note":"PMID: 22759351","shortTitle":"Anemia and survival in chronic obstructive pulmonary disease","journalAbbreviation":"Respiration","language":"eng","author":[{"family":"Boutou","given":"Afroditi K"},{"family":"Karrar","given":"Sarah"},{"family":"Hopkinson","given":"Nicholas S"},{"family":"Polkey","given":"Michael I"}],"issued":{"date-parts":[["2013"]]},"PMID":"22759351"}}],"schema":""} (7) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Uc9xPTXg","properties":{"formattedCitation":"(4)","plainCitation":"(4)"},"citationItems":[{"id":256,"uris":[""],"uri":[""],"itemData":{"id":256,"type":"article-journal","title":"Haemoglobin level and its clinical impact in a cohort of patients with COPD","container-title":"The European respiratory journal","page":"923-929","volume":"29","issue":"5","source":"NCBI PubMed","abstract":"Haemoglobin (Hb) abnormalities in chronic obstructive pulmonary disease (COPD) are not well characterised. The present authors investigated the prevalence and association of abnormal Hb with clinical outcomes. Analysis of a prospective cohort of stable COPD outpatients (n = 683) in a USA Veterans Administration pulmonary clinic was undertaken. Patients were classified as anaemic (Hb <13 g.dL(-1)), polycythemic (Hb > or =17 g.dL(-1) and > or =15 g.dL(-1) for males and females, respectively) or normal. Demographic characteristics and physiological/functional outcomes were compared between groups. Regression models adjusting for confounders examined the independent association of anaemia with clinical outcomes. Anaemia was present in 116 (17%) patients and polycythemia in 40 (6%). While the only values that differed between polycythemic and nonpolycythemic patients were mean body mass index and Hb, anaemic patients showed a significantly higher modified Medical Research Council dyspnoea scale score (2.8 versus 2.6), lower 6-min walk distance (265 versus 325 m) and shorter median survival (49 versus 74 months) than nonanaemic patients. In regression models, anaemia independently predicted dyspnoea and reduced exercise capacity. Anaemia in chronic obstructive pulmonary disease was an independent risk factor for reduced functional capacity. Polycythemia prevalence was low and had no association with worsened outcomes. Further work is required to evaluate the effect of anaemia correction on outcomes in chronic obstructive pulmonary disease.","DOI":"10.1183/09031936.00137106","ISSN":"0903-1936","note":"PMID: 17251227","journalAbbreviation":"Eur. Respir. J.","language":"eng","author":[{"family":"Cote","given":"C"},{"family":"Zilberberg","given":"M D"},{"family":"Mody","given":"S H"},{"family":"Dordelly","given":"L J"},{"family":"Celli","given":"B"}],"issued":{"date-parts":[["2007",5]]},"PMID":"17251227"}}],"schema":""} (4) The only study which used both clinical and laboratory criteria to exclude all potential causes of anemia, apart from anemia of chronic disease, estimated the prevalence of the latter to be 10.2% among stable hospital outpatients. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"J7LUMZ8Y","properties":{"formattedCitation":"(8)","plainCitation":"(8)"},"citationItems":[{"id":198,"uris":[""],"uri":[""],"itemData":{"id":198,"type":"article-journal","title":"Anemia of chronic disease in chronic obstructive pulmonary disease: a case-control study of cardiopulmonary exercise responses","container-title":"Respiration; international review of thoracic diseases","page":"237-245","volume":"82","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia may be present in patients with chronic obstructive pulmonary disease (COPD) and further impair their functional capacity.\nOBJECTIVES: This study investigated the prevalence of anemia of chronic disease (ACD) in COPD patients and its impact on dyspnea and exercise capacity, utilizing cardiopulmonary exercise testing (CPET).\nMETHODS: ACD prevalence was assessed in 283 consecutive patients with stable COPD (263 males, 60 females; age 60.31 ± 5.34 years; percent forced expiratory volume in 1 s 46.94 ± 6.12). ACD diagnosis was based on a combination of clinical and laboratory parameters [hemoglobin (Hb) <13 g/dl for males, <12 g/dl for females; ferritin >30 ng/ml; total iron-binding capacity <250 μg/dl, and transferrin saturation rate between 15 and 50%]. Twenty-seven patients who were identified with ACD (cases) and 27 matched nonanemic patients (controls) completed maximal CPET, and data were compared between the groups.\nRESULTS: ACD was diagnosed in 29 patients, which represents a prevalence of 10.24%; the severity of anemia was generally mild (mean Hb: 12.19 ± 0.66 g/dl). Patients with ACD had a higher Medical Research Council dyspnea score compared to controls (2.78 ± 0.44 vs. 2.07 ± 0.55; p <0.001) and lower peak O(2) uptake (VO(2)) (59.54 ± 17.17 vs. 71.26 ± 11.85% predicted; p <0.05), peak work rate (54.94 ± 21.42 vs. 68.72 ± 20.81% predicted; p <0.05) and peak VO(2)/heart rate (69.07 ± 17.26 vs. 82.04 ± 18.22% predicted; p <0.05). There was also a trend for a lower anaerobic threshold (48.48 ± 15.16 vs. 55.42 ± 9.99% predicted; p = 0.062). No exercise parameter indicative of respiratory limitation differed between the groups.\nCONCLUSIONS: ACD occurs in approximately 10% of stable COPD patients and has a negative impact on dyspnea and circulatory efficiency during exercise.","DOI":"10.1159/000326899","ISSN":"1423-0356","note":"PMID: 21576921","shortTitle":"Anemia of chronic disease in chronic obstructive pulmonary disease","journalAbbreviation":"Respiration","language":"eng","author":[{"family":"Boutou","given":"Afroditi K"},{"family":"Stanopoulos","given":"Ioannis"},{"family":"Pitsiou","given":"Georgia G"},{"family":"Kontakiotis","given":"Theodoros"},{"family":"Kyriazis","given":"George"},{"family":"Sichletidis","given":"Lazaros"},{"family":"Argyropoulou","given":"Paraskevi"}],"issued":{"date-parts":[["2011"]]},"PMID":"21576921"}}],"schema":""} (8) Interestingly, the prevalence of anemia in selected populations with respiratory failure was not very different from that seen in hospital outpatients. Chambellan et al reported that 12.6% male and 8.2% female of the total 2,542 outpatients receiving LTOT were anemic ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"fpZdLFJR","properties":{"formattedCitation":"(3)","plainCitation":"(3)"},"citationItems":[{"id":232,"uris":[""],"uri":[""],"itemData":{"id":232,"type":"article-journal","title":"Prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy","container-title":"Chest","page":"1201-1208","volume":"128","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Although traditionally associated with polycythemia, COPD has a systemic inflammatory component that could interfere with erythropoiesis. This study describes the distribution and prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy (LTOT).\nMETHODS: A total of 2,524 patients with COPD, FEV1/vital capacity (VC) < 70%, FEV1 < 80% of predicted, and Pa(O2) < 7.3 kPa in whom a hematocrit was available at entry was identified between 1980 and 1999 in the French Association Nationale pour le Traitement à Domicile de l'Insuffisance Respiratoire chronic respiratory insufficiency and home-care database (male/female ratio, 5/1; mean +/- SD age, 68 +/- 10 years for men, and 70 +/- 10 years for women). Correlations between hematocrit, demographic data, and pulmonary function data were examined. A multivariate Cox proportional hazard regression was performed to identify prognostic factors.\nRESULTS: Mean hematocrit was 45.9 +/- 7.0% in men and 43.9 +/- 6.0% in women (< 39% in 12.6% of men, and < 36% in 8.2% of women) according to the World Health Organization definition of anemia. Hematocrit was negatively correlated with age (r = - 0.245) and FEV1/VC (r = - 0.068) and was positively correlated with Pa(CO2) (r = 0.161) and body mass index (r = 0.127). Multivariate analysis found hematocrit to be an independent predictor of survival, hospital admission rate, and cumulative duration of hospitalization. The 3-year survival was 24% (95% confidence interval, 16 to 33%) when the hematocrit was < 35%, and 70% (63 to 76%) when the hematocrit was > or = 55%.\nCONCLUSIONS: A low hematocrit is not uncommon in LTOT/COPD patients. Hematocrit is negatively associated with mortality and morbidity. Whether the association is causative or not and whether or not corrective measures are warranted remain to be determined.","DOI":"10.1378/chest.128.3.1201","ISSN":"0012-3692","note":"PMID: 16162707","journalAbbreviation":"Chest","language":"eng","author":[{"family":"Chambellan","given":"Arnaud"},{"family":"Chailleux","given":"Edmond"},{"family":"Similowski","given":"Thomas"},{"family":"ANTADIR Observatory Group","given":""}],"issued":{"date-parts":[["2005",9]]},"PMID":"16162707"}}],"schema":""} (3); these results were similar to the ones of Dal Negro et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"XeW1UOws","properties":{"formattedCitation":"(19)","plainCitation":"(19)"},"citationItems":[{"id":176,"uris":[""],"uri":[""],"itemData":{"id":176,"type":"article-journal","title":"Changes in blood hemoglobin and blood gases PaO2 and PaCO2 in severe COPD overa three-year telemonitored program of long-term oxygen treatment","container-title":"Multidisciplinary respiratory medicine","page":"15","volume":"7","issue":"1","source":"NCBI PubMed","abstract":"BACKGROUND: Information on the effects of long-term oxygen treatment (LTOT) on blood hemoglobin (Hb) in severe COPD are limited. The aim was to assess blood Hb values in severe COPD, and investigate the time-course of both Hb and blood gas changes during a 3-year telemetric LTOT.\nMETHODS: A cohort of 132 severe COPD patients (94 males; 71.4?years?±?8.8?sd), newly admitted to the tele-LTOT program, was investigated. Subjects were divided according to their original blood Hb: group A: <13?g/dL; group B: ≥13?<?15?g/dL; group C: ≥ 5?<?16?g/dL; group D: ≥16?g/dL. Blood Hb (g/dL), PaO2 and PaCO2 (mmHg), SaO2 (%), and BMI were measured at LTOT admission (t0), and at least quarterly over three years (t1-t3). Wilcoxon test was used to compare t0 vs. t1 values; linear regression to assess a possible Hb-BMI relationship; ANOVA to compare changes in Hb time-courses over the 3?years.\nRESULTS: LTOT induced a systematic increase of PaO2, and changes were significant since the first year (from 52.1?mmHg?±?6.6sd to 65.1?mmHg?±?8.7?sd, p?<?0.001). Changes in SaO2 were quite similar. Comparable and equally significant trends were seen in all subgroups (p?<?0.001). PaCO2 dropped within the first year of LTOT (from 49.4?mmHg?±?9.1sd to 45.9?mmHg ±7.5?sd, p?<?0.001): the t0-t1 comparison proved significant (p?<?0.01) only in subgroups with the highest basal Hb, who showed a further PaCO2 decline over the remaining two years (p?<?0.001). Hb tended to normalization during LTOT only in subgroups with basal Hb?>?15?g/dl (ANOVA p?<?0.001); anemic subjects (Hb?<?13?g/dl) ameliorated not significantly in the same period (ANOVA?=?0.5). Survival was independent of the original blood Hb. Anemia and polyglobulia are differently prevalent in COPD, the latter being the most represented in our cohort. LTOT affected both conditions, but to a different extent and according to different time-courses. The most striking Hb improvement was in polyglobulic patients in whom also PaO2, PaCO2 and SaO2 dramatically improved. In anemic subjects effects were smaller and slower, oxygenation being equally ameliorated by LTOT.\nCONCLUSIONS: LTOT effects on Hb and PaCO2 are regulated by an Hb-dependent gradient which seems independent of the original impairment of blood gases and of effects on oxygenation.","DOI":"10.1186/2049-6958-7-15","ISSN":"2049-6958","note":"PMID: 22958465","journalAbbreviation":"Multidiscip Respir Med","language":"eng","author":[{"family":"Dal Negro","given":"Roberto W"},{"family":"Tognella","given":"Silvia"},{"family":"Bonadiman","given":"Luca"},{"family":"Turco","given":"Paola"}],"issued":{"date-parts":[["2012"]]},"PMID":"22958465"}}],"schema":""} (19) and of Kollert et al, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"nAeF9LBX","properties":{"formattedCitation":"(5)","plainCitation":"(5)"},"citationItems":[{"id":174,"uris":[""],"uri":[""],"itemData":{"id":174,"type":"article-journal","title":"Hemoglobin Levels Above Anemia Thresholds Are Maximally Predictive for Long-Term Survival in COPD With Chronic Respiratory Failure","container-title":"Respiratory care","page":"1204-1212","volume":"58","issue":"7","source":"NCBI PubMed","abstract":"BACKGROUND: In patients with COPD, chronic anemia is known as an unfavorable prognostic factor. Whether the association between hemoglobin (Hb) levels and long-term survival is restricted to anemia or extends to higher Hb levels has not yet been systematically assessed.\nMETHODS: We determined Hb levels in 309 subjects with COPD and chronic respiratory failure prior to initiation of noninvasive ventilation, accounting for confounders that might affect Hb. Subjects were categorized as anemic (Hb < 12 g/dL in females, Hb < 13 g/dL in males), polycythemic (Hb ≥ 15 g/dL in females, Hb ≥ 17 g/dL in males), or normocythemic. In addition, percentiles of Hb values were analyzed with regard to mortality from any cause.\nRESULTS: Two-hundred seven subjects (67.0%) showed normal Hb levels, 46 (14.9%) had anemia, and 56 (18.1%) had polycythemia. Polycythemic subjects showed a higher survival rate than anemic (P = .01) and normocythemic subjects (P = .043). In a univariate Cox hazards model, Hb was associated with long-term survival (hazard ratio 0.855; 95% CI 0.783-0.934, P < .001). The 58th percentiles of Hb (14.3 g/dL in females, 15.1 g/dL in males) yielded the highest discriminative value for predicting survival (hazard ratio 0.463, 95% CI 0.324-0.660, P < .001). In the multivariate analysis this cutoff was an independent predictor for survival (hazard ratio 0.627, 95% CI 0.414-0.949, P = .03), in addition to age and body mass index.\nCONCLUSIONS: In subjects with COPD and chronic respiratory failure undergoing treatment with noninvasive ventilation and LTOT, high Hb levels are associated with better long-term survival. The optimal cutoff level for prediction was above the established threshold defining anemia. Thus, predicting survival only on the basis of anemia does not fully utilize the prognostic potential of Hb values in COPD.","DOI":"10.4187/respcare.01961","ISSN":"1943-3654","note":"PMID: 23232736","journalAbbreviation":"Respir Care","language":"eng","author":[{"family":"Kollert","given":"Florian"},{"family":"Tippelt","given":"Andrea"},{"family":"Müller","given":"Carolin"},{"family":"J?rres","given":"Rudolf A"},{"family":"Porzelius","given":"Christine"},{"family":"Pfeifer","given":"Michael"},{"family":"Budweiser","given":"Stephan"}],"issued":{"date-parts":[["2013",7]]},"PMID":"23232736"}}],"schema":""} (5) who reported an anemia prevalence of 11.3% and 14.9% among outpatients under long-term oxygen treatment or domiciliary non-invasive ventilation, correspondingly. Conversely, two large population-based studies estimated a lower prevalence of anemia among COPD patients, ranging between 7.3-7.5% ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ih3aL0Iq","properties":{"formattedCitation":"(10)","plainCitation":"(10)"},"citationItems":[{"id":178,"uris":[""],"uri":[""],"itemData":{"id":178,"type":"article-journal","title":"Comorbidities of chronic obstructive pulmonary disease in Koreans: a population-based study","container-title":"Journal of Korean medical science","page":"901-906","volume":"27","issue":"8","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) includes pulmonary components with increased comorbidity rates, as well as being a systemic disease. Comorbidities may frequently occur in COPD patients over 40 yr old. We report the comorbidities of patients with COPD, diagnosed by spirometry, in a population-based epidemiologic survey in Korea. Data were derived from the fourth Korean Health and Nutrition Examination Survey in 2008, a stratified multistage clustered probability design survey of a sample representing the entire population of Korea. Results of spirometry and various health-related questionnaires were analyzed in 2,177 subjects aged ≥ 40 yr. The prevalence of COPD (FEV(1)/FVC < 0.7) in subjects ≥ 40 yr of age was 14.1%. Multivariate analysis showed that underweight (odds ratio [OR] 3.07, 95% confidence interval [CI] 1.05-8.98), coronary heart disease (OR, 0.43; 95% CI, 0.20-0.93) and dyslipidemia (OR, 0.61; 95% CI, 0.45-0.82) were significantly associated with COPD, whereas allergic rhinitis, anemia, arthritis, chronic renal failure, depression, diabetes mellitus, hypertension, gastrointestinal ulcer, and osteoporosis were not. Underweight might be more prevalent but coronary heart disease and dyslipidemia are less prevalent in Koreans with than without COPD in population setting.","DOI":"10.3346/jkms.2012.27.8.901","ISSN":"1598-6357","note":"PMID: 22876057","shortTitle":"Comorbidities of chronic obstructive pulmonary disease in Koreans","journalAbbreviation":"J. Korean Med. Sci.","language":"eng","author":[{"family":"Joo","given":"Hyejin"},{"family":"Park","given":"Jinkyeong"},{"family":"Lee","given":"Sang Do"},{"family":"Oh","given":"Yeon-Mok"}],"issued":{"date-parts":[["2012",8]]},"PMID":"22876057"}}],"schema":""} (10) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Te4zGL2A","properties":{"formattedCitation":"(11)","plainCitation":"(11)"},"citationItems":[{"id":226,"uris":[""],"uri":[""],"itemData":{"id":226,"type":"article-journal","title":"Association between anemia and quality of life in a population sample of individuals with chronic obstructive pulmonary disease","container-title":"BMC pulmonary medicine","page":"23","volume":"6","source":"NCBI PubMed","abstract":"BACKGROUND: Several studies investigated the association of anemia with health related quality of life (HRQL) in patients with chronic disease. However, there is little evidence regarding the association of anemia with HRQL in patients with chronic obstructive pulmonary disease (COPD).\nMETHODS: This is a post-hoc analysis of a study which enrolled a population of adults aged 35-79 randomly selected from residents of Erie and Niagara Counties, NY, between 1996 and 2000. In addition to demographic information and physical measurements, we obtained spirometry data and hemoglobin levels. We used modified Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria to define COPD, and World Health Organization (WHO) criteria to define anemia. To assess HRQL we used the Short Form-36 (SF-36) to assess physical functioning (PF), physical component summary (PCS) measures and mental component summary (MCS) measures.\nRESULTS: In the entire study population (n = 2704), respondents with anemia had lower scores on the physical functioning domain [45.4 (SD10.9) vs. 49.2 (SD 9.1); p < 0.0001]. Among patients with COPD (n = 495) the PF scores (39.9 vs. 45.4) and the PCS (41.9 vs. 45.9) were significantly lower in individuals with anemia compared to those without. In multiple regression analysis, the association between hemoglobin and PCS was positive (regression coefficient 0.02, p = 0.003). There was no significant association of hemoglobin with PF scores or the mental component summary measure after adjusting for covariates in patients with COPD.\nCONCLUSION: In patients with moderate to very severe COPD anemia may be associated with worse HRQL. However, co-morbidities may explain part or all of this association in these patients.","DOI":"10.1186/1471-2466-6-23","ISSN":"1471-2466","note":"PMID: 16953872","journalAbbreviation":"BMC Pulm Med","language":"eng","author":[{"family":"Krishnan","given":"Gokul"},{"family":"Grant","given":"Brydon J"},{"family":"Muti","given":"Paola C"},{"family":"Mishra","given":"Archana"},{"family":"Ochs-Balcom","given":"Heather M"},{"family":"Freudenheim","given":"Jo L"},{"family":"Trevisan","given":"Maurizio"},{"family":"Schünemann","given":"Holger J"}],"issued":{"date-parts":[["2006"]]},"PMID":"16953872"}}],"schema":""} (11); the inclusion of COPD patients with less severe disease burden compared to the ones with respiratory failure or under a hospital follow-up, is probably the main reason for this discrepancy.As expected, anemia is even more frequent among patients hospitalized for AECOPD or other causes. In a retrospective study of a series of patients with various disorders who were discharged from hospital, anemia prevalence among COPD patients was 23.1%, comparable to the one among individuals with heart failure. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"863tZ2FH","properties":{"formattedCitation":"(23)","plainCitation":"(23)"},"citationItems":[{"id":230,"uris":[""],"uri":[""],"itemData":{"id":230,"type":"article-journal","title":"Prevalence of anemia in chronic obstructive pulmonary disease: comparison to other chronic diseases","container-title":"International journal of cardiology","page":"365-370","volume":"111","issue":"3","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) is a multisystemic inflammatory disease characterized by pulmonary and extrapulmonary symptoms. The impaired lung function has long-term implications on metabolism and homeostasis of many organ systems such as the skeleton, heart, brain and skeletal muscle. The occurrence and prevalence of anemia in COPD has rarely been studied. Anemia is such a common and simple clinical finding that we may underestimate its physiological relevance in COPD. The aim of the study was to retrospectively investigate the prevalence of anemia in a large population of COPD patients and to compare it to patients with chronic heart failure, renal insufficiency, cancer and asthma. A population of 7337 patients that was treated in the University Hospital Charité, Berlin, Germany, from 1996 to 2003 was subsetted according to the ICD-9/10 code of the discharge diagnoses into the above-mentioned diagnoses groups. The overall prevalence of anemia in COPD patients was 23.1%. It was comparable to the prevalence of anemia we found in patients with chronic heart failure (23.3%). Patients with renal insufficiency and cancer presented the highest anemia frequencies. The high prevalence of anemia in hospitalised COPD patients that were treated mostly for exacerbations gives evidence that anemia is also a comorbidity in COPD and may contribute to exercise limitation and dyspnoea.","DOI":"10.1016/j.ijcard.2005.07.043","ISSN":"0167-5273","note":"PMID: 16242192","shortTitle":"Prevalence of anemia in chronic obstructive pulmonary disease","journalAbbreviation":"Int. J. Cardiol.","language":"eng","author":[{"family":"John","given":"Matthias"},{"family":"Lange","given":"Andre"},{"family":"Hoernig","given":"Soeren"},{"family":"Witt","given":"Christian"},{"family":"Anker","given":"Stefan D"}],"issued":{"date-parts":[["2006",8,28]]},"PMID":"16242192"}}],"schema":""} (23) In a longitudinal study by Almagro et al anemia prevalence among hospitalized patients for AECOPD was 19.3%, while other authors have reported even higher frequencies, ranging from 26 to 33%. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"aDeDFCKj","properties":{"formattedCitation":"(15)","plainCitation":"(15)"},"citationItems":[{"id":208,"uris":[""],"uri":[""],"itemData":{"id":208,"type":"article-journal","title":"Modification of COPD presentation during the last 25 years","container-title":"COPD","page":"345-351","volume":"7","issue":"5","source":"NCBI PubMed","abstract":"During the last decades progress has been made in the treatment of Chronic Obstructive Pulmonary Disease (COPD). We compared a random sample of patients admitted for an exacerbation in the period 2001-2005 (n = 101), with a random sample of patients hospitalized for the same reason in the period 1980-1984 (n = 51). Patients of the 2001-2005 cohort had a lower FEV1 (48 ± 3 vs. 41 ± 2% predicted, p = 0.01) for similar mean age, gender and body- mass index when compared to the historical sample. Co-morbidities, according to the Charlson's index, were more prevalent in the 2001-2005 cohort compared to the 1980-1984 cohort, with a reduction of hemoglobin (13.9 ± 0.2 gr/dl vs. 14.9 ± 0.2, p < 0.01) and higher prevalence of anemia in the most recent cohort. We found an increase in the use of cardiovascular drugs and respiratory medications over time with exception for the long-term use of oxygen. Despite lower FEV1 and more prevalent co-morbidities, no difference in length of hospitalization (13.6 ± 1.4 days vs. 12.7 ± 0.7 days, p = 0.52) and 30 months survival post-exacerbation was noted (66.6% vs. 69.3%, p = 0.85). Over the course of 20 years, the presentation of COPD patients admitted for an exacerbation seems to be changed towards a more severe phenotype with lower FEV1 and more co-morbidities. As the length of hospitalization and the overall survival were not different between the two samples, a currently improved management of COPD can be hypothesized.","DOI":"10.3109/15412555.2010.510546","ISSN":"1541-2563","note":"PMID: 20854049","journalAbbreviation":"COPD","language":"eng","author":[{"family":"Fremault","given":"Antoine"},{"family":"Janssens","given":"Wim"},{"family":"Beaucage","given":"Fran?ois"},{"family":"Celis","given":"Geert"},{"family":"Pérez-Bogerd","given":"Silvia"},{"family":"Decramer","given":"Marc"}],"issued":{"date-parts":[["2010",10]]},"PMID":"20854049"}}],"schema":""} (15) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UjPx5ZX3","properties":{"formattedCitation":"(28)","plainCitation":"(28)"},"citationItems":[{"id":190,"uris":[""],"uri":[""],"itemData":{"id":190,"type":"article-journal","title":"Anemia is a mortality predictor in hospitalized patients for COPD exacerbation","container-title":"COPD","page":"243-250","volume":"9","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia is a recognized prognostic factor in many chronic illnesses, but there is limited information about its impact on outcomes in patients hospitalized for acute COPD exacerbation (AECOPD).\nAIM: To investigate whether anemia exerts an effect on mortality in patients admitted for AECOPD after one year of follow-up. Methods. From November 2007 to November 2009 we recruited 117 patients who required hospitalization due to an AECOPD. Clinical, functional and laboratory parameters on admission were prospectively assessed. Patients were followed up during one year. Mortality and days-to-death were collected.\nRESULTS: Mean age 72 (SD ± 9); FEV? 37.4 (SD ± 12); mortality after 1 year was 22.2%. Mean survival: 339 days. Comparing patients who died to those who survived we found significant differences (p < 0,000) in hemoglobin (Hb) (12.4 vs 13.8 mg/dl) and hematocrit (Ht) (38 vs 41%). Anemia (Hb < 13 g.dl??) prevalence was 33%. Those who died had experienced 3.5 exacerbations in previous year vs 1.5 exacerbations in the case of the survivors (p = 0.000). Lung function and nutritional status were similar, except for percentage of muscle mass (%) (35 vs 39%; p = 0.015) and albumin (33 vs 37 mg/dl; p = 0.039). These variables were included in a Multivariate Cox Proportional Hazards Model; anemia and previous exacerbations resulted as independent factors for mortality. Mortality risk for patients with anemia was 5.9(CI: 1.9-19); for patients with > 1 exacerbation in the previous year was 5.9(CI: 1.3-26.5).\nCONCLUSION: Anemia and previous exacerbations were independent predictors of mortality after one year in patients hospitalized for AECOPD.","DOI":"10.3109/15412555.2011.647131","ISSN":"1541-2563","note":"PMID: 22360381","journalAbbreviation":"COPD","language":"eng","author":[{"family":"Martinez-Rivera","given":"Carlos"},{"family":"Portillo","given":"Karina"},{"family":"Mu?oz-Ferrer","given":"Aida"},{"family":"Martínez-Ortiz","given":"María Luisa"},{"family":"Molins","given":"Elena"},{"family":"Serra","given":"Pere"},{"family":"Ruiz-Manzano","given":"Joan"},{"family":"Morera","given":"Josep"}],"issued":{"date-parts":[["2012",6]]},"PMID":"22360381"}}],"schema":""} (28) Hospital-acquired anemia ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KtVbdLiS","properties":{"formattedCitation":"(29)","plainCitation":"(29)"},"citationItems":[{"id":318,"uris":[""],"uri":[""],"itemData":{"id":318,"type":"article-journal","title":"Hospital-acquired anemia","container-title":"Journal of the Medical Association of Thailand = Chotmaihet thangphaet","page":"63-67","volume":"89","issue":"1","source":"NCBI PubMed","abstract":"OBJECTIVE: The incidence and etiologies of hospital-acquired anemia has not been well defined A prospective study was conducted to determine the incidence and etiologies of hospital-acquired anemia developed in patients admitted in the medical ward of a tertiary care university hospital.\nMATERIAL AND METHOD: All non-anemic (hemoglobin (Hb) > or = 13 g/dl in male, > or = 12 g/dl in female) patients who were admitted to the general medical wards for at least 1 week, between March 2001 to October 2001, were included in the present study. Outcome of interest was anemia developed during hospital stay. The total volume of blood collected for investigations were recorded.\nRESULTS: Of the 98 evaluable patients, 64 (65.3%) developed anemia. Thirty-five percent of the patients had mild anemia (Hb > 10.0 g/dl) and 7% had severe anemia (Hb < or = 8.0 g/dl). Anemia of chronic disease was the most common cause found in 57.4% of anemic patients. Mean total volume of blood collected for investigation was higher in the anemic compared with the non-anemic group (147.0 ml vs. 52.0 ml, p < 0.05). Total volume of investigational blood also correlated significantly with degree of anemia (r = 0.638, p < 0.05).\nCONCLUSION: Anemia was a common complication occurring in almost two-thirds of patients admitted to the hospital. Even though anemia of chronic disease was the leading cause, investigational blood loss was also an important contributing factor.","ISSN":"0125-2208","note":"PMID: 16583583","journalAbbreviation":"J Med Assoc Thai","language":"eng","author":[{"family":"Wong","given":"Peerapon"},{"family":"Intragumtornchai","given":"Tanin"}],"issued":{"date-parts":[["2006",1]]},"PMID":"16583583"}}],"schema":""} (29) is a unique entity affecting patients with various disorders who are admitted in hospital; nevertheless, during AECOPD the burst of systemic inflammation is a factor further inhibiting erythropoiesis, as described below in detail. In contrast to previous data, Nowinski et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tGEKsRlu","properties":{"formattedCitation":"(1)","plainCitation":"(1)"},"citationItems":[{"id":260,"uris":[""],"uri":[""],"itemData":{"id":260,"type":"article-journal","title":"[The impact of comorbidities on the length of hospital treatment in patients with chronic obstructive pulmonary disease]","container-title":"Pneumonologia i alergologia polska","page":"388-396","volume":"79","issue":"6","source":"NCBI PubMed","abstract":"INTRODUCTION: The aim of this study was to assess relationships of chronic obstructive pulmonary disease (COPD) comorbidities number, with the duration of hospital stay due to acute AE COPD in longitudinal prospective study.\nMATERIAL AND METHODS: We evaluated the number of re-hospitalizations, length of stay and number of comorbidities in 464 consecutive COPD patients admitted to the tertiary respiratory hospital due to AE COPD enrolled in longitudinal prospective study from 2005 to 2009 year.\nRESULTS: GOLD II stage COPD patients had 4.1 ± 1.2 comorbidities (p = 0.002), stage III 3.4 ± 1.3 and stage IV had 3.6 ± 1.2 comorbidities. Duration of hospital stay (medians) was longer in more severe patients. Duration of hospitalization correlated with urea level (r = 0.19 p 〈 0.001), pCO(2) (r = 0.193, p = 0.0003), HCO(3) (r = 0.25, p 〈 0.0001), haemoglobin (r = -0.18, p 〈 0.001), and hematocrit (r = -0.13, p = 0.008). The patients with the risk of readmission had more severe GOLD stage and were hypercapnic (pCO(2) = 47.6 mmHg v. 43.9 mmHg in those without hospitalization).\nCONCLUSIONS: The haemoglobin level, hypercapnia and renal function are predictors of prolonged hospitalization. Patients with more severe airflow limitation and higher pCO(2) have increased risk for readmission to the hospital. More severe disease stage, clinical diagnosis of cor pulmonale or bronchiectasis was related to longer hospital stay.","ISSN":"0867-7077","note":"PMID: 22028117","journalAbbreviation":"Pneumonol Alergol Pol","language":"pol","author":[{"family":"Nowiński","given":"Adam"},{"family":"Kamiński","given":"Dariusz"},{"family":"Korzybski","given":"Damian"},{"family":"Stok?osa","given":"Anna"},{"family":"Górecka","given":"Dorota"}],"issued":{"date-parts":[["2011"]]},"PMID":"22028117"}}],"schema":""} (1) and Barbra et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"PdYEkNs4","properties":{"formattedCitation":"(13)","plainCitation":"(13)"},"citationItems":[{"id":188,"uris":[""],"uri":[""],"itemData":{"id":188,"type":"article-journal","title":"Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor","container-title":"Current medical research and opinion","page":"617-622","volume":"28","issue":"4","source":"NCBI PubMed","abstract":"OBJECTIVE: The prevalence of comorbid anemia in patients with COPD ranges from 7.5% to 34%. The aim of this study is to determine if anemia is a risk factor for readmission in COPD patients.\nMETHODS: This study analyzed the hospital data of 289,077 adults with acute exacerbations of COPD admitted to the hospital at any public center in Spain, in 2006 and 2007. We calculated the prevalence of anemia and compared readmissions between COPD patients with and without anemia. Multiple regression analyses were carried out with the aim of determining the risk of readmission attributable to anemia, after the correction of possible confounding variables.\nRESULTS: Of the patients with COPD, 9.8% (n?=?26,899) had a diagnosis of anemia. Anemic patients were older, more likely to be female and had a greater comorbidity burden than non-anemic individuals. Multiple regression modeling revealed that multiple independent factors were associated with an increased risk of readmission in persons with COPD. Anemia was one of the greatest risks: anemic patients had a 25% higher risk of readmission than non-anemic patients (odds ratio [OR], 1.25; 95% confidence interval [CI] 1.21-1.29).\nCONCLUSION: Utilizing an administrative database the authors found that anemia correlates independently with readmission in COPD patients.\nLIMITATIONS: This is a retrospective cohort study and thus subject to multiple forms of bias. Although spirometric evidence of COPD was not available, our case identification methods have been previously validated and found to be accurate in recognizing COPD.","DOI":"10.1185/03007995.2012.675318","ISSN":"1473-4877","note":"PMID: 22409165","shortTitle":"Anemia in chronic obstructive pulmonary disease","journalAbbreviation":"Curr Med Res Opin","language":"eng","author":[{"family":"Barba","given":"Raquel"},{"family":"de Casasola","given":"Gonzalo García"},{"family":"Marco","given":"Javier"},{"family":"Emilio Losa","given":"Juan"},{"family":"Plaza","given":"Susana"},{"family":"Canora","given":"Jesús"},{"family":"Zapatero","given":"Antonio"}],"issued":{"date-parts":[["2012",4]]},"PMID":"22409165"}}],"schema":""} (13) reported a much lower frequency for anemia among patients with AECOPD (4.9% and 9.8%, respectively); however, the different methodology used to define the parameters of interest in studies might have caused this discrepancy (Table 1). Much of the information regarding the frequency of anemia came from two large retrospective studies using healthcare databases. Shorr et al studied a population of 2,404 COPD patients and identified that 788 (33%) of them were anemic. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pI5W9fA3","properties":{"formattedCitation":"(24)","plainCitation":"(24)"},"citationItems":[{"id":216,"uris":[""],"uri":[""],"itemData":{"id":216,"type":"article-journal","title":"Anemia in chronic obstructive pulmonary disease: epidemiology and economic implications","container-title":"Current medical research and opinion","page":"1123-1130","volume":"24","issue":"4","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia in chronic illness is associated with increased healthcare resource utilization (HRU) and costs. In COPD, it occurs frequently and influences both clinical and economic outcomes. Because no data studies have been performed either in a single center or a subpopulation of COPD patients, anemia's influence on the outcomes is not fully understood.\nRESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study in a large healthcare database to quantify prevalence, HRU and costs of anemia in COPD. From 1997 to 2005, patients > or = 45 years of age with an ICD-9 diagnosis code for COPD and > 3.5 years of follow-up were included. Anemia was defined by the WHO criteria. Other disease states for which anemia is a known complication were excluded. We calculated the prevalence of anemia and compared annual HRU and costs between COPD patients with and without anemia. Multiple regression analysis adjusted for the effects of age, gender, race, length of enrollment, diagnosing physician specialty, co-morbidity burden, anemia and COPD severity.\nRESULTS: Of the 2404 patients with COPD, 33% (n = 788) had a diagnosis of anemia. Anemic patients were older, more likely to be male and non-Caucasian, and had a greater co-morbidity burden than non-anemic individuals. Annual costs for COPD patients with anemia were more than twice those for patients without anemia ($17,240 vs. 6492, p < 0.001, unadjusted). HRU was also significantly greater among anemic than non-anemic COPD patients (p < 0.0001). In a multiple regression analysis, anemia accounted for $7929 per patient (95% CI: $5572-10,599) of the total costs of care.\nLIMITATIONS: This is a retrospective cohort study and thus subject to multiple forms of bias. Although spirometric evidence of COPD was available only for a subgroup of patients, our case identification methods have been previously validated and found to be accurate in recognizing COPD.\nCONCLUSIONS: Anemia is a common co-morbidity in COPD. It is significantly associated with an increase in HRU and costs of care for COPD, independent of demographic and clinical patient characteristics.","DOI":"10.1185/030079908X280699","ISSN":"1473-4877","note":"PMID: 18331668","shortTitle":"Anemia in chronic obstructive pulmonary disease","journalAbbreviation":"Curr Med Res Opin","language":"eng","author":[{"family":"Shorr","given":"Andrew F"},{"family":"Doyle","given":"John"},{"family":"Stern","given":"Lee"},{"family":"Dolgitser","given":"Margarita"},{"family":"Zilberberg","given":"Marya D"}],"issued":{"date-parts":[["2008",4]]},"PMID":"18331668"}}],"schema":""} (24) The study used the WHO definition of anemia and was conducted in a large patient population; however, patients with chronic kidney disease were not excluded, while there is no information whether hemoglobin was measured during stable state or hospitalization. Halpern et al indicated that out of the 132,424 COPD patients who were included in the US Medicare Claims Database, 27,932 COPD (21%) were anemic. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sAhTW8m9","properties":{"formattedCitation":"(22)","plainCitation":"(22)"},"citationItems":[{"id":222,"uris":[""],"uri":[""],"itemData":{"id":222,"type":"article-journal","title":"Anemia, costs and mortality in chronic obstructive pulmonary disease","container-title":"Cost effectiveness and resource allocation: C/E","page":"17","volume":"4","source":"NCBI PubMed","abstract":"BACKGROUND: Little is known about cost implications of anemia and its association with mortality in chronic obstructive pulmonary disease (COPD). This claims analysis addresses these questions.\nMETHODS: Using the the US Medicare claims database (1997-2001), this study identified Medicare enrollees with an ICD-9 diagnosis of COPD. Concomitant anemia was identified based on ICD-9 codes or receipt of transfusions. Persons with anemia secondary to another disease state, a nutritional deficiency or a hereditary disease were excluded. Medicare claims and payments, resource utilization and mortality were compared between COPD patients with and without anemia.\nRESULTS: Of the 132,424 enrollees with a COPD diagnosis, 21% (n = 27,932) had concomitant anemia. At baseline, anemic patients were older, had more co-morbidities and higher rates of health care resource use than non-anemic individuals with COPD. In a univariate analysis annual Medicare payments for persons with anemia were more than double for those without anemia ($1,466 vs. $649, p < 0.001), the direction maintained in all categories of payments. Adjusting for demographics, co-morbidities, and other markers of disease severity revealed that anemia was independently associated with $3,582 incremental increase per patient (95% CI: $3,299 to $3,865) in Medicare annual reimbursements. The mortality rate among COPD patients with anemia was 262 vs. 133 deaths per 1,000 person-years among those without anemia (p < 0.001).\nCONCLUSION: Anemia was present in 21% of COPD patients. Although more prevalent in more severely ill COPD patients, anemia significantly and independently contributes to the costs of care for COPD and is associated with increased mortality.","DOI":"10.1186/1478-7547-4-17","ISSN":"1478-7547","note":"PMID: 17042950","journalAbbreviation":"Cost Eff Resour Alloc","language":"eng","author":[{"family":"Halpern","given":"Michael T"},{"family":"Zilberberg","given":"Marya D"},{"family":"Schmier","given":"Jordana K"},{"family":"Lau","given":"Edmund C"},{"family":"Shorr","given":"Andrew F"}],"issued":{"date-parts":[["2006"]]},"PMID":"17042950"}}],"schema":""} (22) Although it is not known whether anemia was identified on an inpatient or outpatient basis, the lower percentages of anemia are probably due to the exclusion of patients with renal insufficiency, along with other causes of anemia. Although these two studies do not offer further information regarding the specific anemia prevalence in different COPD populations, they indicate that in a general COPD population of various severity and several comorbidities, anemia is a common complication.In summary, although anemia occurs frequently in COPD patient, its prevalence varies widely in the published literature. The baseline characteristics of the study population, the various comorbidities present and the different methodology adopted to define the measures of interest are the main causes of this discrepancy, which make the results of published studies difficult to compare.Pathogenesis of anemia in COPDAlthough the presence of anemia has been repeatedly reported, studies that have investigated the specific causes of anemia in COPD are scarce and many potential etiological mechanisms, which are not mutually exclusive, exist.(Figure 1) Nevertheless, COPD has been increasingly recognized as a disorder with important systemic manifestations, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6QJgQl2r","properties":{"formattedCitation":"(30)","plainCitation":"(30)"},"citationItems":[{"id":835,"uris":[""],"uri":[""],"itemData":{"id":835,"type":"article-journal","title":"Systemic inflammation and comorbidity in COPD: a result of 'overspill' of inflammatory mediators from the lungs? Review of the evidence","container-title":"Thorax","page":"930-936","volume":"65","issue":"10","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) is characterised by an inflammatory response by the lungs to inhaled substances such as cigarette smoking and air pollutants. In addition to the pulmonary features of COPD, several systemic effects have been recognised even after controlling for common aetiological factors such as smoking or steroid use. These include skeletal muscle dysfunction, cardiovascular disease, osteoporosis and diabetes. Individuals with COPD have significantly raised levels of several circulating inflammatory markers indicating the presence of systemic inflammation. This raises the issue of cause and effect. The role of tumour necrosis factor α in COPD is thought to be central to both lung and systemic inflammation and has been implicated in skeletal muscle dysfunction, osteoporosis and type 2 diabetes. It has been hypothesised that inflammation in the lung results in 'overspill' into the circulation causing systemic inflammation. There is supportive evidence that protein movement can occur from the lung surface to the systemic circulation. Evidence from inhaled substances such as air pollutants and cigarette smoke has demonstrated a temporal link between the inflammatory process in the lung and systemic inflammation. Also, studies have shown alterations in circulating inflammatory cells in patients with COPD compared with controls which may reflect the effects of inflammatory mediators (derived from the lung) on circulating cells or the bone marrow. This paper considers the concept of 'overspill' in depth, reviews the current evidence and highlights problems in generating direct evidence to support or refute this concept.","DOI":"10.1136/thx.2009.130260","ISSN":"1468-3296","note":"PMID: 20627907","shortTitle":"Systemic inflammation and comorbidity in COPD","journalAbbreviation":"Thorax","language":"eng","author":[{"family":"Sinden","given":"Nicola J"},{"family":"Stockley","given":"Robert A"}],"issued":{"date-parts":[["2010",10]]},"PMID":"20627907"}}],"schema":""} (30) so the development of “anemia of chronic disease” (ACD) among COPD patients could be expected.Pathogenesis of anemia of chronic diseaseACD is an immune-driven disorder; ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Eqg1xsdz","properties":{"formattedCitation":"(31)","plainCitation":"(31)"},"citationItems":[{"id":326,"uris":[""],"uri":[""],"itemData":{"id":326,"type":"article-journal","title":"Anemia of chronic disease","container-title":"The New England journal of medicine","page":"1011-1023","volume":"352","issue":"10","source":"NCBI PubMed","DOI":"10.1056/NEJMra041809","ISSN":"1533-4406","note":"PMID: 15758012","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Weiss","given":"Guenter"},{"family":"Goodnough","given":"Lawrence T"}],"issued":{"date-parts":[["2005",3,10]]},"PMID":"15758012"}}],"schema":""} (31) it accompanies several diseases which are characterized by sub-acute or chronic immune activation, such as malignancies, systemic autoimmune disorders and inflammatory diseases. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TbybGCrQ","properties":{"unsorted":true,"formattedCitation":"(32)","plainCitation":"(32)"},"citationItems":[{"id":324,"uris":[""],"uri":[""],"itemData":{"id":324,"type":"article-journal","title":"Pathogenesis and treatment of anaemia of chronic disease","container-title":"Blood reviews","page":"87-96","volume":"16","issue":"2","source":"NCBI PubMed","abstract":"Anaemia of chronic disease (ACD), the most frequent anaemia among hospitalized patients, develops under chronic inflammatory disorders such as chronic infections, cancer or autoimmune diseases. A number of different pathways contribute to ACD, such as diversion of iron traffic, a diminished erythropoiesis, a blunted response to erythropoietin, erythrophagocytosis and bone marrow invasion by tumour cells and pathogens. Nevertheless, ACD is a reflection of an activated immune system and possibly results from an innovative defence strategy of the body in order to withdraw the essential growth factor iron from invading pathogens and to increase the efficacy of cell-mediated immunity. Diagnosis of ACD can be assessed by examination of chances in serum iron parameters with low to normal serum iron, transferrin saturation and transferrin concentrations on the one hand and normal to increased ferritin, zinc protoporphyrin IX and cytokine levels on the other side. Therapy of ACD includes the cure of the underlying the disease. Apart from this transfusions for rapid correction of haemoglobin levels, and human recombinant erythropoietin for prolonged therapy are used. However, response rates to recombinant erythropoietin are sometimes low. Iron alone should be strictly avoided due to its growth-promoting effect towards micro-organisms and tumour cells and because of it capacity to inhibit T-cell-mediated immune effector pathways. We urgently need prospective clinical trials to gain knowledge about the effects of anaemia correction and/or the use of erythropoietin towards the course of the underlying disease, to find out if a combination therapy with erythropoietin and iron may be beneficial in ACD and to define therapeutic end-points.","ISSN":"0268-960X","note":"PMID: 12127952","journalAbbreviation":"Blood Rev.","language":"eng","author":[{"family":"Weiss","given":"Günter"}],"issued":{"date-parts":[["2002",6]]},"PMID":"12127952"}}],"schema":""} (32) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"W9ob03GE","properties":{"formattedCitation":"(33)","plainCitation":"(33)"},"citationItems":[{"id":837,"uris":[""],"uri":[""],"itemData":{"id":837,"type":"article-journal","title":"The anemia of chronic disorders","container-title":"Seminars in hematology","page":"351-375","volume":"3","issue":"4","source":"NCBI PubMed","ISSN":"0037-1963","note":"PMID: 5341723","journalAbbreviation":"Semin. Hematol.","language":"eng","author":[{"family":"Cartwright","given":"G E"}],"issued":{"date-parts":[["1966",10]]},"PMID":"5341723"}}],"schema":""} (33) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"u0b1Pxqd","properties":{"formattedCitation":"(34)","plainCitation":"(34)"},"citationItems":[{"id":839,"uris":[""],"uri":[""],"itemData":{"id":839,"type":"article-journal","title":"Prevalence and causes of anemia in elderly hospitalized patients","container-title":"Gerontology","page":"113-119","volume":"25","issue":"2","source":"NCBI PubMed","abstract":"The prevalence and causes of anemia have been studied in 104 patients over 60 years of age admitted to a general medical ward in Jerusalem. In males and females, mean hemoglobin levels were about 1 g less than in the corresponding groups of healthy younger controls. A primary nutritional anemia could not be implicated in any of the 15 patients with hemoglobins below 11 g/dl. The most important causes of anemia were chronic renal failure, metastatic carcinoma, gastrointestinal bleeding, and infection. Conversely, in diseases with no adverse effect on erythropoiesis such as chronic ischemic heart disease, hypertension and diabetes, hemoglobin levels were equal to those of the younger controls. These findings indicate that although diminished serum iron and RBC folate levels may occasionally be found in elderly subjects, nutritional deficiency is seldom responsible for anemia in this age group in Israel- and anemia when present is often the manifestation of a chronic underlying disease.","ISSN":"0304-324X","note":"PMID: 311745","journalAbbreviation":"Gerontology","language":"eng","author":[{"family":"Matzner","given":"Y"},{"family":"Levy","given":"S"},{"family":"Grossowicz","given":"N"},{"family":"Izak","given":"G"},{"family":"Hershko","given":"C"}],"issued":{"date-parts":[["1979"]]},"PMID":"311745"}}],"schema":""} (34) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"StzCWgSA","properties":{"formattedCitation":"(35)","plainCitation":"(35)"},"citationItems":[{"id":841,"uris":[""],"uri":[""],"itemData":{"id":841,"type":"article-journal","title":"Recent developments in the anemia of chronic disease","container-title":"Current hematology reports","page":"116-121","volume":"2","issue":"2","source":"NCBI PubMed","abstract":"The anemia of chronic disease (ACD) is a hypoproliferative anemia defined by a low serum or plasma iron concentration in the presence of adequate reticuloendothelial iron stores. It is been established that ACD results from the effects of cytokines that mediate the immune or inflammatory response. During the past 3 years, the clinical scope of this syndrome has been expanded beyond the traditional chronic infectious, inflammatory, or neoplastic diseases to include other, often acute, syndromes in which the same pathogenetic mechanisms are operating. An improved understanding of the use of the soluble transferrin receptor concentration in clinical medicine has enhanced the ability to diagnose ACD, and further experience with the use of recombinant human erythropoietin in the management of severely affected patients with ACD has provided a basis for rational and effective management. Ongoing studies of the mechanisms contributing to the development of ACD continue to elucidate the pathogenesis of this common and clinically significant syndrome.","ISSN":"1540-3408","note":"PMID: 12901142","journalAbbreviation":"Curr. Hematol. Rep.","language":"eng","author":[{"family":"Means","given":"Robert T, Jr"}],"issued":{"date-parts":[["2003",3]]},"PMID":"12901142"}}],"schema":""} (35) For this reason ACD has also been characterized as “anemia of inflammation”. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pNDO4M9o","properties":{"formattedCitation":"(31)","plainCitation":"(31)"},"citationItems":[{"id":326,"uris":[""],"uri":[""],"itemData":{"id":326,"type":"article-journal","title":"Anemia of chronic disease","container-title":"The New England journal of medicine","page":"1011-1023","volume":"352","issue":"10","source":"NCBI PubMed","DOI":"10.1056/NEJMra041809","ISSN":"1533-4406","note":"PMID: 15758012","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Weiss","given":"Guenter"},{"family":"Goodnough","given":"Lawrence T"}],"issued":{"date-parts":[["2005",3,10]]},"PMID":"15758012"}}],"schema":""} (31) ACD can be classified as anemia due to reduced erythropoiesis and is usually a mild to moderate normochromic, normocytic anemia, though less frequently, it can have a hypochromic microcytic pattern. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"3NxFyVyU","properties":{"formattedCitation":"(36)","plainCitation":"(36)"},"citationItems":[{"id":845,"uris":[""],"uri":[""],"itemData":{"id":845,"type":"article-journal","title":"Progress in understanding the pathogenesis of the anemia of chronic disease [see comments]","container-title":"Blood","page":"1639-1647","volume":"80","issue":"7","source":"bloodjournal.","abstract":"Improved understanding of the inflammatory response and the identification and characterization of the specific cytokines involved, as well as improved understanding of erythropoiesis, and the availability of recombinant human growth factors such as EPO, have greatly enhanced our appreciation of the pathogenesis of ACD by allowing development of a number of informative models for studying this syndrome. It appears that a variety of cytokines are involved in all aspects of the pathogenesis of ACD, from the inhibition of erythroid progenitors and EPO production to impairment of iron release. A schematic of the contributions of some of these cytokines to the development of ACD is shown in Fig 6. The exact biochemical mechanisms by which these effects occur is still to be determined. The progress outlined in this report has allowed us to develop a more precise understanding of the pathogenesis of this common and important clinical syndrome. In 1983, Hansen subtitled a review of ACD “A Bag of Unsolved Questions.” Although this description is still accurate, our understanding of ACD has now developed to the point where we can offer a more defined subtitle: “A Bag of Cytokines.”","ISSN":"0006-4971, 1528-0020","note":"PMID: 1391934","journalAbbreviation":"Blood","language":"en","author":[{"family":"Means","given":"RT Jr"},{"family":"Krantz","given":"S. B."}],"issued":{"date-parts":[["1992",10,1]]},"accessed":{"date-parts":[["2014",3,24]]},"PMID":"1391934"}}],"schema":""} (36) The pathophysiological background of ACD is immunological; cytokines and cells of the reticuloendothelial system induce changes in: a) iron homeostasis, b) proliferation and differentiation of progenitor erythroid cells and c) production of erythropoietin which all contribute to its establishment. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Y4Ro86Xd","properties":{"formattedCitation":"(31)","plainCitation":"(31)"},"citationItems":[{"id":326,"uris":[""],"uri":[""],"itemData":{"id":326,"type":"article-journal","title":"Anemia of chronic disease","container-title":"The New England journal of medicine","page":"1011-1023","volume":"352","issue":"10","source":"NCBI PubMed","DOI":"10.1056/NEJMra041809","ISSN":"1533-4406","note":"PMID: 15758012","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Weiss","given":"Guenter"},{"family":"Goodnough","given":"Lawrence T"}],"issued":{"date-parts":[["2005",3,10]]},"PMID":"15758012"}}],"schema":""} (31)a) disorders of iron homeostasisOne of the most characteristic features of ACD is the development of disorders in iron homeostasis, with enhanced uptake and retention of iron within the cells of the reticuloendothelial system. This leads to a diversion of iron from the circulation, resulting in reduced intake of iron from erythroid progenitor cells and, thus, to restricted erythropoiesis. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2kMjEYx7","properties":{"formattedCitation":"(31)","plainCitation":"(31)"},"citationItems":[{"id":326,"uris":[""],"uri":[""],"itemData":{"id":326,"type":"article-journal","title":"Anemia of chronic disease","container-title":"The New England journal of medicine","page":"1011-1023","volume":"352","issue":"10","source":"NCBI PubMed","DOI":"10.1056/NEJMra041809","ISSN":"1533-4406","note":"PMID: 15758012","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Weiss","given":"Guenter"},{"family":"Goodnough","given":"Lawrence T"}],"issued":{"date-parts":[["2005",3,10]]},"PMID":"15758012"}}],"schema":""} (31)Iron homeostasis involves several mechanisms. Dietary iron is transported, as ferrous iron, across the apical surface of the intestinal epithelium cell membrane by means of a transmembrane protein, the divalent metal transporter 1 (DMT1), via a coupling-proton mechanism. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lXLsQJxM","properties":{"formattedCitation":"(37)","plainCitation":"(37)"},"citationItems":[{"id":336,"uris":[""],"uri":[""],"itemData":{"id":336,"type":"article-journal","title":"Molecular control of iron transport","container-title":"Journal of the American Society of Nephrology: JASN","page":"394-400","volume":"18","issue":"2","source":"NCBI PubMed","abstract":"The iron-regulatory hormone hepcidin is a 25-amino acid peptide that is synthesized in hepatocytes. Hepcidin binds to the cellular iron export channel ferroportin and causes its internalization and degradation and thereby decreases iron efflux from iron exporting tissues into plasma. By this mechanism, hepcidin inhibits dietary iron absorption, the efflux of recycled iron from splenic and hepatic macrophages, and the release of iron from storage in hepatocytes. Hepcidin synthesis is stimulated by plasma iron and iron stores and is inhibited by erythropoietic activity, ensuring that extracellular plasma iron concentrations and iron stores remain stable and the erythropoietic demand for iron is met. During inflammation, increased hepcidin concentrations cause iron sequestration in macrophages, resulting in hypoferremia and eventually anemia of inflammation. Hepcidin deficiency plays a central role in most iron overload disorders. The role of hepcidin abnormalities in anemias that are associated with renal disease and in resistance to erythropoietic therapies remains to be elucidated.","DOI":"10.1681/ASN.2006070802","ISSN":"1046-6673","note":"PMID: 17229910","journalAbbreviation":"J. Am. Soc. Nephrol.","language":"eng","author":[{"family":"Ganz","given":"Tomas"}],"issued":{"date-parts":[["2007",2]]},"PMID":"17229910"}}],"schema":""} (37) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FTJFOq10","properties":{"formattedCitation":"(38)","plainCitation":"(38)"},"citationItems":[{"id":851,"uris":[""],"uri":[""],"itemData":{"id":851,"type":"article-journal","title":"An iron-regulated ferric reductase associated with the absorption of dietary iron","container-title":"Science (New York, N.Y.)","page":"1755-1759","volume":"291","issue":"5509","source":"NCBI PubMed","abstract":"The ability of intestinal mucosa to absorb dietary ferric iron is attributed to the presence of a brush-border membrane reductase activity that displays adaptive responses to iron status. We have isolated a complementary DNA, Dcytb (for duodenal cytochrome b), which encoded a putative plasma membrane di-heme protein in mouse duodenal mucosa. Dcytb shared between 45 and 50% similarity to the cytochrome b561 family of plasma membrane reductases, was highly expressed in the brush-border membrane of duodenal enterocytes, and induced ferric reductase activity when expressed in Xenopus oocytes and cultured cells. Duodenal expression levels of Dcytb messenger RNA and protein were regulated by changes in physiological modulators of iron absorption. Thus, Dcytb provides an important element in the iron absorption pathway.","DOI":"10.1126/science.1057206","ISSN":"0036-8075","note":"PMID: 11230685","journalAbbreviation":"Science","language":"eng","author":[{"family":"McKie","given":"A T"},{"family":"Barrow","given":"D"},{"family":"Latunde-Dada","given":"G O"},{"family":"Rolfs","given":"A"},{"family":"Sager","given":"G"},{"family":"Mudaly","given":"E"},{"family":"Mudaly","given":"M"},{"family":"Richardson","given":"C"},{"family":"Barlow","given":"D"},{"family":"Bomford","given":"A"},{"family":"Peters","given":"T J"},{"family":"Raja","given":"K B"},{"family":"Shirali","given":"S"},{"family":"Hediger","given":"M A"},{"family":"Farzaneh","given":"F"},{"family":"Simpson","given":"R J"}],"issued":{"date-parts":[["2001",3,2]]},"PMID":"11230685"}}],"schema":""} (38) After iron has entered the cells, it can either be stored in cytoplasmic storage, ferritin, or be exported to the plasma through protein-carriers of the basolateral membrane, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zTaTIqKU","properties":{"formattedCitation":"(39)","plainCitation":"(39)"},"citationItems":[{"id":853,"uris":[""],"uri":[""],"itemData":{"id":853,"type":"article-journal","title":"Iron transport & homeostasis mechanisms: their role in health & disease","container-title":"The Indian journal of medical research","page":"533-544","volume":"128","issue":"4","source":"NCBI PubMed","abstract":"Iron is an essential trace metal required by all living organisms and is toxic in excess. Nature has evolved a delicately balanced network to monitor iron entry, transport it to sites of need, and serve as a unique storage and recycling system, in the absence of an excretory system, to remove excess iron. Due to the unique nature of iron metabolism, iron homeostasis is achieved by integrated specialized mechanisms that operate at the cellular and organism level. The use of positional cloning approaches by multiple researchers has led to the identification and characterization of various proteins and peptides that play a critical role in iron metabolism. These efforts have led to elucidation of the molecular mechanisms involved in the uptake of iron by the enterocytes, transportation across the membrane to circulation, and delivery to diverse tissues for use and storage and sensor system to co-ordinate and achieve homeostasis. Molecular understanding of these processes and the key regulatory molecules involved in maintaining homeostasis will provide novel insights into understanding human disorders associated with either iron deficiency or overload.","ISSN":"0971-5916","note":"PMID: 19106445","shortTitle":"Iron transport & homeostasis mechanisms","journalAbbreviation":"Indian J. Med. Res.","language":"eng","author":[{"family":"Nadadur","given":"S S"},{"family":"Srirama","given":"K"},{"family":"Mudipalli","given":"Anuradha"}],"issued":{"date-parts":[["2008",10]]},"PMID":"19106445"}}],"schema":""} (39) the most significant of which is ferroprotein. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"znwhhoQd","properties":{"formattedCitation":"(40)","plainCitation":"(40)"},"citationItems":[{"id":859,"uris":[""],"uri":[""],"itemData":{"id":859,"type":"article-journal","title":"Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter","container-title":"Nature","page":"776-781","volume":"403","issue":"6771","source":"NCBI PubMed","abstract":"Defects in iron absorption and utilization lead to iron deficiency and overload disorders. Adult mammals absorb iron through the duodenum, whereas embryos obtain iron through placental transport. Iron uptake from the intestinal lumen through the apical surface of polarized duodenal enterocytes is mediated by the divalent metal transporter, DMTi. A second transporter has been postulated to export iron across the basolateral surface to the circulation. Here we have used positional cloning to identify the gene responsible for the hypochromic anaemia of the zebrafish mutant weissherbst. The gene, ferroportin1, encodes a multiple-transmembrane domain protein, expressed in the yolk sac, that is a candidate for the elusive iron exporter. Zebrafish ferroportin1 is required for the transport of iron from maternally derived yolk stores to the circulation and functions as an iron exporter when expressed in Xenopus oocytes. Human Ferroportin1 is found at the basal surface of placental syncytiotrophoblasts, suggesting that it also transports iron from mother to embryo. Mammalian Ferroportin1 is expressed at the basolateral surface of duodenal enterocytes and could export cellular iron into the circulation. We propose that Ferroportin1 function may be perturbed in mammalian disorders of iron deficiency or overload.","DOI":"10.1038/35001596","ISSN":"0028-0836","note":"PMID: 10693807","journalAbbreviation":"Nature","language":"eng","author":[{"family":"Donovan","given":"A"},{"family":"Brownlie","given":"A"},{"family":"Zhou","given":"Y"},{"family":"Shepard","given":"J"},{"family":"Pratt","given":"S J"},{"family":"Moynihan","given":"J"},{"family":"Paw","given":"B H"},{"family":"Drejer","given":"A"},{"family":"Barut","given":"B"},{"family":"Zapata","given":"A"},{"family":"Law","given":"T C"},{"family":"Brugnara","given":"C"},{"family":"Lux","given":"S E"},{"family":"Pinkus","given":"G S"},{"family":"Pinkus","given":"J L"},{"family":"Kingsley","given":"P D"},{"family":"Palis","given":"J"},{"family":"Fleming","given":"M D"},{"family":"Andrews","given":"N C"},{"family":"Zon","given":"L I"}],"issued":{"date-parts":[["2000",2,17]]},"PMID":"10693807"}}],"schema":""} (40) Exported iron is then bound to plasma transferrin, which is the primary form by which iron is transported in blood and delivered to various cells. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gdekPBrF","properties":{"formattedCitation":"(39)","plainCitation":"(39)"},"citationItems":[{"id":853,"uris":[""],"uri":[""],"itemData":{"id":853,"type":"article-journal","title":"Iron transport & homeostasis mechanisms: their role in health & disease","container-title":"The Indian journal of medical research","page":"533-544","volume":"128","issue":"4","source":"NCBI PubMed","abstract":"Iron is an essential trace metal required by all living organisms and is toxic in excess. Nature has evolved a delicately balanced network to monitor iron entry, transport it to sites of need, and serve as a unique storage and recycling system, in the absence of an excretory system, to remove excess iron. Due to the unique nature of iron metabolism, iron homeostasis is achieved by integrated specialized mechanisms that operate at the cellular and organism level. The use of positional cloning approaches by multiple researchers has led to the identification and characterization of various proteins and peptides that play a critical role in iron metabolism. These efforts have led to elucidation of the molecular mechanisms involved in the uptake of iron by the enterocytes, transportation across the membrane to circulation, and delivery to diverse tissues for use and storage and sensor system to co-ordinate and achieve homeostasis. Molecular understanding of these processes and the key regulatory molecules involved in maintaining homeostasis will provide novel insights into understanding human disorders associated with either iron deficiency or overload.","ISSN":"0971-5916","note":"PMID: 19106445","shortTitle":"Iron transport & homeostasis mechanisms","journalAbbreviation":"Indian J. Med. Res.","language":"eng","author":[{"family":"Nadadur","given":"S S"},{"family":"Srirama","given":"K"},{"family":"Mudipalli","given":"Anuradha"}],"issued":{"date-parts":[["2008",10]]},"PMID":"19106445"}}],"schema":""} (39) Different cells use iron in different ways; however, erythrocytes, hepatocytes and reticuloendothelial macrophages are the most important. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dH6rWahR","properties":{"formattedCitation":"(41)","plainCitation":"(41)"},"citationItems":[{"id":338,"uris":[""],"uri":[""],"itemData":{"id":338,"type":"article-journal","title":"Iron homeostasis: insights from genetics and animal models","container-title":"Nature Reviews Genetics","page":"208-217","volume":"1","issue":"3","source":"","abstract":"Disorders that perturb iron balance are among the most prevalent human diseases, but until recently iron transport remained poorly understood. Over the past five years, genetic studies of patients with inherited iron homeostasis disorders and the analysis of mutant mice, rats and zebrafish have helped to identify several important iron-transport proteins. With information being mined from the genomes of four species, the study of iron metabolism has benefited enormously from positional-cloning efforts. Complementing the genomic strategy, targeted mutagenesis in mice has produced new models of human iron diseases. The animal models described in this review offer valuable tools for investigating iron homeostasis in vivo.","DOI":"10.1038/35042073","ISSN":"1471-0056","shortTitle":"Iron homeostasis","journalAbbreviation":"Nat Rev Genet","language":"en","author":[{"family":"Andrews","given":"Nancy C."}],"issued":{"date-parts":[["2000",12]]},"accessed":{"date-parts":[["2013",8,22]]}}}],"schema":""} (41) This complex iron homeostasis is regulated by several molecules, with hepcidin - a 25 amino acid protein secreted by liver - being the most important. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1T49kaLy","properties":{"formattedCitation":"(42)","plainCitation":"(42)"},"citationItems":[{"id":861,"uris":[""],"uri":[""],"itemData":{"id":861,"type":"article-journal","title":"Hepcidin, a Urinary Antimicrobial Peptide Synthesized in the Liver","container-title":"Journal of Biological Chemistry","page":"7806-7810","volume":"276","issue":"11","source":"","abstract":"Cysteine-rich antimicrobial peptides are abundant in animal and plant tissues involved in host defense. In insects, most are synthesized in the fat body, an organ analogous to the liver of vertebrates. From human urine, we characterized a cysteine-rich peptide with three forms differing by amino-terminal truncation, and we named it hepcidin (Hepc) because of its origin in the liver and its antimicrobial properties. Two predominant forms, Hepc20 and Hepc25, contained 20 and 25 amino acid residues with all 8 cysteines connected by intramolecular disulfide bonds. Reverse translation and search of the data bases found homologous liver cDNAs in species from fish to human and a corresponding human genomic sequence on human chromosome 19. The full cDNA by 5′ rapid amplification of cDNA ends was 0.4 kilobase pair, in agreement with hepcidin mRNA size on Northern blots. The liver was the predominant site of mRNA expression. The encoded prepropeptide contains 84 amino acids, but only the 20–25-amino acid processed forms were found in urine. Hepcidins exhibited antifungal activity against Candida albicans,Aspergillus fumigatus, and Aspergillus nigerand antibacterial activity against Escherichia coli,Staphylococcus aureus, Staphylococcus epidermidis, and group B Streptococcus. Hepcidin may be a vertebrate counterpart of cysteine-rich antimicrobial peptides produced in the fat body of insects.","ISSN":"0021-9258, 1083-351X","note":"PMID: 11113131","journalAbbreviation":"J. Biol. Chem.","language":"en","author":[{"family":"Park","given":"Christina H."},{"family":"Valore","given":"Erika V."},{"family":"Waring","given":"Alan J."},{"family":"Ganz","given":"Tomas"}],"issued":{"date-parts":[["2001",3,16]]},"accessed":{"date-parts":[["2014",3,24]]},"PMID":"11113131"}}],"schema":""} (42) Studies in both mice and humans have indicated that hepcidin is involved in the mechanisms of response to hypoxia and anemia; in these conditions hepcidin levels decrease, its inhibitory effect on iron is diminished, and more iron is made available from diet and the iron storage of macrophages for erythropoiesis. The opposite happens during infection or systemic inflammation; hepcidin synthesis is markedly induced and, thus, iron availability decreases. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Bs3A6aJV","properties":{"formattedCitation":"(43)","plainCitation":"(43)"},"citationItems":[{"id":341,"uris":[""],"uri":[""],"itemData":{"id":341,"type":"article-journal","title":"Hepcidin and its role in regulating systemic iron metabolism","container-title":"Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program","page":"29-35, 507","source":"NCBI PubMed","abstract":"Maintenance of stable extracellular iron concentrations requires the coordinate regulation of iron transport into plasma from dietary sources in the duodenum, from recycled senescent red cells in macrophages and from storage in hepatocytes. Moreover, during fetal development, the iron requirements of the fetus must be matched by the transport of maternal iron across the placenta. Hepcidin is a 25-amino acid disulfide-rich peptide synthesized in the liver that acts as a systemic iron-regulatory hormone by regulating iron transport from iron-exporting tissues into plasma. Hepcidin inhibits the cellular efflux of iron by binding to, and inducing the degradation of, ferroportin, the sole iron exporter in iron-transporting cells. In turn, hepcidin synthesis is increased by iron loading and decreased by anemia and hypoxia. Additionally, hepcidin synthesis is greatly increased during inflammation, trapping iron in macrophages, decreasing plasma iron concentrations and causing iron-restricted erythropoiesis characteristic of anemia of inflammation (anemia of chronic disease). Recent studies indicate that hepcidin deficiency underlies most known forms of hereditary hemochromatosis. This implies that, with the exception of very rare mutations that affect the hepcidin gene itself or modify ferroportin to make it less responsive to hepcidin, hemochromatosis genes encode molecules that regulate hepcidin synthesis. The central involvement of hepcidin in iron regulation and its pathologies should make the eventual hepcidin assay useful for the diagnosis of iron disorders and the monitoring of their treatments. The development of hepcidin agonists and antagonists may provide useful therapeutics for the treatment of iron disorders.","DOI":"10.1182/asheducation-2006.1.29","ISSN":"1520-4391","note":"PMID: 17124036","journalAbbreviation":"Hematology Am Soc Hematol Educ Program","language":"eng","author":[{"family":"Ganz","given":"Tomas"}],"issued":{"date-parts":[["2006"]]},"PMID":"17124036"}}],"schema":""} (43)Chronic inflammation, as seen in ACD, disrupts iron homeostasis in multiple ways. Tumor Necrosis Factor-1α (TNF-a) and Interleukin (IL)-1, increase the synthesis of ferritin by liver cells and macrophages by inducing its transcription and translation. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"XAeAZB7g","properties":{"formattedCitation":"(44)","plainCitation":"(44)"},"citationItems":[{"id":332,"uris":[""],"uri":[""],"itemData":{"id":332,"type":"article-journal","title":"Cytokine-mediated regulation of iron transport in human monocytic cells","container-title":"Blood","page":"4148-4154","volume":"101","issue":"10","source":"bloodjournal.","abstract":"Under chronic inflammatory conditions cytokines induce a diversion of iron traffic, leading to hypoferremia and retention of the metal within the reticuloendothelial system. However, the regulatory pathways underlying these disturbances of iron homeostasis are poorly understood. We investigated transferrin receptor (TfR)–dependent and –independent iron transport mechanisms in cytokine-stimulated human monocytic cell lines THP-1 and U937. Combined treatment of cells with interferon-γ (IFN-γ) and lipopolysaccharide (LPS) reduced TfR mRNA levels, surface expression, and iron uptake, and these effects were reversed by interleukin-10 (IL-10), thus stimulating TfR-mediated iron acquisition. IFN-γ and LPS dose-dependently increased the cellular expression of divalent metal transporter-1, a transmembrane transporter of ferrous iron, and stimulated the uptake of nontransferrin bound iron (NTBI) into cells. At the same time, IFN-γ and LPS down-regulated the expression of ferroportin mRNA, a putative iron exporter, and decreased iron release from monocytes. Preincubation with IL-10 partly counteracted these effects. Our results demonstrate that the proinflammatory stimuli IFN-γ and LPS increase the uptake of NTBI via stimulation of divalent metal transporter-1 expression and cause retention of the metal within monocytes by down-regulating ferroportin synthesis. Opposite, the anti-inflammatory cytokine IL-10 stimulates TfR-mediated iron uptake into activated monocytes. The regulation of iron transport by cytokines is a key mechanism in the pathogenesis of anemia of chronic disease and a promising target for therapeutic intervention.","DOI":"10.1182/blood-2002-08-2459","ISSN":"0006-4971, 1528-0020","note":"PMID: 12522003","journalAbbreviation":"Blood","language":"en","author":[{"family":"Ludwiczek","given":"Susanne"},{"family":"Aigner","given":"Elmar"},{"family":"Theurl","given":"Igor"},{"family":"Weiss","given":"Günter"}],"issued":{"date-parts":[["2003",5,15]]},"accessed":{"date-parts":[["2013",8,21]]},"PMID":"12522003"}}],"schema":""} (44) IL-6 distorts iron metabolism, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xngjx54e","properties":{"formattedCitation":"(45)","plainCitation":"(45)"},"citationItems":[{"id":895,"uris":[""],"uri":[""],"itemData":{"id":895,"type":"article-journal","title":"Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis","container-title":"Blood","page":"4824-4830","volume":"87","issue":"11","source":"bloodjournal.","abstract":"Systemic-onset juvenile chronic arthritis (SoJCA) is associated with high levels of circulating interleukin-6 (IL-6) and is frequently complicated by severe microcytic anemia whose pathogenesis is unclear. Therefore, we studied 20 consecutive SoJCA patients with hemoglobin (Hb) levels <12 g/dL, evaluating erythroid progenitor proliferation, endogenous erythropoietin production, body iron status, and iron supply for erythropoiesis. Hb concentrations ranged from 6.5 to 11.9 g/dL. Hb level was directly related to mean corpuscular volume (r = .82, P < .001) and inversely related to circulating transferrin receptor (r = - .81, P < .001) suggesting that the severity of anemia was directly proportional to the degree of iron-deficient erythropoiesis. Serum ferritin ranged from 18 to 1,660 microgram/L and was unrelated to Hb level. Bone marrow iron stores wore markedly reduced in the three children investigated, and they also showed increased serum transferrin receptor and normal-to-high serum ferritin. All 20 patients had elevated IL-6 levels and normal in vitro growth of erythroid progenitors. Endogenous erythropoietin (epo) production was appropriate for the degree of anemia as judged by both the observed to predicted log (serum epo) ratio 10.95 +/- 0.12) and a comparison of the serum epo- Hb regression found in these subjects with that of thalassemia patients. Multiple regression analysis showed that serum transferrin receptor was the parameter most closely related to hemoglobin concentration: variation in circulating transferrin receptor explained 61% of the variation in Hb level (P < .001). In 10 severely anemic patients, amelioration of anemia following intravenous iron administration resulted in normalization of serum transferrin receptor. Defective iron supply to the erythron rather than blunted epo production is the major cause of the microcytic anemia associated with SoJCA. A true body-iron deficiency caused by decreased iron absorption likely complicates long-lasting inflammation in the most anemic children, and this can be recognized by high serum transferrin receptor levels. Although oral iron is of no benefit, intravenous iron saccharate is a safe and effective means for improving iron availability for erythropoiesis and correcting this anemia. Thus, while chronically high endogenous IL-6 levels do not appear to blunt epo production, they are probably responsible for the observed abnormalities in iron metabolism. Anemia of chronic disease encompasses a variety of anemic conditions whose peculiar features may specifically correlate with the type of cytokine(s) predominantly released.","ISSN":"0006-4971, 1528-0020","note":"PMID: 8639855","journalAbbreviation":"Blood","language":"en","author":[{"family":"Cazzola","given":"M."},{"family":"Ponchio","given":"L."},{"family":"Benedetti","given":"F. de"},{"family":"Ravelli","given":"A."},{"family":"Rosti","given":"V."},{"family":"Beguin","given":"Y."},{"family":"Invernizzi","given":"R."},{"family":"Barosi","given":"G."},{"family":"Martini","given":"A."}],"issued":{"date-parts":[["1996",6,1]]},"accessed":{"date-parts":[["2014",3,25]]},"PMID":"8639855"}}],"schema":""} (45) since it modulates ferritin translation, expression of transferrin mRNA and, possibly, expression of DMT1. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ZCY9HANd","properties":{"formattedCitation":"(32)","plainCitation":"(32)"},"citationItems":[{"id":324,"uris":[""],"uri":[""],"itemData":{"id":324,"type":"article-journal","title":"Pathogenesis and treatment of anaemia of chronic disease","container-title":"Blood reviews","page":"87-96","volume":"16","issue":"2","source":"NCBI PubMed","abstract":"Anaemia of chronic disease (ACD), the most frequent anaemia among hospitalized patients, develops under chronic inflammatory disorders such as chronic infections, cancer or autoimmune diseases. A number of different pathways contribute to ACD, such as diversion of iron traffic, a diminished erythropoiesis, a blunted response to erythropoietin, erythrophagocytosis and bone marrow invasion by tumour cells and pathogens. Nevertheless, ACD is a reflection of an activated immune system and possibly results from an innovative defence strategy of the body in order to withdraw the essential growth factor iron from invading pathogens and to increase the efficacy of cell-mediated immunity. Diagnosis of ACD can be assessed by examination of chances in serum iron parameters with low to normal serum iron, transferrin saturation and transferrin concentrations on the one hand and normal to increased ferritin, zinc protoporphyrin IX and cytokine levels on the other side. Therapy of ACD includes the cure of the underlying the disease. Apart from this transfusions for rapid correction of haemoglobin levels, and human recombinant erythropoietin for prolonged therapy are used. However, response rates to recombinant erythropoietin are sometimes low. Iron alone should be strictly avoided due to its growth-promoting effect towards micro-organisms and tumour cells and because of it capacity to inhibit T-cell-mediated immune effector pathways. We urgently need prospective clinical trials to gain knowledge about the effects of anaemia correction and/or the use of erythropoietin towards the course of the underlying disease, to find out if a combination therapy with erythropoietin and iron may be beneficial in ACD and to define therapeutic end-points.","ISSN":"0268-960X","note":"PMID: 12127952","journalAbbreviation":"Blood Rev.","language":"eng","author":[{"family":"Weiss","given":"Günter"}],"issued":{"date-parts":[["2002",6]]},"PMID":"12127952"}}],"schema":""} (32) TNF-a and Interferon-γ (INF-γ) induce the production of DMT1 and block the release of iron from macrophages by down-regulating ferroprotein expression. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"woKu4hRb","properties":{"formattedCitation":"(31)","plainCitation":"(31)"},"citationItems":[{"id":326,"uris":[""],"uri":[""],"itemData":{"id":326,"type":"article-journal","title":"Anemia of chronic disease","container-title":"The New England journal of medicine","page":"1011-1023","volume":"352","issue":"10","source":"NCBI PubMed","DOI":"10.1056/NEJMra041809","ISSN":"1533-4406","note":"PMID: 15758012","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Weiss","given":"Guenter"},{"family":"Goodnough","given":"Lawrence T"}],"issued":{"date-parts":[["2005",3,10]]},"PMID":"15758012"}}],"schema":""} (31) IL-10 can also impair iron homeostasis by inducing ferritin expression and increasing the acquisition of iron by macrophages. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gATGMyd3","properties":{"formattedCitation":"(46)","plainCitation":"(46)"},"citationItems":[{"id":849,"uris":[""],"uri":[""],"itemData":{"id":849,"type":"article-journal","title":"Role of IL-10 for induction of anemia during inflammation","container-title":"Journal of immunology (Baltimore, Md.: 1950)","page":"2204-2209","volume":"169","issue":"4","source":"NCBI PubMed","abstract":"Anemia is frequently observed in patients suffering from chronic inflammatory disorders. Recent in vitro data suggest that Th2 cytokines, such as IL-10, could be involved in its pathogenesis. We analyzed 1) changes in hemoglobin values in 329 patients with chronic active Crohn's disease receiving the anti-inflammatory cytokine IL-10 as part of a randomized, double-blind, placebo-controlled study, 2) serum iron parameters in a subgroup of these patients (n = 54), and 3) the in vitro effects of IL-10 on ferritin transcription and translation in human monocytic cells (THP-1) by means of Northern blot and immunoprecipitation after metabolic labeling. Patients receiving higher doses of IL-10 developed anemia and presented with a dose-dependent increase of ferritin and soluble transferrin receptor levels, an indicator of iron restriction to erythroid progenitor cells. According to our in vitro data, hyperferritinemia may result from direct stimulation of ferritin translation by IL-10 in activated monocytic cells, most likely by cytokine-mediated reduction of the binding affinity of translational repressors, iron-regulatory proteins, to the 5'-untranslated region of ferritin mRNA. In patients, all observed changes were most pronounced at the end of therapy (day +29), and thereafter hemoglobin levels and serum iron parameters returned to baseline levels within 4 wk of follow-up. Our data demonstrate that IL-10 causes anemia in patients with inflammatory bowel disease which may be referred to the induction of imbalances in iron homeostasis by the cytokine, leading to hyperferritinemia and limited iron availability to erythroid progenitor cells, a condition typically seen in the anemia of chronic inflammation.","ISSN":"0022-1767","note":"PMID: 12165551","journalAbbreviation":"J. Immunol.","language":"eng","author":[{"family":"Tilg","given":"Herbert"},{"family":"Ulmer","given":"Hanno"},{"family":"Kaser","given":"Arthur"},{"family":"Weiss","given":"Günter"}],"issued":{"date-parts":[["2002",8,15]]},"PMID":"12165551"}}],"schema":""} (46) Finally, lipopolysaccharide and IL-6 are major stimulants of hepcidin synthesis, leading to hypoferremia within hours of inflammatory stimulant in animal models. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sjZSOcK4","properties":{"formattedCitation":"(43)","plainCitation":"(43)"},"citationItems":[{"id":341,"uris":[""],"uri":[""],"itemData":{"id":341,"type":"article-journal","title":"Hepcidin and its role in regulating systemic iron metabolism","container-title":"Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program","page":"29-35, 507","source":"NCBI PubMed","abstract":"Maintenance of stable extracellular iron concentrations requires the coordinate regulation of iron transport into plasma from dietary sources in the duodenum, from recycled senescent red cells in macrophages and from storage in hepatocytes. Moreover, during fetal development, the iron requirements of the fetus must be matched by the transport of maternal iron across the placenta. Hepcidin is a 25-amino acid disulfide-rich peptide synthesized in the liver that acts as a systemic iron-regulatory hormone by regulating iron transport from iron-exporting tissues into plasma. Hepcidin inhibits the cellular efflux of iron by binding to, and inducing the degradation of, ferroportin, the sole iron exporter in iron-transporting cells. In turn, hepcidin synthesis is increased by iron loading and decreased by anemia and hypoxia. Additionally, hepcidin synthesis is greatly increased during inflammation, trapping iron in macrophages, decreasing plasma iron concentrations and causing iron-restricted erythropoiesis characteristic of anemia of inflammation (anemia of chronic disease). Recent studies indicate that hepcidin deficiency underlies most known forms of hereditary hemochromatosis. This implies that, with the exception of very rare mutations that affect the hepcidin gene itself or modify ferroportin to make it less responsive to hepcidin, hemochromatosis genes encode molecules that regulate hepcidin synthesis. The central involvement of hepcidin in iron regulation and its pathologies should make the eventual hepcidin assay useful for the diagnosis of iron disorders and the monitoring of their treatments. The development of hepcidin agonists and antagonists may provide useful therapeutics for the treatment of iron disorders.","DOI":"10.1182/asheducation-2006.1.29","ISSN":"1520-4391","note":"PMID: 17124036","journalAbbreviation":"Hematology Am Soc Hematol Educ Program","language":"eng","author":[{"family":"Ganz","given":"Tomas"}],"issued":{"date-parts":[["2006"]]},"PMID":"17124036"}}],"schema":""} (43) b) disorders of proliferation and differentiation of erythroid progenitor cells ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1535jENI","properties":{"formattedCitation":"(47)","plainCitation":"(47)"},"citationItems":[{"id":873,"uris":[""],"uri":[""],"itemData":{"id":873,"type":"article-journal","title":"Recent developments in the anemia of chronic disease","container-title":"Current hematology reports","page":"116-121","volume":"2","issue":"2","source":"NCBI PubMed","abstract":"The anemia of chronic disease (ACD) is a hypoproliferative anemia defined by a low serum or plasma iron concentration in the presence of adequate reticuloendothelial iron stores. It is been established that ACD results from the effects of cytokines that mediate the immune or inflammatory response. During the past 3 years, the clinical scope of this syndrome has been expanded beyond the traditional chronic infectious, inflammatory, or neoplastic diseases to include other, often acute, syndromes in which the same pathogenetic mechanisms are operating. An improved understanding of the use of the soluble transferrin receptor concentration in clinical medicine has enhanced the ability to diagnose ACD, and further experience with the use of recombinant human erythropoietin in the management of severely affected patients with ACD has provided a basis for rational and effective management. Ongoing studies of the mechanisms contributing to the development of ACD continue to elucidate the pathogenesis of this common and clinically significant syndrome.","ISSN":"1540-3408","note":"PMID: 12901142","journalAbbreviation":"Curr. Hematol. Rep.","language":"eng","author":[{"family":"Means","given":"Robert T, Jr"}],"issued":{"date-parts":[["2003",3]]},"PMID":"12901142"}}],"schema":""} (35) Cytokine-mediated stem cell proliferation arrest or induction of apoptosis, as well as an interaction with erythropoietin or other major factors that promote erythropoiesis are the potential underlying mechanisms for these disorders. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dnFqz87Y","properties":{"formattedCitation":"(32)","plainCitation":"(32)"},"citationItems":[{"id":324,"uris":[""],"uri":[""],"itemData":{"id":324,"type":"article-journal","title":"Pathogenesis and treatment of anaemia of chronic disease","container-title":"Blood reviews","page":"87-96","volume":"16","issue":"2","source":"NCBI PubMed","abstract":"Anaemia of chronic disease (ACD), the most frequent anaemia among hospitalized patients, develops under chronic inflammatory disorders such as chronic infections, cancer or autoimmune diseases. A number of different pathways contribute to ACD, such as diversion of iron traffic, a diminished erythropoiesis, a blunted response to erythropoietin, erythrophagocytosis and bone marrow invasion by tumour cells and pathogens. Nevertheless, ACD is a reflection of an activated immune system and possibly results from an innovative defence strategy of the body in order to withdraw the essential growth factor iron from invading pathogens and to increase the efficacy of cell-mediated immunity. Diagnosis of ACD can be assessed by examination of chances in serum iron parameters with low to normal serum iron, transferrin saturation and transferrin concentrations on the one hand and normal to increased ferritin, zinc protoporphyrin IX and cytokine levels on the other side. Therapy of ACD includes the cure of the underlying the disease. Apart from this transfusions for rapid correction of haemoglobin levels, and human recombinant erythropoietin for prolonged therapy are used. However, response rates to recombinant erythropoietin are sometimes low. Iron alone should be strictly avoided due to its growth-promoting effect towards micro-organisms and tumour cells and because of it capacity to inhibit T-cell-mediated immune effector pathways. We urgently need prospective clinical trials to gain knowledge about the effects of anaemia correction and/or the use of erythropoietin towards the course of the underlying disease, to find out if a combination therapy with erythropoietin and iron may be beneficial in ACD and to define therapeutic end-points.","ISSN":"0268-960X","note":"PMID: 12127952","journalAbbreviation":"Blood Rev.","language":"eng","author":[{"family":"Weiss","given":"Günter"}],"issued":{"date-parts":[["2002",6]]},"PMID":"12127952"}}],"schema":""} (32) Several cytokines, exert inhibitory effects on erythroid progenitor cells; IL-1a inhibits erythropoiesis in vivo in mice and in vitro in humans, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"MclDiLH4","properties":{"formattedCitation":"(48)","plainCitation":"(48)"},"citationItems":[{"id":903,"uris":[""],"uri":[""],"itemData":{"id":903,"type":"article-journal","title":"Cellular mechanism of resistance to erythropoietin","container-title":"Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association","page":"27-30","volume":"10 Suppl 6","source":"NCBI PubMed","abstract":"Erythropoiesis is controlled by different regulators. Interleukin 3, granulocyte-macrophage colony-stimulating factor and stem cell factor play regulatory functions in the early steps of erythropoiesis. Erythropoietin (Epo) is the main factor which acts positively on the last steps of the production of erythrocytes in mammals. Epo is specific for the erythroid progenitor cells and has only little effect on other cells. The target cells for Epo are the erythroid progenitors (BFUe and CFUe). Epo acts on these progenitors through surface receptors specific for Epo. Epo induces the proliferation and differentiation of erythroid progenitors leading finally to reticulocytes. During this process, certain conditions are required to permit this differentiation: progenitors must be present in sufficient numbers, the bone marrow environment must be normal, and nutrients such as folic acid, vitamin B12 and particularly iron must be available. Elemental iron is an absolute requirement for adequate haemoglobin formation. Indeed, in a normal adult, without any stimulation, the bone marrow synthesizes 4 x 10(14) molecules of haemoglobin per second, each molecule containing four atoms of iron, which roughly corresponds to 20 mg iron. On the other hand, erythropoiesis is negatively regulated by several cytokines. These are macrophage-derived cytokines, including tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta). All these factors are elevated in the inflammatory state and are implicated in the pathogenesis of anaemia of chronic disease. TNF-alpha has an inhibitory effect on erythroid progenitors either directly or mediated by interferon-beta (INF-beta). IL-1 inhibits erythropoiesis in vivo in mice and in vitro in humans.(ABSTRACT TRUNCATED AT 250 WORDS)","ISSN":"0931-0509","note":"PMID: 8524490","journalAbbreviation":"Nephrol. Dial. Transplant.","language":"eng","author":[{"family":"Casadevall","given":"N"}],"issued":{"date-parts":[["1995"]]},"PMID":"8524490"}}],"schema":""} (47) TNF-a and INF-γ inhibit erythroid colony formation in uremic sera, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"HYBxWByL","properties":{"formattedCitation":"(49)","plainCitation":"(49)"},"citationItems":[{"id":899,"uris":[""],"uri":[""],"itemData":{"id":899,"type":"article-journal","title":"Inhibition of CFU-E colony formation in uremic patients with inflammatory disease: role of IFN-gamma and TNF-alpha","container-title":"Journal of investigative medicine: the official publication of the American Federation for Clinical Research","page":"204-211","volume":"47","issue":"5","source":"NCBI PubMed","abstract":"BACKGROUND: There is evidence for the role of inflammatory cytokines in the inhibition of erythropoiesis in the anemia of chronic disease, but the extent to which they contribute to resistance to erythropoietin (EPO) in patients with chronic renal failure is not clear. The purpose of the present study was to assess the effect of sera from patients with end-stage renal failure with and without infection or inflammatory disease on CFU-E colony formation in vitro.\nMETHODS: Bone marrow was obtained from uremic patients with inflammatory disease and from healthy controls. Standard colony assays were used to assess erythroid colony formation (CFU-E) in response to EPO in the presence or absence of 5% autologous serum. Normal bone marrow mononuclear cells were cultured with 5% v/v sera from three groups of patients: healthy volunteers, uremic controls, and uremic patients with inflammatory disease.\nRESULTS: There was no difference between normal and uremic bone marrow response to EPO. However, when uremic/inflammatory bone marrow was cultured with autologous serum the optimal response to EPO was significantly inhibited. Optimal CFU-E colony formation was suppressed significantly by sera from either uremic group when compared with cultures containing sera from controls. Treatment of parallel cultures with a combination of antibodies to interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) almost completely restored the response to EPO. Additionally, bone marrow from healthy controls incubated with uremic sera showed an increased production of interleukin-1 alpha (IL-1 alpha) and IFN-gamma, and TNF-alpha was present in uremic sera.\nCONCLUSIONS: CFU-E colony formation is inhibited by soluble factors present in the sera of uremic patients with or without inflammatory disease. These soluble factors stimulate the production of IFN-gamma and TNF-alpha, which directly inhibit erythropoiesis at a local level in the bone marrow.","ISSN":"1081-5589","note":"PMID: 10361379","shortTitle":"Inhibition of CFU-E colony formation in uremic patients with inflammatory disease","journalAbbreviation":"J. Investig. Med.","language":"eng","author":[{"family":"Allen","given":"D A"},{"family":"Breen","given":"C"},{"family":"Yaqoob","given":"M M"},{"family":"Macdougall","given":"I C"}],"issued":{"date-parts":[["1999",5]]},"PMID":"10361379"}}],"schema":""} (48) while there is an inverse relationship between INF-γ concentration, reticulocytes count and hemoglobin (Hb) concentration. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"viFpfV5a","properties":{"formattedCitation":"(50)","plainCitation":"(50)"},"citationItems":[{"id":865,"uris":[""],"uri":[""],"itemData":{"id":865,"type":"article-journal","title":"Immune activation and the anaemia associated with chronic inflammatory disorders","container-title":"European journal of haematology","page":"65-70","volume":"46","issue":"2","source":"NCBI PubMed","abstract":"Chronic inflammatory disorders are associated with an increased risk of patients developing anaemia. There is some evidence that cytokines released during cell-mediated immune responses are capable of inhibiting bone marrow haematopoiesis. In vitro, interferon gamma and tumour-necrosis factor alpha inhibit growth of erythroid precursor cells. The mode of action of these cytokines is probably associated with their antiproliferative capacity. Decrease of serum iron and increase of storage iron in patients appears to be a consequence of the defense strategy of macrophages during long-lasting inflammatory disorders. Decreased serum iron correlates to decreased haemoglobin concentrations. In view of this, the development of anaemia seems likely to result from the altered iron metabolism induced by stimulated macrophages. Low haemoglobin levels and associated hypoxia up-regulate the release of erythropoietin, which can explain why increased circulating erythropoietin is usually found in patients with anaemia.","ISSN":"0902-4441","note":"PMID: 1899833","journalAbbreviation":"Eur. J. Haematol.","language":"eng","author":[{"family":"Fuchs","given":"D"},{"family":"Hausen","given":"A"},{"family":"Reibnegger","given":"G"},{"family":"Werner","given":"E R"},{"family":"Werner-Felmayer","given":"G"},{"family":"Dierich","given":"M P"},{"family":"Wachter","given":"H"}],"issued":{"date-parts":[["1991",2]]},"PMID":"1899833"}}],"schema":""} (49). Inflammatory cytokines can also exert a direct toxic effect on progenitor cells, promoting the formation of unstable free radicals such as nitric oxide or peroxide from macrophages. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tDHorCy6","properties":{"formattedCitation":"(31)","plainCitation":"(31)"},"citationItems":[{"id":326,"uris":[""],"uri":[""],"itemData":{"id":326,"type":"article-journal","title":"Anemia of chronic disease","container-title":"The New England journal of medicine","page":"1011-1023","volume":"352","issue":"10","source":"NCBI PubMed","DOI":"10.1056/NEJMra041809","ISSN":"1533-4406","note":"PMID: 15758012","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Weiss","given":"Guenter"},{"family":"Goodnough","given":"Lawrence T"}],"issued":{"date-parts":[["2005",3,10]]},"PMID":"15758012"}}],"schema":""} (31) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8gwbH0uI","properties":{"formattedCitation":"(51)","plainCitation":"(51)"},"citationItems":[{"id":870,"uris":[""],"uri":[""],"itemData":{"id":870,"type":"article-journal","title":"Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha.","container-title":"Journal of Clinical Investigation","page":"1085-1092","volume":"96","issue":"2","source":"PubMed Central","abstract":"IFN-gamma and TNF-alpha, potent inhibitors of hematopoiesis, induce nitric oxide synthase (NOS) in various cell types. When normal human bone marrow (BM) or CD34+ cells were exposed to NO, inhibition of colony formation was dose dependent and direct. NO induced apoptosis in BM progenitors, as shown by electrophoretic detection of DNA degradation and deoxynucleotidyl transferase assay. Using PCR and immunoprecipitation, we found inducible NOS (iNOS) mRNA and iNOS protein in BM after stimulation with IFN-gamma or TNF-alpha. iNOS mRNA was also detected by PCR in highly purified CD34+ cells; TNF-alpha or IFN-gamma increased iNOS expression. The presence of iNOS in CD34+ cells was confirmed in single cells by immunochemical staining. NG-Monomethyl-L-arginine (MM-Arg), an NOS inhibitor, partially reversed the effects of TNF-alpha and, to a lesser extent, IFN-gamma in methylcellulose culture of total BM and CD34+ cells, and inhibited apoptosis of BM cells induced by these cytokines. When the effects of competitive iNOS inhibition were tested on more immature progenitors, MM-Arg increased the number of long-term BM culture-initiating cells in control cultures but failed to protect these cells from the inhibitory action of IFN-gamma and TNF-alpha. Our results suggest that NO may be one mediator of cytokine-induced hematopoietic suppression.","ISSN":"0021-9738","note":"PMID: 7543491\nPMCID: PMC185297","journalAbbreviation":"J Clin Invest","author":[{"family":"Maciejewski","given":"J P"},{"family":"Selleri","given":"C"},{"family":"Sato","given":"T"},{"family":"Cho","given":"H J"},{"family":"Keefer","given":"L K"},{"family":"Nathan","given":"C F"},{"family":"Young","given":"N S"}],"issued":{"date-parts":[["1995",8]]},"accessed":{"date-parts":[["2014",3,24]]},"PMID":"7543491","PMCID":"PMC185297"}}],"schema":""} (50) Moreover, erythropoiesis is further inhibited by the limited availability of iron to erythroid progenitor cells. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OQ4DRoBt","properties":{"formattedCitation":"(32)","plainCitation":"(32)"},"citationItems":[{"id":324,"uris":[""],"uri":[""],"itemData":{"id":324,"type":"article-journal","title":"Pathogenesis and treatment of anaemia of chronic disease","container-title":"Blood reviews","page":"87-96","volume":"16","issue":"2","source":"NCBI PubMed","abstract":"Anaemia of chronic disease (ACD), the most frequent anaemia among hospitalized patients, develops under chronic inflammatory disorders such as chronic infections, cancer or autoimmune diseases. A number of different pathways contribute to ACD, such as diversion of iron traffic, a diminished erythropoiesis, a blunted response to erythropoietin, erythrophagocytosis and bone marrow invasion by tumour cells and pathogens. Nevertheless, ACD is a reflection of an activated immune system and possibly results from an innovative defence strategy of the body in order to withdraw the essential growth factor iron from invading pathogens and to increase the efficacy of cell-mediated immunity. Diagnosis of ACD can be assessed by examination of chances in serum iron parameters with low to normal serum iron, transferrin saturation and transferrin concentrations on the one hand and normal to increased ferritin, zinc protoporphyrin IX and cytokine levels on the other side. Therapy of ACD includes the cure of the underlying the disease. Apart from this transfusions for rapid correction of haemoglobin levels, and human recombinant erythropoietin for prolonged therapy are used. However, response rates to recombinant erythropoietin are sometimes low. Iron alone should be strictly avoided due to its growth-promoting effect towards micro-organisms and tumour cells and because of it capacity to inhibit T-cell-mediated immune effector pathways. We urgently need prospective clinical trials to gain knowledge about the effects of anaemia correction and/or the use of erythropoietin towards the course of the underlying disease, to find out if a combination therapy with erythropoietin and iron may be beneficial in ACD and to define therapeutic end-points.","ISSN":"0268-960X","note":"PMID: 12127952","journalAbbreviation":"Blood Rev.","language":"eng","author":[{"family":"Weiss","given":"Günter"}],"issued":{"date-parts":[["2002",6]]},"PMID":"12127952"}}],"schema":""} (32)c) resistance to the action of erythropoietinErythropoietin (EPO) is a protein hormone which promotes erythroid cell proliferation; the most potent known stimulus for EPO production is tissue hypoxia. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cBGeoWvy","properties":{"formattedCitation":"(52)","plainCitation":"(52)"},"citationItems":[{"id":339,"uris":[""],"uri":[""],"itemData":{"id":339,"type":"article-journal","title":"Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure","container-title":"Nature clinical practice. Nephrology","page":"47-57","volume":"4","issue":"1","source":"NCBI PubMed","abstract":"Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function.","DOI":"10.1038/ncpneph0655","ISSN":"1745-8331","note":"PMID: 18094727","shortTitle":"Mechanisms of Disease","journalAbbreviation":"Nat Clin Pract Nephrol","language":"eng","author":[{"family":"van der Putten","given":"Karien"},{"family":"Braam","given":"Branko"},{"family":"Jie","given":"Kim E"},{"family":"Gaillard","given":"Carlo A J M"}],"issued":{"date-parts":[["2008",1]]},"PMID":"18094727"}}],"schema":""} (51) Most patients with ACD have disproportionately low erythropoietin levels for the severity of anemia present. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Ce4fMOWa","properties":{"formattedCitation":"(53)","plainCitation":"(53)"},"citationItems":[{"id":867,"uris":[""],"uri":[""],"itemData":{"id":867,"type":"article-journal","title":"Decreased Erythropoietin Response in Patients with the Anemia of Cancer","container-title":"New England Journal of Medicine","page":"1689-1692","volume":"322","issue":"24","source":"Taylor and Francis+NEJM","abstract":"THERE can be many causes of anemia in patients with cancer. However, such patients are often anemic even before they receive cytotoxic therapy and even if their bone marrow is not involved by tumor.1 The anemia of cancer is normochromic and normocytic, with an inappropriately low reticulocyte count. Although this anemia is usually mild (hemoglobin level >5.6 mmol per liter [9 g per deciliter]), hemoglobin values as low as 4.3 mmol per liter (7 g per deciliter) are not rare.1 2 3 4 5 Serum iron concentrations and iron-binding capacity are low, and morphologic examination of the bone marrow reveals erythroid precursors with a . . .","DOI":"10.1056/NEJM199006143222401","ISSN":"0028-4793","note":"PMID: 2342534","author":[{"family":"Miller","given":"Carole B."},{"family":"Jones","given":"Richard J."},{"family":"Piantadosi","given":"Steven"},{"family":"Abeloff","given":"Martin D."},{"family":"Spivak","given":"Jerry L."}],"issued":{"date-parts":[["1990"]]},"accessed":{"date-parts":[["2014",3,24]]},"PMID":"2342534"}}],"schema":""} (52) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cccij2Zt","properties":{"formattedCitation":"(54)","plainCitation":"(54)"},"citationItems":[{"id":911,"uris":[""],"uri":[""],"itemData":{"id":911,"type":"article-journal","title":"Proinflammatory state and circulating erythropoietin in persons with and without anemia","container-title":"The American journal of medicine","page":"1288","volume":"118","issue":"11","source":"NCBI PubMed","abstract":"PURPOSE: High circulating levels of proinflammatory cytokines cause anemia, perhaps by interacting with erythropoietin production or biological activity. We characterize the relationships of systemic inflammation, erythropoietin, and hemoglobin.\nMETHODS: Data are from the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study population. A sample of 1270 persons aged 65 years or older and 30 men and 30 women from each age-decade 20 to 70 years were randomly selected from the residents in the Chianti, Italy, geographic area. Of the 1714 eligible persons, 1235 had complete data on inflammatory markers, erythropoietin, hemoglobin, potential causes of anemia, and other relevant covariates. Anemia was defined as hemoglobin less than 12 g/dL in women and less than 13 g/dL in men.\nRESULTS: Independent of age, sex, and hemoglobin, the number of elevated inflammatory markers (C-reactive protein, interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha) was associated with progressively higher erythropoietin in non-anemic participants but lower erythropoietin in anemic participants. Findings were consistent across different causes of anemia. The threshold at which the effect of inflammation on erythropoietin reversed was close to 13.0 g/dL of hemoglobin.\nCONCLUSIONS: Our findings suggest that anemia of inflammation evolves from a \"pre-anemic\" stage characterized by a compensatory increment of erythropoietin that maintains normal hemoglobin levels to a stage of clinically evident anemia in which erythropoietin levels are not high enough to maintain normal hemoglobin, possibly because of the inhibitory effect of inflammation on erythropoietin production. This hypothesis requires testing in a longitudinal study.","DOI":"10.1016/j.amjmed.2005.06.039","ISSN":"1555-7162","note":"PMID: 16271918","journalAbbreviation":"Am. J. Med.","language":"eng","author":[{"family":"Ferrucci","given":"Luigi"},{"family":"Guralnik","given":"Jack M"},{"family":"Woodman","given":"Richard C"},{"family":"Bandinelli","given":"Stefania"},{"family":"Lauretani","given":"Fulvio"},{"family":"Corsi","given":"Anna Maria"},{"family":"Chaves","given":"Paulo H M"},{"family":"Ershler","given":"William B"},{"family":"Longo","given":"Dan L"}],"issued":{"date-parts":[["2005",11]]},"PMID":"16271918"}}],"schema":""} (53) In vitro studies indicate that IL-1 and TNF-α inhibit hypoxia-induced EPO production in a dose-dependent manner, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"nYBCvYme","properties":{"formattedCitation":"(55)","plainCitation":"(55)"},"citationItems":[{"id":794,"uris":[""],"uri":[""],"itemData":{"id":794,"type":"article-journal","title":"Effect of inflammatory cytokines on hypoxia-induced erythropoietin production","container-title":"Blood","page":"1987-1994","volume":"79","issue":"8","source":"bloodjournal.","ISSN":"0006-4971, 1528-0020","note":"PMID: 1373333","journalAbbreviation":"Blood","language":"en","author":[{"family":"Faquin","given":"W. C."},{"family":"Schneider","given":"T. J."},{"family":"Goldberg","given":"M. A."}],"issued":{"date-parts":[["1992",4,15]]},"accessed":{"date-parts":[["2014",3,25]]},"PMID":"1373333"}}],"schema":""} (54) while in anemic individuals high levels of IL-1, IL-6 and TNF-α are associated with low levels of EPO. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7CkZ7qiA","properties":{"formattedCitation":"(54)","plainCitation":"(54)"},"citationItems":[{"id":911,"uris":[""],"uri":[""],"itemData":{"id":911,"type":"article-journal","title":"Proinflammatory state and circulating erythropoietin in persons with and without anemia","container-title":"The American journal of medicine","page":"1288","volume":"118","issue":"11","source":"NCBI PubMed","abstract":"PURPOSE: High circulating levels of proinflammatory cytokines cause anemia, perhaps by interacting with erythropoietin production or biological activity. We characterize the relationships of systemic inflammation, erythropoietin, and hemoglobin.\nMETHODS: Data are from the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study population. A sample of 1270 persons aged 65 years or older and 30 men and 30 women from each age-decade 20 to 70 years were randomly selected from the residents in the Chianti, Italy, geographic area. Of the 1714 eligible persons, 1235 had complete data on inflammatory markers, erythropoietin, hemoglobin, potential causes of anemia, and other relevant covariates. Anemia was defined as hemoglobin less than 12 g/dL in women and less than 13 g/dL in men.\nRESULTS: Independent of age, sex, and hemoglobin, the number of elevated inflammatory markers (C-reactive protein, interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha) was associated with progressively higher erythropoietin in non-anemic participants but lower erythropoietin in anemic participants. Findings were consistent across different causes of anemia. The threshold at which the effect of inflammation on erythropoietin reversed was close to 13.0 g/dL of hemoglobin.\nCONCLUSIONS: Our findings suggest that anemia of inflammation evolves from a \"pre-anemic\" stage characterized by a compensatory increment of erythropoietin that maintains normal hemoglobin levels to a stage of clinically evident anemia in which erythropoietin levels are not high enough to maintain normal hemoglobin, possibly because of the inhibitory effect of inflammation on erythropoietin production. This hypothesis requires testing in a longitudinal study.","DOI":"10.1016/j.amjmed.2005.06.039","ISSN":"1555-7162","note":"PMID: 16271918","journalAbbreviation":"Am. J. Med.","language":"eng","author":[{"family":"Ferrucci","given":"Luigi"},{"family":"Guralnik","given":"Jack M"},{"family":"Woodman","given":"Richard C"},{"family":"Bandinelli","given":"Stefania"},{"family":"Lauretani","given":"Fulvio"},{"family":"Corsi","given":"Anna Maria"},{"family":"Chaves","given":"Paulo H M"},{"family":"Ershler","given":"William B"},{"family":"Longo","given":"Dan L"}],"issued":{"date-parts":[["2005",11]]},"PMID":"16271918"}}],"schema":""} (53) Cytokine overproduction is the most probable cause for hyporesponsiveness to EPO treatment in anemic individuals without iron deficiency. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"X9M9xlas","properties":{"formattedCitation":"(56)","plainCitation":"(56)"},"citationItems":[{"id":883,"uris":[""],"uri":[""],"itemData":{"id":883,"type":"article-journal","title":"Increased Expression of Erythropoiesis Inhibiting Cytokines (IFN-γ, TNF-α, IL-10, and IL-13) by T Cells in Patients Exhibiting a Poor Response to Erythropoietin Therapy","container-title":"Journal of the American Society of Nephrology","page":"1776-1784","volume":"14","issue":"7","source":"jasn.","abstract":"ABSTRACT. Resistance to recombinant human erythropoietin occurs in a small but important proportion of hemodialysis patients. This may be due to increased immune activation because pro-inflammatory cytokines inhibit erythropoiesis in vitro. Using FACScan flow cytometry, the proportion of PMA/ionomycin-stimulated T cells expressing cytokines ex vivo was compared in 18 poor responders to erythropoietin, 14 good responders to erythropoietin, and 14 normal controls. CD4+ T cells from poor responders expressed more interferon-γ (IFN-γ; 19 ± 6%) compared with good responders (11 ± 6%, P < 0.001) and controls (12 ± 6%, P < 0.01). Similarly, CD4+ T cells from poor responders expressed more tumor necrosis factor-α (TNF-α; poor responders: 51 ± 19% versus good responders: 27 ± 15% [P < 0.01] and controls: 30 ± 19% [P < 0.01]). CD4+ expression of IL-10 was also enhanced (poor responders: 1.6 ± 1.1% versus good responders: 0.7 ± 0.6% [P < 0.05] and controls: 0.5 ± 0.2% [P < 0.01]). Likewise, CD4+ expression of interleukin-13 (IL-13) was increased (poor responders: 4.4 ± 4.2% versus good responders: 1.6 ± 1.7% [P < 0.05] and controls: 1.6 ± 1.5% [P < 0.05]). CD8+ T cells from poor responders also showed enhanced expression of cytokines. For IFN-γ, poor responder expression was 48 ± 20% compared with 31 ± 17% (P < 0.05) for good responders and 23 ± 15% (P < 0.01) for controls. TNF-α expression for poor responders was 41 ± 21% versus 25 ± 14% for good responders (P < 0.05) and 21 ± 15% for controls (P < 0.01). IL-10 expression for poor responders was 2.0 ± 1.2% (good responders: 0.7 ± 0.6% [P < 0.01]; controls: 0.5 ± 0.2% [P < 0.001]). These data indicate that T cells from poor responders are in an enhanced activation state possibly as a result of chronic inflammation. In the absence of any other cause (such as iron deficiency), the overproduction of cytokines may account for hyporesponsiveness to erythropoietic therapy in patients with renal failure. E-mail: angela.redrup@kcl.ac.uk","DOI":"10.1097/01.ASN.0000071514.36428.61","ISSN":"1046-6673, 1533-3450","note":"PMID: 12819237","journalAbbreviation":"JASN","language":"en","author":[{"family":"Cooper","given":"Angela C."},{"family":"Mikhail","given":"Ashraf"},{"family":"Lethbridge","given":"Mark W."},{"family":"Kemeny","given":"D. Michael"},{"family":"Macdougall","given":"Iain C."}],"issued":{"date-parts":[["2003",7,1]]},"accessed":{"date-parts":[["2014",3,24]]},"PMID":"12819237"}}],"schema":""} (55) Abnormal iron metabolism also contributes to EPO resistance; iron not only becomes unavailable for erythroid progenitor cells, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"O13Hj1Py","properties":{"formattedCitation":"(31)","plainCitation":"(31)"},"citationItems":[{"id":326,"uris":[""],"uri":[""],"itemData":{"id":326,"type":"article-journal","title":"Anemia of chronic disease","container-title":"The New England journal of medicine","page":"1011-1023","volume":"352","issue":"10","source":"NCBI PubMed","DOI":"10.1056/NEJMra041809","ISSN":"1533-4406","note":"PMID: 15758012","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Weiss","given":"Guenter"},{"family":"Goodnough","given":"Lawrence T"}],"issued":{"date-parts":[["2005",3,10]]},"PMID":"15758012"}}],"schema":""} (31) but its depletion may also impair erythropoietin transgene expression. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jOPVbb1I","properties":{"formattedCitation":"(57)","plainCitation":"(57)"},"citationItems":[{"id":915,"uris":[""],"uri":[""],"itemData":{"id":915,"type":"article-journal","title":"Modulation of transduced erythropoietin expression by iron","container-title":"Experimental hematology","page":"760-764","volume":"28","issue":"7","source":"NCBI PubMed","abstract":"OBJECTIVE: Future prospects for gene therapy of chronic anemias involve expression of the erythropoietin transgene, which is regulated by oxygen tension. However, other factors such as cytokines or the iron load of erythropoietin-expressing cells can concomitantly modulate transgene expression, as shown for the expression of the endogenous erythropoietin gene in human cell lines and in animals. We tested the effects of iron overload or depletion on the expression of the mouse erythropoietin transgene (cDNA), driven by the hypoxia-regulated phosphoglycerate kinase 1 promoter.\nMATERIALS AND METHODS: Retrovirally transduced mouse cells (C3H fibroblasts or C2C12 myoblasts) were cultured in normoxia (room air, O2: 21%) or hypoxia (O2: 1.5%) in the presence or absence of hemin (an iron donor) or deferiprone (an iron chelator), both of which easily enter the cell.\nRESULTS: Hemin inhibited the hypoxia-induced expression of the transgene. In contrast, deferiprone enhanced the hypoxia-induced expression of the erythropoietin transgene and induced its expression in normoxia.\nCONCLUSION: These results show that, in addition to oxygen partial pressure, the intracellular iron content is critical in the modulation of hypoxia-regulated erythropoietin transgene expression.","ISSN":"0301-472X","note":"PMID: 10907637","journalAbbreviation":"Exp. Hematol.","language":"eng","author":[{"family":"Dalle","given":"B"},{"family":"Payen","given":"E"},{"family":"Beuzard","given":"Y"}],"issued":{"date-parts":[["2000",7]]},"PMID":"10907637"}}],"schema":""} (56)Systemic inflammation: the link between COPD and ACD?There is a huge amount of evidence in the published literature regarding the presence of systemic inflammatory responses among patients with COPD. Serum levels of C-reactive protein (CRP), TNF-α, IL-6, IL-8 and fibrinogen ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vr1CaeTi","properties":{"formattedCitation":"(58)","plainCitation":"(58)"},"citationItems":[{"id":786,"uris":[""],"uri":[""],"itemData":{"id":786,"type":"article-journal","title":"The value of C-reactive protein as a marker of systemic inflammation in stable chronic obstructive pulmonary disease","container-title":"European journal of internal medicine","page":"104-108","volume":"19","issue":"2","source":"NCBI PubMed","abstract":"BACKGROUND: Systemic aspects of chronic obstructive pulmonary disease (COPD) include oxidative stress and altered circulating levels of inflammatory mediators and acute-phase proteins. C-reactive protein (CRP) reflects total systemic burden of inflammation in several disorders and has been shown to upregulate the production of proinflammatory cytokines. The aim of this study was to evaluate circulating CRP levels to determine the value of CRP as a biomarker of systemic inflammation and as an indicator of malnutrition or severity of COPD in stable COPD patients in comparison to the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6).\nMETHODS: Thirty-five male patients with stable COPD and 30 age- and sex-matched subjects with normal pulmonary function were admitted to the study. Serum CRP levels were measured using a commercially available kit with the turbidimetric method. Serum TNF-alpha and IL-6 concentrations were measured with ELISA kits.\nRESULTS: Sixty percent of the patients had severe or very severe and 40% moderate COPD. Serum CRP was significantly higher in stable COPD patients than in control subjects (p<0.001), while TNF-alpha and IL-6 concentrations were not statistically different. Serum TNF-alpha was higher in severe or very severe COPD patients (p=0.046). When the COPD patients with a low BMI were compared to those with a normal-to-high BMI, there was a significant difference in CRP (p=0.034) and TNF-alpha (p=0.037).\nCONCLUSION: The present study confirms that circulating CRP levels are higher in stable COPD patients and may thus be regarded as a valid biomarker of low-grade systemic inflammation. In addition, CRP is significantly higher in COPD patients with a low BMI and thus, together with TNF-alpha, may be considered an indicator of malnutrition in COPD patients.","DOI":"10.1016/j.ejim.2007.04.026","ISSN":"1879-0828","note":"PMID: 18249305","journalAbbreviation":"Eur. J. Intern. Med.","language":"eng","author":[{"family":"Karadag","given":"Fisun"},{"family":"Kirdar","given":"Sevin"},{"family":"Karul","given":"Aslihan B"},{"family":"Ceylan","given":"Emel"}],"issued":{"date-parts":[["2008",3]]},"PMID":"18249305"}}],"schema":""} (57) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Cul6Xtn8","properties":{"formattedCitation":"(59)","plainCitation":"(59)"},"citationItems":[{"id":913,"uris":[""],"uri":[""],"itemData":{"id":913,"type":"article-journal","title":"Systemic inflammation in chronic obstructive pulmonary disease: a population-based study","container-title":"Respiratory Research","page":"63","volume":"11","issue":"1","source":"PubMed Central","abstract":"Background\nElevated circulating levels of several inflammatory biomarkers have been described in selected patient populations with COPD, although less is known about their population-based distribution. The aims of this study were to compare the levels of several systemic biomarkers between stable COPD patients and healthy subjects from a population-based sample, and to assess their distribution according to clinical variables.\n\nMethods\nThis is a cross-sectional study design of participants in the EPI-SCAN study (40-80 years of age). Subjects with any other condition associated with an inflammatory process were excluded. COPD was defined as a post-bronchodilator FEV1/FVC < 0.70. The reference group was made of non-COPD subjects without respiratory symptoms, associated diseases or prescription of medication. Subjects were evaluated with quality-of-life questionnaires, spirometry and 6-minute walk tests. Serum C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukins (IL-6 and IL-8), alpha1-antitrypsin, fibrinogen, albumin and nitrites/nitrates (NOx) were measured.\n\nResults\nWe compared 324 COPD patients and 110 reference subjects. After adjusting for gender, age, BMI and tobacco consumption, COPD patients showed higher levels of CRP (0.477 ± 0.023 vs. 0.376 ± 0.041 log mg/L, p = 0.049), TNF-α (13.12 ± 0.59 vs. 10.47 ± 1.06 pg/mL, p = 0.033), IL-8 (7.56 ± 0.63 vs. 3.57 ± 1.13 pg/ml; p = 0.033) and NOx (1.42 ± 0.01 vs. 1.36 ± 0.02 log nmol/l; p = 0.048) than controls. In COPD patients, serum concentrations of some biomarkers were related to severity and their exercise tolerance was related to serum concentrations of CRP, IL-6, IL-8, fibrinogen and albumin.\n\nConclusions\nOur results provide population-based evidence that COPD is independently associated with low-grade systemic inflammation, with a different inflammatory pattern than that observed in healthy subjects.","DOI":"10.1186/1465-9921-11-63","ISSN":"1465-9921","note":"PMID: 20500811\nPMCID: PMC2891677","shortTitle":"Systemic inflammation in chronic obstructive pulmonary disease","journalAbbreviation":"Respir Res","author":[{"family":"Garcia-Rio","given":"Francisco"},{"family":"Miravitlles","given":"Marc"},{"family":"Soriano","given":"Joan B"},{"family":"Munoz","given":"Luis"},{"family":"Duran-Tauleria","given":"Enric"},{"family":"Sanchez","given":"Guadalupe"},{"family":"Sobradillo","given":"Victor"},{"family":"Ancochea","given":"Julio"}],"issued":{"date-parts":[["2010"]]},"accessed":{"date-parts":[["2014",3,25]]},"PMID":"20500811","PMCID":"PMC2891677"}}],"schema":""} (58) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KOEDSnau","properties":{"formattedCitation":"(60)","plainCitation":"(60)"},"citationItems":[{"id":892,"uris":[""],"uri":[""],"itemData":{"id":892,"type":"article-journal","title":"Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obstructive pulmonary disease","container-title":"Clinical science (London, England: 1979)","page":"225-232","volume":"115","issue":"7","source":"NCBI PubMed","abstract":"The aim of the present study was to assess circulating levels of VEGF (vascular endothelial growth factor), a biomarker with prognostic significance in cardiovascular disease, and markers of systemic inflammation in patients with stable and exacerbated COPD (chronic obstructive pulmonary disease). Lung function parameters, arterial blood gas analysis and circulating levels of VEGF, IL-6 (interleukin-6), TNF-alpha (tumour necrosis factor-alpha), CRP (C-reactive protein), fibrinogen and the peripheral blood neutrophil cell count were assessed in 30 patients on admission to the hospital for acute exacerbation of COPD, in 30 age-, gender- and BMI (body mass index)-matched patients with stable COPD, and 30 matched controls with normal lung function. Patients with acute exacerbated COPD had higher circulating concentrations of VEGF (P<0.001), IL-6 (P<0.05) and CRP (P<0.01) and an increased blood neutrophil cell count (P<0.05) compared with patients with stable COPD and healthy controls. VEGF levels in exacerbated COPD correlated with systemic inflammatory markers, such as CRP (r=0.61, P<0.005), IL-6 (r=0.46; P<0.01) and fibrinogen (r=0.39, P<0.05). In patients with stable COPD, there was a significant relationship between circulating VEGF levels and the percentage of the predicted FEV(1) (forced expiratory volume in 1 s) (r=0.47, P<0.01). Recovery from the exacerbation resulted in a significant decrease in both circulating VEGF levels and markers of systemic inflammation. In conclusion, circulating levels of VEGF and markers of systemic inflammation are up-regulated in patients with acute exacerbated COPD and decrease after recovery from the exacerbation.","DOI":"10.1042/CS20070382","ISSN":"1470-8736","note":"PMID: 18307413","journalAbbreviation":"Clin. Sci.","language":"eng","author":[{"family":"Valipour","given":"Arschang"},{"family":"Schreder","given":"Martin"},{"family":"Wolzt","given":"Michael"},{"family":"Saliba","given":"Sleman"},{"family":"Kapiotis","given":"Sonja"},{"family":"Eickhoff","given":"Philipp"},{"family":"Burghuber","given":"Otto Chris"}],"issued":{"date-parts":[["2008",10]]},"PMID":"18307413"}}],"schema":""} (59) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FXowCa9U","properties":{"formattedCitation":"(61)","plainCitation":"(61)"},"citationItems":[{"id":782,"uris":[""],"uri":[""],"itemData":{"id":782,"type":"article-journal","title":"Biomarkers of systemic inflammation in stable and exacerbation phases of COPD","container-title":"Lung","page":"403-409","volume":"186","issue":"6","source":"NCBI PubMed","abstract":"Apart from the deleterious effects on the lungs, chronic obstructive pulmonary disease (COPD) should be considered a complex, systemic disease involving several organs and systems. The nature and course of systemic inflammation in COPD is important since there is a potential for anti-inflammatory therapy. The objective of the current study was to assess biomarkers of systemic inflammation in stable and exacerbation phases of COPD patients as compared to healthy controls. We also investigated the course of these biomarkers after COPD exacerbation to evaluate their usefulness for disease monitoring. Eighty-three stable patients with moderate to very severe COPD, 20 patients in exacerbation phase, and 30 subjects with normal pulmonary function were included. Serum tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO) levels were measured once in stable COPD patients and controls and three times in the COPD exacerbation group during follow-up. TNF-alpha and IL-6 levels were higher than in controls in both stable and exacerbation groups. Although NO was not higher in the stable COPD group than in controls, it was higher in the exacerbation group. In follow-up after the exacerbation period, significant alteration was not detected in cytokine or NO levels compared to admission. Raised serum levels of TNF-alpha and IL-6 support their use as biomarkers of the systemic inflammatory response in stable COPD patients. However, the circulating biomarkers we have studied are not found to be useful either as indicators of COPD exacerbation or for monitoring recovery after exacerbation.","DOI":"10.1007/s00408-008-9106-6","ISSN":"0341-2040","note":"PMID: 18807087","journalAbbreviation":"Lung","language":"eng","author":[{"family":"Karadag","given":"Fisun"},{"family":"Karul","given":"Aslihan B"},{"family":"Cildag","given":"Orhan"},{"family":"Yilmaz","given":"Mustafa"},{"family":"Ozcan","given":"Hatice"}],"issued":{"date-parts":[["2008",12]]},"PMID":"18807087"}}],"schema":""} (60)(61) are only a few of the inflammatory markers that have been found to be significantly increased among patients with stable disease compared to healthy controls. Cytokine levels have already been associated with disease burden, as established by severity of obstruction, BODE index, free fat mass, body mass index and exercise capacity, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VFmtGE52","properties":{"formattedCitation":"(58)","plainCitation":"(58)"},"citationItems":[{"id":786,"uris":[""],"uri":[""],"itemData":{"id":786,"type":"article-journal","title":"The value of C-reactive protein as a marker of systemic inflammation in stable chronic obstructive pulmonary disease","container-title":"European journal of internal medicine","page":"104-108","volume":"19","issue":"2","source":"NCBI PubMed","abstract":"BACKGROUND: Systemic aspects of chronic obstructive pulmonary disease (COPD) include oxidative stress and altered circulating levels of inflammatory mediators and acute-phase proteins. C-reactive protein (CRP) reflects total systemic burden of inflammation in several disorders and has been shown to upregulate the production of proinflammatory cytokines. The aim of this study was to evaluate circulating CRP levels to determine the value of CRP as a biomarker of systemic inflammation and as an indicator of malnutrition or severity of COPD in stable COPD patients in comparison to the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6).\nMETHODS: Thirty-five male patients with stable COPD and 30 age- and sex-matched subjects with normal pulmonary function were admitted to the study. Serum CRP levels were measured using a commercially available kit with the turbidimetric method. Serum TNF-alpha and IL-6 concentrations were measured with ELISA kits.\nRESULTS: Sixty percent of the patients had severe or very severe and 40% moderate COPD. Serum CRP was significantly higher in stable COPD patients than in control subjects (p<0.001), while TNF-alpha and IL-6 concentrations were not statistically different. Serum TNF-alpha was higher in severe or very severe COPD patients (p=0.046). When the COPD patients with a low BMI were compared to those with a normal-to-high BMI, there was a significant difference in CRP (p=0.034) and TNF-alpha (p=0.037).\nCONCLUSION: The present study confirms that circulating CRP levels are higher in stable COPD patients and may thus be regarded as a valid biomarker of low-grade systemic inflammation. In addition, CRP is significantly higher in COPD patients with a low BMI and thus, together with TNF-alpha, may be considered an indicator of malnutrition in COPD patients.","DOI":"10.1016/j.ejim.2007.04.026","ISSN":"1879-0828","note":"PMID: 18249305","journalAbbreviation":"Eur. J. Intern. Med.","language":"eng","author":[{"family":"Karadag","given":"Fisun"},{"family":"Kirdar","given":"Sevin"},{"family":"Karul","given":"Aslihan B"},{"family":"Ceylan","given":"Emel"}],"issued":{"date-parts":[["2008",3]]},"PMID":"18249305"}}],"schema":""} (57) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VimMWqGu","properties":{"formattedCitation":"(59)","plainCitation":"(59)"},"citationItems":[{"id":913,"uris":[""],"uri":[""],"itemData":{"id":913,"type":"article-journal","title":"Systemic inflammation in chronic obstructive pulmonary disease: a population-based study","container-title":"Respiratory Research","page":"63","volume":"11","issue":"1","source":"PubMed Central","abstract":"Background\nElevated circulating levels of several inflammatory biomarkers have been described in selected patient populations with COPD, although less is known about their population-based distribution. The aims of this study were to compare the levels of several systemic biomarkers between stable COPD patients and healthy subjects from a population-based sample, and to assess their distribution according to clinical variables.\n\nMethods\nThis is a cross-sectional study design of participants in the EPI-SCAN study (40-80 years of age). Subjects with any other condition associated with an inflammatory process were excluded. COPD was defined as a post-bronchodilator FEV1/FVC < 0.70. The reference group was made of non-COPD subjects without respiratory symptoms, associated diseases or prescription of medication. Subjects were evaluated with quality-of-life questionnaires, spirometry and 6-minute walk tests. Serum C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukins (IL-6 and IL-8), alpha1-antitrypsin, fibrinogen, albumin and nitrites/nitrates (NOx) were measured.\n\nResults\nWe compared 324 COPD patients and 110 reference subjects. After adjusting for gender, age, BMI and tobacco consumption, COPD patients showed higher levels of CRP (0.477 ± 0.023 vs. 0.376 ± 0.041 log mg/L, p = 0.049), TNF-α (13.12 ± 0.59 vs. 10.47 ± 1.06 pg/mL, p = 0.033), IL-8 (7.56 ± 0.63 vs. 3.57 ± 1.13 pg/ml; p = 0.033) and NOx (1.42 ± 0.01 vs. 1.36 ± 0.02 log nmol/l; p = 0.048) than controls. In COPD patients, serum concentrations of some biomarkers were related to severity and their exercise tolerance was related to serum concentrations of CRP, IL-6, IL-8, fibrinogen and albumin.\n\nConclusions\nOur results provide population-based evidence that COPD is independently associated with low-grade systemic inflammation, with a different inflammatory pattern than that observed in healthy subjects.","DOI":"10.1186/1465-9921-11-63","ISSN":"1465-9921","note":"PMID: 20500811\nPMCID: PMC2891677","shortTitle":"Systemic inflammation in chronic obstructive pulmonary disease","journalAbbreviation":"Respir Res","author":[{"family":"Garcia-Rio","given":"Francisco"},{"family":"Miravitlles","given":"Marc"},{"family":"Soriano","given":"Joan B"},{"family":"Munoz","given":"Luis"},{"family":"Duran-Tauleria","given":"Enric"},{"family":"Sanchez","given":"Guadalupe"},{"family":"Sobradillo","given":"Victor"},{"family":"Ancochea","given":"Julio"}],"issued":{"date-parts":[["2010"]]},"accessed":{"date-parts":[["2014",3,25]]},"PMID":"20500811","PMCID":"PMC2891677"}}],"schema":""} (58) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"inS1hAeK","properties":{"formattedCitation":"(62)","plainCitation":"(62)"},"citationItems":[{"id":909,"uris":[""],"uri":[""],"itemData":{"id":909,"type":"article-journal","title":"Associations between BODE index and systemic inflammatory biomarkers in COPD","container-title":"COPD","page":"408-413","volume":"8","issue":"6","source":"NCBI PubMed","abstract":"BACKGROUND: COPD is a multicomponent disease and systemic inflammation represents one of the possible mechanisms responsible for its systemic manifestations, including skeletal muscle weakness and cachexia. Fat-free mass index (FFMI) that reflects the skeletal muscle mass, has been shown to be associated with both dyspnoea and exercise capacity. We hypothesized that the multidimensional BODE index, that reflects the multicomponent nature of COPD, might be related to biomarkers of systemic inflammation. We further evaluated associations between FFMI and systemic inflammation.\nMETHODS: BODE index and FFMI were calculated in 222 stable COPD patients and 132 smokers or ex-smokers with normal lung function. Systemic inflammation was evaluated with the measurement of leptin, adiponectin, CRP, IL-6, and TNF-α in serum samples of COPD patients.\nRESULTS: In patients with COPD, both BODE index and FFMI presented significant positive and negative associations respectively with leptin levels (R(2) 0.61 and 0.65, respectively), whereas FFMI presented an additional negative association with the levels of TNF-α (R(2) 0.38). No significant associations were observed in smokers or ex-smokers with normal lung function.\nCONCLUSIONS: Both BODE index and FFMI, are related to the circulating levels of leptin in patients with COPD, suggesting a possible role for leptin in the systemic component of COPD. The additional association of FFMI with TNF-α may further support a role of systemic inflammation in muscle wasting in COPD.","DOI":"10.3109/15412555.2011.619599","ISSN":"1541-2563","note":"PMID: 22149400","journalAbbreviation":"COPD","language":"eng","author":[{"family":"Gaki","given":"Eleni"},{"family":"Kontogianni","given":"Konstantina"},{"family":"Papaioannou","given":"Andriana I"},{"family":"Bakakos","given":"Petros"},{"family":"Gourgoulianis","given":"Konstantinos I"},{"family":"Kostikas","given":"Konstantinos"},{"family":"Alchanatis","given":"Manos"},{"family":"Papiris","given":"Spyridon"},{"family":"Loukides","given":"Stelios"}],"issued":{"date-parts":[["2011",12]]},"PMID":"22149400"}}],"schema":""} (62) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KxrNiqw0","properties":{"formattedCitation":"(63)","plainCitation":"(63)"},"citationItems":[{"id":918,"uris":[""],"uri":[""],"itemData":{"id":918,"type":"article-journal","title":"Association between cytokines in induced sputum and severity of chronic obstructive pulmonary disease","container-title":"Respiratory medicine","page":"846-854","volume":"100","issue":"5","source":"NCBI PubMed","abstract":"Cytokines are known to be increased in induced sputum in chronic obstructive pulmonary disease (COPD). In this study, the relationship between the levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumour necrosis factor-alpha (TNF-alpha) in induced sputum of patients with exacerbation of COPD, and the severity of the disease, pulmonary function tests (PFT), arterial blood gases (ABG) were studied. Twenty-four patients with exacerbation of COPD were included in the study. The patients were grouped according to their PFT into two as: Group 1 (FEV1 below 50% of the predicted value, severe-very severe COPD, n=12) and, Group 2 (FEV1 above 50% of the predicted value, mild-moderate COPD, n=12). The levels of IL-6, IL-8 and TNF-alpha in induced sputum of the subjects were measured. The mean levels of IL-6, IL-8 and TNF-alpha in induced sputum were found to be higher in Group 1 (severe-very severe COPD) than in Group 2 (mild-moderate COPD). The differences in IL-6 and IL-8 levels between groups were statistically significant (P<0.05). A significant correlation was observed between the IL-6 value and FEV(1) (r=-0.435, P=0.034), FEV1/FVC (r=-0.446, P=0.029), PaO2 (r=-0.711, P=0.000), SaO2 (r=-0.444, P=0.030) and disease duration (r=0.427, P=0.037), respectively. Also, the level of IL-8 in induced sputum was inversely correlated with FEV1 (r=-0.562, P=0.004), PaO2 (r=-0.540, P=0.006) and SaO2 (r=-0.435, P=0.034). However, all three cytokines were positively correlated with the smoking load (r=0.653, P=0.001; r=0.439, P=0.032; r=0.649, P=0.001). We conclude, therefore, that in exacerbated COPD cases with greater degrees of obstruction of the airways have higher levels of cytokines in induced sputum. This can be interpreted to mean that these cytokines are related to the clinical parameters like the ABG and PFT and seem to be the determinant of the severity of the disease.","DOI":"10.1016/j.rmed.2005.08.022","ISSN":"0954-6111","note":"PMID: 16214322","journalAbbreviation":"Respir Med","language":"eng","author":[{"family":"Hacievliyagil","given":"Suleyman S"},{"family":"Gunen","given":"Hakan"},{"family":"Mutlu","given":"Levent C"},{"family":"Karabulut","given":"Aysun B"},{"family":"Temel","given":"Ismail"}],"issued":{"date-parts":[["2006",5]]},"PMID":"16214322"}}],"schema":""} (63) and with several systemic COPD manifestations and comorbidities, such as muscle cachexia, pulmonary hypertension, heart disease and depression. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"eGs0SJlc","properties":{"formattedCitation":"(64)","plainCitation":"(64)"},"citationItems":[{"id":922,"uris":[""],"uri":[""],"itemData":{"id":922,"type":"article-journal","title":"Metabolic profiling detects biomarkers of protein degradation in COPD patients","container-title":"The European respiratory journal","page":"345-355","volume":"40","issue":"2","source":"NCBI PubMed","abstract":"There is a paucity of biomarkers for chronic obstructive pulmonary disease (COPD). Metabolomics were applied to a defined COPD patient cohort from the ECLIPSE study (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points). Results were correlated with accepted biomarkers for the disease. Baseline control serum (n=66) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II (n=70), III (n=64) and IV (n=44) COPD patients were analysed by proton nuclear magnetic resonance ((1)H NMR). Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to confirm amino acid changes detected by (1)H NMR. Data were correlated with body composition, emphysema and systemic inflammation. (1)H NMR identified decreased lipoproteins, N,N-dimethylglycine, and increased glutamine, phenylalanine, 3-methylhistidine and ketone bodies in COPD patients with decreased branched-chain amino acids (BCAAs) observed in GOLD stage IV patients. BCAAs, their degradation products, 3-methylhistidine, ketone bodies, and triglycerides were correlated negatively with cachexia and positively with systemic inflammation. Emphysema patients also displayed decreased serum creatine, glycine and N,N-dimethylglycine. LC-MS/MS confirmed (1)H NMR findings relating to BCAAs, glutamine and 3-methylhistidine in GOLD stage IV patients. NMR-based metabolomics characterised COPD patients based on systemic effects and lung function parameters. Increased protein turnover occurred in all COPD patients with increased protein degradation in individuals with emphysema and cachexia.","DOI":"10.1183/09031936.00112411","ISSN":"1399-3003","note":"PMID: 22183483","journalAbbreviation":"Eur. Respir. J.","language":"eng","author":[{"family":"Ubhi","given":"Baljit K"},{"family":"Riley","given":"John H"},{"family":"Shaw","given":"Paul A"},{"family":"Lomas","given":"David A"},{"family":"Tal-Singer","given":"Ruth"},{"family":"MacNee","given":"William"},{"family":"Griffin","given":"Julian L"},{"family":"Connor","given":"Susan C"}],"issued":{"date-parts":[["2012",8]]},"PMID":"22183483"}}],"schema":""} (64) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"3b3hYqO6","properties":{"formattedCitation":"(65)","plainCitation":"(65)"},"citationItems":[{"id":924,"uris":[""],"uri":[""],"itemData":{"id":924,"type":"article-journal","title":"Systemic inflammation in patients with COPD and pulmonary hypertension","container-title":"Chest","page":"326-333","volume":"130","issue":"2","source":"NCBI PubMed","abstract":"STUDY OBJECTIVES: COPD is a systemic disorder that is associated with increases of inflammatory proteins in systemic circulation. However, no data on the potential role of systemic inflammation in pulmonary hypertension secondary to COPD are available. Therefore, our aim was to investigate the degree of systemic inflammation reflected by circulatory levels of C-reactive protein (CRP), tumor-necrosis factor (TNF)-alpha, and interleukin (IL)-6 in COPD patients with and without pulmonary hypertension.\nDESIGN: Cross-sectional study.\nSETTING: University hospital, tertiary referral setting.\nPATIENTS AND MEASUREMENTS: In 43 consecutive patients with COPD (mean [+/- SD] age, 65.0 +/- 10.5 years; mean FEV(1), 46.2 +/- 18.1% predicted), lung function was assessed using body plethysmography; pulmonary artery pressure (Ppa) levels were measured by echocardiography. Serum TNF-alpha and IL-6 levels were assessed by enzyme-linked immunosorbent assay, and high-sensitivity serum CRP levels were measured by chemiluminescent immunoassay.\nRESULTS: Pulmonary hypertension was present in 19 patients and was absent in 24 patients. In patients with pulmonary hypertension, serum CRP and TNF-alpha levels were significantly higher than in those patients without hypertension (median, 3.6 mg/L [25th to 75th percentile, 1.4 to 13.0 mg/L] vs 1.8 mg/L [25th to 75th percentile, 0.8 to 2.8 mg/L; p = 0.034]; and median, 4.2 pg/mL [25th to 75th percentile, 3.4 to 10.9 pg/mL] vs 3.1 pg/mL [25th to 75th percentile, 2.1 to 4.2 pg/mL]; p = 0.042, respectively). No differences were seen in serum IL-6 (median, 10.4 pg/mL [25th to 75th percentile, 8.8 to 12.2 pg/mL] vs 10.5 pg/mL [25th to 75th percentile, 9.4 to 39.1 pg/mL]; p = 0.651) between the groups. In multiple linear regression analysis, the following two variables were independent predictors of systolic Ppa (R(2) = 0.373): Pao(2) (p = 0.011); and log-transformed serum CRP level (p = 0.044).\nCONCLUSION: We conclude that increases in Ppa in patients with COPD are associated with higher serum levels of CRP and TNF-alpha, raising the possibility of a pathogenetic role for low-grade systemic inflammation in the pathogenesis of pulmonary hypertension in COPD patients.","DOI":"10.1378/chest.130.2.326","ISSN":"0012-3692","note":"PMID: 16899829","journalAbbreviation":"Chest","language":"eng","author":[{"family":"Joppa","given":"Pavol"},{"family":"Petrasova","given":"Darina"},{"family":"Stancak","given":"Branislav"},{"family":"Tkacova","given":"Ruzena"}],"issued":{"date-parts":[["2006",8]]},"PMID":"16899829"}}],"schema":""} (65) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"opDRAHyG","properties":{"formattedCitation":"(66)","plainCitation":"(66)"},"citationItems":[{"id":926,"uris":[""],"uri":[""],"itemData":{"id":926,"type":"article-journal","title":"Inflammatory response and body composition in chronic obstructive pulmonary disease","container-title":"American journal of respiratory and critical care medicine","page":"1414-1418","volume":"164","issue":"8 Pt 1","source":"NCBI PubMed","abstract":"Weight loss in chronic obstructive airways disease (COPD) is associated with an increased energy cost of breathing. To determine an association between body composition and the inflammatory response we studied 80 clinically stable patients. Body composition was determined anthropometrically and skeletal muscle mass was determined as the creatinine-height index (CHI). Forty patients had their nitrogen balance determined. Circulating concentrations of interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and their soluble receptors were determined for 68 patients. Body mass index (BMI) was normal (> 20 kg/m(2)) in 55 patients, of whom 17 (31%) had a low CHI (< 80% predicted). A reduced CHI was associated with increased circulating levels of IL-6 (p = 0.001), TNF-alpha (p = 0.032) and their soluble receptors IL-6sr (p = 0.002), TNF-alpha sr1 (p = 0.03), and TNF-alpha sr2 (p = 0.001). Patients with a normal BMI and low CHI had inflammatory mediator levels similar to patients with a low BMI and CHI; both were significantly greater than in those with a normal BMI and CHI. Nitrogen balance was similar between normal and low CHI groups, although nitrogen excretion was significantly increased in the low CHI group. Skeletal muscle loss in COPD is probably multifactorial in origin, but our data suggest a link with systemic inflammation, even when weight loss is inapparent.","DOI":"10.1164/ajrccm.164.8.2008109","ISSN":"1073-449X","note":"PMID: 11704588","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","language":"eng","author":[{"family":"Eid","given":"A A"},{"family":"Ionescu","given":"A A"},{"family":"Nixon","given":"L S"},{"family":"Lewis-Jenkins","given":"V"},{"family":"Matthews","given":"S B"},{"family":"Griffiths","given":"T L"},{"family":"Shale","given":"D J"}],"issued":{"date-parts":[["2001",10,15]]},"PMID":"11704588"}}],"schema":""} (66) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"p0DTf2Gn","properties":{"formattedCitation":"(67)","plainCitation":"(67)"},"citationItems":[{"id":928,"uris":[""],"uri":[""],"itemData":{"id":928,"type":"article-journal","title":"Biomarkers of systemic inflammation and depression and fatigue in moderate clinically stable COPD","container-title":"Respiratory Research","page":"3","volume":"12","issue":"1","source":"PubMed Central","abstract":"Introduction\nCOPD is an inflammatory disease with major co-morbidities. It has recently been suggested that depression may be the result of systemic inflammation. We aimed to explore the association between systemic inflammation and symptoms of depression and fatigue in patients with mainly moderate and clinically stable COPD using a range of inflammatory biomarkers, 2 depression and 2 fatigue scales.\n\nMethod\nWe assessed 120 patients with moderate COPD (FEV1% 52, men 62%, age 66). Depression was assessed using the BASDEC and CES-D scales. Fatigue was assessed using the Manchester COPD-fatigue scale (MCFS) and the Borg scale before and after 6MWT. We measured systemic TNF-α, CRP, TNF-α-R1, TNF-α-R2 and IL-6.\n\nResults\nA multivariate linear model of all biomarkers showed that TNF-α only had a positive correlation with BASDEC depression score (p = 0.007). TNF-α remained positively correlated with depression (p = 0.024) after further adjusting for TNF-α-R1, TNF-α-R2, 6MWD, FEV1%, and pack-years. Even after adding the MCFS score, body mass and body composition to the model TNF-α was still associated with the BASDEC score (p = 0.044). Furthermore, patients with higher TNF-α level (> 3 pg/ml, n = 7) had higher mean CES-D depression score than the rest of the sample (p = 0.03). Borg fatigue score at baseline were weakly correlated with TNF-α and CRP, and with TNF-α only after 6MWT. Patients with higher TNF-α had more fatigue after 6MWD (p = 0.054).\n\nConclusion\nThis study indicates a possible association between TNF-α and two frequent and major co-morbidities in COPD; i.e., depression and fatigue.","DOI":"10.1186/1465-9921-12-3","ISSN":"1465-9921","note":"PMID: 21208443\nPMCID: PMC3024938","journalAbbreviation":"Respir Res","author":[{"family":"Al-shair","given":"Khaled"},{"family":"Kolsum","given":"Umme"},{"family":"Dockry","given":"Rachel"},{"family":"Morris","given":"Julie"},{"family":"Singh","given":"Dave"},{"family":"Vestbo","given":"J?rgen"}],"issued":{"date-parts":[["2011"]]},"accessed":{"date-parts":[["2014",3,25]]},"PMID":"21208443","PMCID":"PMC3024938"}}],"schema":""} (67) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xWxzXecT","properties":{"formattedCitation":"(68)","plainCitation":"(68)"},"citationItems":[{"id":920,"uris":[""],"uri":[""],"itemData":{"id":920,"type":"article-journal","title":"Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort","container-title":"Respiratory medicine","page":"1376-1384","volume":"107","issue":"9","source":"NCBI PubMed","abstract":"Comorbidities, are common in COPD, have been associated with poor outcomes and are thought to relate to systemic inflammation. To investigate comorbidities in relation to systemic inflammation and outcomes we recorded comorbidities in a well characterized cohort (ECLIPSE study) for 2164 clinically stable COPD subjects, 337 smokers and 245 non-smokers with normal lung function. COPD patients had a higher prevalence of osteoporosis, anxiety/panic attacks, heart trouble, heart attack, and heart failure, than smokers or nonsmokers. Heart failure (Hazard Ratio [HR] 1.9, 95% Confidence Interval [CI] 1.3-2.9), ischemic heart disease (HR 1.5, 95% CI 1.1-2.0), heart disease (HR 1.5, 95% CI 1.2-2.0), and diabetes (HR 1.7, 95% CI 1.2-2.4) had increased odds of mortality when coexistent with COPD. Multiple comorbidities had accumulative effect on mortality. COPD and cardiovascular disease was associated with poorer quality of life, higher MRC dyspnea scores, reduced 6MWD, higher BODE index scores. Osteoporosis, hypertension and diabetes were associated with higher MRC dyspnea scores and reduced 6MWD. Higher blood concentrations of fibrinogen, IL-6 and IL-8 levels occurred in those with heart disease. Comorbidity is associated with poor clinical outcomes in COPD. The comorbidities of heart disease, hypertension and diabetes are associated with increased systemic inflammation.","DOI":"10.1016/j.rmed.2013.05.001","ISSN":"1532-3064","note":"PMID: 23791463","journalAbbreviation":"Respir Med","language":"eng","author":[{"family":"Miller","given":"Joy"},{"family":"Edwards","given":"Lisa D"},{"family":"Agustí","given":"Alvar"},{"family":"Bakke","given":"Per"},{"family":"Calverley","given":"Peter M A"},{"family":"Celli","given":"Bartolome"},{"family":"Coxson","given":"Harvey O"},{"family":"Crim","given":"Courtney"},{"family":"Lomas","given":"David A"},{"family":"Miller","given":"Bruce E"},{"family":"Rennard","given":"Steve"},{"family":"Silverman","given":"Edwin K"},{"family":"Tal-Singer","given":"Ruth"},{"family":"Vestbo","given":"J?rgen"},{"family":"Wouters","given":"Emiel"},{"family":"Yates","given":"Julie C"},{"family":"Macnee","given":"William"},{"family":"Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators","given":""}],"issued":{"date-parts":[["2013",9]]},"PMID":"23791463"}}],"schema":""} (68)Currently, two studies have evaluated the potential association between inflammatory mediators and anemia in stable COPD patients. John et al studied a population of 101 COPD patients, 13 of whom were anemic, and found that CRP and IL-6 levels were significantly elevated in anemic COPD patients compared to controls, while CRP was also significantly higher in anemic compared to non-anemic COPD patients. EPO concentration was also higher in anemic individuals compared to both non-anemic patients and healthy controls. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"EWSa2pzc","properties":{"formattedCitation":"(9)","plainCitation":"(9)"},"citationItems":[{"id":234,"uris":[""],"uri":[""],"itemData":{"id":234,"type":"article-journal","title":"Anemia and inflammation in COPD","container-title":"Chest","page":"825-829","volume":"127","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: Anemia in patients with COPD and its pathophysiology is an understudied issue.\nMETHODS: In a group of 101 COPD patients (FEV(1) percentage of predicted, 37 +/- 2% [mean +/- SEM]; mean age, 61 +/- 1 years; 35% female gender), the prevalence of anemia and its relationship to body mass and weight loss, inflammatory parameters, and erythropoietin levels was determined. Data were compared to a control group (healthy persons with matched age) in order to identify potential factors that may influence the development of anemia in patients with COPD.\nRESULTS: Anemia was diagnosed in 13 patients (hemoglobin levels < 13.5 mg/dL in male patients and < 12.0 mg/dL in female patients), which represents a prevalence of 13%. Anemic COPD patients showed elevated erythropoietin levels (41.8 +/- 25.4 U/L vs 16.3 +/- 2.9 U/L) and an increased inflammatory response compared to nonanemic patients. A significant inverse correlation of hemoglobin vs erythropoietin (r = - 0.84, p < 0.01) was observed in anemic COPD patients, but not in the nonanemic group.\nCONCLUSION: Anemic COPD patients show high erythropoietin levels, which may indicate presence of erythropoietin resistance. The latter may be mediated through inflammatory mechanisms, which is typical for anemia of chronic illness.","DOI":"10.1378/chest.127.3.825","ISSN":"0012-3692","note":"PMID: 15764763","journalAbbreviation":"Chest","language":"eng","author":[{"family":"John","given":"Matthias"},{"family":"Hoernig","given":"Soeren"},{"family":"Doehner","given":"Wolfram"},{"family":"Okonko","given":"Darlington D"},{"family":"Witt","given":"Christian"},{"family":"Anker","given":"Stefan D"}],"issued":{"date-parts":[["2005",3]]},"PMID":"15764763"}}],"schema":""} (9) In another case-control study where ACD in COPD patients was clinically and laboratory defined, the concentration of all studied cytokines (that is TNF-α, IL-6, IL-10 and INF-γ) was higher in the group of anemic compared to non-anemic COPD patients; However, the between group differences were statistically significant only for INF-γ and IL-10. Likewise, EPO levels were also higher in anemic individuals, indicating the presence of EPO resistance due to systemic inflammation. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VyfPdHyA","properties":{"formattedCitation":"(69)","plainCitation":"(69)"},"citationItems":[{"id":192,"uris":[""],"uri":[""],"itemData":{"id":192,"type":"article-journal","title":"Levels of inflammatory mediators in chronic obstructive pulmonary disease patients with anemia of chronic disease: a case-control study","container-title":"QJM: monthly journal of the Association of Physicians","page":"657-663","volume":"105","issue":"7","source":"NCBI PubMed","abstract":"BACKGROUND: Although a subset of patients with chronic obstructive pulmonary disease (COPD) display anemia, the role of elevated pro-inflammatory cytokines in COPD-related anemia of chronic disease (ACD) has not been fully investigated.\nAIM: To examine the levels of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-alpha (TNFα), interferon-gamma (IFNγ), C-reactive protein (CRP) and erythropoietin in stable COPD outpatients with and without ACD.\nDESIGN: A case-control design was followed.\nMETHODS: Fifty-four patients with stable COPD were studied. Among them, 27 had ACD according to strict clinical and laboratory criteria (group of cases), while another 27 nonanemic COPD patients, carefully matched to cases for age, gender, height, lung function and smoking status represented the controls. Serum levels of IL-1β, IL-6, IL-10, TNFα, IFNγ, CRP and erythropoietin were measured in both groups.\nRESULTS: Patients with ACD had significantly higher levels of IL-10 [25.6 (1.9-95.2) vs. 4.1 (1.9-31.9) pg/ml, P?=?0.049] and IFNγ [15.2 (2.2-106.9) vs. 2 (1.2-18.3) pg/ml, P?=?0.026] and had more frequently elevated CRP than controls. Levels of IL-1β [26.2 (9.8-96.4) vs. 7.9 (2.1-28.4) pg/ml, P?=?0.073], IL-6 [20.3 (2.1-125.4) vs. 6.2 (1.2-33.8) pg/ml, P?=?0.688] and TNFα [30.1 (3.2-107.5) vs. 10.1 (3.2-50.4) pg/ml, P?=?0.131] were also higher in cases, but the differences did not reach statistical significance. Patients with ACD also displayed significantly higher erythropoietin levels than controls [(21.9 (8.4-101.7) vs. 9.7 (6.3-21.7) mIU/ml, P?=?0.010], indicating erythropoietin resistance.\nCONCLUSION: This study shows that in stable COPD outpatients with strictly defined ACD, levels of inflammatory mediators and erythropoietin are elevated compared to nonanemic controls.","DOI":"10.1093/qjmed/hcs024","ISSN":"1460-2393","note":"PMID: 22355163","shortTitle":"Levels of inflammatory mediators in chronic obstructive pulmonary disease patients with anemia of chronic disease","journalAbbreviation":"QJM","language":"eng","author":[{"family":"Boutou","given":"A K"},{"family":"Pitsiou","given":"G G"},{"family":"Stanopoulos","given":"I"},{"family":"Kontakiotis","given":"T"},{"family":"Kyriazis","given":"G"},{"family":"Argyropoulou","given":"P"}],"issued":{"date-parts":[["2012",7]]},"PMID":"22355163"}}],"schema":""} (69) Systemic inflammation and ACD: The role of exacerbationsOne of the most important complications in the course of COPD is acute exacerbation (AECOPD), during which a further burst of inflammatory mediators occurs. Sputum or serum levels of CRP, TNF-α, IL-6, IL-8, IL-1β, IL-10, fibrinogen and total cell counts are significantly increased, compared to stable patients or controls, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xRgJigrV","properties":{"formattedCitation":"(60)","plainCitation":"(60)"},"citationItems":[{"id":892,"uris":[""],"uri":[""],"itemData":{"id":892,"type":"article-journal","title":"Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obstructive pulmonary disease","container-title":"Clinical science (London, England: 1979)","page":"225-232","volume":"115","issue":"7","source":"NCBI PubMed","abstract":"The aim of the present study was to assess circulating levels of VEGF (vascular endothelial growth factor), a biomarker with prognostic significance in cardiovascular disease, and markers of systemic inflammation in patients with stable and exacerbated COPD (chronic obstructive pulmonary disease). Lung function parameters, arterial blood gas analysis and circulating levels of VEGF, IL-6 (interleukin-6), TNF-alpha (tumour necrosis factor-alpha), CRP (C-reactive protein), fibrinogen and the peripheral blood neutrophil cell count were assessed in 30 patients on admission to the hospital for acute exacerbation of COPD, in 30 age-, gender- and BMI (body mass index)-matched patients with stable COPD, and 30 matched controls with normal lung function. Patients with acute exacerbated COPD had higher circulating concentrations of VEGF (P<0.001), IL-6 (P<0.05) and CRP (P<0.01) and an increased blood neutrophil cell count (P<0.05) compared with patients with stable COPD and healthy controls. VEGF levels in exacerbated COPD correlated with systemic inflammatory markers, such as CRP (r=0.61, P<0.005), IL-6 (r=0.46; P<0.01) and fibrinogen (r=0.39, P<0.05). In patients with stable COPD, there was a significant relationship between circulating VEGF levels and the percentage of the predicted FEV(1) (forced expiratory volume in 1 s) (r=0.47, P<0.01). Recovery from the exacerbation resulted in a significant decrease in both circulating VEGF levels and markers of systemic inflammation. In conclusion, circulating levels of VEGF and markers of systemic inflammation are up-regulated in patients with acute exacerbated COPD and decrease after recovery from the exacerbation.","DOI":"10.1042/CS20070382","ISSN":"1470-8736","note":"PMID: 18307413","journalAbbreviation":"Clin. Sci.","language":"eng","author":[{"family":"Valipour","given":"Arschang"},{"family":"Schreder","given":"Martin"},{"family":"Wolzt","given":"Michael"},{"family":"Saliba","given":"Sleman"},{"family":"Kapiotis","given":"Sonja"},{"family":"Eickhoff","given":"Philipp"},{"family":"Burghuber","given":"Otto Chris"}],"issued":{"date-parts":[["2008",10]]},"PMID":"18307413"}}],"schema":""} (59) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ah013YgZ","properties":{"formattedCitation":"(70)","plainCitation":"(70)"},"citationItems":[{"id":931,"uris":[""],"uri":[""],"itemData":{"id":931,"type":"article-journal","title":"Molecular mechanisms of inflammation during exacerbations of chronic obstructive pulmonary disease","container-title":"Archivos de bronconeumología","page":"176-183","volume":"47","issue":"4","source":"NCBI PubMed","abstract":"INTRODUCTION: Exacerbations of chronic obstructive pulmonary disease (COPD) are characterised by an inflammatory and systemic response that persists for some time after their clinical resolution. The mechanisms of this inflammatory process are not well known.\nOBJECTIVES: To explore the inflammatory changes and possible mechanisms during COPD exacerbation.\nMETHODS: We determined the inflammatory cell concentrations in blood and sputum, nitric oxide in exhaled air (FeNO), C-reactive protein (CRP) in plasma, cytokines (IL-6, 8, 1β, 10, 12, TNF-α) and SLPI (leukocyte protease inhibitor) and total antioxidant status (TAS) in blood and sputum, the activity of nuclear kappa B factor (NF-κ B) and of the histone deacetylase enzyme (HDAC) in 17 patients during COPD exacerbation and in stable phase, as well as in 17 smoker and 11 non-smoker controls.\nRESULTS: COPD exacerbations are characterised by high levels of FeNO (p<0.05), plasma CRP (p<0.001) and IL-8, IL-1B, IL-10 in sputum (p<0.05) greater activation of NF-κ appaB in sputum macrophages compared with stable COPD and controls. During the stable phase, there continue to be high levels of oxidative stress, SLPI, IL-8, IL-6 and TNF-alfa, with no observed changes in either HDAC activity or in the amount of neutrophils in sputum, despite presenting a significant improvement (p<0.05) in lung function.\nCONCLUSIONS: Changes were observed in different pulmonary and systemic inflammatory markers during COPD exacerbation, which did not completely resolve during stable phase. However, current treatment does not allow for HDAC activity to be modified, which limits its anti-inflammatory effects.","DOI":"10.1016/j.arbres.2010.12.003","ISSN":"1579-2129","note":"PMID: 21454005","journalAbbreviation":"Arch. Bronconeumol.","language":"eng","author":[{"family":"Kersul","given":"Ana L"},{"family":"Iglesias","given":"Amanda"},{"family":"Ríos","given":"?ngel"},{"family":"Noguera","given":"Aina"},{"family":"Forteza","given":"Aina"},{"family":"Serra","given":"Enrique"},{"family":"Agustí","given":"Alvar"},{"family":"Cosío","given":"Borja G"}],"issued":{"date-parts":[["2011",4]]},"PMID":"21454005"}}],"schema":""} (70) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Y4S6lGf0","properties":{"formattedCitation":"(71)","plainCitation":"(71)"},"citationItems":[{"id":935,"uris":[""],"uri":[""],"itemData":{"id":935,"type":"article-journal","title":"Change in inflammation in out-patient COPD patients from stable phase to a subsequent exacerbation","container-title":"International journal of chronic obstructive pulmonary disease","page":"101-109","volume":"4","source":"NCBI PubMed","abstract":"BACKGROUND: Inflammation increases during exacerbations of COPD, but only a few studies systematically assessed these changes. Better identification of these changes will increase our knowledge and potentially guide therapy, for instance by helping with quicker distinction of bacterially induced exacerbations from other causes.\nAIM: To identify which inflammatory parameters increase during COPD exacerbations compared to stable disease, and to compare bacterial and non-bacterial exacerbations.\nMETHODS: In 45 COPD patients (37 male/8 female, 21 current smokers, mean age 65, FEV(1) 52% predicted, pack years 38) sputum was collected during a stable phase and subsequently during an exacerbation.\nRESULTS: Sputum total cell counts (9.0 versus 7.9 x 10(6)/mL), eosinophils (0.3 versus 0.2 x 10(6)/mL), neutrophils (6.1 versus 5.8 x 10(6)/mL), and lymphocytes (0.07 versus 0.02 x 10(6)/mL) increased significantly during an exacerbation compared to stable disease. A bacterial infection was demonstrated by culture in 8 sputum samples obtained during an exacerbation. These exacerbations had significantly increased sputum total cell and neutrophil counts, leukotriene-B4, myeloperoxidase, interleukin-8 and interleukin-6, and tumor necrosis factor-alpha (TNF-alpha) levels, and were also associated with more systemic inflammation compared to exacerbations without a bacterial infection. Sputum TNF-alpha level during an exacerbation had the best test characteristics to predict a bacterial infection.\nCONCLUSION: Sputum eosinophil, neutrophil, and lymphocyte counts increase during COPD exacerbations. The increase in systemic inflammation during exacerbations seems to be limited to exacerbations caused by bacterial infections of the lower airways. Sputum TNF-alpha is a candidate marker for predicting airway bacterial infection.","ISSN":"1178-2005","note":"PMID: 19436694 \nPMCID: PMC2672798","journalAbbreviation":"Int J Chron Obstruct Pulmon Dis","language":"eng","author":[{"family":"Bathoorn","given":"Erik"},{"family":"Liesker","given":"Jeroen J W"},{"family":"Postma","given":"Dirkje S"},{"family":"Ko?ter","given":"Gerard H"},{"family":"van der Toorn","given":"Marco"},{"family":"van der Heide","given":"Sicco"},{"family":"Ross","given":"H Alec"},{"family":"van Oosterhout","given":"Antoon J M"},{"family":"Kerstjens","given":"Huib A M"}],"issued":{"date-parts":[["2009"]]},"PMID":"19436694","PMCID":"PMC2672798"}}],"schema":""} (71) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"X5PQRw8U","properties":{"formattedCitation":"(72)","plainCitation":"(72)"},"citationItems":[{"id":937,"uris":[""],"uri":[""],"itemData":{"id":937,"type":"article-journal","title":"Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD","container-title":"Respiratory medicine","page":"2409-2415","volume":"101","issue":"11","source":"NCBI PubMed","abstract":"BACKGROUND: Acute exacerbations are important in the clinical course of COPD, yet the underlying mechanisms are poorly understood. Systemic inflammation is now considered as an important component in the disease process. In this study we evaluated longitudinally the systemic inflammation during hospital treatment for acute exacerbation and after clinical recovery.\nMETHODS: Blood was collected on day 0, 1, 4 and 8 in 21 patients admitted for an acute exacerbation of COPD and at 1 month, 3 months and 6 months after discharge. Systemic inflammation was determined by measurement of the pro-inflammatory markers interleukin (IL)-6, soluble tumor necrosis factor (TNF) receptors sTNFR55 and sTNFR75, the anti-inflammatory mediator sIL-1RII, and bactericidal permeability increasing protein (BPI) as a marker of neutrophil activation. In addition, plasma level of Trolox antioxidant capacity (TEAC) was determined. Healthy age-matched controls were measured for the same markers at one time-point.\nRESULTS: All inflammatory markers analyzed were elevated on first day of admission for exacerbation of COPD, as compared to healthy controls. During treatment, levels of IL-6, and sTNFR75 rapidly decreased, whereas sTNFR55 and BPI remained elevated. Moreover, sIL-1RII and TEAC increased during first 8 days of treatment. In the stable condition all inflammatory markers returned to values comparable to healthy controls, with the exception of BPI, which remained persistently elevated compared to healthy controls.\nCONCLUSION: This study clearly demonstrates upregulation of systemic inflammation in acute exacerbations of COPD. Attenuation of systemic inflammation may offer new perspectives in the management of COPD patients to reduce the burden of exacerbations.","DOI":"10.1016/j.rmed.2007.05.026","ISSN":"0954-6111","note":"PMID: 17644367","journalAbbreviation":"Respir Med","language":"eng","author":[{"family":"Groenewegen","given":"Karin H"},{"family":"Dentener","given":"Mieke A"},{"family":"Wouters","given":"Emiel F M"}],"issued":{"date-parts":[["2007",11]]},"PMID":"17644367"}}],"schema":""} (72) and this increase often persists after the improvement of lung function. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ZoqeQriF","properties":{"formattedCitation":"(70)","plainCitation":"(70)"},"citationItems":[{"id":931,"uris":[""],"uri":[""],"itemData":{"id":931,"type":"article-journal","title":"Molecular mechanisms of inflammation during exacerbations of chronic obstructive pulmonary disease","container-title":"Archivos de bronconeumología","page":"176-183","volume":"47","issue":"4","source":"NCBI PubMed","abstract":"INTRODUCTION: Exacerbations of chronic obstructive pulmonary disease (COPD) are characterised by an inflammatory and systemic response that persists for some time after their clinical resolution. The mechanisms of this inflammatory process are not well known.\nOBJECTIVES: To explore the inflammatory changes and possible mechanisms during COPD exacerbation.\nMETHODS: We determined the inflammatory cell concentrations in blood and sputum, nitric oxide in exhaled air (FeNO), C-reactive protein (CRP) in plasma, cytokines (IL-6, 8, 1β, 10, 12, TNF-α) and SLPI (leukocyte protease inhibitor) and total antioxidant status (TAS) in blood and sputum, the activity of nuclear kappa B factor (NF-κ B) and of the histone deacetylase enzyme (HDAC) in 17 patients during COPD exacerbation and in stable phase, as well as in 17 smoker and 11 non-smoker controls.\nRESULTS: COPD exacerbations are characterised by high levels of FeNO (p<0.05), plasma CRP (p<0.001) and IL-8, IL-1B, IL-10 in sputum (p<0.05) greater activation of NF-κ appaB in sputum macrophages compared with stable COPD and controls. During the stable phase, there continue to be high levels of oxidative stress, SLPI, IL-8, IL-6 and TNF-alfa, with no observed changes in either HDAC activity or in the amount of neutrophils in sputum, despite presenting a significant improvement (p<0.05) in lung function.\nCONCLUSIONS: Changes were observed in different pulmonary and systemic inflammatory markers during COPD exacerbation, which did not completely resolve during stable phase. However, current treatment does not allow for HDAC activity to be modified, which limits its anti-inflammatory effects.","DOI":"10.1016/j.arbres.2010.12.003","ISSN":"1579-2129","note":"PMID: 21454005","journalAbbreviation":"Arch. Bronconeumol.","language":"eng","author":[{"family":"Kersul","given":"Ana L"},{"family":"Iglesias","given":"Amanda"},{"family":"Ríos","given":"?ngel"},{"family":"Noguera","given":"Aina"},{"family":"Forteza","given":"Aina"},{"family":"Serra","given":"Enrique"},{"family":"Agustí","given":"Alvar"},{"family":"Cosío","given":"Borja G"}],"issued":{"date-parts":[["2011",4]]},"PMID":"21454005"}}],"schema":""} (70)Two studies have studied the potential association between systemic inflammation and EPO levels during an AECOPD, but results are conflicting. Markoulaki et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"k2LG7nvH","properties":{"formattedCitation":"(73)","plainCitation":"(73)"},"citationItems":[{"id":204,"uris":[""],"uri":[""],"itemData":{"id":204,"type":"article-journal","title":"Hemoglobin, erythropoietin and systemic inflammation in exacerbations of chronic obstructive pulmonary disease","container-title":"European journal of internal medicine","page":"103-107","volume":"22","issue":"1","source":"NCBI PubMed","abstract":"BACKGROUND: Systemic inflammation may represent a possible cause of anemia. Previous data support that anemic patients with COPD present high erythropoietin (EPO) levels, suggestive of EPO resistance, possibly mediated through inflammatory mechanisms.\nOBJECTIVES: We aimed to determine whether systemic inflammation, which is usually up-regulated during exacerbations of COPD (ECOPD) is associated with low hemoglobin levels expressing erythropoietin resistance.\nMETHODS: Hemoglobin (Hb), EPO and serum biomarkers of systemic inflammation [CRP, TNF-α, fibrinogen and IL-6] were assessed at three time points (admission, resolution and stable phases) in a selected cohort of 93 COPD patients.\nRESULTS: Hemoglobin levels were significantly lower on admission compared to resolution and stable phases (median 12.1 g/dl [interquartile ranges 11.2-12.7], vs 13.5 [12.4-14.3] vs 13.4 [12.7-14.08], respectively p=0.002), whereas EPO was significantly higher on admission compared to resolution and stable phases. A negative association between Hb and IL-6 and a positive association between EPO and IL-6 were observed only during the acute phase of exacerbation. EPO and Hb were negatively associated during the acute phase, whereas they were positively associated during discharge and stable phase.\nCONCLUSIONS: In this observational study we have shown that during admission for ECOPD Hb levels are decreased and EPO levels are increased. We have also identified a negative association between Hb and EPO. The above association is mainly related to increased IL-6 levels, indicating a possible EPO resistance through the mechanism of increased systemic inflammatory process.","DOI":"10.1016/j.ejim.2010.07.010","ISSN":"1879-0828","note":"PMID: 21238904","journalAbbreviation":"Eur. J. Intern. Med.","language":"eng","author":[{"family":"Markoulaki","given":"Despoina"},{"family":"Kostikas","given":"Konstantinos"},{"family":"Papatheodorou","given":"Georgios"},{"family":"Koutsokera","given":"Angela"},{"family":"Alchanatis","given":"Manos"},{"family":"Bakakos","given":"Petros"},{"family":"Gourgoulianis","given":"Konstantinos I"},{"family":"Roussos","given":"Charis"},{"family":"Koulouris","given":"Nikolaos G"},{"family":"Loukides","given":"Stelios"}],"issued":{"date-parts":[["2011",2]]},"PMID":"21238904"}}],"schema":""} (73) used measurements at three time points in a selected cohort of 93 COPD patients who presented with AECOPD. Haemoglobin levels were significantly decreased and EPO levels were significantly increased during the acute phase compared to resolution and steady phases; EPO and Hb were negatively correlated during the acute phase and positively correlated during resolution and stable phases. Moreover, IL-6 levels were negatively correlated with Hb and positively correlated with EPO, indicating the presence of EPO resistance during the acute phase of AECOPD.In a previous report Sala et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"03N5SYKa","properties":{"formattedCitation":"(74)","plainCitation":"(74)"},"citationItems":[{"id":296,"uris":[""],"uri":[""],"itemData":{"id":296,"type":"article-journal","title":"Low erythropoietin plasma levels during exacerbations of COPD","container-title":"Respiration; international review of thoracic diseases","page":"190-197","volume":"80","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: It is known that pro-inflammatory cytokines suppress in vitro the gene expression and protein production of erythropoietin (Epo). We hypothesized that systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) may influence Epo production, particularly during episodes of exacerbation of the disease (ECOPD) where an inflammatory burst is known to occur.\nOBJECTIVES: We compared the plasma levels of Epo and high-sensitivity (hs) C-reactive protein (hsC-RP) in patients hospitalized because of ECOPD (n = 26; FEV(1): 48 +/- 15% predicted), patients with clinically stable COPD (n = 31; FEV(1): 49 +/- 17% predicted), smokers with normal lung function (n = 9), and healthy never smokers (n = 9).\nMETHODS: Venous blood samples were taken between 9 and 10 a.m. after an overnight fast into tubes with EDTA (10 ml) or without EDTA (10 ml). Plasma levels of Epo (R&D Systems Inc., Minneapolis, Minn., USA) and hsC-RP (BioSource, Belgium) were determined by ELISA.\nRESULTS: Log-Epo plasma levels were significantly lower (0.46 +/- 0.32 mU/ml) in ECOPD than in stable COPD (1.05 +/- 0.23 mU/ml), smokers (0.95 +/- 0.11 mU/ml) and never smokers with normal lung function (0.92 +/- 0.19 mU/ml) (p < 0.01, each). In a subset of 8 COPD patients who could be studied both during ECOPD and clinical stability, log-Epo increased from 0.49 +/- 0.42 mU/ml during ECOPD to 0.97 +/- 0.19 mU/ml during stability (p < 0.01). In patients with COPD log-Epo was significantly related to hsC-RP (r = -0.55, p < 0.0001) and circulating neutrophils (r = -0.48, p < 0.0001).\nCONCLUSIONS: These results show that the plasma levels of Epo are reduced during ECOPD likely in relation to a burst of systemic inflammation.","DOI":"10.1159/000264604","ISSN":"1423-0356","note":"PMID: 19955699","journalAbbreviation":"Respiration","language":"eng","author":[{"family":"Sala","given":"Ernest"},{"family":"Balaguer","given":"Catalina"},{"family":"Villena","given":"Cristina"},{"family":"Ríos","given":"Angel"},{"family":"Noguera","given":"Aina"},{"family":"Nú?ez","given":"Belén"},{"family":"Agustí","given":"Alvar"}],"issued":{"date-parts":[["2010"]]},"PMID":"19955699"}}],"schema":""} (74) identified lower levels of EPO among exacerbated COPD patients, compared to stable COPD patients, non-COPD smokers and healthy controls. In COPD patients EPO levels correlated with CRP and circulating neutrophils, while in a small (n=8) subgroup of COPD patients who were studied both at AECOPD and stable phase, EPO levels significantly increased, when acute phase resolved. These conflicting results indicate that more studies are needed to reveal the complex pathophysiology underlying EPO regulation during AECOPD, especially now that a distinct COPD phenotype, “the frequent exacerbator” with increased airway and systemic inflammation and a high prevalence of extrapulmonary comorbidities has been proposed. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"edUFgXA9","properties":{"formattedCitation":"(75)","plainCitation":"(75)"},"citationItems":[{"id":939,"uris":[""],"uri":[""],"itemData":{"id":939,"type":"article-journal","title":"Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease","container-title":"BMC medicine","page":"181","volume":"11","source":"NCBI PubMed","abstract":"Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients. Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the 'frequent exacerbator' phenotype. This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes. These patients are therefore a priority for research and treatment. The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection. Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment. Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype. This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.","DOI":"10.1186/1741-7015-11-181","ISSN":"1741-7015","note":"PMID: 23945277 \nPMCID: PMC3750926","journalAbbreviation":"BMC Med","language":"eng","author":[{"family":"Wedzicha","given":"Jadwiga A"},{"family":"Brill","given":"Simon E"},{"family":"Allinson","given":"James P"},{"family":"Donaldson","given":"Gavin C"}],"issued":{"date-parts":[["2013"]]},"PMID":"23945277","PMCID":"PMC3750926"}}],"schema":""} (75) Oxygen supplementationAs described above, tissue hypoxia is the most potent trigger for EPO production which results in increased erythropoiesis. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"RBi0hrSF","properties":{"formattedCitation":"(52)","plainCitation":"(52)"},"citationItems":[{"id":339,"uris":[""],"uri":[""],"itemData":{"id":339,"type":"article-journal","title":"Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure","container-title":"Nature clinical practice. Nephrology","page":"47-57","volume":"4","issue":"1","source":"NCBI PubMed","abstract":"Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function.","DOI":"10.1038/ncpneph0655","ISSN":"1745-8331","note":"PMID: 18094727","shortTitle":"Mechanisms of Disease","journalAbbreviation":"Nat Clin Pract Nephrol","language":"eng","author":[{"family":"van der Putten","given":"Karien"},{"family":"Braam","given":"Branko"},{"family":"Jie","given":"Kim E"},{"family":"Gaillard","given":"Carlo A J M"}],"issued":{"date-parts":[["2008",1]]},"PMID":"18094727"}}],"schema":""} (51) Thus, one could hypothesize that the treatment of hypoxia in COPD patients would result to the reduction of EPO production and inhibition of erythroid progenitor cells proliferation, leading to anemia. However, results from human studies regarding both the EPO response to hypoxia and the impact of oxygen treatment on EPO concentration are conflicting and sometimes paradoxical.Guidet et al studied 21 COPD patients with severe hypoxemia to find that EPO levels were not significantly different between polycythemic and non-polycythemic groups. The absence of adaptive polycythemia in the presence of severe hypoxia was not associated with a quantitative deficit of EPO, nor to a lack of sensitivity of progenitor cells to its action. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"IPjsgzdh","properties":{"formattedCitation":"(76)","plainCitation":"(76)"},"citationItems":[{"id":1015,"uris":[""],"uri":[""],"itemData":{"id":1015,"type":"article-journal","title":"Polycythemia in chronic obstructive pulmonary disease. A study of serum and urine erythropoietin and medullary erythroid progenitors","container-title":"Chest","page":"867-870","volume":"92","issue":"5","source":"NCBI PubMed","abstract":"In order to investigate the mechanism of polycythemia in chronic obstructive pulmonary disease (COPD), serum and urinary levels of erythropoietin and medullary erythroid progenitors were studied in 21 patients; nine were nonpolycythemic (hematocrit, 39 +/- 4 percent; red blood cell [RBC] mass, 28 +/- 5 ml/kg; forced expiratory volume in one second [FEV1], 0.6 +/- 0.1 L), and 12 patients were polycythemic (hematocrit, 52 +/- 7 percent; RBC mass, 46 +/- 7 ml/kg; FEV1, 0.9 +/- 0.3 L). Hypoxia was severe in both groups, with mean arterial oxygen pressure of 47 mm Hg. The following parameters of tissue oxygenation were not significantly different between the two groups: arterial and mixed-venous oxygen saturations; cardiac output; oxygen utilization coefficient; 2, 3-diphosphoglycerate, and carboxyhemoglobin level. The level of erythropoietin was measured by bioassay in vitro. The level was increased in the serum of 85 percent (18) and in the urine of 38 percent (8) of the patients. There was no significant difference between the nonpolycythemic and polycythemic groups. Without exogenous erythropoietin, none of the subjects showed spontaneous colonies of erythroid progenitors. The addition of one unit of erythropoietin induced a similar normal proliferation of erythroid progenitors in both groups. The absence of adaptative polycythemia in the nonpolycythemic group with severe hypoxia was seemingly related neither to a quantitative deficit of erythropoietin nor to a lack of sensitivity of erythroid progenitors to its action.","ISSN":"0012-3692","note":"PMID: 3665602","journalAbbreviation":"Chest","language":"eng","author":[{"family":"Guidet","given":"B"},{"family":"Offenstadt","given":"G"},{"family":"Boffa","given":"G"},{"family":"Najman","given":"A"},{"family":"Baillou","given":"C"},{"family":"Hatzfeld","given":"C"},{"family":"Amstutz","given":"P"}],"issued":{"date-parts":[["1987",11]]},"PMID":"3665602"}}],"schema":""} (76) In a case-control study of 32 patients and 34 matched non-smokers healthy subjects, Tsantes et al found that although erythrocytocis and macrocytosis, which are both induced by hypoxia, occur more often among hypoxemic COPD subjects, they are not a consistent feature of hypoxia in COPD. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TPdbjjqA","properties":{"formattedCitation":"(77)","plainCitation":"(77)"},"citationItems":[{"id":1017,"uris":[""],"uri":[""],"itemData":{"id":1017,"type":"article-journal","title":"Red cell macrocytosis in hypoxemic patients with chronic obstructive pulmonary disease","container-title":"Respiratory medicine","page":"1117-1123","volume":"98","issue":"11","source":"NCBI PubMed","abstract":"Macrocytosis is a common finding in patients with chronic obstructive pulmonary disease (COPD). The cause for the elevation of mean corpuscular volume (MCV) in these patients remains elusive. In an attempt to determine the extent of macrocytosis in COPD patients and search for possible causative factors, we evaluated the hematologic parameters, F-cell percentage, blood gases and serum erythropoietin (Epo) Levels in 32 COPD clinically stable patients and 34 sex- and age-matched non-smoker healthy volunteers. An increased MCV was observed in almost half of the hypoxemic COPD cases (14/32 or 43.75%), while erythrocytosis developed to a lesser degree (37.5%). The erythropoietic response did not correlate with the severity of hypoxia. Moreover, no significant correlation was found between macrocytosis and hypoxemia or erythrocytosis and red cell size. In some cases the two phenomena occurred independently. The F-cell percentage was significantly elevated in the COPD group (P < 0.01) and was associated with MCV values (n = 32, r5 = 0.41, P < 0.05). This finding supports the hypothesis we put forward to explain the macrocytosis often observed in COPD, i.e., that the acute erythropoietic stress occurring repeatedly in these patients as a result of the frequent exacerbations may lead to waves of release of relatively immature, large red cells from the marrow, including an increased number of F-cells, reflecting the recruitment of normally dormant BFU-E (bursts forming units of erythrocyte precursors), which maintain the program for gamma-chain synthesis. The fact that erythrocytosis and macrocytosis, both being triggered by hypoxemia, do not occur consistently in all COPD patients indicates that many other factors may also intervene.","ISSN":"0954-6111","note":"PMID: 15526813","journalAbbreviation":"Respir Med","language":"eng","author":[{"family":"Tsantes","given":"Argirios E"},{"family":"Papadhimitriou","given":"Stefanos I"},{"family":"Tassiopoulos","given":"Stergios T"},{"family":"Bonovas","given":"Stefanos"},{"family":"Paterakis","given":"George"},{"family":"Meletis","given":"Ioannis"},{"family":"Loukopoulos","given":"Dimitrios"}],"issued":{"date-parts":[["2004",11]]},"PMID":"15526813"}}],"schema":""} (77) Moreover, the severity of hypoxemia could be of some importance, apart from its presence; Fitzpatrick et al ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QAdPkFhz","properties":{"formattedCitation":"(78)","plainCitation":"(78)"},"citationItems":[{"id":1019,"uris":[""],"uri":[""],"itemData":{"id":1019,"type":"article-journal","title":"Nocturnal desaturation and serum erythropoietin: a study in patients with chronic obstructive pulmonary disease and in normal subjects","container-title":"Clinical science (London, England: 1979)","page":"319-324","volume":"84","issue":"3","source":"NCBI PubMed","abstract":"1. To clarify the relationship between nocturnal oxygen desaturation and erythropoietin production in patients with chronic obstructive pulmonary disease, we determined arterial oxygen saturation and serum immunoreactive erythropoietin levels over 24 h in eight patients with chronic obstructive pulmonary disease and in nine normal subjects. 2. In the normal subjects, there was a significant circadian variation in serum erythropoietin levels with the highest mean deviation from the geometric mean at 22.00 hours and the nadir at 05.00 hours. 3. The three patients with chronic obstructive pulmonary disease with the most marked nocturnal desaturation (lowest arterial oxygen saturation < 57%) and most marked daytime hypoxaemia (daytime arterial partial pressure of oxygen < 6 kPa) had raised nocturnal serum erythropoietin levels. In two of these patients, the serum erythropoietin level was raised throughout the 24 h and erythrocyte mass was also raised. In the other patient, the serum erythropoietin level was not raised in five daytime samples and erythrocyte mass was normal. 4. The other five patients with chronic obstructive pulmonary disease with less severe nocturnal hypoxaemia (lowest arterial oxygen saturation range 78-86%) had serum erythropoietin levels (range 14-36 m-i.u./ml) which were indistinguishable from normal (range 12-44 m-i.u./ml) and showed circadian changes which were not significantly different (P = 0.35) from those in the normal subjects. 5. Thus, mild nocturnal oxygen desaturation is not associated with elevation of serum erythropoietin levels, whereas daytime hypoxaemia with associated severe nocturnal desaturation is associated with increased serum erythropoietin levels both by day and by night.","ISSN":"0143-5221","note":"PMID: 8384954","shortTitle":"Nocturnal desaturation and serum erythropoietin","journalAbbreviation":"Clin. Sci.","language":"eng","author":[{"family":"Fitzpatrick","given":"M F"},{"family":"Mackay","given":"T"},{"family":"Whyte","given":"K F"},{"family":"Allen","given":"M"},{"family":"Tam","given":"R C"},{"family":"Dore","given":"C J"},{"family":"Henley","given":"M"},{"family":"Cotes","given":"P M"},{"family":"Douglas","given":"N J"}],"issued":{"date-parts":[["1993",3]]},"PMID":"8384954"}}],"schema":""} (78) concluded, after studying 8 COPD and 9 healthy subjects, that, mild nocturnal oxygen desaturation is not associated with elevated EPO levels, whereas daytime hypoxaemia accompanied by severe nocturnal desaturation is associated with increased serum EPO levels both by day and by night. After comparing a cohort of 40 COPD patients with 40 healthy subjects, Casale et al indicated that normal circardian rhythm of circulating serum EPO levels is lost in COPD patients and mean daily levels of EPO are significantly higher, suggesting that daytime hypoxemia and severe nocturnal desaturation might be the cause of this abnormality. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"x21qXGO3","properties":{"formattedCitation":"(79)","plainCitation":"(79)"},"citationItems":[{"id":1021,"uris":[""],"uri":[""],"itemData":{"id":1021,"type":"article-journal","title":"Diurnal rhythm of serum erythropoietin circulating levels in chronic obstructive pulmonary disease","container-title":"Panminerva medica","page":"183-185","volume":"39","issue":"3","source":"NCBI PubMed","abstract":"OBJECTIVE: Since erythropoietin (Epo) presents a diurnal rhythm in its circulating serum levels and it is reported increased in patients with chronic obstructive pulmonary disease (COPD), the circadian rhythm of Epo was investigated in a group of 40 normocytemic patients with chronic obstructive pulmonary disease compared with 40 clinically healthy subjects.\nMETHODS: Venous blood samples were drawn in each subject during the span of a whole day every four hours, starting from midnight, for the determination of serum Epo levels by RIA. Statistical analysis was carried out by chronograms and by means of the \"cosinor\" method.\nRESULTS: The control group presents a significant (p < 0.001) circadian rhythm in serum Epo levels, with maximum in the afternoon, whereas no rhythm (p > 0.05) is detected in the patient group. This has significantly (p < 0.05) higher mean daily levels and lower diurnal variations of serum Epo than the control group; a significant (p < 0.05) difference exists between the two groups regarding the peaks of rhythms.\nCONCLUSION: These data confirm the presence of circadian rhythm in serum Epo levels and suggest that the COPD, by daytime hypoxemia with associated severe nocturnal desaturation, is associated with increased serum Epo levels both by day and by night, so that the physiological circadian rhythm is lost in these patients.","ISSN":"0031-0808","note":"PMID: 9360419","journalAbbreviation":"Panminerva Med","language":"eng","author":[{"family":"Casale","given":"R"},{"family":"Pasqualetti","given":"P"}],"issued":{"date-parts":[["1997",9]]},"PMID":"9360419"}}],"schema":""} (79) Against this background, Pavlisa et al studied the impact of hypoxemia correction in 57 COPD patients with chronic hypoxemia during AECOPD. Following correction of hypoxemia, EPO significantly decreased, but not all patients showed the same pattern; in those with lower initial EPO levels and erythrocyte count, EPO levels significantly increased. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7JpMbo79","properties":{"formattedCitation":"(80)","plainCitation":"(80)"},"citationItems":[{"id":1007,"uris":[""],"uri":[""],"itemData":{"id":1007,"type":"article-journal","title":"Erythropoietin response after correction of severe hypoxaemia due to acute respiratory failure in chronic obstructive pulmonary disease patients","container-title":"Clinical Science","page":"43","volume":"106","issue":"1","source":"CrossRef","DOI":"10.1042/CS20030165","ISSN":"01435221, 14708736","author":[{"family":"Pavlisa","given":"Gordana"},{"family":"Vrbanic","given":"Veljko"},{"family":"Kusec","given":"Vesna"},{"family":"Jaksic","given":"Branimir"}],"issued":{"date-parts":[["2004",1,1]]},"accessed":{"date-parts":[["2014",3,27]]}}}],"schema":""} (80) In another longitudinal study of 132 severe COPD patients using LTOT who were followed for 3 years, Hb levels decreased significantly among polycythemic patients, but effects in anemic patients were smaller. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4gLAiUYb","properties":{"formattedCitation":"(81)","plainCitation":"(81)"},"citationItems":[{"id":1012,"uris":[""],"uri":[""],"itemData":{"id":1012,"type":"article-journal","title":"Changes in blood hemoglobin and blood gases PaO2 and PaCO2 in severe COPD overa three-year telemonitored program of long-term oxygen treatment","container-title":"Multidisciplinary Respiratory Medicine","page":"15","volume":"7","issue":"1","source":"PubMed Central","abstract":"Background\nInformation on the effects of long-term oxygen treatment (LTOT) on blood hemoglobin (Hb) in severe COPD are limited. The aim was to assess blood Hb values in severe COPD, and investigate the time-course of both Hb and blood gas changes during a 3-year telemetric LTOT.\n\nMethods\nA cohort of 132 severe COPD patients (94 males; 71.4?years?±?8.8?sd), newly admitted to the tele-LTOT program, was investigated. Subjects were divided according to their original blood Hb: group A: <13?g/dL; group B: ≥13?<?15?g/dL; group C: ≥ 5?<?16?g/dL; group D: ≥16?g/dL. Blood Hb (g/dL), PaO2 and PaCO2 (mmHg), SaO2 (%), and BMI were measured at LTOT admission (t0), and at least quarterly over three years (t1-t3). Wilcoxon test was used to compare t0 vs. t1 values; linear regression to assess a possible Hb-BMI relationship; ANOVA to compare changes in Hb time-courses over the 3?years.\n\nResults\nLTOT induced a systematic increase of PaO2, and changes were significant since the first year (from 52.1?mmHg?±?6.6sd to 65.1?mmHg?±?8.7?sd, p?<?0.001). Changes in SaO2 were quite similar. Comparable and equally significant trends were seen in all subgroups (p?<?0.001). PaCO2 dropped within the first year of LTOT (from 49.4?mmHg?±?9.1sd to 45.9?mmHg ±7.5?sd, p?<?0.001): the t0-t1 comparison proved significant (p?<?0.01) only in subgroups with the highest basal Hb, who showed a further PaCO2 decline over the remaining two years (p?<?0.001). Hb tended to normalization during LTOT only in subgroups with basal Hb?>?15?g/dl (ANOVA p?<?0.001); anemic subjects (Hb?<?13?g/dl) ameliorated not significantly in the same period (ANOVA?=?0.5). Survival was independent of the original blood Hb. Anemia and polyglobulia are differently prevalent in COPD, the latter being the most represented in our cohort. LTOT affected both conditions, but to a different extent and according to different time-courses. The most striking Hb improvement was in polyglobulic patients in whom also PaO2, PaCO2 and SaO2 dramatically improved. In anemic subjects effects were smaller and slower, oxygenation being equally ameliorated by LTOT.\n\nConclusions\nLTOT effects on Hb and PaCO2 are regulated by an Hb-dependent gradient which seems independent of the original impairment of blood gases and of effects on oxygenation.","DOI":"10.1186/2049-6958-7-15","ISSN":"1828-695X","note":"PMID: 22958465\nPMCID: PMC3436709","journalAbbreviation":"Multidiscip Respir Med","author":[{"family":"Dal Negro","given":"Roberto W"},{"family":"Tognella","given":"Silvia"},{"family":"Bonadiman","given":"Luca"},{"family":"Turco","given":"Paola"}],"issued":{"date-parts":[["2012",7,17]]},"accessed":{"date-parts":[["2014",3,27]]},"PMID":"22958465","PMCID":"PMC3436709"}}],"schema":""} (81) These results indicate that the association between hypoxia, EPO levels and Hb concentration is complex, meaning that the impact of LTOT on hematocrit level cannot be reliably predicted. Renal impairmentRenal failure is an important comorbidity, the high prevalence of which, among COPD patients, has recently been recognized. The study of Incalzi et al among 356 consecutive elderly (>65 years old) COPD outpatients was the first to indicate that 20.8% of COPD patients presented with reduced glomerular filtration rate (GFR) (<60ml/min/1.73m2) and abnormal serum creatinine and 22.2% with reduced GFR without abnormal serum creatinine levels. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"LZa6GmdK","properties":{"formattedCitation":"(82)","plainCitation":"(82)"},"citationItems":[{"id":973,"uris":[""],"uri":[""],"itemData":{"id":973,"type":"article-journal","title":"Chronic renal failure: A neglected comorbidity of copd","container-title":"CHEST Journal","page":"831-837","volume":"137","issue":"4","source":"Silverchair","abstract":"Background:?\nTo the best of our knowledge, the association between COPD and chronic renal failure (CRF) has never been assessed. Lean mass is frequently reduced in COPD, and the glomerular filtration rate (GFR) might be depressed in spite of normal serum creatinine (concealed CRF). We investigated the prevalence and correlates of both concealed and overt CRF in elderly patients with COPD.Methods:\nWe evaluated 356 consecutive elderly outpatients with COPD enrolled in the Extrapulmonary Consequences of COPD in the Elderly Study and 290 age-matched outpatients free from COPD. The GFR was estimated using the Modification of Diet in Renal Disease Study Group equation. Patients were categorized as having normal renal function (GFR ≥ 60 mL/min/1.73 m2), concealed CRF (normal serum creatinine and reduced GFR), or overt CRF (increased serum creatinine and reduced GFR). Independent correlates of CRF were investigated by logistic regression analysis.Results:\nThe prevalence of concealed and overt CRF in patients with COPD was 20.8% and 22.2%, respectively. Corresponding figures in controls were 10.0% and 13.4%, respectively. COPD and age were significantly associated with both concealed CRF (COPD: odds ratio [OR] = 2.19, 95% CI = 1.17-4.12; age: OR = 1.06, 95% CI = 1.04-1.09) and overt CRF (COPD: OR = 1.94, 95% CI = 1.01-4.66; age: OR = 1.06, 95% CI = 1.04-1.10). Diabetes (OR = 1.96, 95% CI = 1.02-3.76), hypoalbuminemia (OR = 2.83, 95% CI = 1.70-4.73), and muscle-skeletal diseases (OR = 1.78, 95% CI = 1.01-3.16) were significant correlates of concealed CRF. BMI (OR = 1.05, 95% CI = 1.01-1.10) and diabetes (OR = 2.25, 95% CI = 1.26-4.03) were significantly associated with overt CRF.Conclusions:\nCRF is highly prevalent in patients with COPD, even with normal serum creatinine, and might contribute to explaining selected conditions such as anemia that are frequent complications of COPD.","DOI":"10.1378/chest.09-1710","ISSN":"0012-3692","shortTitle":"Chronic renal failure","journalAbbreviation":"Chest","author":[{"family":"Incalzi","given":"Raffaele Antonelli"},{"family":"Corsonello","given":"Andrea"},{"family":"Pedone","given":"Claudio"},{"family":"Battaglia","given":"Salvatore"},{"family":"Paglino","given":"Giuseppe"},{"family":"Bellia","given":"Vincenzo"}],"issued":{"date-parts":[["2010",4,1]]},"accessed":{"date-parts":[["2014",3,26]]}}}],"schema":""} (82) More recent studies have confirmed the high prevalence of microalbuminuria ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TJ1OT3qr","properties":{"formattedCitation":"(83)","plainCitation":"(83)"},"citationItems":[{"id":765,"uris":[""],"uri":[""],"itemData":{"id":765,"type":"article-journal","title":"Microalbuminuria and hypoxemia in patients with chronic obstructive pulmonary disease","container-title":"American journal of respiratory and critical care medicine","page":"1004-1010","volume":"182","issue":"8","source":"NCBI PubMed","abstract":"RATIONALE: Microalbuminuria (MAB), a marker of endovascular dysfunction, is a predictor of cardiovascular events and all-cause mortality in the general population. There is evidence of vascular dysfunction in patients with chronic obstructive pulmonary disease (COPD).\nOBJECTIVES: To assess the prevalence and relationship of MAB with clinical and physiological parameters in stable patients with COPD.\nMETHODS: We measured urinary albumin rate (urinary albumin to creatinine ratio: UACR), smoking history, arterial blood pressure, gas exchange, body mass index, lung function, BODE index (body mass index, airflow obstruction, dyspnea, exercise performance), and comorbidity index in 129 patients with stable COPD and 51 smokers with normal spirometry without known cardiovascular disease. MAB levels were compared between groups. A multivariate analysis was performed to determine the best determinants of MAB levels.\nMEASUREMENTS AND MAIN RESULTS: MAB was higher in patients with COPD than in control smokers (8 [5th-95th percentile (P????), 2.9-113] vs. 4.2 [P????, 1.8-22.7] mg/g, P < 0.001]). The difference remained significant even after using the standard pathologic threshold (MAB, 30-299 mg/g in women and 20-299 mg/g in men; 24% in patients with COPD vs. 6% in control smokers; P = 0.005). In patients with COPD, there was a negative correlation between Pa(O?) and MAB (r = -0.40, P < 0.001). Using multivariate analysis, MAB was only associated with the Pa(O?) (relative risk, 0.934; 95% confidence interval, 0.880-0.992; P < 0.001) and with the systolic arterial blood pressure (relative risk, 1.034; 95% confidence interval, 1.011-1.057; P = 0.003).\nCONCLUSIONS: MAB is frequent in patients with COPD and is associated with hypoxemia independent of other cardiovascular risk factors. Further studies are necessary to investigate whether MAB could be an early simple biomarker of cardiovascular compromise in patients with COPD.","DOI":"10.1164/rccm.201003-0360OC","ISSN":"1535-4970","note":"PMID: 20558625","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","language":"eng","author":[{"family":"Casanova","given":"Ciro"},{"family":"de Torres","given":"Juan P"},{"family":"Navarro","given":"Juan"},{"family":"Aguirre-Jaíme","given":"Armando"},{"family":"Toledo","given":"Pablo"},{"family":"Cordoba","given":"Elizabeth"},{"family":"Baz","given":"Rebeca"},{"family":"Celli","given":"Bartolomé R"}],"issued":{"date-parts":[["2010",10,15]]},"PMID":"20558625"}}],"schema":""} (83) and renal dysfunction among COPD patients compared to controls, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tVdV0uQ8","properties":{"formattedCitation":"(84)","plainCitation":"(84)"},"citationItems":[{"id":955,"uris":[""],"uri":[""],"itemData":{"id":955,"type":"article-journal","title":"Prevalence of renal and hepatobiliary disease, laboratory abnormalities, and potentially toxic medication exposures among persons with COPD","container-title":"International Journal of Chronic Obstructive Pulmonary Disease","page":"127-134","volume":"8","source":"PubMed Central","abstract":"Background\nThe purpose of this study was to describe the prevalence of renal and hepatic disease, related laboratory abnormalities, and potentially hepatotoxic and nephrotoxic medication use in a population-based cohort of persons with chronic obstructive pulmonary disease (COPD).\n\nMethods\nThis was a retrospective case-control cohort analysis of COPD patients enrolled in one regional health system for at least 12 months during a 36-month study period (n = 2284). Each COPD patient was matched by age and gender to up to three persons not diagnosed with COPD (n = 5959).\n\nResults\nThe mean age for cases and controls was 70.3 years, and 52.5% were women. The COPD cohort had significantly higher prevalences (cases/100) of acute, chronic, and unspecified renal failure as compared with controls (1.40 versus 0.59, 2.89 versus 0.79, and 1.09 versus 0.44, respectively). Among the cases, 31.3% had at least one renal or urinary tract diagnosis during the study period, as compared with 21.1% of controls. COPD cases also had more gallbladder disease (2.76 versus 1.63) and pancreatic disease (1.40 versus 0.60), but not hepatic disease. COPD patients were more likely to have at least one serum creatinine level (5.1 versus 2.1) or liver aspartate aminotransferase level (4.5 versus 2.7) that was more than twice the upper limit of normal. COPD patients had prescription fills for an average of 17.6 potentially nephrotoxic and 27.4 hepatotoxic drugs during the study period, as compared with 13.6 and 19.9 for the controls (P value for all comparisons < 0.01).\n\nConclusion\nCOPD patients have a substantially increased prevalence of renal, gallbladder, and pancreatic diseases, as well as abnormal renal and hepatic laboratory values, but not diagnosed liver disease. COPD patients are also more likely to be prescribed medications with potentially toxic renal or hepatic side effects.","DOI":"10.2147/COPD.S40123","ISSN":"1176-9106","note":"PMID: 23515180\nPMCID: PMC3600938","journalAbbreviation":"Int J Chron Obstruct Pulmon Dis","author":[{"family":"Mapel","given":"Douglas W"},{"family":"Marton","given":"Jeno P"}],"issued":{"date-parts":[["2013"]]},"accessed":{"date-parts":[["2014",3,26]]},"PMID":"23515180","PMCID":"PMC3600938"}}],"schema":""} (84) although rates were lower in younger COPD cohorts. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8VWBpspY","properties":{"formattedCitation":"(85)","plainCitation":"(85)"},"citationItems":[{"id":958,"uris":[""],"uri":[""],"itemData":{"id":958,"type":"article-journal","title":"The prevalence of undiagnosed renal failure in a cohort of COPD patients in western Norway","container-title":"Respiratory medicine","page":"361-366","volume":"106","issue":"3","source":"NCBI PubMed","abstract":"Patients with COPD are at risk for other comorbid diseases, like heart failure, coronary heart disease, and depression. However, little is known about COPD phenotypes and prevalence of sub-clinical renal failure. 433 COPD patients and 233 subjects without COPD, from Western Norway, age 40-75, GOLD stage II-IV, were examined in 2006/07 upon entry to the Bergen COPD Cohort Study. Plasma creatinine was measured in 422 of the COPD patients. The Glomerular Flow Rate (GFR) was determined with the Cockcroft Gault formula, and having a GFR?<?60 was defined as renal failure. Examined explanatory factors were sex, age, smoking habits, GOLD stage, hypoxemia, exacerbation history, cachexia, use of daily inhaled steroids, Charlson comorbidity score, use of ACE inhibitors and/or ARBs, and the inflammatory plasma markers C-reactive protein (CRP), soluble tumor necrosis factor receptor 1 (sTNF-R1) and neutrophil gelatinase associated lipocalin (NGAL). Associations between explanatory variables and renal failure were examined by a logistic regression analysis. The prevalence of having GFR?<?60 was 9.6% in female COPD patients and 5.1% in male COPD patients (p?=?0.08). In multivariable analysis, female sex, higher age, cachexia, and the inflammatory markers sTNF-R1 and NGAL were all independently associated with a higher risk for renal failure, whereas use of inhaled steroids, Charlson score, GOLD stage, respiratory failure, and exacerbation frequency were not. Undiagnosed renal failure is a concern particularly in elderly COPD patients and COPD patients with cachexia.","DOI":"10.1016/j.rmed.2011.10.004","ISSN":"1532-3064","note":"PMID: 22129490","journalAbbreviation":"Respir Med","language":"eng","author":[{"family":"Gjerde","given":"Bjarte"},{"family":"Bakke","given":"Per S"},{"family":"Ueland","given":"Thor"},{"family":"Hardie","given":"Jon A"},{"family":"Eagan","given":"Tomas M L"}],"issued":{"date-parts":[["2012",3]]},"PMID":"22129490"}}],"schema":""} (85) The cause of anemia due to renal impairment is multifactorial. The most well-known cause is reduced EPO production from the peritubular capillary endothelial cells. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Ifemwlxy","properties":{"formattedCitation":"(86)","plainCitation":"(86)"},"citationItems":[{"id":968,"uris":[""],"uri":[""],"itemData":{"id":968,"type":"article-journal","title":"Mechanisms of Anemia in CKD","container-title":"Journal of the American Society of Nephrology : JASN","page":"1631-1634","volume":"23","issue":"10","source":"PubMed Central","abstract":"Anemia is a common feature of CKD associated with poor outcomes. The current management of patients with anemia in CKD is controversial, with recent clinical trials demonstrating increased morbidity and mortality related to erythropoiesis stimulating agents. Here, we examine recent insights into the molecular mechanisms underlying anemia of CKD. These insights hold promise for the development of new diagnostic tests and therapies that directly target the pathophysiologic processes underlying this form of anemia.","DOI":"10.1681/ASN.2011111078","ISSN":"1046-6673","note":"PMID: 22935483\nPMCID: PMC3458456","journalAbbreviation":"J Am Soc Nephrol","author":[{"family":"Babitt","given":"Jodie L."},{"family":"Lin","given":"Herbert Y."}],"issued":{"date-parts":[["2012",9,28]]},"accessed":{"date-parts":[["2014",3,26]]},"PMID":"22935483","PMCID":"PMC3458456"}}],"schema":""} (86) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"w9KuwVWU","properties":{"formattedCitation":"(87)","plainCitation":"(87)"},"citationItems":[{"id":960,"uris":[""],"uri":[""],"itemData":{"id":960,"type":"article-journal","title":"Anemia in renal disease: diagnosis and management","container-title":"Blood reviews","page":"39-47","volume":"24","issue":"1","source":"NCBI PubMed","abstract":"Chronic kidney disease (CKD) is a widespread health problem in the world and anemia is a common complication. Anemia conveys significant risk for cardiovascular disease, faster progression of renal failure and decreased quality of life. Patients with CKD can have anemia for many reasons, including but not invariably their renal insufficiency. These patients require a thorough evaluation to identify and correct causes of anemia other than erythropoietin deficiency. The mainstay of treatment of anemia secondary to CKD has become erythropoiesis-stimulating agents (ESAs). The use of ESAs does carry risks and these agents need to be used judiciously. Iron deficiency often co-exists in this population and must be evaluated and treated. Correction of iron deficiency can improve anemia and reduce ESA requirements. Partial, but not complete, correction of anemia is associated with improved outcomes in patients with CKD.","DOI":"10.1016/j.blre.2009.09.001","ISSN":"1532-1681","note":"PMID: 19833421","shortTitle":"Anemia in renal disease","journalAbbreviation":"Blood Rev.","language":"eng","author":[{"family":"Lankhorst","given":"Christina E"},{"family":"Wish","given":"Jay B"}],"issued":{"date-parts":[["2010",1]]},"PMID":"19833421"}}],"schema":""} (87) Although important, this is not the only mechanism. In patients with chronic kidney disease, the life span of erythrocytes is reduced, from approximately 120 to 60-90 days, possibly due to mechanical, uremic or other metabolic factors which induce cell apoptosis. (87) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Mz0u1J1S","properties":{"formattedCitation":"(88)","plainCitation":"(88)"},"citationItems":[{"id":975,"uris":[""],"uri":[""],"itemData":{"id":975,"type":"article-journal","title":"Erythropoiesis in patients with renal failure undergoing chronic dialysis","container-title":"The New England journal of medicine","page":"653-658","volume":"276","issue":"12","source":"NCBI PubMed","DOI":"10.1056/NEJM196703232761202","ISSN":"0028-4793","note":"PMID: 6018456","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Eschbach","given":"J W, Jr"},{"family":"Funk","given":"D"},{"family":"Adamson","given":"J"},{"family":"Kuhn","given":"I"},{"family":"Scribner","given":"B H"},{"family":"Finch","given":"C A"}],"issued":{"date-parts":[["1967",3,23]]},"PMID":"6018456"}}],"schema":""} (88) Limited availability of iron to erythroid progenitor cells also results to defective erythropoiesis; Iron deficiency could be either true or functional, due to increased systemic inflammation which is often present in patients with renal failure. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6RWKUcC6","properties":{"formattedCitation":"(89)","plainCitation":"(89)"},"citationItems":[{"id":977,"uris":[""],"uri":[""],"itemData":{"id":977,"type":"article-journal","title":"End-stage renal disease: a state of chronic inflammation and hyperleptinemia","container-title":"European journal of clinical investigation","page":"527-528","volume":"33","issue":"6","source":"NCBI PubMed","ISSN":"0014-2972","note":"PMID: 12795652","shortTitle":"End-stage renal disease","journalAbbreviation":"Eur. J. Clin. Invest.","language":"eng","author":[{"family":"Pecoits-Filho","given":"R"},{"family":"Lindholm","given":"B"},{"family":"Stenvinkel","given":"P"}],"issued":{"date-parts":[["2003",6]]},"PMID":"12795652"}}],"schema":""} (89) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VH41Fw0o","properties":{"formattedCitation":"(90)","plainCitation":"(90)"},"citationItems":[{"id":979,"uris":[""],"uri":[""],"itemData":{"id":979,"type":"article-journal","title":"Cardiac biomarkers and chronic renal diseases","container-title":"Bratislavské lekárske listy","page":"341-344","volume":"109","issue":"8","source":"NCBI PubMed","abstract":"Accelerated atherosclerosis can lead to an increased prevalence of coronary artery disease, heart failure, brain stroke and peripheral arterial disease. Thus, subjects with chronic renal failure are exposed to increased morbidity and mortality from cardiovascular events. A strong and pervasive link exists between kidney failure and cardiac disease. A variety of individual biomarkers have been evaluated and several have been found to successfully predict the outcome in patients with kidney disease. These include markers of myocardial necrosis, such as cardiac troponin T and I, markers of heart failure, such as B-type of natriuretic peptide and its associated inactive N-terminal fragment, markers of systemic inflammation--C-reactive protein, and an endogenous inhibitor of nitric oxide synthase-asymmetric dimethyl arginin. Increased concentrations of C-reactive protein, B-type of natriuretic peptide, asymmetric dimethyl arginine, and troponin predict a high risk of cardiovascular mortality as well as a mortality due to other causes in patients with chronic renal failure or end stage renal disease (Tab. 1, Ref. 33). Full Text (Free, PDF) bmj.sk.","ISSN":"0006-9248","note":"PMID: 18837240","journalAbbreviation":"Bratisl Lek Listy","language":"eng","author":[{"family":"Valocikova","given":"I"},{"family":"Kristofova","given":"B"},{"family":"Valocik","given":"G"}],"issued":{"date-parts":[["2008"]]},"PMID":"18837240"}}],"schema":""} (90) The role of hepcidin in this defective iron utilization is crucial, since decreased GFR can result to higher serum hepcidin levels, amplifying iron metabolism abnormalities. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ULkOeKjI","properties":{"formattedCitation":"(91)","plainCitation":"(91)"},"citationItems":[{"id":246,"uris":[""],"uri":[""],"itemData":{"id":246,"type":"article-journal","title":"Anaemia in chronic obstructive pulmonary disease. Does it really matter?","container-title":"International journal of clinical practice","page":"558-565","volume":"67","issue":"6","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic diseases, with an increasing rate in morbidity and mortality. In recent years, there has been a greater awareness about the clinical importance of systemic effects and other chronic conditions associated with COPD, as these significantly impact on the course of disease. The most studied extrapulmonary manifestations in COPD include the presence of concomitant cardiovascular disease, skeletal muscle wasting, osteoporosis and lung cancer. Anaemia is a recognised independent marker of mortality in several chronic diseases. Recent studies have shown that anaemia in patients with COPD may be more frequent than expected, with a prevalence ranging from 5% to 33%. Some evidence suggests that systemic inflammation may play an important pathogenic role, but anaemia in COPD is probably multifactorial and may be caused by others factors, such as concealed chronic renal failure, decreased androgenic levels, iron depletion, angiotensin-converting enzyme inhibitor treatment and exacerbations. Low levels of haemoglobin and haematocrit in COPD patients have been associated with poor clinical and functional outcomes as well as with mortality and increased healthcare costs. Despite the potential clinical benefit of successfully treating anaemia in these patients, evidence supporting the importance of its correction on the prognosis of COPD is uncertain.","DOI":"10.1111/ijcp.12125","ISSN":"1742-1241","note":"PMID: 23679907","journalAbbreviation":"Int. J. Clin. Pract.","language":"eng","author":[{"family":"Portillo","given":"K"},{"family":"Martinez-Rivera","given":"C"},{"family":"Ruiz-Manzano","given":"J"}],"issued":{"date-parts":[["2013",6]]},"PMID":"23679907"}}],"schema":""} (91) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QjhNdj7S","properties":{"formattedCitation":"(92)","plainCitation":"(92)"},"citationItems":[{"id":981,"uris":[""],"uri":[""],"itemData":{"id":981,"type":"article-journal","title":"Hepcidin--a potential novel biomarker for iron status in chronic kidney disease","container-title":"Clinical journal of the American Society of Nephrology: CJASN","page":"1051-1056","volume":"4","issue":"6","source":"NCBI PubMed","abstract":"BACKGROUND AND OBJECTIVES: Hepcidin is a key regulator of iron homeostasis, but its study in the setting of chronic kidney disease (CKD) has been hampered by the lack of validated serum assays.\nDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study reports the first measurements of bioactive serum hepcidin using a novel competitive ELISA in 48 pediatric (PCKD2-4) and 32 adult (ACKD2-4) patients with stages 2 to 4 CKD along with 26 pediatric patients with stage 5 CKD (PCKD5D) on peritoneal dialysis.\nRESULTS: When compared with their respective controls (pediatric median = 25.3 ng/ml, adult = 72.9 ng/ml), hepcidin was significantly increased in PCKD2-4 (127.3 ng/ml), ACKD2-4 (269.9 ng/ml), and PCKD5D (652.4 ng/ml). Multivariate regression analysis was used to assess the relationship between hepcidin and indicators of anemia, iron status, inflammation, and renal function. In PCKD2-4 (R(2) = 0.57), only ferritin correlated with hepcidin. In ACKD2-4 (R(2) = 0.78), ferritin and soluble transferrin receptor were associated with hepcidin, whereas GFR was inversely correlated. In PCKD5D (R(2) = 0.52), percent iron saturation and ferritin were predictors of hepcidin. In a multivariate analysis that incorporated all three groups (R(2) = 0.6), hepcidin was predicted by ferritin, C-reactive protein, and whether the patient had stage 5D versus stages 2 to 4 CKD.\nCONCLUSIONS: These findings suggest that increased hepcidin across the spectrum of CKD may contribute to abnormal iron regulation and erythropoiesis and may be a novel biomarker of iron status and erythropoietin resistance.","DOI":"10.2215/CJN.05931108","ISSN":"1555-905X","note":"PMID: 19406957 \nPMCID: PMC2689881","journalAbbreviation":"Clin J Am Soc Nephrol","language":"eng","author":[{"family":"Zaritsky","given":"Joshua"},{"family":"Young","given":"Brian"},{"family":"Wang","given":"He-Jing"},{"family":"Westerman","given":"Mark"},{"family":"Olbina","given":"Gordana"},{"family":"Nemeth","given":"Elizabeta"},{"family":"Ganz","given":"Tomas"},{"family":"Rivera","given":"Seth"},{"family":"Nissenson","given":"Allen R"},{"family":"Salusky","given":"Isidro B"}],"issued":{"date-parts":[["2009",6]]},"PMID":"19406957","PMCID":"PMC2689881"}}],"schema":""} (92) The renin-angiotensin-aldosterone systemAngiotensin converting enzyme (ACE) is expressed in lungs in very high concentrations. Hypoxia, especially when accompanied by hypercarbia, increases ACE activity, in both animal and human studies. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cshcbHyG","properties":{"formattedCitation":"(93)","plainCitation":"(93)"},"citationItems":[{"id":992,"uris":[""],"uri":[""],"itemData":{"id":992,"type":"article-journal","title":"Hypoxia stimulates endothelial cell angiotensin-converting enzyme antigen synthesis","container-title":"The American journal of physiology","page":"C1231-1238","volume":"256","issue":"6 Pt 1","source":"NCBI PubMed","abstract":"Previous studies from our laboratory indicate that exposure of the rat to chronic normobaric hypoxia reduces stores of active angiotensin-converting enzyme (ACE) in the lung. This study assesses directly the effects of hypoxia on ACE synthesis in cultured porcine pulmonary artery endothelial cells. Confluent cultures were exposed to hypoxia [2.5% O2 at 1 atmosphere (atm)] in a triple gas incubator; controls were cultured in normoxic conditions. After 24-, 48-, and 72-h exposure to hypoxic or normoxic conditions, followed by incubation with [35S]methionine for an additional 24 h under the same conditions, newly synthesized radiolabeled ACE was quantitated. Radiolabeled ACE was isolated by an immunobead procedure using either anti-ACE (porcine lung) immunoglobin G (IgG) or nonimmune IgG. A single radiolabeled peak (150 kDa) with the same electrophoretic mobility as purified porcine lung ACE was observed. There was a significant time-dependent increase in endothelial cell ACE antigen synthesis without a concomitant change in either cell number or total trichloroacetic (TCA)-precipitable protein in hypoxic cells compared with normoxic controls. In contrast, ACE activity, assessed by conversion of 125I-labeled angiotensin I to 125I-labeled angiotensin II was unchanged in cultures exposed to hypoxia (2.5% O2). This suggests that an inactive form of ACE is synthesized by cultured pulmonary artery endothelial cells under hypoxic conditions.","ISSN":"0002-9513","note":"PMID: 2544094","journalAbbreviation":"Am. J. Physiol.","language":"eng","author":[{"family":"King","given":"S J"},{"family":"Booyse","given":"F M"},{"family":"Lin","given":"P H"},{"family":"Traylor","given":"M"},{"family":"Narkates","given":"A J"},{"family":"Oparil","given":"S"}],"issued":{"date-parts":[["1989",6]]},"PMID":"2544094"}}],"schema":""} (93) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"WbJ7YQkt","properties":{"formattedCitation":"(94)","plainCitation":"(94)"},"citationItems":[{"id":983,"uris":[""],"uri":[""],"itemData":{"id":983,"type":"article-journal","title":"Inhibition of the renin–angiotensin system in severe COPD","container-title":"European Respiratory Journal","page":"1130-1130","volume":"32","issue":"4","source":"erj.","DOI":"10.1183/09031936.00082308","ISSN":"0903-1936, 1399-3003","note":"PMID: 18827168","journalAbbreviation":"Eur Respir J","language":"en","author":[{"family":"Mascitelli","given":"L."},{"family":"Pezzetta","given":"F."},{"family":"Goldstein","given":"M. R."}],"issued":{"date-parts":[["2008",10,1]]},"accessed":{"date-parts":[["2014",3,26]]},"PMID":"18827168"}}],"schema":""} (94) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2YBHjWam","properties":{"formattedCitation":"(95)","plainCitation":"(95)"},"citationItems":[{"id":996,"uris":[""],"uri":[""],"itemData":{"id":996,"type":"article-journal","title":"Renin, ACTH, and aldosterone during acute hypercapnia and hypoxia in conscious rats","container-title":"The American journal of physiology","page":"R431-435","volume":"254","issue":"3 Pt 2","source":"NCBI PubMed","abstract":"The control of aldosterone secretion may be altered during acute changes in arterial blood gases. We studied the blood gas, plasma electrolyte, renin (PRA), adrenocorticotropic hormone (ACTH), and aldosterone (ALDO) responses to acute hypercapnia (4 and 8% CO2), acute hypocapnic hypoxia (10% O2), acute severe normocapnic hypoxia (7% O2-4% CO2), and acute hypercapnic hypoxia (7% O2-8% CO2) in conscious, cannulated Long-Evans rats. Normoxia resulted in normal levels of PRA (6.9 +/- 2.0 ng.ml-1.h-1), ACTH (96 +/- 32 pg/ml), and ALDO (10 +/- 3 ng/dl). Hypercapnia had no effect on PRA but did lead to an increase in ACTH (to 298 +/- 69 pg/ml) and ALDO (to 33 +/- 7 ng/dl) during 8% CO2 exposure. Normocapnic hypoxia resulted in a significant increase in ACTH (to 196 +/- 14 pg/ml) and ALDO (to 30 +/- 3 ng/dl). Hypercapnic hypoxia resulted in the greatest increases in PRA (to 30 +/- 2 ng.ml-1.h-1), ACTH (to 397 +/- 114 pg/ml), and ALDO (to 41 +/- 5 ng/dl). We conclude that in conscious rats 1) hypercapnia (less than 80 Torr) had no significant effect on PRA, 2) isocapnic, severe hypoxia (Po2 approximately 34 Torr) increased ACTH, and 3) the combination of hypercapnia and hypoxia was a very potent stimulus to PRA, ACTH, and ALDO. The ALDO responses to increases in endogenous ACTH and angiotensin II appear to be normal in conscious rats during acute hypoxia and/or hypercapnia.","ISSN":"0002-9513","note":"PMID: 2831742","journalAbbreviation":"Am. J. Physiol.","language":"eng","author":[{"family":"Raff","given":"H"},{"family":"Roarty","given":"T P"}],"issued":{"date-parts":[["1988",3]]},"PMID":"2831742"}}],"schema":""} (95) Angiotensin II is a growth factor for erythroid progenitor cells, resulting in an increase in red blood cell mass, and it also acts as an EPO secretagogue. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"NTLiNwMo","properties":{"formattedCitation":"(96)","plainCitation":"(96)"},"citationItems":[{"id":989,"uris":[""],"uri":[""],"itemData":{"id":989,"type":"article-journal","title":"The Role of the Renin-Angiotensin System in the Regulation of Erythropoiesis","container-title":"American Journal of Kidney Diseases","page":"558-565","volume":"56","issue":"3","source":"ScienceDirect","abstract":"The renin-angiotensin system is the major regulator of blood pressure by virtue of controlling vascular resistance and plasma volume. Much less recognition exists for the role of the renin-angiotensin system in regulating erythropoiesis, a biological function critical for oxygen delivery to tissues. In this review, we present evidence that angiotensin II (Ang II) is a physiologically important regulator of erythropoiesis with 2 key actions. First, Ang II is a growth factor of erythroid progenitors and, in cooperation with erythropoietin, increases red blood cell mass. Second, Ang II acts as an erythropoietin secretagogue to maintain increased erythropoietin levels despite increments in hematocrit. Among a multitude of physiologic and pathophysiologic implications, these lines of evidence provide an explanation for the effect of angiotensin-converting enzyme inhibitors and Ang II type 1 receptor blockers to decrease hematocrit or cause anemia in various clinical conditions.","DOI":"10.1053/j.ajkd.2009.12.042","ISSN":"0272-6386","journalAbbreviation":"American Journal of Kidney Diseases","author":[{"family":"Vlahakos","given":"Demetrios V."},{"family":"Marathias","given":"Katerina P."},{"family":"Madias","given":"Nicolaos E."}],"issued":{"date-parts":[["2010",9]]},"accessed":{"date-parts":[["2014",3,26]]}}}],"schema":""} (96) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"17F2boUX","properties":{"formattedCitation":"(97)","plainCitation":"(97)"},"citationItems":[{"id":998,"uris":[""],"uri":[""],"itemData":{"id":998,"type":"article-journal","title":"Angiotensin II stimulates proliferation of normal early erythroid progenitors.","container-title":"Journal of Clinical Investigation","page":"2310-2314","volume":"100","issue":"9","source":"PubMed Central","abstract":"Angiotensin II exerts a mitogenic effect in several in vitro models, but a direct effect on erythroid progenitors has not been documented. Angiotensin-converting enzyme inhibitors and losartan, an angiotensin II type 1 receptor (AT1) antagonist, ameliorate posttransplant erythrocytosis, without altering serum erythropoietin levels. We studied erythroid differentiation and the effect of angiotensin II on proliferation of erythroid progenitors by culturing CD34+ hematopoietic progenitor cells in liquid serum-free medium favoring growth of erythroid precursors. Aliquots of cells were collected every third day, and were used for RNA preparation. AT1 mRNA was detected after 6 d. In these same samples, erythroid-specific mRNA (erythropoietin receptor) was also detected. AT1 protein was detected in 7-d-old burst-forming units-erythroid colonies by Western blotting. The CD34+ cell liquid cultures were used to incubate erythroid precursors with angiotensin II from days 6-9. After incubation, cells were transferred to semisolid medium and cultured with erythropoietin. Angiotensin II increased proliferation of early erythroid progenitors, defined as increased numbers of burst-forming units-erythroid colonies. Losartan completely abolished this stimulatory effect of angiotensin II. Moreover, we observed increased numbers of erythroid progenitors in the peripheral blood of posttransplant erythrocytosis patients. Thus, activation of AT1 with angiotensin II enhances erythropoietin-stimulated erythroid proliferation in vitro. A putative defect in the angiotensin II/AT1 pathway may contribute to the pathogenesis of posttransplant erythrocytosis.","ISSN":"0021-9738","note":"PMID: 9410909\nPMCID: PMC508427","journalAbbreviation":"J Clin Invest","author":[{"family":"Mrug","given":"M"},{"family":"Stopka","given":"T"},{"family":"Julian","given":"B A"},{"family":"Prchal","given":"J F"},{"family":"Prchal","given":"J T"}],"issued":{"date-parts":[["1997",11,1]]},"accessed":{"date-parts":[["2014",3,26]]},"PMID":"9410909","PMCID":"PMC508427"}}],"schema":""} (97) Thus, an intact and activated renin-angiotensin-aldosterone system (RAAS) may be of important significance in determining erythropoiesis in a variety of clinical conditions, including COPD. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rtRyr6FH","properties":{"formattedCitation":"(98)","plainCitation":"(98)"},"citationItems":[{"id":236,"uris":[""],"uri":[""],"itemData":{"id":236,"type":"article-journal","title":"Hematocrit-lowering effect following inactivation of renin-angiotensin system with angiotensin converting enzyme inhibitors and angiotensin receptor blockers","container-title":"Current topics in medicinal chemistry","page":"483-486","volume":"4","issue":"4","source":"NCBI PubMed","abstract":"Several clinical and experimental observations suggest that an intact and activated renin-angiotensin system (RAS) may be an important determinant of erythropoiesis in a variety of clinical conditions, including hypertension, chronic renal insufficiency or failure, chronic obstructive pulmonary disease, and congestive heart failure. Accordingly, RAS inactivation may confer susceptibility to the hematocrit-lowering effects of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Indeed, a dose-dependent decrease in hematocrit is observed within the first month of such therapy. In the majority of patients with hypertension decreases in hematocrit values after RAS inactivation are small and not clinically important. In extreme conditions, however, such as erythrocytosis after successful renal transplantation, secondary polycythemia of chronically hypoxemic COPD patients, erythrocytosis associated with renovascular hypertension, severe cardiac or renal failure, the hematocrit-lowering effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blocker may be profound and even lead to or worsen anemia. Hematocrit reaches its nadir value within three months, and then it remains stable during long-term observations. After discontinuation of RAS blockade, hematocrit values rise gradually over the next three to four months towards the pretreatment levels. The mechanism(s) related to this phenomenon is not yet fully understood, but angiotensin II seems to be responsible for inappropriately sustaining secretion of erythropoietin despite hematocrit elevation and capable to directly stimulate the erythroid progenitors in bone marrow to produce erythrocytes.","ISSN":"1568-0266","note":"PMID: 14965314","journalAbbreviation":"Curr Top Med Chem","language":"eng","author":[{"family":"Marathias","given":"K P"},{"family":"Agroyannis","given":"B"},{"family":"Mavromoustakos","given":"T"},{"family":"Matsoukas","given":"J"},{"family":"Vlahakos","given":"D V"}],"issued":{"date-parts":[["2004"]]},"PMID":"14965314"}}],"schema":""} (98)In a previous study of 12 hypoxic COPD patients with secondary erythrocytocis and 12 hypoxic COPD matched controls without erythrocytocis, plasma renin and aldosterone levels were three fold increased among patients with erythrocytosis compared to controls, while EPO levels were similar between the groups. Plasma renin and oxygen arterial partial pressure, but not EPO, were independently associated with hematocrit. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"0tCG5ZSb","properties":{"formattedCitation":"(99)","plainCitation":"(99)"},"citationItems":[{"id":270,"uris":[""],"uri":[""],"itemData":{"id":270,"type":"article-journal","title":"Association between activation of the renin-angiotensin system and secondary erythrocytosis in patients with chronic obstructive pulmonary disease","container-title":"The American journal of medicine","page":"158-164","volume":"106","issue":"2","source":"NCBI PubMed","abstract":"PURPOSE: An association between activation of the renin-angiotensin system and enhanced erythropoiesis has been observed in patients with several diseases, including congestive heart failure and hypertension. Our goal was to examine whether the renin-angiotensin system is associated with secondary erythrocytosis in patients with chronic obstructive pulmonary disease (COPD).\nSUBJECTS AND METHODS: Plasma renin activity, plasma aldosterone concentration, serum erythropoietin level, and serum angiotensin converting enzyme (ACE) activity were measured in 12 patients with COPD and secondary erythrocytosis [mean (+/-SD) hematocrit of 53% +/- 3%] and in 12 matched controls with COPD who did not have erythrocytosis (hematocrit 45% +/- 5%). All patients had chronic hypoxemia (PaO2 <60 mm Hg).\nRESULTS: Both plasma renin and aldosterone levels were threefold greater in patients with secondary erythrocytosis compared to controls. No difference in erythropoietin levels was observed between patients with or without secondary erythrocytosis. Renin levels (r = 0.45; P = 0.02) but not erythropoietin levels (r = 0.15; P = 0.47) were correlated with hematocrit in the entire sample. Renin levels and PaO2 were the only variables independently and significantly associated with hematocrit values in a multiple linear regression model.\nCONCLUSION: Activation of the renin-angiotensin system is associated with the development of secondary erythrocytosis in chronically hypoxemic patients with COPD. The exact mechanism is not yet fully understood, but angiotensin II may be responsible for inappropriately sustained erythropoietin secretion or direct stimulation of erythroid progenitors.","ISSN":"0002-9343","note":"PMID: 10230744","journalAbbreviation":"Am. J. Med.","language":"eng","author":[{"family":"Vlahakos","given":"D V"},{"family":"Kosmas","given":"E N"},{"family":"Dimopoulou","given":"I"},{"family":"Ikonomou","given":"E"},{"family":"Jullien","given":"G"},{"family":"Vassilakos","given":"P"},{"family":"Marathias","given":"K P"}],"issued":{"date-parts":[["1999",2]]},"PMID":"10230744"}}],"schema":""} (99)The authors concluded that the activity of RAAS could partly explain why some patients develop erythrocytosis and some do not, having the same degree of hypoxemia. Andreas et al conducted a randomized controlled trial in 60 COPD patients who received either the angiotensin II receptor blocker (ARB) irbesartan or a placebo over 4 months and reported a significant decrease of hematocrit in the active treatment group, but not in the placebo group. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"hwSyKVS3","properties":{"formattedCitation":"(100)","plainCitation":"(100)"},"citationItems":[{"id":964,"uris":[""],"uri":[""],"itemData":{"id":964,"type":"article-journal","title":"Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial","container-title":"European Respiratory Journal","page":"972-979","volume":"27","issue":"5","source":"erj.","abstract":"In chronic obstructive pulmonary disease (COPD), the sympathetic nervous system, as well as the renin–angiotensin system, is activated with possible negative systemic effects on skeletal muscles. Angiotensin II type-1 receptor blockers inhibit the sympathetic and renin–angiotensin systems and might improve skeletal and respiratory muscle strength in patients in whom these systems are activated.\nThe effects of the angiotensin receptor blocker irbesartan given over 4 months was evaluated in 60 patients with COPD and a forced expiratory volume in one second of <50% of the predicted value and without obvious cardiovascular disease that would necessitate the administration of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.\nIrbesartan was well tolerated, but did not exert a significant effect on the primary end-point maximum inspiratory pressure. Spirometric results were not affected, but total lung capacity was reduced. Irbesartan led to a significant decrease in haematocrit (46.4±3.6 to 43.9±4.3% versus 47.5±2.4 to 48.7±3.0% with placebo).\nIn conclusion, respiratory muscle strength in chronic obstructive pulmonary disease patients was not influenced by angiotensin II receptor blockade. However, the changes in haematocrit and total lung capacity following irbesartan raise the possibility that well-known cardiovascular drugs can produce unanticipated beneficial effects in chronic obstructive pulmonary disease patients.","DOI":"10.1183/09031936.06.00098105","ISSN":"0903-1936, 1399-3003","note":"PMID: 16446313","shortTitle":"Angiotensin II blockers in obstructive pulmonary disease","journalAbbreviation":"Eur Respir J","language":"en","author":[{"family":"Andreas","given":"S."},{"family":"Herrmann-Lingen","given":"C."},{"family":"Raupach","given":"T."},{"family":"Lüthje","given":"L."},{"family":"Fabricius","given":"J. A."},{"family":"Hruska","given":"N."},{"family":"K?rber","given":"W."},{"family":"Büchner","given":"B."},{"family":"Criée","given":"C.-P."},{"family":"Hasenfu?","given":"G."},{"family":"Calverley","given":"P."}],"issued":{"date-parts":[["2006",5,1]]},"accessed":{"date-parts":[["2014",3,27]]},"PMID":"16446313"}}],"schema":""} (100) Given the emerging evidence that the blockade of RAAS with either ACE inhibitors or ARBs could be beneficial in COPD in terms of skeletal muscle function and cardiac co-morbidity, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ACOta9jD","properties":{"formattedCitation":"(101)","plainCitation":"(101)"},"citationItems":[{"id":1005,"uris":[""],"uri":[""],"itemData":{"id":1005,"type":"article-journal","title":"Renin-angiotensin system blockade: a novel therapeutic approach in chronic obstructive pulmonary disease","container-title":"Clinical science (London, England: 1979)","page":"487-498","volume":"123","issue":"8","source":"NCBI PubMed","abstract":"ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) are already widely used for the treatment and prevention of cardiovascular disease and their potential role in other disease states has become increasingly recognized. COPD (chronic obstructive pulmonary disease) is characterized by pathological inflammatory processes involving the lung parenchyma, airways and vascular bed. The aim of the present review is to outline the role of the RAS (renin-angiotensin system) in the pathogenesis of COPD, including reference to results from fibrotic lung conditions and pulmonary hypertension. The review will, in particular, address the emerging evidence that ACE inhibition could have a beneficial effect on skeletal muscle function and cardiovascular co-morbidity in COPD patients. The evidence to support the effect of RAS blockade as a novel therapeutic approach in COPD will be discussed.","DOI":"10.1042/CS20120081","ISSN":"1470-8736","note":"PMID: 22757959","shortTitle":"Renin-angiotensin system blockade","journalAbbreviation":"Clin. Sci.","language":"eng","author":[{"family":"Shrikrishna","given":"Dinesh"},{"family":"Astin","given":"Ronan"},{"family":"Kemp","given":"Paul R"},{"family":"Hopkinson","given":"Nicholas S"}],"issued":{"date-parts":[["2012",10]]},"PMID":"22757959"}}],"schema":""} (101) the potential impact on erythropoiesis should be taken into consideration in the designing of clinical trials and in the evaluation of their outcome. Theophylline treatmentTheophylline is a non-selective adenosine receptor antagonist, which can inhibit renal vasoconstriction in response to exogenous and endogenous adenosine. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VrHQhxnF","properties":{"formattedCitation":"(102)","plainCitation":"(102)"},"citationItems":[{"id":1056,"uris":[""],"uri":[""],"itemData":{"id":1056,"type":"article-journal","title":"Adenosine receptors: development of selective agonists and antagonists","container-title":"Progress in clinical and biological research","page":"41-63","volume":"230","source":"NCBI PubMed","abstract":"Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a \"functionalized congener\" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the \"functionalized congener\" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the \"functionalized congener\" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors.","ISSN":"0361-7742","note":"PMID: 3588607","shortTitle":"Adenosine receptors","journalAbbreviation":"Prog. Clin. Biol. Res.","language":"eng","author":[{"family":"Daly","given":"J W"},{"family":"Jacobson","given":"K A"},{"family":"Ukena","given":"D"}],"issued":{"date-parts":[["1987"]]},"PMID":"3588607"}}],"schema":""} (102) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VG2Wdd5A","properties":{"formattedCitation":"(103)","plainCitation":"(103)"},"citationItems":[{"id":1096,"uris":[""],"uri":[""],"itemData":{"id":1096,"type":"article-journal","title":"Therapeutic use of theophylline to antagonize renal effects of adenosine","container-title":"Clinical nephrology","page":"S33-37","volume":"43 Suppl 1","source":"NCBI PubMed","abstract":"Experiments in laboratory animals clearly show that adenosine acts as a vasoconstrictive metabolite in the kidney. Adenosine receptor antagonists like theophylline can inhibit renal vasoconstriction in response to exogenous and endogenous adenosine. Based on these findings a number of experiments have been performed to test whether the vasoconstrictive action of adenosine in the kidney might be important also in pathophysiological states. In various animal models theophylline and other methylxanthine derivatives have been successfully employed to improve renal function after induction of acute renal failure. Clinical implications of these experimental findings comprise the prevention of acute renal failure following the administration of radio contrast media by theophylline. Another therapeutic aspect derives from experimental and clinical data showing that theophylline controls erythropoietin production in erythrocytosis after renal transplantation.","ISSN":"0301-0430","note":"PMID: 7781203","journalAbbreviation":"Clin. Nephrol.","language":"eng","author":[{"family":"Osswald","given":"H"},{"family":"Gleiter","given":"C"},{"family":"Mühlbauer","given":"B"}],"issued":{"date-parts":[["1995",1]]},"PMID":"7781203"}}],"schema":""} (103) In vitro studies have shown that adenosine mediates hypoxia-induced renal EPO production, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"iMo9z6En","properties":{"formattedCitation":"(104)","plainCitation":"(104)"},"citationItems":[{"id":1094,"uris":[""],"uri":[""],"itemData":{"id":1094,"type":"article-journal","title":"Modulation of erythropoietin production by selective adenosine agonists and antagonists in normal and anemic rats","container-title":"Life sciences","page":"761-771","volume":"59","issue":"9","source":"NCBI PubMed","abstract":"Hypoxia or anemia is the fundamental stimulus for erythropoietin (EPO) production. Recent in vitro studies suggest that EPO secretion in response to hypoxia is regulated by adenosine in the kidney. In order to examine the in vivo effect of adenosine on EPO production, we determined the effects of adenosine receptor agonists and antagonists on serum EPO concentration in normal and anemic rats. In normal rats, intravenous injection of adenosine agonists (NECA, CHA and CGS-21680) dose-dependently stimulated EPO production. Pretreatment with KW-3902, an adenosine A1 antagonist with modest A2b antagonistic action, or KF17837, an adenosine A2a antagonist, inhibited the NECA (0.1 mg/kg, i.v.)-stimulated EPO production. Anemic hypoxia, induced by 2% (v/w body weight) blood withdrawal, increased serum EPO concentration from 38 +/- 2 to 352 +/- 76 mU/ml, with the increased serum adenosine concentration in the renal vein. KF17837 (0.1 mg/kg, i.v.), but not KW-3902 (0.1 mg/kg, i.v.), inhibited the anemic hypoxia-induced increase in EPO production. The present findings support the notion that adenosine mediates the EPO production in response to hypoxia in the kidney.","ISSN":"0024-3205","note":"PMID: 8761029","journalAbbreviation":"Life Sci.","language":"eng","author":[{"family":"Nagashima","given":"K"},{"family":"Karasawa","given":"A"}],"issued":{"date-parts":[["1996"]]},"PMID":"8761029"}}],"schema":""} (104) so adenosine receptor antagonists could have an impact on hematocrit level and possibly induce anemia. Previous reports have indicated that theophylline attenuates EPO production in both normal subjects and patients with erythrocytosis after renal transplantation, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1P1nh3qK","properties":{"formattedCitation":"(105)","plainCitation":"(105)"},"citationItems":[{"id":1098,"uris":[""],"uri":[""],"itemData":{"id":1098,"type":"article-journal","title":"Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation","container-title":"The New England journal of medicine","page":"86-90","volume":"323","issue":"2","source":"NCBI PubMed","abstract":"BACKGROUND: Erythrocytosis occurs in 10 to 15 percent of renal-transplant recipients, and there is in vitro evidence that the production of erythropoietin is modulated by adenosine.\nMETHODS: We prospectively evaluated the effects of theophylline, a nonselective adenosine antagonist, in eight patients with erythrocytosis after renal transplantation and in five normal controls.\nRESULTS: After an eight-week course of theophylline treatment, the mean (+/- SEM) serum erythropoietin levels were significantly reduced in both the renal-transplant recipients (from 60 +/- 14 units per liter at base line to 9 +/- 7 units after treatment; P less than 0.05) and the normal subjects (from 6.9 +/- 0.8 units per liter at base line to 4.7 +/- 0.5 units per liter after treatment; P less than 0.05). Similarly, the hematocrits were reduced in both the transplant recipients (from 0.58 +/- 0.04 at base line to 0.46 +/- 0.03 after treatment; P less than 0.05) and the normal subjects (from 0.43 +/- 0.01 at base line to 0.39 +/- 0.01; P less than 0.05). In the renal-transplant recipients, red-cell mass was also reduced after eight weeks of theophylline (from 3197 +/- 82 ml at base line to 2273 +/- 69 ml after treatment; P less than 0.05). The previous requirement of weekly phlebotomy was eliminated in all recipients. Plasma and urinary cyclic AMP levels were not increased. These effects were reproducible when the subjects were rechallenged with theophylline after a recovery period.\nCONCLUSIONS: Theophylline attenuates the production of erythropoietin in both normal subjects and patients with erythrocytosis after renal transplantation and may be useful in the treatment of the latter condition.","DOI":"10.1056/NEJM199007123230203","ISSN":"0028-4793","note":"PMID: 2163024","journalAbbreviation":"N. Engl. J. Med.","language":"eng","author":[{"family":"Bakris","given":"G L"},{"family":"Sauter","given":"E R"},{"family":"Hussey","given":"J L"},{"family":"Fisher","given":"J W"},{"family":"Gaber","given":"A O"},{"family":"Winsett","given":"R"}],"issued":{"date-parts":[["1990",7,12]]},"PMID":"2163024"}}],"schema":""} (105) while the retrospective study of 204 COPD patients by Oren et al indicated that the ones treated with theophylline had significantly lower Hb levels, compared to the untreated ones. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bsywWu0U","properties":{"formattedCitation":"(106)","plainCitation":"(106)"},"citationItems":[{"id":1023,"uris":[""],"uri":[""],"itemData":{"id":1023,"type":"article-journal","title":"Effect of theophylline on erythrocytosis in chronic obstructive pulmonary disease","container-title":"Archives of internal medicine","page":"1474-1478","volume":"157","issue":"13","source":"NCBI PubMed","abstract":"BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) tend to develop secondary erythrocytosis to compensate for their chronic hypoxia. Theophylline has recently been shown to reduce hematocrit and erythropoietin blood levels in normal subjects and in patients with erythrocytosis after renal transplantation.\nOBJECTIVE: To determine whether theophylline may be used to lower the hematocrit in patients with COPD.\nMETHODS: Two hundred four patients with COPD were studied retrospectively and 10 patients prospectively (8 starting treatment with the drug [group 1] and 2 who suspended its long-term use [group 2]) for the correlation between theophylline therapy and hematocrit and erythropoietin level.\nRESULTS: In the patients studied retrospectively, lower hematocrits were found in the theophylline-treated than in the untreated patients (0.43 +/- 0.006 vs 0.46 +/- 0.007, respectively; P < .002). Twelve untreated patients and 2 of those treated with theophylline had hematocrits above 52%. Oxygen saturation levels were similar in both groups, and exclusion of patients with oxygen saturation lower than 88% did not change the pattern, suggesting that the effect of theophylline could not be entirely explained by improved oxygen availability. Seven of the 8 patients studied prospectively in group 1 (P < .02) and the 2 patients in group 2 showed inverse correlations between hematocrits and theophylline administration. A similar pattern was observed with serum erythropoietin levels in 5 of 7 patients studied. The effects were reproducible on rechallenge in 3 of the 4 patients in group 1 and the 2 patients in group 2.\nCONCLUSIONS: Theophylline may have a beneficial effect in treatment and prevention of erythrocytosis in patients with COPD.","ISSN":"0003-9926","note":"PMID: 9224226","journalAbbreviation":"Arch. Intern. Med.","language":"eng","author":[{"family":"Oren","given":"R"},{"family":"Beeri","given":"M"},{"family":"Hubert","given":"A"},{"family":"Kramer","given":"M R"},{"family":"Matzner","given":"Y"}],"issued":{"date-parts":[["1997",7,14]]},"PMID":"9224226"}}],"schema":""} (106) Confounding by disease severity may have been an issue in this population.Androgen deficiencySex hormone disturbances are common in COPD; a recent review estimated the prevalence of testosterone deficiency in male COPD patients between 22-69%. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"JOWAphll","properties":{"formattedCitation":"(107)","plainCitation":"(107)"},"citationItems":[{"id":1036,"uris":[""],"uri":[""],"itemData":{"id":1036,"type":"article-journal","title":"Hypogonadism in chronic obstructive pulmonary disease: incidence and effects","container-title":"Current opinion in pulmonary medicine","page":"112-117","volume":"18","issue":"2","source":"NCBI PubMed","abstract":"PURPOSE OF REVIEW: This review summarizes the literature on hypogonadism in men with chronic obstructive pulmonary disease (COPD).\nRECENT FINDINGS: COPD is a systemic disease with effects beyond the lungs. Many prior studies have shown that middle-aged and elderly COPD patients may develop hypogonadism. Prevalence of hypogonadism in men with COPD can range from 22 to 69% and has been associated with several other systemic manifestations including osteoporosis, depression, and muscle weakness. Recent studies have revealed conflicting results with regards to these previous perceptions. The discrepancies in the findings can be mainly attributed to small sample size, differences in patient selection, and inconsistent findings. Testosterone replacement therapy may result in modest improvements in fat-free mass and limb muscle strength but its therapeutic efficacy in COPD patients still remains controversial.\nSUMMARY: The relationship between hypogonadism and COPD still remains poorly understood. The current literature is at best circumstantial.","DOI":"10.1097/MCP.0b013e32834feb37","ISSN":"1531-6971","note":"PMID: 22234275","shortTitle":"Hypogonadism in chronic obstructive pulmonary disease","journalAbbreviation":"Curr Opin Pulm Med","language":"eng","author":[{"family":"Balasubramanian","given":"Vijay"},{"family":"Naing","given":"Soe"}],"issued":{"date-parts":[["2012",3]]},"PMID":"22234275"}}],"schema":""} (107) The cause of this deficiency is multifactorial and it includes chronic hypoxia, disease severity, smoking, corticosteroid therapy, chronic inflammation and aging itself. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ikTUdCBr","properties":{"formattedCitation":"(108)","plainCitation":"(108)"},"citationItems":[{"id":1032,"uris":[""],"uri":[""],"itemData":{"id":1032,"type":"article-journal","title":"Endocrinological disturbances in chronic obstructive pulmonary disease","container-title":"European Respiratory Journal","page":"76s-80s","volume":"22","issue":"46 suppl","source":"erj.","abstract":"In this overview, the available literature on endocrinological disturbances in chronic obstructive pulmonary disease (COPD) is reviewed, with stress on growth hormone/insulin-like growth factor I (IGF‐I), thyroid hormone and the anabolic steroids.\nIn COPD, little is known about circulating growth hormone or IGF‐I concentrations. Some authors find a decrease in growth hormone or IGF‐I, others an increase. An increase of growth hormone might reflect a nonspecific response of the body to stress (for instance, hypoxaemia). Until now, only one controlled study on growth hormone supplementation has been published, which however did not reveal any functional benefits. Before growth hormone supplementation can be advised as part of the treatment in COPD, further controlled studies must be performed to investigate its functional efficacy. The prevalence of thyroid dysfunction in COPD and its role in pulmonary cachexia has not been extensively studied. So far, there is no evidence that thyroid function is consistently altered in COPD, except perhaps in a subgroup of patients with severe hypoxaemia. Further research is required to more extensively study the underlying mechanisms and consequences of disturbed thyroid function in this subgroup of COPD patients.\nA few studies have reported the results of anabolic steroid supplementation in chronic obstructive pulmonary disease. Although some studies have discerned that low circulating levels of testosterone are common in males with chronic obstructive pulmonary disease, little is known about the prevalence, the underlying causes or functional consequences of hypogonadism in these patients. The use of systemic glucocorticosteroids and an influence of the systemic inflammatory response have been suggested as contributing to low testosterone levels. It can be hypothesised that low anabolic hormones will reduce muscle mass and eventually result in a diminished muscle function. Further evidence is required before testosterone replacement can be recommended for males with chronic obstructive pulmonary disease.","DOI":"10.1183/09031936.03.00004610","ISSN":"0903-1936, 1399-3003","note":"PMID: 14621109","journalAbbreviation":"Eur Respir J","language":"en","author":[{"family":"Creutzberg","given":"E. C."},{"family":"Casaburi","given":"R."}],"issued":{"date-parts":[["2003",11,2]]},"accessed":{"date-parts":[["2014",3,28]]},"PMID":"14621109"}}],"schema":""} (108) Animal and human studies have shown that testosterone is a stimulant of erythropoiesis; its administration is associated with an increase in Hb concentration, via stimulation of EPO production, reduction of hepcidin levels and increase of iron utilization. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Uljt9TIN","properties":{"formattedCitation":"(109)","plainCitation":"(109)"},"citationItems":[{"id":1027,"uris":[""],"uri":[""],"itemData":{"id":1027,"type":"article-journal","title":"Testosterone Suppresses Hepcidin in Men: A Potential Mechanism for Testosterone-Induced Erythrocytosis","container-title":"The Journal of Clinical Endocrinology and Metabolism","page":"4743-4747","volume":"95","issue":"10","source":"PubMed Central","abstract":"Context: The mechanisms by which testosterone increases hemoglobin and hematocrit are unknown., Objective: The aim was to test the hypothesis that testosterone-induced increase in hematocrit is associated with suppression of the iron regulatory peptide hepcidin., Participants: Healthy younger men (ages 19–35 yr; n = 53) and older men (ages 59–75 yr; n = 56) were studied., Methods: Weekly doses of testosterone enanthate (25, 50, 125, 300, and 600 mg) were administered over 20 wk, whereas endogenous testosterone was suppressed by monthly GnRH agonist administration. Blood and serum parameters from each individual were measured at wk 0, 1, 2, 4, 8, and 20. Longitudinal analyses were performed to examine the relationship between hepcidin, hemoglobin, hematocrit, and testosterone while controlling for potential confounders., Results: High levels of testosterone markedly suppressed serum hepcidin within 1 wk. Hepcidin suppression in response to testosterone administration was dose-dependent in older men and more pronounced than in young men, and this corresponded to a greater rise in hemoglobin in older men. Serum hepcidin levels at 4 and 8 wk were predictive of change in hematocrit from baseline to peak levels., Conclusion: Testosterone administration is associated with suppression of serum hepcidin. Greater increases in hematocrit in older men during testosterone therapy are related to greater suppression of hepcidin., Testosterone suppresses the iron regulatory peptide hepcidin in men, and this effect is more pronounced in older men who also experience greater erythrocytosis.","DOI":"10.1210/jc.2010-0864","ISSN":"0021-972X","note":"PMID: 20660052\nPMCID: PMC3050108","shortTitle":"Testosterone Suppresses Hepcidin in Men","journalAbbreviation":"J Clin Endocrinol Metab","author":[{"family":"Bachman","given":"Eric"},{"family":"Feng","given":"Rui"},{"family":"Travison","given":"Thomas"},{"family":"Li","given":"Michelle"},{"family":"Olbina","given":"Gordana"},{"family":"Ostland","given":"Vaughn"},{"family":"Ulloor","given":"Jagadish"},{"family":"Zhang","given":"Anqi"},{"family":"Basaria","given":"Shehzad"},{"family":"Ganz","given":"Tomas"},{"family":"Westerman","given":"Mark"},{"family":"Bhasin","given":"Shalender"}],"issued":{"date-parts":[["2010",10]]},"accessed":{"date-parts":[["2014",3,28]]},"PMID":"20660052","PMCID":"PMC3050108"}}],"schema":""} (109) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"hko9JwNi","properties":{"formattedCitation":"(110)","plainCitation":"(110)"},"citationItems":[{"id":1025,"uris":[""],"uri":[""],"itemData":{"id":1025,"type":"article-journal","title":"Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells","container-title":"Aging cell","page":"280-291","volume":"12","issue":"2","source":"NCBI PubMed","abstract":"Testosterone administration increases hemoglobin levels and has been used to treat anemia of chronic disease. Erythrocytosis is the most frequent adverse event associated with testosterone therapy of hypogonadal men, especially older men. However, the mechanisms by which testosterone increases hemoglobin remain unknown. Testosterone administration in male and female mice was associated with a greater increase in hemoglobin and hematocrit, reticulocyte count, reticulocyte hemoglobin concentration, and serum iron and transferrin saturation than placebo. Testosterone downregulated hepatic hepcidin mRNA expression, upregulated renal erythropoietin mRNA expression, and increased erythropoietin levels. Testosterone-induced suppression of hepcidin expression was independent of its effects on erythropoietin or hypoxia-sensing mechanisms. Transgenic mice with liver-specific constitutive hepcidin over-expression failed to exhibit the expected increase in hemoglobin in response to testosterone administration. Testosterone upregulated splenic ferroportin expression and reduced iron retention in spleen. After intravenous administration of transferrin-bound (58) Fe, the amount of (58) Fe incorporated into red blood cells was significantly greater in testosterone-treated mice than in placebo-treated mice. Serum from testosterone-treated mice stimulated hemoglobin synthesis in K562 erythroleukemia cells more than that from vehicle-treated mice. Testosterone administration promoted the association of androgen receptor (AR) with Smad1 and Smad4 to reduce their binding to bone morphogenetic protein (BMP)-response elements in hepcidin promoter in the liver. Ectopic expression of AR in hepatocytes suppressed hepcidin transcription; this effect was blocked dose-dependently by AR antagonist flutamide. Testosterone did not affect hepcidin mRNA stability. In conclusion, testosterone inhibits hepcidin transcription through its interaction with BMP/Smad signaling. Testosterone administration is associated with increased iron incorporation into red blood cells.","DOI":"10.1111/acel.12052","ISSN":"1474-9726","note":"PMID: 23399021 \nPMCID: PMC3602280","journalAbbreviation":"Aging Cell","language":"eng","author":[{"family":"Guo","given":"Wen"},{"family":"Bachman","given":"Eric"},{"family":"Li","given":"Michelle"},{"family":"Roy","given":"Cindy N"},{"family":"Blusztajn","given":"Jerzy"},{"family":"Wong","given":"Siu"},{"family":"Chan","given":"Stephen Y"},{"family":"Serra","given":"Carlo"},{"family":"Jasuja","given":"Ravi"},{"family":"Travison","given":"Thomas G"},{"family":"Muckenthaler","given":"Martina U"},{"family":"Nemeth","given":"Elizabeta"},{"family":"Bhasin","given":"Shalender"}],"issued":{"date-parts":[["2013",4]]},"PMID":"23399021","PMCID":"PMC3602280"}}],"schema":""} (110) Currently, no study has evaluated the association between testosterone deficiency and anemia establishment in COPD patients. However, in a large population study of 1273 men, low free testosterone levels were associated with lower hematocrit levels, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TvW8hy2p","properties":{"formattedCitation":"(111)","plainCitation":"(111)"},"citationItems":[{"id":1038,"uris":[""],"uri":[""],"itemData":{"id":1038,"type":"article-journal","title":"Association between sex steroid hormones and hematocrit in a nationally representative sample of men","container-title":"Journal of andrology","page":"1332-1341","volume":"33","issue":"6","source":"NCBI PubMed","abstract":"Low or high hematocrit levels are associated with increased morbidity and mortality, mediated via anemia or thromboembolic events, respectively. It is therefore important to identify factors that influence hematocrit. Although androgens are known to stimulate hematopoietic cells, it is unknown whether circulating sex steroid hormones affect hematocrit. The association between serum sex steroid hormone concentrations and hematocrit in men aged ≥ 20 years was evaluated in a cross-sectional study of 1273 men in the Third National Health and Nutrition Examination Survey (1988-1991). Outcomes were low (<10th percentile), high (>90th percentile), and mean hematocrit. Men with low free testosterone levels had a lower hematocrit than men with normal free testosterone levels (P = .03), although no relationship was found between total testosterone level and hematocrit. The relationship between sex hormone-binding globulin (SHBG) and hematocrit was complex, with both low (P < .001) and high (P = .01) SHBG levels associated with lower hematocrit in men aged ≥ 20 years and only high (P = .01) SHBG levels in men aged ≥ 50 years. The odds ratio (OR) of high vs normal hematocrit increased as total estradiol (OR, 2.84; P trend = .04) and free estradiol (OR, 2.23; P trend = .09) levels increased. In this nationally representative study of men, sex steroid hormone levels, particularly low free testosterone and high SHBG levels, were associated with lower hematocrit, and high total and free estradiol levels were associated with high hematocrit. Thus, changes in sex hormone levels with aging may contribute to the increased prevalence of anemia and thromboembolic stroke in men as they age.","DOI":"10.2164/jandrol.111.015651","ISSN":"1939-4640","note":"PMID: 22604627 \nPMCID: PMC3774012","journalAbbreviation":"J. Androl.","language":"eng","author":[{"family":"Paller","given":"Channing J"},{"family":"Shiels","given":"Meredith S"},{"family":"Rohrmann","given":"Sabine"},{"family":"Menke","given":"Andy"},{"family":"Rifai","given":"Nader"},{"family":"Nelson","given":"William G"},{"family":"Platz","given":"Elizabeth A"},{"family":"Dobs","given":"Adrian S"}],"issued":{"date-parts":[["2012",12]]},"PMID":"22604627","PMCID":"PMC3774012"}}],"schema":""} (111) a result likely to be applicable in COPD patients, too. Growth hormone and Insulin-like growth factor-1 abnormalitiesThere is evidence that the growth hormone (GH) release axis is disturbed in COPD patients, resulting in the establishment of acquired GH resistance. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"EeAVvh5h","properties":{"formattedCitation":"(112)","plainCitation":"(112)"},"citationItems":[{"id":1146,"uris":[""],"uri":[""],"itemData":{"id":1146,"type":"article-journal","title":"Anorexia in chronic obstructive pulmonary disease--association to cachexia and hormonal derangement","container-title":"International journal of cardiology","page":"83-89","volume":"119","issue":"1","source":"NCBI PubMed","abstract":"BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD) weight loss frequently occurs that may ultimately lead to cachexia as a serious co-morbidity, indicating severely impaired functional capacity, health status and increased mortality. Increased energy expenditure due to mechanic and metabolic inefficiency and systemic inflammation are determinants of a hypermetabolic state that is not balanced by dietary intake. Anorexia may importantly contribute to weight loss in COPD, however, the association between immune and hormonal derangement and altered appetite has not been studied in detail.\nAIM: The aim of the present study was to investigate whether anorexia in COPD is related to inflammation and hormonal derangement in association to weight loss.\nMETHODS: We prospectively enrolled 103 consecutive patients with COPD (age 59.8+/-1.3 years, 35% female, mean FEV1 38.3+/-1.7%) in comparison to healthy controls of similar age (n=15).\nRESULTS: In 34 patients (33%) cachexia was diagnosed (weight loss >7.5%, BMI < or = 24 kg/m2). Cachectic COPD patients had lower BMI (19.0+/-0.5 vs 25.6+/-0.7 kg/m2) and impaired lung function (FEV1 31+/-2% vs 42+/-2%, FVC 51+/-3 vs 59+/-3%, both p<0.001). Inflammatory immune activation (IL-6 and IL-6/IL-10 ratio) was significantly higher in cachectic COPD patients. Analysis of the extent of anorexia (visual analogue scale) revealed that cachectic COPD patients had significantly decreased subjective desire to eat compared to non-cachectic patients (3.5+/-0.3 vs 6.3+/-0.2, p<0.001). Patients with COPD and cachexia showed evidence of acquired GH resistance (decreased IGF-1/GH ratio) and insulin resistance (HOMA). Anorexia showed a direct correlation with the IGF-1/GH ratio (r=0.34, p<0.05) and was further related to BMI and % weight loss (both p<0.001).\nCONCLUSION: In COPD anorexia relates to hormonal derangement and inflammatory immune activation. Anorexia contributes to development of cachexia. The concept of appetite stimulating therapy emerges as a novel therapeutic option in cachectic COPD patients.","DOI":"10.1016/j.ijcard.2006.07.088","ISSN":"1874-1754","note":"PMID: 17064790","journalAbbreviation":"Int. J. Cardiol.","language":"eng","author":[{"family":"Koehler","given":"Friedrich"},{"family":"Doehner","given":"Wolfram"},{"family":"Hoernig","given":"Soeren"},{"family":"Witt","given":"Christian"},{"family":"Anker","given":"Stefan D"},{"family":"John","given":"Matthias"}],"issued":{"date-parts":[["2007",6,25]]},"PMID":"17064790"}}],"schema":""} (112) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qb9YBUrg","properties":{"formattedCitation":"(113)","plainCitation":"(113)"},"citationItems":[{"id":1123,"uris":[""],"uri":[""],"itemData":{"id":1123,"type":"article-journal","title":"Nutritional status in chronic obstructive pulmonary disease: role of hypoxia","container-title":"Nutrition (Burbank, Los Angeles County, Calif.)","page":"138-143","volume":"27","issue":"2","source":"NCBI PubMed","abstract":"In patients with chronic obstructive pulmonary disease (COPD), malnutrition and limited physical activity are very common and contribute to disease prognosis, whereas a balance between caloric intake and exercise allows body weight stability and muscle mass preservation. The goal of this review is to analyze the implications of chronic hypoxia on three key elements involved in energy homeostasis and its role in COPD cachexia. The first one is energy intake. Body weight loss, often observed in patients with COPD, is related to lack of appetite. Inflammatory cytokines are known to be involved in anorexia and to be correlated to arterial partial pressure of oxygen. Recent studies in animals have investigated the role of hypoxia in peptides involved in food consumption such as leptin, ghrelin, and adenosine monophosphate activated protein kinase. The second element is muscle function, which is strongly related to energy use. In COPD, muscle atrophy and muscle fiber shift to the glycolytic type might be an adaptation to chronic hypoxia to preserve the muscle from oxidative stress. Muscle atrophy could be the result of a marked activation of the ubiquitin-proteasome pathway as found in muscle of patients with COPD. Hypoxia, via hypoxia inducible factor-1, is implicated in mitochondrial biogenesis and autophagy. Third, hormonal control of energy balance seems to be affected in patients with COPD. Insulin resistance has been described in this group of patients as well as a sort of \"growth hormone resistance.\" Hypoxia, by hypoxia inducible factor-1, accelerates the degradation of tri-iodothyronine and thyroxine, decreasing cellular oxygen consumption, suggesting an adaptive mechanism rather than a primary cause of COPD cachexia. COPD rehabilitation aimed at maintaining function and quality of life needs to address body weight stabilization and, in particular, muscle mass preservation.","DOI":"10.1016/j.nut.2010.07.009","ISSN":"1873-1244","note":"PMID: 21145207","shortTitle":"Nutritional status in chronic obstructive pulmonary disease","journalAbbreviation":"Nutrition","language":"eng","author":[{"family":"Raguso","given":"Comasia A"},{"family":"Luthy","given":"Christophe"}],"issued":{"date-parts":[["2011",2]]},"PMID":"21145207"}}],"schema":""} (113) Several of the effects of GH on metabolism and erythropoiesis are mediated by Insulin-like growth factor-1 (IGF-1) and the presence of GH resistance is characterized by the decreased IGF-1/GH ratio. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OgFCFihW","properties":{"formattedCitation":"(112)","plainCitation":"(112)"},"citationItems":[{"id":1146,"uris":[""],"uri":[""],"itemData":{"id":1146,"type":"article-journal","title":"Anorexia in chronic obstructive pulmonary disease--association to cachexia and hormonal derangement","container-title":"International journal of cardiology","page":"83-89","volume":"119","issue":"1","source":"NCBI PubMed","abstract":"BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD) weight loss frequently occurs that may ultimately lead to cachexia as a serious co-morbidity, indicating severely impaired functional capacity, health status and increased mortality. Increased energy expenditure due to mechanic and metabolic inefficiency and systemic inflammation are determinants of a hypermetabolic state that is not balanced by dietary intake. Anorexia may importantly contribute to weight loss in COPD, however, the association between immune and hormonal derangement and altered appetite has not been studied in detail.\nAIM: The aim of the present study was to investigate whether anorexia in COPD is related to inflammation and hormonal derangement in association to weight loss.\nMETHODS: We prospectively enrolled 103 consecutive patients with COPD (age 59.8+/-1.3 years, 35% female, mean FEV1 38.3+/-1.7%) in comparison to healthy controls of similar age (n=15).\nRESULTS: In 34 patients (33%) cachexia was diagnosed (weight loss >7.5%, BMI < or = 24 kg/m2). Cachectic COPD patients had lower BMI (19.0+/-0.5 vs 25.6+/-0.7 kg/m2) and impaired lung function (FEV1 31+/-2% vs 42+/-2%, FVC 51+/-3 vs 59+/-3%, both p<0.001). Inflammatory immune activation (IL-6 and IL-6/IL-10 ratio) was significantly higher in cachectic COPD patients. Analysis of the extent of anorexia (visual analogue scale) revealed that cachectic COPD patients had significantly decreased subjective desire to eat compared to non-cachectic patients (3.5+/-0.3 vs 6.3+/-0.2, p<0.001). Patients with COPD and cachexia showed evidence of acquired GH resistance (decreased IGF-1/GH ratio) and insulin resistance (HOMA). Anorexia showed a direct correlation with the IGF-1/GH ratio (r=0.34, p<0.05) and was further related to BMI and % weight loss (both p<0.001).\nCONCLUSION: In COPD anorexia relates to hormonal derangement and inflammatory immune activation. Anorexia contributes to development of cachexia. The concept of appetite stimulating therapy emerges as a novel therapeutic option in cachectic COPD patients.","DOI":"10.1016/j.ijcard.2006.07.088","ISSN":"1874-1754","note":"PMID: 17064790","journalAbbreviation":"Int. J. Cardiol.","language":"eng","author":[{"family":"Koehler","given":"Friedrich"},{"family":"Doehner","given":"Wolfram"},{"family":"Hoernig","given":"Soeren"},{"family":"Witt","given":"Christian"},{"family":"Anker","given":"Stefan D"},{"family":"John","given":"Matthias"}],"issued":{"date-parts":[["2007",6,25]]},"PMID":"17064790"}}],"schema":""} (112) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9CkxicwX","properties":{"formattedCitation":"(114)","plainCitation":"(114)"},"citationItems":[{"id":1125,"uris":[""],"uri":[""],"itemData":{"id":1125,"type":"article-journal","title":"Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease","container-title":"BMC Pulmonary Medicine","page":"11","volume":"9","source":"PubMed Central","abstract":"Background\nRecent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-α). Insulin-like growth factor I (IGF-I) mediates the metabolic effects of growth hormone (GH). The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD). The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I) levels and furthermore, whether these changes are related to systemic inflammation.\n\nMethods\nWe measured serum leptin, IGF-I, TNF-α, interleukin 1β (IL-1β), interleukin 6 (IL-6) and interleukin 8 (IL-8) levels in 52 COPD patients with acute exacerbation on admission to hospital (Day 1) and two weeks later (Day 15). 25 healthy age-matched subjects served as controls. COPD patients were also divided into two subgroups (29 with chronic bronchitis and 23 with emphysema). Serum leptin and IGF-I were measured by radioimmunoassay and TNF-α, IL-1β, IL-6 and IL-8 were measured by ELISA.\n\nResults\nSerum leptin levels were significantly higher and serum IGF-I levels significantly lower in COPD patients on Day 1 than in healthy controls (p < 0.001). A positive correlation was observed between leptin and TNF-α on Day 1 (r = 0.620, p < 0.001). Emphysematous patients had significantly lower IGF-I levels compared to those with chronic bronchitis both on Day 1 and Day 15 (p = 0.003 and p < 0.001 respectively).\n\nConclusion\nInappropriately increased circulating leptin levels along with decreased IGF-I levels occured during acute exacerbations of COPD. Compared to chronic bronchitis, patients with emphysema had lower circulating IGF-I levels both at the onset of the exacerbation and two weeks later.","DOI":"10.1186/1471-2466-9-11","ISSN":"1471-2466","note":"PMID: 19344528\nPMCID: PMC2670813","journalAbbreviation":"BMC Pulm Med","author":[{"family":"Kythreotis","given":"Prokopis"},{"family":"Kokkini","given":"Ageliki"},{"family":"Avgeropoulou","given":"Stavrina"},{"family":"Hadjioannou","given":"Argyro"},{"family":"Anastasakou","given":"Efgenia"},{"family":"Rasidakis","given":"Antonis"},{"family":"Bakakos","given":"Petros"}],"issued":{"date-parts":[["2009",4,5]]},"accessed":{"date-parts":[["2014",4,1]]},"PMID":"19344528","PMCID":"PMC2670813"}}],"schema":""} (114) In a case-control study Ye et al indicated that levels of IGF-1 are reduced in COPD patients compared to controls and they are even lower among COPD patients during an acute exacerbation compared to patients in stable disease state. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"3GRGCCpa","properties":{"formattedCitation":"(115)","plainCitation":"(115)"},"citationItems":[{"id":1142,"uris":[""],"uri":[""],"itemData":{"id":1142,"type":"article-journal","title":"Evaluation of the significance of circulating insulin-like growth factor-1 and C-reactive protein in patients with chronic obstructive pulmonary disease","container-title":"The Journal of international medical research","page":"1025-1035","volume":"40","issue":"3","source":"NCBI PubMed","abstract":"OBJECTIVES: This study in patients with chronic obstructive pulmonary disease (COPD) investigated whether acute exacerbation of COPD (AECOPD) and clinically stable COPD (CSCOPD) are associated with changes in circulating insulin-like growth factor-1 (IGF-1) and C-reactive protein (CRP) concentrations, and whether changes in IGF-1 and CRP levels are related to changes in the indicators of malnutrition and muscle wasting.\nMETHODS: A total of 61 patients with AECOPD, 43 patients with CSCOPD and 20 healthy age-matched controls were included in the study. Circulating IGF-1 and CRP levels, together with erythrocyte sedimentation rate and indicators of malnutrition and muscle wasting, were measured in all the study participants.\nRESULTS: Circulating IGF-1 levels were significantly lower and CRP levels significantly higher in COPD patients than in controls. In addition, IGF-1 levels were significantly lower and CRP levels significantly higher in AECOPD patients than in CSCOPD patients. In COPD patients, indicators of malnutrition and muscle wasting (weight, body mass index, thigh circumference and albumin level) were significantly positively correlated with logIGF-1; thigh circumference and albumin level were significantly inversely correlated with logCRP.\nCONCLUSION: Circulating IGF-1 and CRP levels may have potential as indicators of exacerbation, malnutrition and muscle wasting in patients with COPD.","ISSN":"1473-2300","note":"PMID: 22906275","journalAbbreviation":"J. Int. Med. Res.","language":"eng","author":[{"family":"Ye","given":"M"},{"family":"Yu","given":"H"},{"family":"Yu","given":"W"},{"family":"Zhang","given":"G"},{"family":"Xiao","given":"L"},{"family":"Zheng","given":"X"},{"family":"Wu","given":"J"}],"issued":{"date-parts":[["2012"]]},"PMID":"22906275"}}],"schema":""} (115) Similar were the results of Kythreotis et al, who reported a significant decrease of circulating IGF-1 during AECOPD ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TvEttaWy","properties":{"formattedCitation":"(114)","plainCitation":"(114)"},"citationItems":[{"id":1125,"uris":[""],"uri":[""],"itemData":{"id":1125,"type":"article-journal","title":"Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease","container-title":"BMC Pulmonary Medicine","page":"11","volume":"9","source":"PubMed Central","abstract":"Background\nRecent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-α). Insulin-like growth factor I (IGF-I) mediates the metabolic effects of growth hormone (GH). The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD). The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I) levels and furthermore, whether these changes are related to systemic inflammation.\n\nMethods\nWe measured serum leptin, IGF-I, TNF-α, interleukin 1β (IL-1β), interleukin 6 (IL-6) and interleukin 8 (IL-8) levels in 52 COPD patients with acute exacerbation on admission to hospital (Day 1) and two weeks later (Day 15). 25 healthy age-matched subjects served as controls. COPD patients were also divided into two subgroups (29 with chronic bronchitis and 23 with emphysema). Serum leptin and IGF-I were measured by radioimmunoassay and TNF-α, IL-1β, IL-6 and IL-8 were measured by ELISA.\n\nResults\nSerum leptin levels were significantly higher and serum IGF-I levels significantly lower in COPD patients on Day 1 than in healthy controls (p < 0.001). A positive correlation was observed between leptin and TNF-α on Day 1 (r = 0.620, p < 0.001). Emphysematous patients had significantly lower IGF-I levels compared to those with chronic bronchitis both on Day 1 and Day 15 (p = 0.003 and p < 0.001 respectively).\n\nConclusion\nInappropriately increased circulating leptin levels along with decreased IGF-I levels occured during acute exacerbations of COPD. Compared to chronic bronchitis, patients with emphysema had lower circulating IGF-I levels both at the onset of the exacerbation and two weeks later.","DOI":"10.1186/1471-2466-9-11","ISSN":"1471-2466","note":"PMID: 19344528\nPMCID: PMC2670813","journalAbbreviation":"BMC Pulm Med","author":[{"family":"Kythreotis","given":"Prokopis"},{"family":"Kokkini","given":"Ageliki"},{"family":"Avgeropoulou","given":"Stavrina"},{"family":"Hadjioannou","given":"Argyro"},{"family":"Anastasakou","given":"Efgenia"},{"family":"Rasidakis","given":"Antonis"},{"family":"Bakakos","given":"Petros"}],"issued":{"date-parts":[["2009",4,5]]},"accessed":{"date-parts":[["2014",4,1]]},"PMID":"19344528","PMCID":"PMC2670813"}}],"schema":""} (114) and of Coskun et al, who indicated that the greater the disease severity, the lower were serum levels of IGF-1. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vX5mfMJ6","properties":{"formattedCitation":"(116)","plainCitation":"(116)"},"citationItems":[{"id":1144,"uris":[""],"uri":[""],"itemData":{"id":1144,"type":"article-journal","title":"Evaluation of thyroid hormone levels and somatomedin-C (IGF-1) in patients with chronic obstructive pulmonary disease (COPD) and relation with the severity of the disease","container-title":"Tüberküloz ve toraks","page":"369-375","volume":"57","issue":"4","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) has recently become a significant cause of mortality and morbidity. In the present study, we aimed to investigate the relationship between the severity of the disease and levels of serum thyroid hormones and somatomedin-C [Insulin-Like Growth Factor (IGF-1)]. Sixty one COPD cases (group 1) were enrolled. Control group (group 2) consisted of 20 healthy individuals. Blood samples were obtained for the analysis of arterial blood gases and hormone levels and respiratory function tests were performed on the same day. Measured hormone levels were compared between group 1 and group 2. Among thyroid hormone levels, there was no significant difference in thyroid stimulating hormone and free T3 between group 1 and 2 whereas free T4 levels were significantly higher in group 1 (p< 0.01). Additionally, mean IGF-1 levels were significantly lower in group 1 (p< 0.005). When three groups, classified according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, were compared, significant differences were observed between mild-moderate COPD cases and severe patients with respect to free T3 and IGF-1 levels (p< 0.05). Hormone levels in COPD patients change depending on the severity of the disease. In the future hormone therapies can use for the COPD treatments. Further studies with larger sample sizes are required to confirm our conclusions.","ISSN":"0494-1373","note":"PMID: 20037851","journalAbbreviation":"Tuberk Toraks","language":"eng","author":[{"family":"Co?kun","given":"Funda"},{"family":"Ege","given":"Ercüment"},{"family":"Uzaslan","given":"Esra"},{"family":"Ediger","given":"Dane"},{"family":"Karada?","given":"Mehmet"},{"family":"G?zü","given":"Oktay"}],"issued":{"date-parts":[["2009"]]},"PMID":"20037851"}}],"schema":""} (116) On the other hand, there is some evidence that GH levels are significantly elevated in COPD patients compared to healthy controls, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FR1uzWMN","properties":{"formattedCitation":"(117)","plainCitation":"(117)"},"citationItems":[{"id":1130,"uris":[""],"uri":[""],"itemData":{"id":1130,"type":"article-journal","title":"Plasma hormone levels and haemodynamics in patients with chronic obstructive lung disease","container-title":"Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS [and] Istituto di clinica tisiologica e malattie apparato respiratorio, Università di Napoli, Secondo ateneo","page":"380-386","volume":"51","issue":"5","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) is associated with right heart failure and salt and water retention. The possible roles of haemodynamically active hormones in the early stages of COPD have not previously been described. Adrenaline, noradrenaline, renin activity, aldosterone, vasopressin, cortisol, growth hormone, prolactin and atrial natriuretic peptide (ANP) were measured during right heart catheterization in mixed venous blood and in a peripheral artery, in the supine and standing position, in two groups of patients with COPD: Group A with arterial oxygen tension (Pa,O2) < 8.0 kPa (60 mmHg) and Group B with Pa,O2 > 8.0 kPa (60 mmHg). A group of 15 control subjects was studied to obtain control hormonal measurements with a venous blood sample only. Haemodynamic and blood gas values and hormone levels were measured in the supine and standing positions to record changes in the various parameters in COPD patients, and the relationship between pulmonary haemodynamics and hormone levels. No differences were found in hormonal samples between peripheral artery and mixed venous blood. In comparison with the control group, both groups of COPD patients showed a significant reduction in cortisol (p < 0.0001) and in vasopressin (p < 0.005), and an increase in ANP (p < 0.05) and growth hormone (p < 0.05). A marked, but not significant, increase in renin activity, and aldosterone was also found. After standing the increment of adrenaline was significantly higher in COPD patients (p < 0.02). A significant inverse relationship was recorded between forced expiratory volume in one second (FEV1) and noradrenaline (p < 0.02). There is a complex hormonal response even in the early phase of chronic obstructive pulmonary disease. An increase of plasma levels of atrial natriuretic peptide appears to be the earliest neuroendocrine response in these patients.","ISSN":"1122-0643","note":"PMID: 9009625","journalAbbreviation":"Monaldi Arch Chest Dis","language":"eng","author":[{"family":"Scalvini","given":"S"},{"family":"Volterrani","given":"M"},{"family":"Vitacca","given":"M"},{"family":"Clark","given":"A L"},{"family":"Solfrini","given":"R"},{"family":"Panzali","given":"A M"},{"family":"Ferrari","given":"R"},{"family":"Levi","given":"G F"}],"issued":{"date-parts":[["1996",10]]},"PMID":"9009625"}}],"schema":""} (117) while a study in mechanically ventilated patients without pulmonary disease indicated that hypercarbia is associated with an increase in GH levels. These two abnormalities (decrease of IGF-1 and increase of GH) in combination reflect the establishment of GH resistance in COPD patients.The specific impact of these hormones on erythropoiesis is evident in several other disease models. In children with primary growth hormone insensitivity and concomitant IGF-1 deficiency, treatment with IGF-1 resulted in a significant increase in red blood cell count, confirming its strong stimulatory effect on erythropoiesis. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KKgmFMhL","properties":{"formattedCitation":"(118)","plainCitation":"(118)"},"citationItems":[{"id":1138,"uris":[""],"uri":[""],"itemData":{"id":1138,"type":"article-journal","title":"Effects of insulin-like growth factor-I deficiency and replacement therapy on the hematopoietic system in patients with Laron syndrome (primary growth hormone insensitivity)","container-title":"Journal of pediatric endocrinology & metabolism: JPEM","page":"509-520","volume":"16","issue":"4","source":"NCBI PubMed","abstract":"BACKGROUND: Primary insulin-like growth factor-I (IGF-I) deficiencies, such as in Laron syndrome (LS), are a unique model in man to study the consequences resulting from defects in growth hormone (GH) signal transmission.\nOBJECTIVE: To assess retrospectively the effect of IGF-I deficiency and its therapy on the various cells of the hematopoietic system as reflected by peripheral blood counts.\nPATIENTS AND METHODS: Two groups of patients were studied. The first group consisted of 11 untreated patients with LS, seven males and four females, who were followed from childhood into adult age. Average age at the time of data analysis was 45.4 +/- 9.6 years. The second group included ten children with LS, six males and four females, who received IGF-I replacement therapy for an average period of 6 years, ranging in age from 0.9-11 years. The mean age at initiation of therapy was 6.9 +/- 4.28 years. Only the seven children treated for 5 years or more were included in the analysis. Data on blood counts were collected from the patients' charts. Blood samples were drawn at baseline, weekly during the first month, once a month during the first year, and once every 3 months thereafter. Statistical analysis of the change over time was performed using repeated measures ANOVA.\nRESULTS: Children with LS had red cell indices in the lower normal range and an elevated monocyte count. A statistically significant rise in red blood cell (RBC) indices was seen in children during IGF-I therapy: RBC rose from 4.66 x 10(6)/ml to 4.93 x 10(6)/ml (p = 0.011); hemoglobin from 11.55 g/dl to 13.01 g/dl (p < 0.001); hematocrit from 34.94% to 38.52% (p = 0.007), and mean corpuscular volume from 72.27 fl to 79.93 fl (p < 0.001). The platelet count diminished significantly during IGF-I therapy from 316 x 10(3)/ml to 219 x 10(3)/ml (p = 0.02), and the monocyte count from 0.74 x 10(3)/ml to 0.49 x 10(3)/ml (p < 0.001).\nCONCLUSIONS: The present investigation, the first of its kind in this syndrome, confirms that IGF-I has a strong stimulatory effect on erythropoiesis. In addition, IGF-I therapy had a reducing effect on monocytes and platelets, an effect not previously described. The mechanism by which IGF-I mediates these effects needs further elucidation.","ISSN":"0334-018X","note":"PMID: 12793602","journalAbbreviation":"J. Pediatr. Endocrinol. Metab.","language":"eng","author":[{"family":"Sivan","given":"Bezalel"},{"family":"Lilos","given":"Pearl"},{"family":"Laron","given":"Zvi"}],"issued":{"date-parts":[["2003",5]]},"PMID":"12793602"}}],"schema":""} (118) In patients with diabetic chronic kidney disease, IGF-1 levels were independently associated with hemoglobin concentration, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5nKzpd7a","properties":{"formattedCitation":"(119)","plainCitation":"(119)"},"citationItems":[{"id":1140,"uris":[""],"uri":[""],"itemData":{"id":1140,"type":"article-journal","title":"IGF-1 is an independent risk factor for anemia in diabetic pre-dialysis patients","container-title":"The Korean journal of internal medicine","page":"186-191","volume":"22","issue":"3","source":"NCBI PubMed","abstract":"BACKGROUND: We investigated whether the presence of diabetes mellitus (DM) was related to the degree of the anemia in predialytic patients with renal failure and what was the most relevant factor for anemia in patients with chronic kidney disease (CKD) from DM (DM-CKD).\nMETHODS: Seventy seven patients (47 predialytic patients with long-term type 2 DM (DM-CKD) and 30 predialytic patients whose disease was due to other causes (non DM-CKD)) were enrolled in this study. The blood hemoglobin (Hb) and hematocrit, and the creatinine, ferritin, vitamin B12, folate, iron, LDH, albumin, hs-CRP, intact-PTH, erythropoietin, leptin and Insulin-like growth factor I (IGF-1) levels were measured using standard methods. The estimated GFR was calculated using the abbreviated MDRD equation.\nRESULTS: The two groups did not significantly differ as to age, gender, the serum creatinine level and the inflammatory status. The Hb level was significantly lower in the DM-CKD patients than that in the non DM-CKD patients (8.5+/-1.7 g/dL vs 9.6+/-1.6 g/dL, respectively, p=0.01). The Hb level was significantly lower in the DM-CKD patients who were being treated with ACE inhibitors (the DM-ACE patients) than that in the non DM-CKD patients who were being treated with ACE inhibitors (the non DM-ACE patients) (8.5+/-1.5 g/dL vs 10.8+/-1.6 g/dL, respectively, p=0.001). Multiple regression analysis indicated that serum IGF-1 concentration was independently associated with the Hb level (beta=0.425, p=0.02) in the DM-CKD patients.\nCONCLUSIONS: The Hb concentration was significantly lower in the DM-CKD patients than that in the non DM-CKD patients. It was independently associated with the serum IGF-1 concentration in the DM-CKD patients.","ISSN":"1226-3303","note":"PMID: 17939336","journalAbbreviation":"Korean J. Intern. Med.","language":"eng","author":[{"family":"Kim","given":"Do-Hyoung"},{"family":"Kim","given":"Tae-Young"},{"family":"Kim","given":"Sun-Min"},{"family":"Yoo","given":"Soo-Jeong"},{"family":"Oh","given":"Dong-Jin"},{"family":"Yu","given":"Suk-Hee"}],"issued":{"date-parts":[["2007",9]]},"PMID":"17939336"}}],"schema":""} (119) while in patients with erythrocytosis, IGF-1 levels were positively associated with hematocrit level, even in the absence of increased EPO production. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"XSyLoh1t","properties":{"formattedCitation":"(120)","plainCitation":"(120)"},"citationItems":[{"id":1134,"uris":[""],"uri":[""],"itemData":{"id":1134,"type":"article-journal","title":"Influence of angiotensin-converting enzyme polymorphism gene, IGF-1, and other factors in the response rate of hematocrit to enalapril treatment in patients with posttransplant erythrocytosis","container-title":"Transplantation proceedings","page":"1012-1013","volume":"37","issue":"2","source":"NCBI PubMed","abstract":"A significant relationship between hematocrit values and serum parameters such as the insulin like growth factor (IGF-1) and calcium was observed in patients with posttransplant erythrocytosis (PTE). Since angiotensin-converting enzyme inhibitors (ACEI) decrease hematocrit (Ht) levels in these patients, ACE genotype should play an important role. We designed this study to investigate whether ACE genotype or baseline concentrations of IGF-1, IGF-blood binding protein 3 (BP3), growth hormone (GH), or Ca influenced the response of Ht to ACEI treatment. Twenty-one kidney graft recipients with PTE were treated with enalapril (2.5 to 5 mg/d) for 1 year. IGF-1, BP3, GH, Ca, and Ht were determined before as well as 15, 30, 90, 180, and 365 days after enalapril treatment. ACE polymorphism was also determined. Enalapril treatment significantly decreased Ht levels. Only IGF-1 baseline levels showed a positive correlation to the decreased Ht (P < .025). ACE genotype as determined in 18 patients, showed no correlation with the response to enalapril. Patients with ACE genotype II showed a tendency to an earlier display of PTE. We conclude that low doses of enalapril decrease Ht levels in PTE patients; that PTE begins earlier in patients with II ACE genotype; and that only IGF-1 baseline levels influence the Ht decrease after treatment. These observations suggest that ACEI decrease the Ht via an inhibitory effect on IGF-1, which has a stimulary effect on erythropoiesis.","DOI":"10.1016/j.transproceed.2004.11.078","ISSN":"0041-1345","note":"PMID: 15848608","journalAbbreviation":"Transplant. Proc.","language":"eng","author":[{"family":"Jimeno","given":"L"},{"family":"Rodado","given":"R"},{"family":"Barrios","given":"Y"},{"family":"Campos","given":"M"},{"family":"Llorente","given":"S"},{"family":"Nicolas","given":"F"},{"family":"Minguela","given":"A"}],"issued":{"date-parts":[["2005",3]]},"PMID":"15848608"}}],"schema":""} (120) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rmvDWlyR","properties":{"formattedCitation":"(121)","plainCitation":"(121)"},"citationItems":[{"id":1151,"uris":[""],"uri":[""],"itemData":{"id":1151,"type":"article-journal","title":"Insulin-like growth factor I plays a role in regulating erythropoiesis in patients with end-stage renal disease and erythrocytosis","container-title":"Journal of the American Society of Nephrology: JASN","page":"315-322","volume":"10","issue":"2","source":"NCBI PubMed","abstract":"Erythroid progenitor growth, the serum hormones that regulate erythropoiesis, and the effect of patient's serum on the growth of normal erythroid progenitors were assessed in eight patients with end-stage renal disease (ESRD) and erythrocytosis. All patients were male and had been on maintenance dialysis, they had a hematocrit >50% and/or a red blood cell count >6 x 10(12)/L and an arterial oxygen saturation >95%. Four had acquired cystic disease of the kidney (ACDK), and four other non-ACDK patients did not have known causes of secondary erythrocytosis after appropriate investigations and long-term follow-up. The methylcellulose culture technique was used to assay the erythroid progenitor (BFU-E/CFU-E) growth. Serum erythropoietin (EPO) and insulin-like growth factor I (IGF-I) levels were measured by RIA. Paired experiments were performed to determine the effects of 10% sera from ESRD patients and control subjects on normal marrow CFU-E growth. The numbers of EPO-dependent BFU-E in marrow and/or blood of patients with ESRD and erythrocytosis were higher than those of normal controls. No EPO-independent erythroid colonies were found. Serum EPO levels were constantly normal in one patient and elevated in three patients with ACDK; for non-ACDK patients, EPO levels were normal or low in two patients and persistently increased in one, but fluctuated in the remaining one on serial assays. There was no correlation between serum EPO levels and hematocrit values. The serum IGF-I levels in patients with ESRD and erythrocytosis were significantly increased compared with normal subjects or ESRD patients with anemia. We found an inverse correlation between serum EPO and IGF-I levels. Sera from patients with ESRD and erythrocytosis exhibited a stimulating effect on normal marrow CFU-E growth. The stimulating effect of sera from patients who had a normal serum EPO level and an elevated IGF-I level could be partially blocked by anti-IGF-I. The present study suggests that IGF-I plays an important role in the regulation of erythropoiesis in patients with ESRD and erythrocytosis who did not have an increased EPO production.","ISSN":"1046-6673","note":"PMID: 10215331","journalAbbreviation":"J. Am. Soc. Nephrol.","language":"eng","author":[{"family":"Shih","given":"L Y"},{"family":"Huang","given":"J Y"},{"family":"Lee","given":"C T"}],"issued":{"date-parts":[["1999",2]]},"PMID":"10215331"}}],"schema":""} (121) Although this hypothesis has not yet been tested in COPD patients, these data indicate that abnormal IGF-1 and/or GH levels could be another potential cause of anemia establishment in this population. A few trials of GH or ghrelin therapy in COPD exist but changes in hemoglobin were not reported. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"89NhL6Fh","properties":{"formattedCitation":"(122)","plainCitation":"(122)"},"citationItems":[{"id":736,"uris":[""],"uri":[""],"itemData":{"id":736,"type":"article-journal","title":"Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized, controlled study","container-title":"American journal of respiratory and critical care medicine","page":"1800-1806","volume":"156","issue":"6","source":"NCBI PubMed","abstract":"Patients with chronic obstructive pulmonary disease (COPD) often develop weight loss, which is associated with increased mortality. Recombinant human growth hormone (rhGH) treatment has been proposed to improve nitrogen balance and to increase muscle strength in these patients. The aim of this study was to assess the effects of rhGH administration on the nutritional status, resting metabolism, muscle strength, exercise tolerance, dyspnea, and subjective well-being of underweight patients with stable COPD. Sixteen patients attending a pulmonary rehabilitation program (age: 66 +/- 9 yr; weight: 77 +/- 7% of ideal body weight; FEV1: 39 +/- 13% of predicted) were randomly treated daily with either 0.15 IU/kg rhGH or placebo during 3 wk in a double-blind fashion. Measurements were made at the beginning (DO) and at the end (D21) of treatment and 2 mo later (D81). Body weight was similar in the two groups during the study, but lean body mass was significantly higher in the rhGH group at D21 (p < 0.01) and D81 (p < 0.05). The increase in lean body mass was 2.3 +/- 1.6 kg in the rhGH group and 1.1 +/- 0.9 kg in the control group at D21 and 1.9 +/- 1.6 kg in the rhGH group and 0.7 +/- 2.1 kg in the control group at D81. At D21, the resting energy expenditure was increased in the rhGH group (107.8% of DO, p < 0.001 compared with the control group). At D21 and D81, the changes in maximal respiratory pressures, handgrip strength, maximal exercise capacity, and subjective well-being were similar in the two groups. At D21, the 6-min walking distance decreased in the rhGH group (-13 +/- 31%) and increased in the control group (+10 +/- 14%; p < 0.01). We conclude that the daily administration of 0.15 IU/kg rhGH during 3 wk increases lean body mass but does not improve muscle strength or exercise tolerance in underweight patients with COPD.","DOI":"10.1164/ajrccm.156.6.9704142","ISSN":"1073-449X","note":"PMID: 9412558","journalAbbreviation":"Am. J. Respir. Crit. Care Med.","language":"eng","author":[{"family":"Burdet","given":"L"},{"family":"de Muralt","given":"B"},{"family":"Schutz","given":"Y"},{"family":"Pichard","given":"C"},{"family":"Fitting","given":"J W"}],"issued":{"date-parts":[["1997",12]]},"PMID":"9412558"}}],"schema":""} (122) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xWMLVloD","properties":{"formattedCitation":"(123)","plainCitation":"(123)"},"citationItems":[{"id":734,"uris":[""],"uri":[""],"itemData":{"id":734,"type":"article-journal","title":"Ghrelin treatment of cachectic patients with chronic obstructive pulmonary disease: a multicenter, randomized, double-blind, placebo-controlled trial","container-title":"PloS one","page":"e35708","volume":"7","issue":"5","source":"NCBI PubMed","abstract":"BACKGROUND: Pulmonary cachexia is common in advanced chronic obstructive pulmonary disease (COPD), culminating in exercise intolerance and a poor prognosis. Ghrelin is a novel growth hormone (GH)-releasing peptide with GH-independent effects. The efficacy and safety of adding ghrelin to pulmonary rehabilitation (PR) in cachectic COPD patients were investigated.\nMETHODOLOGY/PRINCIPAL FINDINGS: In a multicenter, randomized, double-blind, placebo-controlled trial, 33 cachectic COPD patients were randomly assigned PR with intravenous ghrelin (2 ?g/kg) or placebo twice daily for 3 weeks in hospital. The primary outcomes were changes in 6-min walk distance (6-MWD) and the St. George Respiratory Questionnaire (SGRQ) score. Secondary outcomes included changes in the Medical Research Council (MRC) scale, and respiratory muscle strength. At pre-treatment, serum GH levels were increased from baseline levels by a single dose of ghrelin (mean change, +46.5 ng/ml; between-group p<0.0001), the effect of which continued during the 3-week treatment. In the ghrelin group, the mean change from pre-treatment in 6-MWD was improved at Week 3 (+40 m, within-group p?=?0.033) and was maintained at Week 7 (+47 m, within-group p?=?0.017), although the difference between ghrelin and placebo was not significant. At Week 7, the mean changes in SGRQ symptoms (between-group p?=?0.026), in MRC (between-group p?=?0.030), and in maximal expiratory pressure (MEP; between-group p?=?0.015) were better in the ghrelin group than in the placebo group. Additionally, repeated-measures analysis of variance (ANOVA) indicated significant time course effects of ghrelin versus placebo in SGRQ symptoms (p?=?0.049) and MEP (p?=?0.021). Ghrelin treatment was well tolerated.\nCONCLUSIONS/SIGNIFICANCE: In cachectic COPD patients, with the safety profile, ghrelin administration provided improvements in symptoms and respiratory strength, despite the lack of a significant between-group difference in 6-MWD.\nTRIAL REGISTRATION: UMIN Clinical Trial Registry C000000061.","DOI":"10.1371/journal.pone.0035708","ISSN":"1932-6203","note":"PMID: 22563468 \nPMCID: PMC3341383","shortTitle":"Ghrelin treatment of cachectic patients with chronic obstructive pulmonary disease","journalAbbreviation":"PLoS ONE","language":"eng","author":[{"family":"Miki","given":"Keisuke"},{"family":"Maekura","given":"Ryoji"},{"family":"Nagaya","given":"Noritoshi"},{"family":"Nakazato","given":"Masamitsu"},{"family":"Kimura","given":"Hiroshi"},{"family":"Murakami","given":"Shinsuke"},{"family":"Ohnishi","given":"Shunsuke"},{"family":"Hiraga","given":"Toru"},{"family":"Miki","given":"Mari"},{"family":"Kitada","given":"Seigo"},{"family":"Yoshimura","given":"Kenji"},{"family":"Tateishi","given":"Yoshitaka"},{"family":"Arimura","given":"Yasuji"},{"family":"Matsumoto","given":"Nobuhiro"},{"family":"Yoshikawa","given":"Masanori"},{"family":"Yamahara","given":"Kenichi"},{"family":"Kangawa","given":"Kenji"}],"issued":{"date-parts":[["2012"]]},"PMID":"22563468","PMCID":"PMC3341383"}}],"schema":""} (123)NutritionInvoluntary weight loss and cachexia is a common manifestation of advanced COPD. Its aetiology is multifactorial; however, inadequate oral intake is one of the identified causes. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"NZ5zgCQQ","properties":{"formattedCitation":"(124)","plainCitation":"(124)"},"citationItems":[{"id":1100,"uris":[""],"uri":[""],"itemData":{"id":1100,"type":"article-journal","title":"Nutritional aspects of chronic obstructive pulmonary disease","container-title":"Proceedings of the American Thoracic Society","page":"519-523","volume":"5","issue":"4","source":"NCBI PubMed","abstract":"It is clear that being underweight is a poor prognostic sign in chronic obstructive pulmonary disease (COPD). It is also clear that undernutrition is at least in part associated with the severity of airflow obstruction. While both weight and body mass index are useful screening tools in the initial nutritional evaluation, fat-free mass (FFM) may be a better marker of undernutrition in patients with COPD. The causes of cachexia in patients with COPD are multifactorial and include decreased oral intake, the effect of increased work of breathing due to abnormal respiratory mechanics, and the effect of chronic systemic inflammation. Active nutritional supplementation in undernourished patients with COPD can lead to weight gain and improvements in respiratory muscle function and exercise performance. However, long-term effects of nutritional supplementation are not clear. In addition, the optimal type of nutritional supplementation needs to be explored further. The role of novel forms of treatment, such as androgens or appetite stimulants designed to increase FFM, also needs to be further studied. Thus, in the absence of definitive data, it cannot be said that long-term weight gain, either using enhanced caloric intake, with or without anabolic steroids or appetite stimulants, offers survival or other benefits to patients with COPD. However, there are indications from single-center trials that this is an avenue well worth exploring.","DOI":"10.1513/pats.200707-092ET","ISSN":"1546-3222","note":"PMID: 18453365 \nPMCID: PMC2645329","journalAbbreviation":"Proc Am Thorac Soc","language":"eng","author":[{"family":"King","given":"Daniel A"},{"family":"Cordova","given":"Francis"},{"family":"Scharf","given":"Steven M"}],"issued":{"date-parts":[["2008",5,1]]},"PMID":"18453365","PMCID":"PMC2645329"}}],"schema":""} (124) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"XRPEq0E1","properties":{"formattedCitation":"(125)","plainCitation":"(125)"},"citationItems":[{"id":1102,"uris":[""],"uri":[""],"itemData":{"id":1102,"type":"article-journal","title":"Ageing and COPD affect different domains of nutritional status: the ECCE study","container-title":"The European respiratory journal","page":"1340-1345","volume":"37","issue":"6","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) and ageing may contribute to malnutrition. We aimed to explore whether COPD and ageing determine malnutrition in different manners. 460 stable COPD outpatients (376 males and 84 females) from the Extrapulmonary Consequences of COPD in the Elderly (ECCE) study database were investigated (age 75.0±5.9 yrs; forced expiratory volume in 1 s 54.7±18.3% predicted). Nutritional status was evaluated using the Mini Nutritional Assessment? (MNA) questionnaire. From the MNA, three scores exploring the domains of the nutritional status were calculated: body composition, energy intake and body functionality scores. Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages were negatively correlated with five MNA items exploring mobility, patient's perception of own nutrition and health status, and arm and calf circumferences (lowest Spearman's rho (rs)=-0.011; highest p=0.039). GOLD stages were independently correlated with body composition and body functionality scores (model r2=0.073). Age was negatively correlated with four MNA items exploring loss of appetite, fluid intake, mobility and autonomy in daily life (lowest rs=-0.013; highest p=0.030). Age was independently correlated with body functionality score (model r2=0.037). Severe COPD and ageing are independent and probably concurrent conditions leading to malnutrition. The MNA questionnaire allows a valuable insight into the complexity of components of nutritional status and may provide useful clues for treatment strategies.","DOI":"10.1183/09031936.00032310","ISSN":"1399-3003","note":"PMID: 21071469","shortTitle":"Ageing and COPD affect different domains of nutritional status","journalAbbreviation":"Eur. Respir. J.","language":"eng","author":[{"family":"Battaglia","given":"S"},{"family":"Spatafora","given":"M"},{"family":"Paglino","given":"G"},{"family":"Pedone","given":"C"},{"family":"Corsonello","given":"A"},{"family":"Scichilone","given":"N"},{"family":"Antonelli-Incalzi","given":"R"},{"family":"Bellia","given":"V"}],"issued":{"date-parts":[["2011",6]]},"PMID":"21071469"}}],"schema":""} (125) Obase et al reported that daily iron intake among 13 COPD patients was about half of that of 27 age matched controls; ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Ylyd9PDm","properties":{"formattedCitation":"(126)","plainCitation":"(126)"},"citationItems":[{"id":312,"uris":[""],"uri":[""],"itemData":{"id":312,"type":"article-journal","title":"Nutritional deficits in elderly smokers with respiratory symptoms that do not fulfill the criteria for COPD","container-title":"International journal of chronic obstructive pulmonary disease","page":"679-683","volume":"6","source":"NCBI PubMed","abstract":"BACKGROUND AND OBJECTIVE: Whereas nutrition deficits are recognized as an expression of systemic inflammation in the elderly with diagnosed chronic obstructive pulmonary disease (COPD), if they occur in symptomatic elderly smokers, unfulfilled COPD criteria are not confirmed.\nMETHODS: Respiratory function, anthropometry assessment, and diet intake evaluation of 13 COPD patients (COPD group), ten symptomatic elderly smokers (SYSM group), and 27 healthy volunteers (control group) were compared. All were 70 years old or older.\nRESULTS: The SYSM group had lower body weight, body mass index, percentage ideal body weight, body fat percentage, arm muscle circumference, tricep skin fold thickness, serum albumin, prealbumin, and transferrin than the control group and were similar to the COPD group (P < 0.05 each and nonsignificant each). Resting energy expenditure was no different among the groups. Intake of energy, vitamins (A, B1, B2, and C), calcium, iron, fiber, and sodium was also lower in the SYSM group than in the control group (P < 0.05 all) and was similar to the COPD group.\nCONCLUSION: Elderly smokers who are symptomatic but who do not fulfill the COPD diagnostic criteria have nutritional deficits related to insufficient energy intake that are similar to those seen in COPD patients.","DOI":"10.2147/COPD.S25293","ISSN":"1178-2005","note":"PMID: 22259244","journalAbbreviation":"Int J Chron Obstruct Pulmon Dis","language":"eng","author":[{"family":"Obase","given":"Yasushi"},{"family":"Mouri","given":"Keiji"},{"family":"Shimizu","given":"Hiroki"},{"family":"Ohue","given":"Yoshihiro"},{"family":"Kobashi","given":"Yoshihiro"},{"family":"Kawahara","given":"Kazue"},{"family":"Oka","given":"Mikio"}],"issued":{"date-parts":[["2011"]]},"PMID":"22259244"}}],"schema":""} (126) however, literature data on mineral intake among COPD patients is limited, so the frequency and severity of true iron deficiency as a cause of anemia cannot be accurately estimated. Nevertheless, previous studies have indicated that the intake of other micronutrients, such as vitamin B12 and folic acid is low among COPD patients, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"A5KHPivC","properties":{"formattedCitation":"(127)","plainCitation":"(127)"},"citationItems":[{"id":1104,"uris":[""],"uri":[""],"itemData":{"id":1104,"type":"article-journal","title":"Hyperhomocysteinaemia and poor vitamin B status in chronic obstructive pulmonary disease","container-title":"Nutrition, metabolism, and cardiovascular diseases: NMCD","page":"654-659","volume":"19","issue":"9","source":"NCBI PubMed","abstract":"BACKGROUND AND AIMS: Patients with chronic obstructive pulmonary disease (COPD) are at increased atherothrombotic risk. Preliminary findings have suggested that COPD patients may have increased plasma total homocysteine (tHcy), a cardiovascular risk factor often caused by a poor B vitamin status, but plasma levels of such vitamins were not measured. The aim of this study was to investigate hyperhomocysteinaemia in COPD and to determine whether it may be secondary to poor plasma concentrations of B vitamins.\nMETHODS AND RESULTS: We performed a case-control, cross-sectional study of 42 patients with COPD and 29 control subjects. Folate, vitamin B12, vitamin B6, tHcy, renal function, C-reactive protein, blood gases and lipids were measured in patients and controls. COPD patients had higher plasma tHcy (median: 13.9mumol/l, interquantile range [IQR]: 12.1-18.5 versus 11.5, IQR: 10.1-14, p=0.002) and lower circulating folate (median: 2.5ng/ml, IQR: 1.2-3.3 versus 2.8, IQR: 2.1-4 of controls, p=0.03) than controls had. Compared to the control group, COPD was associated with higher tHcy concentrations also after adjusting for smoking, heart failure, renal function and C-reactive protein with logistic regression analysis (OR 1.36, 95% CI 1.06-1.72, p=0.01). In the COPD group, low levels of folate (beta=-0.27, p=0.02) and vitamin B12 (beta=-0.24, p=0.04), and hypertriglyceridaemia (beta=0.580, p<0.0001) were independent predictors of the presence of high tHcy concentrations in a multiple linear regression model (adjusted R(2)=0.522).\nCONCLUSION: COPD patients have a poor B vitamin status and, as a consequence, increased tHcy. These abnormalities may contribute to the COPD-related atherothrombotic risk.","DOI":"10.1016/j.numecd.2008.12.006","ISSN":"1590-3729","note":"PMID: 19282159","journalAbbreviation":"Nutr Metab Cardiovasc Dis","language":"eng","author":[{"family":"Fimognari","given":"F L"},{"family":"Loffredo","given":"L"},{"family":"Di Simone","given":"S"},{"family":"Sampietro","given":"F"},{"family":"Pastorelli","given":"R"},{"family":"Monaldo","given":"M"},{"family":"Violi","given":"F"},{"family":"D'Angelo","given":"A"}],"issued":{"date-parts":[["2009",11]]},"PMID":"19282159"}}],"schema":""} (127) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UMCmhr5k","properties":{"formattedCitation":"(128)","plainCitation":"(128)"},"citationItems":[{"id":1106,"uris":[""],"uri":[""],"itemData":{"id":1106,"type":"article-journal","title":"Vitamin and mineral status in elderly patients with chronic obstructive pulmonary disease","container-title":"The clinical respiratory journal","page":"23-29","volume":"1","issue":"1","source":"NCBI PubMed","abstract":"INTRODUCTION: Eating problems are common in patients with chronic obstructive pulmonary disease (COPD), and intake of micronutrients might be lower than recommended.\nOBJECTIVE: To study dietary intake, serum and urinary concentration of trace elements and vitamins in elderly underweight patients with established severe COPD. Methods: Outpatients at a university clinic for lung medicine, with COPD, 70-85 years old, with no other serious disease, and with a body mass index (BMI) of <or=20 kg/m(2) and an FEV(1)of <50 % predicted were recruited. Body composition and bone density were evaluated with dual energy X-ray absorptiometry. Dietary intake was studied by a trained dietitian using diet-history interview. Blood and urine samples were analysed for various vitamins and trace elements.\nRESULTS: Seventeen of 30 recruited patients took part. Osteoporosis or osteopaenia was found in 16 patients. Dietary intake of energy and macronutrients was in line with recommendations for healthy individuals. Intake of protein did not meet recommendations for COPD patients. Intake of polyunsaturated fatty acids was lower than recommended and intake of saturated fatty acids was higher than recommended. Mean intake of vitamin D and folic acid was far below recommendations. Serum concentrations for folic acid and methylmalonate and plasma concentrations for homocysteine were below normal in several patients.\nCONCLUSION: Intake of vitamin D and calcium is often low in older COPD patients, which might contribute to osteoporosis. Low intake of folic acid might also be a problem. The results support prophylaxis with calcium, vitamin D and folic acid.","DOI":"10.1111/j.1752-699X.2007.00003.x","ISSN":"1752-699X","note":"PMID: 20298274","journalAbbreviation":"Clin Respir J","language":"eng","author":[{"family":"Andersson","given":"Ingalill"},{"family":"Gr?nberg","given":"AnneMarie"},{"family":"Slinde","given":"Frode"},{"family":"Bosaeus","given":"Ingvar"},{"family":"Larsson","given":"Sven"}],"issued":{"date-parts":[["2007",7]]},"PMID":"20298274"}}],"schema":""} (128) and this could contribute to the establishment of anemia. AgingThe prevalence of COPD increases with age, so the course of the disease can be further complicated by the clinical manifestations of aging itself. Anemia prevalence is high among elderly individuals, with a frequency of 10-11% among subjects >65 years old and more than 20% among subjects >80 years old. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rDi181Ga","properties":{"formattedCitation":"(129)","plainCitation":"(129)"},"citationItems":[{"id":824,"uris":[""],"uri":[""],"itemData":{"id":824,"type":"article-journal","title":"Anemia in the Elderly","container-title":"Transactions of the American Clinical and Climatological Association","page":"230-237","volume":"124","source":"PubMed Central","abstract":"As the population ages, increasing attention has become focused on the prevalence of anemia in elderly individuals. Anemia occurs in more than 10% of individuals who are older than the age of 65 years, and it increases to more than 50% in individuals who are older than the age of 80 years. Although the anemia is typically mild and unlikely to result in symptoms, it is uniformly associated with increased morbidity and mortality as assessed in large cohort studies. Anemia is an independent predictor of these adverse outcomes both in healthy community-dwelling subjects and in patients with significant co-morbidities. Efforts to understand the pathophysiology of anemia in this population, especially the one third of patients with “unexplained” anemia, have focused on the potential contributions of inflammatory pathways, erythropoietin resistance, and changes in hematopoietic stem cells to the age-dependent decrease in red cell mass. We would argue that these pathways are closely interrelated and combine to lead to anemia in aging individuals. This brief review summarizes the current understanding of this entity and our studies aimed at further delineating its pathophysiology.","ISSN":"0065-7778","note":"PMID: 23874029\nPMCID: PMC3715932","journalAbbreviation":"Trans Am Clin Climatol Assoc","author":[{"family":"Berliner","given":"Nancy"}],"issued":{"date-parts":[["2013"]]},"accessed":{"date-parts":[["2014",3,23]]},"PMID":"23874029","PMCID":"PMC3715932"}}],"schema":""} (129) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"P80Kx8rh","properties":{"formattedCitation":"(130)","plainCitation":"(130)"},"citationItems":[{"id":1111,"uris":[""],"uri":[""],"itemData":{"id":1111,"type":"article-journal","title":"Anemia in Elderly Patients: An Emerging Problem for the 21st Century","container-title":"ASH Education Program Book","page":"271-275","volume":"2010","issue":"1","source":"asheducationbook.","abstract":"Anemia is a significant problem in elderly patients. Although many anemic elderly patients can be diagnosed with nutritional deficiency, anemia of chronic inflammation or comorbid diseases that explain their decreased hematocrit, the etiology of anemia in a significant fraction remains obscure. There is evidence to suggest that the hematopoietic stem cell displays increasing erythropoietin (EPO) resistance with age. EPO levels rise in elderly, nonanemic patients, and it is hypothesized that there is an interplay between this rising demand for EPO and the decreasing ability of the aging kidney to produce adequate hormone to meet that need. There is further considerable evidence that aging is associated with increased proinflammatory cytokine expression and that many of these cytokines can contribute to EPO insensitivity. Consequently, genetic variation in the expression of these proinflammatory cytokines may influence the development of anemia in elderly patients, both through induction of hepcidin expression (anemia of inflammation) and through cytokine suppression of erythroid colony formation. The impact of inflammatory mediators, EPO insensitivity, and other factors that may act on the hematopoietic stem cell to decrease erythropoiesis are under active study and should serve to elucidate the pathophysiology of this important cause of morbidity and mortality in elderly individuals. A better understanding of the pathophysiology of anemia in elderly patients should provide critical entry points for interventions that will improve survival and quality of life in the aging population.","DOI":"10.1182/asheducation-2010.1.271","ISSN":"1520-4391, 1520-4383","note":"PMID: 21239805","shortTitle":"Anemia in Elderly Patients","journalAbbreviation":"Hematology","language":"en","author":[{"family":"Vanasse","given":"Gary J."},{"family":"Berliner","given":"Nancy"}],"issued":{"date-parts":[["2010",12,4]]},"accessed":{"date-parts":[["2014",3,31]]},"PMID":"21239805"}}],"schema":""} (130) The cause of anemia is multifactorial. Increased systemic inflammatory markers, such as TNF-α and IL-6, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"WSuUjshC","properties":{"formattedCitation":"(131)","plainCitation":"(131)"},"citationItems":[{"id":1117,"uris":[""],"uri":[""],"itemData":{"id":1117,"type":"article-journal","title":"Age-related inflammatory cytokines and disease","container-title":"Immunology and allergy clinics of North America","page":"15-39","volume":"23","issue":"1","source":"NCBI PubMed","abstract":"Aging is associated with chronic low-grade increases in circulating levels of inflammatory markers. A wide range of environmental factors, including smoking, infections, and obesity, genetic factors, and the declining function of sex hormones may contribute to systemic low-grade inflammatory activity in older individuals. Age-associated disease may exacerbate this phenomenon. The multifunctional cytokines TNF-alpha and IL-6 have been associated with morbidity and mortality in the elderly. Evidence supports the direct role of TNF-alpha in the pathogeneses of atherosclerosis, type 2 DM, and AD in older individuals. Age-related increases in systemic levels of TNF-alpha could provide a unifying basis for these disorders. Furthermore, TNF-alpha induces a catabolic state that causes frailty. Circulating levels of IL-6 seem to be a strong risk factor for frailty in the elderly, which could reflect its association with increased production of TNF-alpha. IL-6 also may be a risk factor for thromboembolic complications. In healthy, elderly populations, high circulating levels of TNF-alpha and IL-6 predict mortality, independent of comorbidity, indicating that TNF-alpha and IL-6 cause morbidity and mortality. In cohorts of frail, older individuals, TNF-alpha and IL-6 also act as disease markers. Circulating levels of TNF-alpha seem to be the best predictor of mortality in frail, elderly populations with a high mortality rate, whereas IL-6 seems to be the strongest risk marker in healthy, elderly populations. This finding could reflect that in relatively healthy old populations the increase in circulating levels of IL-6 represent a systemic response to local proinflammatory activities; however, when age-related inflammatory diseases progress, levels of TNF-alpha increase in the circulation and become gradually a stronger risk marker than IL-6. In conclusion low-grade elevations in levels of circulating cytokines are strong independent risk factors of morbidity and mortality in the elderly, and lifestyle factors and comorbidities may modulate these levels. Exercise and dietary interventions may be possible strategies to decrease inflammatory activity and improve the health status of the elderly.","ISSN":"0889-8561","note":"PMID: 12645876","journalAbbreviation":"Immunol Allergy Clin North Am","language":"eng","author":[{"family":"Brüünsgaard","given":"Helle"},{"family":"Pedersen","given":"Bente Klarlund"}],"issued":{"date-parts":[["2003",2]]},"PMID":"12645876"}}],"schema":""} (131) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zA7NknhY","properties":{"formattedCitation":"(132)","plainCitation":"(132)"},"citationItems":[{"id":1119,"uris":[""],"uri":[""],"itemData":{"id":1119,"type":"article-journal","title":"The origins of age-related proinflammatory state","container-title":"Blood","page":"2294-2299","volume":"105","issue":"6","source":"NCBI PubMed","abstract":"We hypothesized that the rising levels of inflammatory markers with aging is explained by cardiovascular risk factors and morbidity becoming progressively more prevalent in older persons. Information on inflammatory markers, cardiovascular risk factors, and diseases was collected in 595 men and 748 women sampled from the general population (age, 20-102 years). In both men and women, older age was associated with higher levels of interleukin-6 (IL-6), IL-1 receptor antagonist (IL-1ra), IL-18, C-reactive protein (CRP), and fibrinogen, while soluble IL-6 receptor (sIL-6r) increased significantly with age only in men. Adjusting for cardiovascular risk factors and morbidity, the age regression coefficients became substantially smaller in models predicting IL-6, IL-1ra, IL-18, and fibrinogen and larger in the model predicting sIL6r. Adjustment for cardiovascular morbidity substantially reduced the effect of age on CRP in men but not in women. Findings were confirmed in a subgroup of 51 men and 45 women with low risk profile and no cardiovascular morbidity. Part of the \"proinflammatory state\" in older persons is related to the high prevalence of cardiovascular risk factor and morbidity.","DOI":"10.1182/blood-2004-07-2599","ISSN":"0006-4971","note":"PMID: 15572589","journalAbbreviation":"Blood","language":"eng","author":[{"family":"Ferrucci","given":"Luigi"},{"family":"Corsi","given":"Annamaria"},{"family":"Lauretani","given":"Fulvio"},{"family":"Bandinelli","given":"Stefania"},{"family":"Bartali","given":"Benedetta"},{"family":"Taub","given":"Dennis D"},{"family":"Guralnik","given":"Jack M"},{"family":"Longo","given":"Dan L"}],"issued":{"date-parts":[["2005",3,15]]},"PMID":"15572589"}}],"schema":""} (132) decreased sensitivity of erythroid progenitor cells to EPO, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jtgqjEes","properties":{"formattedCitation":"(133)","plainCitation":"(133)"},"citationItems":[{"id":1121,"uris":[""],"uri":[""],"itemData":{"id":1121,"type":"article-journal","title":"Serum erythropoietin levels in the elderly","container-title":"Gerontology","page":"345-348","volume":"37","issue":"6","source":"NCBI PubMed","abstract":"We evaluated the relationship between erythropoietin (EPO) and hemoglobin (Hb) concentrations in 156 normal subjects ranging from 60 to 98 years old. EPO was determined by a radioimmunoassay. The serum EPO concentration in subjects with Hb concentrations greater than 12.0 g/dl (26.9 +/- 15.2 mU/ml), was significantly higher than that in younger controls (15.8 +/- 5.0 mU/ml, p less than 0.001). No sex difference in serum EPO level was detected. In addition, there was an inverse semilogarithmic relationship between EPO and Hb concentrations in subjects with Hb concentrations less than 12.0 g/dl (r = -0.559, p less than 0.001). EPO concentrations in the elderly were lower than those in young subjects with iron deficiency anemia with the same Hb level. Thus, in the elderly, a high EPO concentration may be preventing a decrease in the Hb concentration. However, a decreased EPO response to low Hb concentrations may be a contributing factor in anemia in the elderly.","ISSN":"0304-324X","note":"PMID: 1765284","journalAbbreviation":"Gerontology","language":"eng","author":[{"family":"Kario","given":"K"},{"family":"Matsuo","given":"T"},{"family":"Nakao","given":"K"}],"issued":{"date-parts":[["1991"]]},"PMID":"1765284"}}],"schema":""} (133) lower ability of the aging kidney to produce adequate EPO quantities, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tq7DaCvq","properties":{"formattedCitation":"(130)","plainCitation":"(130)"},"citationItems":[{"id":1111,"uris":[""],"uri":[""],"itemData":{"id":1111,"type":"article-journal","title":"Anemia in Elderly Patients: An Emerging Problem for the 21st Century","container-title":"ASH Education Program Book","page":"271-275","volume":"2010","issue":"1","source":"asheducationbook.","abstract":"Anemia is a significant problem in elderly patients. Although many anemic elderly patients can be diagnosed with nutritional deficiency, anemia of chronic inflammation or comorbid diseases that explain their decreased hematocrit, the etiology of anemia in a significant fraction remains obscure. There is evidence to suggest that the hematopoietic stem cell displays increasing erythropoietin (EPO) resistance with age. EPO levels rise in elderly, nonanemic patients, and it is hypothesized that there is an interplay between this rising demand for EPO and the decreasing ability of the aging kidney to produce adequate hormone to meet that need. There is further considerable evidence that aging is associated with increased proinflammatory cytokine expression and that many of these cytokines can contribute to EPO insensitivity. Consequently, genetic variation in the expression of these proinflammatory cytokines may influence the development of anemia in elderly patients, both through induction of hepcidin expression (anemia of inflammation) and through cytokine suppression of erythroid colony formation. The impact of inflammatory mediators, EPO insensitivity, and other factors that may act on the hematopoietic stem cell to decrease erythropoiesis are under active study and should serve to elucidate the pathophysiology of this important cause of morbidity and mortality in elderly individuals. A better understanding of the pathophysiology of anemia in elderly patients should provide critical entry points for interventions that will improve survival and quality of life in the aging population.","DOI":"10.1182/asheducation-2010.1.271","ISSN":"1520-4391, 1520-4383","note":"PMID: 21239805","shortTitle":"Anemia in Elderly Patients","journalAbbreviation":"Hematology","language":"en","author":[{"family":"Vanasse","given":"Gary J."},{"family":"Berliner","given":"Nancy"}],"issued":{"date-parts":[["2010",12,4]]},"accessed":{"date-parts":[["2014",3,31]]},"PMID":"21239805"}}],"schema":""} (130) malnutrition ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"H62miARX","properties":{"formattedCitation":"(125)","plainCitation":"(125)"},"citationItems":[{"id":1102,"uris":[""],"uri":[""],"itemData":{"id":1102,"type":"article-journal","title":"Ageing and COPD affect different domains of nutritional status: the ECCE study","container-title":"The European respiratory journal","page":"1340-1345","volume":"37","issue":"6","source":"NCBI PubMed","abstract":"Chronic obstructive pulmonary disease (COPD) and ageing may contribute to malnutrition. We aimed to explore whether COPD and ageing determine malnutrition in different manners. 460 stable COPD outpatients (376 males and 84 females) from the Extrapulmonary Consequences of COPD in the Elderly (ECCE) study database were investigated (age 75.0±5.9 yrs; forced expiratory volume in 1 s 54.7±18.3% predicted). Nutritional status was evaluated using the Mini Nutritional Assessment? (MNA) questionnaire. From the MNA, three scores exploring the domains of the nutritional status were calculated: body composition, energy intake and body functionality scores. Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages were negatively correlated with five MNA items exploring mobility, patient's perception of own nutrition and health status, and arm and calf circumferences (lowest Spearman's rho (rs)=-0.011; highest p=0.039). GOLD stages were independently correlated with body composition and body functionality scores (model r2=0.073). Age was negatively correlated with four MNA items exploring loss of appetite, fluid intake, mobility and autonomy in daily life (lowest rs=-0.013; highest p=0.030). Age was independently correlated with body functionality score (model r2=0.037). Severe COPD and ageing are independent and probably concurrent conditions leading to malnutrition. The MNA questionnaire allows a valuable insight into the complexity of components of nutritional status and may provide useful clues for treatment strategies.","DOI":"10.1183/09031936.00032310","ISSN":"1399-3003","note":"PMID: 21071469","shortTitle":"Ageing and COPD affect different domains of nutritional status","journalAbbreviation":"Eur. Respir. J.","language":"eng","author":[{"family":"Battaglia","given":"S"},{"family":"Spatafora","given":"M"},{"family":"Paglino","given":"G"},{"family":"Pedone","given":"C"},{"family":"Corsonello","given":"A"},{"family":"Scichilone","given":"N"},{"family":"Antonelli-Incalzi","given":"R"},{"family":"Bellia","given":"V"}],"issued":{"date-parts":[["2011",6]]},"PMID":"21071469"}}],"schema":""} (125) and high burden of comorbidities ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"747LBOXP","properties":{"formattedCitation":"(129)","plainCitation":"(129)"},"citationItems":[{"id":824,"uris":[""],"uri":[""],"itemData":{"id":824,"type":"article-journal","title":"Anemia in the Elderly","container-title":"Transactions of the American Clinical and Climatological Association","page":"230-237","volume":"124","source":"PubMed Central","abstract":"As the population ages, increasing attention has become focused on the prevalence of anemia in elderly individuals. Anemia occurs in more than 10% of individuals who are older than the age of 65 years, and it increases to more than 50% in individuals who are older than the age of 80 years. Although the anemia is typically mild and unlikely to result in symptoms, it is uniformly associated with increased morbidity and mortality as assessed in large cohort studies. Anemia is an independent predictor of these adverse outcomes both in healthy community-dwelling subjects and in patients with significant co-morbidities. Efforts to understand the pathophysiology of anemia in this population, especially the one third of patients with “unexplained” anemia, have focused on the potential contributions of inflammatory pathways, erythropoietin resistance, and changes in hematopoietic stem cells to the age-dependent decrease in red cell mass. We would argue that these pathways are closely interrelated and combine to lead to anemia in aging individuals. This brief review summarizes the current understanding of this entity and our studies aimed at further delineating its pathophysiology.","ISSN":"0065-7778","note":"PMID: 23874029\nPMCID: PMC3715932","journalAbbreviation":"Trans Am Clin Climatol Assoc","author":[{"family":"Berliner","given":"Nancy"}],"issued":{"date-parts":[["2013"]]},"accessed":{"date-parts":[["2014",3,23]]},"PMID":"23874029","PMCID":"PMC3715932"}}],"schema":""} (129) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tU3ANRaH","properties":{"formattedCitation":"(130)","plainCitation":"(130)"},"citationItems":[{"id":1111,"uris":[""],"uri":[""],"itemData":{"id":1111,"type":"article-journal","title":"Anemia in Elderly Patients: An Emerging Problem for the 21st Century","container-title":"ASH Education Program Book","page":"271-275","volume":"2010","issue":"1","source":"asheducationbook.","abstract":"Anemia is a significant problem in elderly patients. Although many anemic elderly patients can be diagnosed with nutritional deficiency, anemia of chronic inflammation or comorbid diseases that explain their decreased hematocrit, the etiology of anemia in a significant fraction remains obscure. There is evidence to suggest that the hematopoietic stem cell displays increasing erythropoietin (EPO) resistance with age. EPO levels rise in elderly, nonanemic patients, and it is hypothesized that there is an interplay between this rising demand for EPO and the decreasing ability of the aging kidney to produce adequate hormone to meet that need. There is further considerable evidence that aging is associated with increased proinflammatory cytokine expression and that many of these cytokines can contribute to EPO insensitivity. Consequently, genetic variation in the expression of these proinflammatory cytokines may influence the development of anemia in elderly patients, both through induction of hepcidin expression (anemia of inflammation) and through cytokine suppression of erythroid colony formation. The impact of inflammatory mediators, EPO insensitivity, and other factors that may act on the hematopoietic stem cell to decrease erythropoiesis are under active study and should serve to elucidate the pathophysiology of this important cause of morbidity and mortality in elderly individuals. A better understanding of the pathophysiology of anemia in elderly patients should provide critical entry points for interventions that will improve survival and quality of life in the aging population.","DOI":"10.1182/asheducation-2010.1.271","ISSN":"1520-4391, 1520-4383","note":"PMID: 21239805","shortTitle":"Anemia in Elderly Patients","journalAbbreviation":"Hematology","language":"en","author":[{"family":"Vanasse","given":"Gary J."},{"family":"Berliner","given":"Nancy"}],"issued":{"date-parts":[["2010",12,4]]},"accessed":{"date-parts":[["2014",3,31]]},"PMID":"21239805"}}],"schema":""} (130) all contribute to the establishment of anemia in the elderly. Treatment perspectivesIt seems clear that frank deficiency of vitamin B12, folate or iron should be investigated and treated in COPD patients in the same way as patients who do not have COPD. Recently an interventional outpatient study reported that the combined EPO and intravenous iron treatment of 12 anemic COPD patients with concomitant chronic renal insufficiency led to an improvement of hemoglobin concentration and a reduction in dyspnea. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9MoDVthZ","properties":{"formattedCitation":"(134)","plainCitation":"(134)"},"citationItems":[{"id":242,"uris":[""],"uri":[""],"itemData":{"id":242,"type":"article-journal","title":"The potential impact of anaemia of chronic disease in COPD","container-title":"The European respiratory journal","page":"390-396","volume":"27","issue":"2","source":"NCBI PubMed","abstract":"Anaemia of chronic disease (ACD), with chronically low levels of circulating haemoglobin, is an immune driven abnormality that occurs in many inflammatory diseases, and also in chronic heart failure. Although chronic obstructive pulmonary disease (COPD) is \"traditionally\" associated with polycythaemia, the systemic inflammation that is now recognised as a feature of COPD makes it a possible cause of ACD. If present in COPD, anaemia could worsen dyspnoea and limit exercise tolerance. Preliminary evidence suggests that anaemia in COPD patients may be more prevalent than expected, concerning 10-15% of patients suffering from severe forms of the disease. A database study conducted in 2,524 COPD patients being prescribed long-term oxygen therapy has shown that a low haematocrit is a strong predictor of survival in this population, before body mass index, and is associated with more hospitalisations and a longer cumulative duration of hospitalisation. COPD patients with low haemoglobin levels have a poorer prognosis than COPD patients with normal haemoglobin levels in the event of acute gastrointestinal bleeding or after elective aneurysm repair. Raising haemoglobinaemia through transfusion decreases minute ventilation and work of breathing in COPD patients. These preliminary evidences point to the need to study the prevalence of anaemia, and its physiological and clinical impact in chronic obstructive pulmonary disease. When this body of knowledge is available, the question of the putative benefits of raising haemoglobinaemia in chronic obstructive pulmonary disease will have to be addressed.","DOI":"10.1183/09031936.06.00143704","ISSN":"0903-1936","note":"PMID: 16452598","journalAbbreviation":"Eur. Respir. J.","language":"eng","author":[{"family":"Similowski","given":"T"},{"family":"Agustí","given":"A"},{"family":"MacNee","given":"W"},{"family":"Sch?nhofer","given":"B"}],"issued":{"date-parts":[["2006",2]]},"PMID":"16452598"}}],"schema":""} (134) The more intriguing question is whether patients with COPD, normal renal function and low levels of ferritin, with or without anemia establishment, could benefit from intravenous iron therapy alone. In this regard, the parallels with iron deficiency in heart failure are appealing. Apart from its role in erythropoiesis, iron is a key element for oxygen transport and storage and for oxidative metabolism in skeletal muscle. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bMj8wT7f","properties":{"formattedCitation":"(135)","plainCitation":"(135)"},"citationItems":[{"id":1262,"uris":[""],"uri":[""],"itemData":{"id":1262,"type":"article-journal","title":"Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency","container-title":"New England Journal of Medicine","page":"2436-2448","volume":"361","issue":"25","source":"Taylor and Francis+NEJM","abstract":"Recent developments in the management of chronic heart failure in patients with an impaired left ventricular ejection fraction have changed the natural history of this clinical syndrome and improved patients' outcomes.1,2 However, the normal daily activities of many patients with heart failure remain restricted; they report symptoms of fatigue and dyspnea that adversely affect their quality of life, leading to high morbidity.3,4 Therapeutic options to improve functional capacity in patients with heart failure are limited, and novel therapies are needed. Numerous mechanisms unrelated to hemodynamic dysfunction may underlie impaired exercise tolerance in patients with chronic heart failure. Among . . .","DOI":"10.1056/NEJMoa0908355","ISSN":"0028-4793","note":"PMID: 19920054","author":[{"family":"Anker","given":"Stefan D."},{"family":"Comin Colet","given":"Josep"},{"family":"Filippatos","given":"Gerasimos"},{"family":"Willenheimer","given":"Ronnie"},{"family":"Dickstein","given":"Kenneth"},{"family":"Drexler","given":"Helmut"},{"family":"Lüscher","given":"Thomas F."},{"family":"Bart","given":"Boris"},{"family":"Banasiak","given":"Waldemar"},{"family":"Niegowska","given":"Joanna"},{"family":"Kirwan","given":"Bridget-Anne"},{"family":"Mori","given":"Claudio"},{"family":"von Eisenhart Rothe","given":"Barbara"},{"family":"Pocock","given":"Stuart J."},{"family":"Poole-Wilson","given":"Philip A."},{"family":"Ponikowski","given":"Piotr"}],"issued":{"date-parts":[["2009"]]},"accessed":{"date-parts":[["2014",5,14]]},"PMID":"19920054"}}],"schema":""} (135) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cnl77kpA","properties":{"formattedCitation":"(136)","plainCitation":"(136)"},"citationItems":[{"id":1411,"uris":[""],"uri":[""],"itemData":{"id":1411,"type":"article-journal","title":"Iron uptake and metabolism in the new millennium","container-title":"Trends in cell biology","page":"93-100","volume":"17","issue":"2","source":"NCBI PubMed","abstract":"Iron is an essential element for metabolic processes intrinsic to life, and yet the properties that make iron a necessity also make it potentially deleterious. To avoid harm, iron homeostasis is achieved through iron transport, storage and regulatory proteins. The functions of some of these molecules are well described, for example transferrin and transferrin receptor-1, whereas the roles of others, such as the transferrin homolog melanotransferrin, remain unclear. The past decade has seen the identification of new molecules involved in iron metabolism, such as divalent metal transporter-1, ferroportin-1, hepcidin, hemojuvelin and heme carrier protein-1. Here, we focus on these intriguing new molecules and the insights gained from them into cellular iron uptake and the regulation of iron metabolism.","DOI":"10.1016/j.tcb.2006.12.003","ISSN":"1879-3088","note":"PMID: 17194590","journalAbbreviation":"Trends Cell Biol.","language":"eng","author":[{"family":"Dunn","given":"Louise L"},{"family":"Suryo Rahmanto","given":"Yohan"},{"family":"Richardson","given":"Des R"}],"issued":{"date-parts":[["2007",2]]},"PMID":"17194590"}}],"schema":""} (136) Both COPD and heart failure are characterized in part by impaired oxygen transport (because of ventilator limitation or pump failure respectively). One large ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zJkUEAmJ","properties":{"formattedCitation":"(135)","plainCitation":"(135)"},"citationItems":[{"id":1262,"uris":[""],"uri":[""],"itemData":{"id":1262,"type":"article-journal","title":"Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency","container-title":"New England Journal of Medicine","page":"2436-2448","volume":"361","issue":"25","source":"Taylor and Francis+NEJM","abstract":"Recent developments in the management of chronic heart failure in patients with an impaired left ventricular ejection fraction have changed the natural history of this clinical syndrome and improved patients' outcomes.1,2 However, the normal daily activities of many patients with heart failure remain restricted; they report symptoms of fatigue and dyspnea that adversely affect their quality of life, leading to high morbidity.3,4 Therapeutic options to improve functional capacity in patients with heart failure are limited, and novel therapies are needed. Numerous mechanisms unrelated to hemodynamic dysfunction may underlie impaired exercise tolerance in patients with chronic heart failure. Among . . .","DOI":"10.1056/NEJMoa0908355","ISSN":"0028-4793","note":"PMID: 19920054","author":[{"family":"Anker","given":"Stefan D."},{"family":"Comin Colet","given":"Josep"},{"family":"Filippatos","given":"Gerasimos"},{"family":"Willenheimer","given":"Ronnie"},{"family":"Dickstein","given":"Kenneth"},{"family":"Drexler","given":"Helmut"},{"family":"Lüscher","given":"Thomas F."},{"family":"Bart","given":"Boris"},{"family":"Banasiak","given":"Waldemar"},{"family":"Niegowska","given":"Joanna"},{"family":"Kirwan","given":"Bridget-Anne"},{"family":"Mori","given":"Claudio"},{"family":"von Eisenhart Rothe","given":"Barbara"},{"family":"Pocock","given":"Stuart J."},{"family":"Poole-Wilson","given":"Philip A."},{"family":"Ponikowski","given":"Piotr"}],"issued":{"date-parts":[["2009"]]},"accessed":{"date-parts":[["2014",5,14]]},"PMID":"19920054"}}],"schema":""} (135) and several smaller studies ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FqMDmPJv","properties":{"formattedCitation":"(137)","plainCitation":"(137)"},"citationItems":[{"id":1398,"uris":[""],"uri":[""],"itemData":{"id":1398,"type":"article-journal","title":"Intravenous iron alone for the treatment of anemia in patients with chronic heart failure","container-title":"Journal of the American College of Cardiology","page":"1225-1227","volume":"48","issue":"6","source":"NCBI PubMed","abstract":"OBJECTIVES: This study was undertaken to assess the hematologic, clinical, and biochemical response to intravenous iron in patients with chronic heart failure (CHF) and anemia.\nBACKGROUND: Anemia is common in patients with CHF and is associated with higher morbidity and mortality. The combination of erythropoietin (EPO) and iron increases hemoglobin (Hb) and improves symptoms and exercise capacity in anemic CHF patients. It is not known whether intravenous iron alone is an effective treatment for anemia associated with CHF.\nMETHODS: Sixteen anemic patients (Hb < or =12 g/dl) with stable CHF (age 68.3 +/- 11.5 years, 12 men, 9 participants New York Heart Association [NYHA] functional class II and the remainder class III, left ventricular ejection fraction 26 +/- 13%) received a maximum of 1 g of iron sucrose by bolus intravenous injections over a 12-day treatment phase in an outpatient setting. Mean follow-up was 92 +/- 6 days.\nRESULTS: Hemoglobin rose from 11.2 +/- 0.7 to 12.6 +/- 1.2 g/dl (p = 0.0007), Minnesota Living with Heart Failure (MLHF) score fell (denoting improvement) from 33 +/- 19 to 19 +/- 14 (p = 0.02), 6-min walk distance increased from 242 +/- 78 m to 286 +/- 72 m (p = 0.01), and all patients recorded NYHA class II at study end (p < 0.02). Changes in MLHF score and 6-min walk distance related closely to changes in Hb (r = 0.76, p = 0.002; r = 0.56, p = 0.03, respectively). Of all baseline measurements, only iron and transferrin saturation correlated with increases in Hb (r = 0.60, p = 0.02; r = 0.60, p = 0.01, respectively). There were no adverse events relating to drug administration or during follow-up.\nCONCLUSIONS: Intravenous iron sucrose, when used without concomitant EPO, is a simple and safe therapy that increases Hb, reduces symptoms, and improves exercise capacity in anemic patients with CHF. Further assessment of its efficacy should be made in a multicenter, randomized, placebo-controlled trial.","DOI":"10.1016/j.jacc.2006.07.015","ISSN":"1558-3597","note":"PMID: 16979010","journalAbbreviation":"J. Am. Coll. Cardiol.","language":"eng","author":[{"family":"Bolger","given":"Aidan P"},{"family":"Bartlett","given":"Frederick R"},{"family":"Penston","given":"Helen S"},{"family":"O'Leary","given":"Justin"},{"family":"Pollock","given":"Noel"},{"family":"Kaprielian","given":"Raffi"},{"family":"Chapman","given":"Callum M"}],"issued":{"date-parts":[["2006",9,19]]},"PMID":"16979010"}}],"schema":""} (137) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Pv9ecXXe","properties":{"formattedCitation":"(138)","plainCitation":"(138)"},"citationItems":[{"id":1400,"uris":[""],"uri":[""],"itemData":{"id":1400,"type":"article-journal","title":"Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial","container-title":"Journal of the American College of Cardiology","page":"103-112","volume":"51","issue":"2","source":"NCBI PubMed","abstract":"OBJECTIVES: We tested the hypothesis that intravenous iron improves exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure (CHF) and iron deficiency.\nBACKGROUND: Anemia is common in heart failure. Iron metabolism is disturbed, and administration of iron might improve both symptoms and exercise tolerance.\nMETHODS: We randomized 35 patients with CHF (age 64 +/- 13 years, peak oxygen consumption [pVO2] 14.0 +/- 2.7 ml/kg/min) to 16 weeks of intravenous iron (200 mg weekly until ferritin >500 ng/ml, 200 mg monthly thereafter) or no treatment in a 2:1 ratio. Ferritin was required to be <100 ng/ml or ferritin 100 to 300 ng/ml with transferrin saturation <20%. Patients were stratified according to hemoglobin levels (<12.5 g/dl [anemic group] vs. 12.5 to 14.5 g/dl [nonanemic group]). The observer-blinded primary end point was the change in absolute pVO2.\nRESULTS: The difference (95% confidence interval [CI]) in the mean changes from baseline to end of study between the iron and control groups was 273 (151 to 396) ng/ml for ferritin (p < 0.0001), 0.1 (-0.8 to 0.9) g/dl for hemoglobin (p = 0.9), 96 (-12 to 205) ml/min for absolute pVO2 (p = 0.08), 2.2 (0.5 to 4.0) ml/kg/min for pVO2/kg (p = 0.01), 60 (-6 to 126) s for treadmill exercise duration (p = 0.08), -0.6 (-0.9 to -0.2) for New York Heart Association (NYHA) functional class (p = 0.007), and 1.7 (0.7 to 2.6) for patient global assessment (p = 0.002). In anemic patients (n = 18), the difference (95% CI) was 204 (31 to 378) ml/min for absolute pVO2 (p = 0.02), and 3.9 (1.1 to 6.8) ml/kg/min for pVO2/kg (p = 0.01). In nonanemic patients, NYHA functional class improved (p = 0.06). Adverse events were similar.\nCONCLUSIONS: Intravenous iron loading improved exercise capacity and symptoms in patients with CHF and evidence of abnormal iron metabolism. Benefits were more evident in anemic patients. (Effect of Intravenous Ferrous Sucrose on Exercise Capacity in Chronic Heart Failure; ; NCT00125996).","DOI":"10.1016/j.jacc.2007.09.036","ISSN":"1558-3597","note":"PMID: 18191732","shortTitle":"Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF","journalAbbreviation":"J. Am. Coll. Cardiol.","language":"eng","author":[{"family":"Okonko","given":"Darlington O"},{"family":"Grzeslo","given":"Agnieszka"},{"family":"Witkowski","given":"Tomasz"},{"family":"Mandal","given":"Amit K J"},{"family":"Slater","given":"Robert M"},{"family":"Roughton","given":"Michael"},{"family":"Foldes","given":"Gabor"},{"family":"Thum","given":"Thomas"},{"family":"Majda","given":"Jacek"},{"family":"Banasiak","given":"Waldemar"},{"family":"Missouris","given":"Constantinos G"},{"family":"Poole-Wilson","given":"Philip A"},{"family":"Anker","given":"Stefan D"},{"family":"Ponikowski","given":"Piotr"}],"issued":{"date-parts":[["2008",1,15]]},"PMID":"18191732"}}],"schema":""} (138) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"w8sEHhpx","properties":{"formattedCitation":"(139)","plainCitation":"(139)"},"citationItems":[{"id":1402,"uris":[""],"uri":[""],"itemData":{"id":1402,"type":"article-journal","title":"Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency","container-title":"Journal of the American College of Cardiology","page":"1657-1665","volume":"50","issue":"17","source":"NCBI PubMed","abstract":"OBJECTIVES: Our objective was to evaluate in a double-blind, randomized, placebo-controlled study possible modifications in NT-pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) levels together with clinical and functional parameters, in a group of anemic patients with chronic heart failure (CHF) and chronic renal failure (CRF) receiving intravenous iron therapy, without recombinant human erythropoietin (rhEPO), versus placebo.\nBACKGROUND: Chronic heart failure and CRF associated with absolute or relative iron deficiency anemia is a common problem. This situation is linked with a variable inflammatory status. Both NT-proBNP and CRP are recognized markers for left ventricular dysfunction and inflammatory status, respectively. In this double-blind, randomized, placebo-controlled study, modifications in NT-proBNP and CRP level and clinical and functional parameters, in anemic patients with CHF and CRF receiving intravenous iron therapy, without rhEPO, versus placebo were evaluated.\nMETHODS: Forty patients with hemoglobin (Hb) <12.5 g/dl, transferrin saturation <20%, ferritin <100 ng/ml, creatinine clearance (CrCl) <90 ml/min, and left ventricular ejection fraction (LVEF) < or =35% were randomized into 2 groups (n = 20 for each). For 5 weeks, group A received isotonic saline solution and group B received iron sucrose complex, 200 mg weekly. Minnesota Living with Heart Failure Questionnaire (MLHFQ) and 6-min walk (6MW) test were performed. NT-pro brain natriuretic peptide and CRP were evaluated throughout the study. No patients received erythroprotein any time.\nRESULTS: After 6 months follow-up, group B showed better hematology values and CrCl (p < 0.01) and lower NT-proBNP (117.5 +/- 87.4 pg/ml vs. 450.9 +/- 248.8 pg/ml, p < 0.01) and CRP (2.3 +/- 0.8 mg/l vs. 6.5 +/- 3.7 mg/l, p < 0.01). There was a correlation initially (p < 0.01) between Hb and NT-proBNP (group A: r = -0.94 and group B: r = -0.81) and after 6 months only in group A: r = -0.80. Similar correlations were observed with Hb and CRP. Left ventricular ejection fraction percentage (35.7 +/- 4.7 vs. 28.8 +/- 2.4), MLHFQ score, and 6MW test were all improved in group B (p < 0.01). Additionally, group B had fewer hospitalizations: 0 of 20 versus group A, 5 of 20 (p < 0.01; relative risk = 2.33).\nCONCLUSIONS: Intravenous iron therapy without rhEPO substantially reduced NT-proBNP and inflammatory status in anemic patients with CHF and moderate CRF. This situation was associated with an improvement in LVEF, NYHA functional class, exercise capacity, renal function, and better quality of life.","DOI":"10.1016/j.jacc.2007.07.029","ISSN":"1558-3597","note":"PMID: 17950147","journalAbbreviation":"J. Am. Coll. Cardiol.","language":"eng","author":[{"family":"Toblli","given":"Jorge Eduardo"},{"family":"Lombra?a","given":"Alejandra"},{"family":"Duarte","given":"Patricio"},{"family":"Di Gennaro","given":"Federico"}],"issued":{"date-parts":[["2007",10,23]]},"PMID":"17950147"}}],"schema":""} (139) in heart failure have shown symptom and exercise improvement when iron replacement is given to patients with ferritin levels at the lower end of the normal range and we speculate that such a study may be merited in COPD.Conclusions Anemia is a frequent clinical manifestation in COPD, although its exact prevalence remains to be determined. Instead of attempting to make general estimations regarding its frequency, it may be more useful to refer to its prevalence according to the specific characteristics of each COPD population (such as inpatients or outpatients, patients with stable disease or with AECOPD, subjects with mild disorder or severe comorbidities), since these characteristics produce, among other factors, a huge variation in anemia prevalence, making the results of published studies difficult to compare.The cause of anemia in COPD is multifactorial and lately, there has been a growing amount of research regarding the role of systemic inflammation both in stable disease and during acute exacerbations. Although important, inflammation is not the sole factor inhibiting erythropoiesis among COPD patients, and this is probably why results regarding EPO production during AECOPD, where systemic inflammation is magnified, have been conflicting. Large prospective studies aiming to investigate the potential mechanisms of anemia induction in COPD patients are currently lacking and much of the current knowledge come from studies on other patient groups or disease models. Although the role of renal impairment and nutritional deficit seem to be rather straightforward, the impact of hypoxia and hypercarbia (which may be exaggerated during exacerbations or exercise) and their reversal on erythropoiesis, the activity of RAAS and its inhibition, hormonal abnormalities and aging all seem to contribute to a different extent to the establishment of anemia; However, their exact role among COPD patients still remains to be determined (Figure 1). Current data indicate that genetic polymorphisms of several of these factors, such as the TNF, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1yPoSOSl","properties":{"formattedCitation":"(140)","plainCitation":"(140)"},"citationItems":[{"id":1155,"uris":[""],"uri":[""],"itemData":{"id":1155,"type":"article-journal","title":"Tumour necrosis factor gene polymorphism and disease prevalence","container-title":"Scandinavian journal of immunology","page":"522-547","volume":"74","issue":"6","source":"NCBI PubMed","abstract":"Tumour necrosis factor (TNF), an important proinflammatory cytokine, plays a role in the regulation of cell differentiation, proliferation and death, as well as in inflammation, innate and adaptive immune responses, and also implicated in a wide variety of human diseases. The presence of DNA sequence variations in regulatory region might interfere with transcription of TNF gene, influencing the circulating level of TNF and thus increases the susceptibility to human diseases (infectious, cancer, autoimmune, neurodegenerative and other diseases). In this review, we have comprehensively analysed various published case-control studies of different types of human diseases, in which TNF gene polymorphism played a role, and computationally predicted several single nucleotide polymorphisms (SNPs) lie in transcription factor-binding sites (TFBS) of transcription factors (TFs). It has been observed that TNF enhancer polymorphism is implicated in several diseases, and TNF rs1800629 and rs361525 SNPs are the most important in human disease susceptibility as these might influence the transcription of TNF gene. Thirty-two SNPs lies in TFBS of 20 TFs have been detected in the TNF upstream region. It has been found that TNF enhancer polymorphism influences the serum level of TNF in different human diseases and thus affects the susceptibility to diseases. The presence of DNA sequence variation in TNF gene causes the modification of transcriptional regulation and thus responsible for association of susceptibility/resistance with human diseases.","DOI":"10.1111/j.1365-3083.2011.02602.x","ISSN":"1365-3083","note":"PMID: 21790707","journalAbbreviation":"Scand. J. Immunol.","language":"eng","author":[{"family":"Qidwai","given":"T"},{"family":"Khan","given":"F"}],"issued":{"date-parts":[["2011",12]]},"PMID":"21790707"}}],"schema":""} (140) RAS pathway, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7lM4iDyd","properties":{"formattedCitation":"(141)","plainCitation":"(141)"},"citationItems":[{"id":1153,"uris":[""],"uri":[""],"itemData":{"id":1153,"type":"article-journal","title":"Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease","container-title":"Pediatric nephrology (Berlin, Germany)","page":"1037-1051","volume":"23","issue":"7","source":"NCBI PubMed","abstract":"Chronic kidney disease (CKD) in children is irreversible. It is associated with renal failure progression and atherosclerotic cardiovascular (CV) abnormalities. Nearly 60% of children with CKD are affected since birth with congenital or inherited kidney disorders. Preliminary evidence primarily from adult CKD studies indicates common genetic risk factors for CKD and atherosclerotic CV disease. Although multiple physiologic pathways share common genes for CKD and CV disease, substantial evidence supports our attention to the renin angiotensin system (RAS) and the interlinked inflammatory cascade because they modulate the progressions of renal and CV disease. Gene polymorphisms in the RAS-cytokine pathway, through altered gene expression of inflammatory cytokines, are potential factors that modulate the rate of CKD progression and CV abnormalities in patients with CKD. For studying such hypotheses, the cooperative efforts among scientific groups and the availability of robust and affordable technologies to genotype thousands of single nucleotide polymorphisms (SNPs) across the genome make genome-wide association studies an attractive paradigm for studying polygenic diseases such as CKD. Although attractive, such studies should be interpreted carefully, with a fundamental understanding of their potential weaknesses. Nevertheless, whole-genome association studies for diabetic nephropathy and future studies pertaining to other types of CKD will offer further insight for the development of targeted interventions to treat CKD and associated atherosclerotic CV abnormalities in the pediatric CKD population.","DOI":"10.1007/s00467-008-0816-z","ISSN":"0931-041X","note":"PMID: 18481112 \nPMCID: PMC2413095","journalAbbreviation":"Pediatr. Nephrol.","language":"eng","author":[{"family":"Wong","given":"Craig"},{"family":"Kanetsky","given":"Peter"},{"family":"Raj","given":"Dominic"}],"issued":{"date-parts":[["2008",7]]},"PMID":"18481112","PMCID":"PMC2413095"}}],"schema":""} (141) and IGF-1, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"LJHxN9kj","properties":{"formattedCitation":"(142)","plainCitation":"(142)"},"citationItems":[{"id":1159,"uris":[""],"uri":[""],"itemData":{"id":1159,"type":"article-journal","title":"Insulin-like growth factor-1 gene polymorphism in rheumatoid arthritis patients","container-title":"Scandinavian journal of rheumatology","page":"421-425","volume":"41","issue":"6","source":"NCBI PubMed","abstract":"OBJECTIVES: Insulin-like growth factor-1 (IGF-1) regulates several biological functions, and low plasma levels of IGF-1 are known to contribute towards the pathogenesis of rheumatoid arthritis (RA). In view of the biological significance of IGF-1, we investigated the association of RA with the polymorphism of a 192-bp allele which is cytosine-adenosine repeat located 1 kb upstream from the IGF-1 gene transcription site and is known to regulate serum IGF-1 levels.\nMETHODS: Blood samples were collected from 52 healthy controls (HC) and 68 RA patients to measure the levels of IGF-1 and to isolate genomic DNA. Polymorphism of the IGF-1 gene was examined using polymerase chain reaction (PCR). Disease severity, duration, and activity were recorded for all RA patients.\nRESULTS: We observed that 97% of all the subjects who participated in this study showed the presence of a 192-bp allele of the IGF-1 gene. All healthy controls exhibited the presence of 192-bp wild-type allele. All non-carriers of the 192-bp allele were Arabs and had RA. Gender correlated significantly with allele frequencies as 14% of the male and only 2% of the female RA patients were non-carriers of 192-bp allele. Plasma IGF-1 levels were significantly lower (p < 0.01) in RA patients compared to HC, and all RA patients who were non-carriers of the 192-bp allele had a significantly high disease activity score. No correlation was found between the duration of RA and the presence or absence of this allele.\nCONCLUSIONS: This study suggests a possible association of the IGF-1 gene polymorphism with developing RA, particularly in males as non-carriers of the 192-bp allele.","DOI":"10.3109/03009742.2012.691177","ISSN":"1502-7732","note":"PMID: 22839688","journalAbbreviation":"Scand. J. Rheumatol.","language":"eng","author":[{"family":"Dhaunsi","given":"G S"},{"family":"Uppal","given":"S S"},{"family":"Haider","given":"M Z"}],"issued":{"date-parts":[["2012"]]},"PMID":"22839688"}}],"schema":""} (142) are associated with the establishment and progression of various disorders. Moreover, in patients with end-stage renal disease and anemia, several genetic polymorphisms have been associated with the interindividual variability in the severity of established anemia and the need of exogenous EPO. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QF0TBQQh","properties":{"formattedCitation":"(143)","plainCitation":"(143)"},"citationItems":[{"id":1161,"uris":[""],"uri":[""],"itemData":{"id":1161,"type":"article-journal","title":"Gene polymorphism association studies in dialysis: anemia and host immunity","container-title":"Seminars in dialysis","page":"227-231","volume":"19","issue":"3","source":"NCBI PubMed","abstract":"The typical complications of end-stage renal disease (ESRD) vary in frequency and severity. Whereas anemia of chronic kidney disease might require high doses of exogenous erythropoietin (EPO) in some individuals, others hardly ever need hormone replacement. The same observation can be made for immune defense functions in patients with ESRD. Our understanding of the functional consequences of genetic polymorphisms in a wide array of genes has recently gained momentum. In patients with ESRD, interindividual differences in anemia parameters have been linked in part to genetic polymorphisms. Indeed, although inflammation is an important predictor of the need for EPO, to date a link to cytokine gene polymorphisms has not been established. However, the need for EPO has been linked to polymorphisms in the angiotensin-converting enzyme (ACE) and vitamin D receptor genes. In contrast, in dialysis patients, interindividual variability in host immune responses, including nonspecific (bacterial) and antigen-specific (viral) immune mechanisms has been linked to variations in the interleukin-10 and myeloperoxidase genes as well as variability in human leukocyte antigens (HLAs). In conclusion, the role of genetic polymorphisms in predicting the development and severity of anemia in chronic kidney disease as well as host immune competence is in its infancy and warrants further inquiry.","DOI":"10.1111/j.1525-139X.2006.00159.x","ISSN":"0894-0959","note":"PMID: 16689974","shortTitle":"Gene polymorphism association studies in dialysis","journalAbbreviation":"Semin Dial","language":"eng","author":[{"family":"Girndt","given":"Matthias"},{"family":"Heine","given":"Gunnar H"},{"family":"K?hler","given":"Hans"},{"family":"DialGene Consortium","given":""}],"issued":{"date-parts":[["2006",6]]},"PMID":"16689974"}}],"schema":""} (143) These data indicate that the balance between factors which inhibit and stimulate erythropoiesis in COPD patients may be influenced by genetic factors. Research should go one step beyond, since identifying distinct genetic phenotypes might give an answer to the question why some patients develop anemia and others do not.Table 1. Studies which were included in the review process and their characteristicsFirst authorYear of publicationCountryStudy designCOPD population characteristicsSize of COPD populationCOPD diagnosisAnemia diagnosisAnemia prevalenceAlmagro (14)2012SpainLongitudinal, multicenterHospitalized for AECOPD606Postbronchodilator FEV1<80% predicted and FEV1/FVC<0.70Based on a questionnaire19.3%Barbra (13)2012SpainRetrospective, multicenter(Basic Minimum Data Set records)Hospitalized for AECOPD289,077ICD-9-CM codesICD-9-CM codes9.8%Boutou (8)2011GreeceProspective case-controlStable hospital outpatients283Postbronchodilator FEV1/FVC<0.70Males: Hb<13 g/dlFemales: Hb<12 g/dlPlus clinical and laboratory criteria for ACD10.2%Boutou (7)2013UKRetrospective (institution’s clinical COPD database)Stable hospital outpatients294Postbronchodilator FEV1/FVC<0.70Hb: <13 g/dl for both male and female15.6%Chambellan (3)2005FranceRetrospective, multicenter(ANDATIR database)Hypoxemic patients under LTOT2,524FEV1<80% and FEV1/FVC<70%Male: Ht<39%; Female: Ht<36%Male:12.6%Female:8.2%Comeche Casanova (26)2013SpainProspectiveStable hospital outpatients130GOLD criteriaMale: Hb<13g/dlFemale Hb<12 g/dl6.2%Copur (2)2013USARetrospectivePatients referred for LTOT evaluation317Postbronchodilator FEV1/FVC<0.70 plus ≥20 pack/year smoking historyHb<13 g/dl for both male and female38%Cote (4)2007USAHb was retrospectively and all other variables were prospectively collectedStable hospital outpatients683Post bronchodilator FEV1/FVC<0.70 plus >20 pack/years Hb<13 g/dl for both male and female17%Dal Negro (19)2012ItalyLongitudinal, observationalOutpatients under LTOT132Criteria according to dedicated institutional database (ISO 9001-2000 certified)Hb<13 g/dl for both male and female11.3%Freemault (15)2011Belgium1st cohort retrospectively (1980-1984)2nd cohort prospectively (2001-2005) studiedHospitalized for AECOPD1st: 512nd: 1011st: ICD-92nd: FEV1/FVC<0.70 plus ≥10 pack/year smoking history Male: Hb<13g/dlFemale Hb<12 g/dl1st: 9.8%2nd: 27.7%Halpern (22)2006USARetrospective (1999-2001 US Medicare Claims database)Both inpatients and outpatients >65 years old132,424ICD-9 codesICD-9 codes21%John (9)2006GermanyRetrospectiveDischarged from hospital312ICD-9/10 codesSeverity according to GOLDMale: Hb<13.5 g/dlFemale: Hb<12 g/dl23.1%John (23)2005GermanyProspectiveStable outpatients101According to ATS guidelinesMale: Hb<13.5 g/dlFemale: Hb<12 g/dl13%Joo (10)2012KoreaRetrospective-data derived from a population survey (Korean Health and Nutrition Examination Survey)Patients with COPD in the general population238FEV1/FVC <0.7 among subjects >40 years oldMale: Hb<13 g/dlFemale Hb<12 g/dl (non-pregnant)Female: Hb<11 g/dl (pregnant)7.3%Kollert (5)2013GermanyRetrospective (database ofthe Donaustauf Hospital Center for Pneumology)Patients with CRF prior initiating NIV309Clinical history and EV1/FVC<70%Plus GOLD criteria for stages III/IVMale: Hb<13 g/dlFemale: Hb<12 g/dl14.9%Krishnan (11)2006USARetrospective (post-hoc analysis form data derived from a population study)Patients with COPD in the general population495According to ATS guidelines in subjects 35-79 years old.Severity according to GOLDMale: Hb<13 g/dlFemale: Hb<12 g/dl7.5%Martinez-Rivera (28)2012SpainProspectiveHospitalized for AECOPD117Airflow obstruction according to GOLD plus clinical evaluation and ≥10 pack/year smoking historyHb<13 g/dl for both male and female33%Nowinski (1)2011PolandLongitudinal prospectiveHospitalized for AECOPD464Diagnostic criteria not described. Severity categorized by GOLDMale: Hb<13.5 g/dlFemale: Hb:<12 g/dl4.9%Nowinski (16)2013PolandRetrospectiveHospitalized for AECOPD402According to Polish Society for Lung Diseases criteriaMale: Hb<13 g/dlFemale: Hb<12 g/dl26%Rasmunssen (18)2011DenmarkRetrospectiveIntubated for AECOPD222According to GOLD for those with spirometry.Based on physical examination and history for the restHb<12 g/dl for both male and female18%Rutten (21)2013NetherlandsRetrospectivePatients with moderate to severe COPD, screened for PR321According to ERS/ATS guidelinesMale: Hb<13 g/dlFemale: Hb<12 g/dl20%Shorr (24)2008USARetrospective ( healthcare maintenance organization database)Both inpatients and outpatients2,404ICD-9Male: Hb<13 g/dlFemale: Hb<12 g/dl33%Watz (6)2008GermanyCross-sectionalStable outpatients (recruited form institution’s database)170Established by spirometry (no further details given).Severity by GOLD and BODE indexHb<13 g/dl5.3%Zavarreh (12)2013IranCross-sectionalStable outpatients74Established by spirometry (no further details given).Severity by GOLD Male: Hb<13 g/dlFemale: Hb<12 g/dl27%AECOPD: Acute COPD exacerbation; FEV1: Forced Expiratory Volume in 1 second; FVC: Forced Vital Capacity; Hb: Hemoglobin; ICD: International Code of Diseases; GOLD: Global Initiative for Obstructive Lung Disease; Ht: hematocrit; ATS: American Thoracic Society; ERS: European Respiratory Society; LTOT: Long-Term Oxygen Treatment; CRF: Chronic Respiratory Failure; NIV: Non-Invasive Ventilation; PR: Pulmonary RehabilitationFigure 1. The complex pathophysiology of anemia in COPD.References ADDIN ZOTERO_BIBL {"custom":[]} CSL_BIBLIOGRAPHY 1. Nowiński A, Kamiński D, Korzybski D, Stok?osa A and Górecka D.(2011) [The impact of comorbidities on the length of hospital treatment in patients with chronic obstructive pulmonary disease]. Pneumonol Alergol Pol, 79(6):388–96. 2. Copur AS, Fulambarker A, Molnar J, Nadeem R, McCormack C, Ganesh A, Kheir F and Hamon S.(2013) Role of Anemia in Home Oxygen Therapy in Chronic Obstructive Pulmonary Disease Patients. Am J Ther (Epub ahead of print) 3. Chambellan A, Chailleux E, Similowski T and ANTADIR Observatory Group. (2005) Prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy. Chest, 128(3):1201–8. 4. Cote C, Zilberberg MD, Mody SH, Dordelly LJ and Celli B. (2007) Haemoglobin level and its clinical impact in a cohort of patients with COPD. Eur Respir J, 29(5):923–9. 5. Kollert F, Tippelt A, Müller C, J?rres RA, Porzelius C, Pfeifer M and Budweiser S. (2013) Hemoglobin levels above anemia thresholds are maximally predictive for long-term survival in COPD with chronic respiratory failure. Respir Care, 58(7):1204–12. 6. Watz H, Waschki B, Boehme C, Claussen M, Meyer T and Magnussen H. (2008) Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: a cross-sectional study. Am J Respir Crit Care Med, 177(7):743–51. 7. Boutou AK, Karrar S, Hopkinson NS and Polkey MI. (2013) Anemia and survival in chronic obstructive pulmonary disease: a dichotomous rather than a continuous predictor. Respiration, 85(2):126–31. 8. Boutou AK, Stanopoulos I, Pitsiou GG, Kontakiotis T, Kyriazis G, Sichletidis L and Argyropoulou P. (2011) Anemia of chronic disease in chronic obstructive pulmonary disease: a case-control study of cardiopulmonary exercise responses. Respiration, 82(3):237–45. 9. John M, Hoernig S, Doehner W, Okonko DD, Witt C and Anker SD. (2005) Anemia and inflammation in COPD. Chest, 127(3):825–9. 10. Joo H, Park J, Lee SD and Oh Y-M. (2012) Comorbidities of chronic obstructive pulmonary disease in Koreans: a population-based study. J Korean Med Sci., 27(8):901–6. 11. Krishnan G, Grant BJ, Muti PC, Mishra A, Ochs-Balcom HM, Freudenheim JL, Trevisan M and Schünemann HJ. (2006) Association between anemia and quality of life in a population sample of individuals with chronic obstructive pulmonary disease. BMC Pulm Med, 6:23. 12. Zavarreh RH, Zahmatkesh M-M, Vakili M, Shahriari-Ahmadi A, Zohal MA, Arabi M, Mahmoudian A, Gheisuri A, Kian A and Fahimi Al. (2013) Association between anemia and COPD in Iranian population. Int J Hematol Oncol Stem Cell Res., 7(2):6–10. 13. Barba R, de Casasola GG, Marco J, Emilio Losa J, Plaza S, Canora J and Zapatero A. (2012) Anemia in chronic obstructive pulmonary disease: a readmission prognosis factor. Curr Med Res Opin, 28(4):617–22. 14. Almagro P, Cabrera FJ, Diez J, Boixeda R, Alonso Ortiz MB, Murio C, Soriano JB; Working Group on COPD, Spanish Society of Internal Medicine. (2012) Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de medicina interna (ESMI) study. Chest, 142(5):1126–33. 15. Fremault A, Janssens W, Beaucage F, Celis G, Pérez-Bogerd S and Decramer M. (2010) Modification of COPD presentation during the last 25 years. COPD, 7(5):345–51. 16. Nowiński A, Kamiński D, Kram M, Korzybski D, Stok?osa A and Górecka D.(2013) Impact of mild anaemia on dyspnoea during exertion and exercise tolerance in patients with acute exacerbation of chronic obstructive pulmonary disease. Pneumonol Alergol Pol, 81(3):200–6. 17. Ornek T, Tor M, Alt?n R, Atalay F, Geredeli E, Soylu O and Erboy F. (2012) Clinical factors affecting the direct cost of patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease. Int J Med Sci, 9(4):285–90. 18. Rasmussen L, Christensen S, Lenler-Petersen P, Johnsen SP.(2011) Anemia and 90-day mortality in COPD patients requiring invasive mechanical ventilation. Clin Epidemiol, 3:1–5. 19. Dal Negro RW, Tognella S, Bonadiman L, Turco P. (2012) Changes in blood hemoglobin and blood gases PaO2 and PaCO2 in severe COPD overa three-year telemonitored program of long-term oxygen treatment. Multidiscip Respir Med, 7(1):15. 20. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD and Rodriguez-Roisin R. (2013) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med, 15;187(4):347–65. 21. Rutten EPA, Franssen FME, Spruit MA, Wouters EFM. (2013) Anemia is associated with bone mineral density in chronic obstructive pulmonary disease. COPD, 10(3):286–92. 22. Halpern MT, Zilberberg MD, Schmier JK, Lau E and Shorr AF. (2006) Anemia, costs and mortality in chronic obstructive pulmonary disease. Cost Eff Resour Alloc, 4:17. 23. John M, Lange A, Hoernig S, Witt C and Anker SD. (2006) Prevalence of anemia in chronic obstructive pulmonary disease: comparison to other chronic diseases. Int J Cardiol, 28;111(3):365–70. 24. Shorr AF, Doyle J, Stern L, Dolgitser M and Zilberberg MD. (2008) Anemia in chronic obstructive pulmonary disease: epidemiology and economic implications. Curr Med Res Opin,24(4):1123–30. 25. Report of a WHO scientific group. (1968) Nutritional anaemias. World Health Organ Tech Rep Ser, 405:5–37. 26. Comeche Casanova L, Echave-Sustaeta JM, García Luján R, Albarrán Lozano I, Alonso González P and Llorente Alonso MJ. (2013) Prevalence of Anaemia Associated With Chronic Obstructive Pulmonary Disease. Study of Associated Variables. Arch Bronconeumol, 49(9):383-7 27. Guralnik JM, Ershler WB, Schrier SL and Picozzi VJ. (2005) Anemia in the elderly: a public health crisis in hematology. Hematol Am Soc Hematol Educ Program, 528–32. 28. Martinez-Rivera C, Portillo K, Mu?oz-Ferrer A, Martínez-Ortiz ML, Molins E, Serra P, Ruiz-Manzano J and Morera J. (2012) Anemia is a mortality predictor in hospitalized patients for COPD exacerbation. COPD, 9(3):243–50. 29. Wong P and Intragumtornchai T. Hospital-acquired anemia.(2006) J Med Assoc Thail, 89(1):63–7. 30. Sinden NJ and Stockley RA. (2010) Systemic inflammation and comorbidity in COPD: a result of “overspill” of inflammatory mediators from the lungs? Review of the evidence. Thorax, 65(10):930–6. 31. Weiss G and Goodnough LT. (2005) Anemia of chronic disease. N Engl J Med, 10;352(10):1011–23. 32. Weiss G. (2002) Pathogenesis and treatment of anaemia of chronic disease. Blood Rev, 16(2):87–96. 33. Cartwright GE. (1966) The anemia of chronic disorders. Semin Hematol, 3(4):351–75. 34. Matzner Y, Levy S, Grossowicz N, Izak G and Hershko C. (1979) Prevalence and causes of anemia in elderly hospitalized patients. Gerontology, 25(2):113–9. 35. Means RT Jr. (2003) Recent developments in the anemia of chronic disease. Curr Hematol Rep., 2(2):116–21. 36. Means RJ and Krantz SB. (1992) Progress in understanding the pathogenesis of the anemia of chronic disease. Blood, 1;80(7):1639–47. 37. Ganz T. (2007) Molecular control of iron transport. J Am Soc Nephrol, 18(2):394–400. 38. McKie AT, Barrow D, Latunde-Dada GO, Rolfs A, Sager G, Mudaly E, Mudaly M, Richardson C, Barlow D, Bomford A, Peters TJ, Raja KB, Shirali S, Hediger MA, Farzaneh F and Simpson RJ. (2001) An iron-regulated ferric reductase associated with the absorption of dietary iron. Science, 2;291(5509):1755–9. 39. Nadadur SS, Srirama K and Mudipalli A. (2008) Iron transport & homeostasis mechanisms: their role in health & disease. Indian J Med Res, 128(4):533–44. 40. Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC and Zon LI. (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature, 17;403(6771):776–81. 41. Andrews NC. (2000) Iron homeostasis: insights from genetics and animal models. Nat Rev Genet, 1(3):208–17. 42. Park CH, Valore EV, Waring AJ and Ganz T. (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem, 16;276(11):7806–10. 43. Ganz T. (2006) Hepcidin and its role in regulating systemic iron metabolism. Hematology Am Soc Hematol Educ Program, 29–35, 507. 44. Ludwiczek S, Aigner E, Theurl I and Weiss G. (2003) Cytokine-mediated regulation of iron transport in human monocytic cells. Blood, 15;101(10):4148–54. 45. Cazzola M, Ponchio L, Benedetti F de, Ravelli A, Rosti V, Beguin Y, Invernizzi R, Barosi G and Martini A. (1996) Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis. Blood, 1;87(11):4824–30. 46. Tilg H, Ulmer H, Kaser A and Weiss G. (2002) Role of IL-10 for induction of anemia during inflammation. J Immunol, 15;169(4):2204–9. 47. Casadevall N. (1995) Cellular mechanism of resistance to erythropoietin. Nephrol Dial Transplant, 10 Suppl 6:27–30. 48. Allen DA, Breen C, Yaqoob MM and Macdougall IC. (1999) Inhibition of CFU-E colony formation in uremic patients with inflammatory disease: role of IFN-gamma and TNF-alpha. J Investig Med, 47(5):204–11. 49. Fuchs D, Hausen A, Reibnegger G, Werner ER, Werner-Felmayer G, Dierich MP and Wachter H. (1991) Immune activation and the anaemia associated with chronic inflammatory disorders. Eur J Haematol, 46(2):65–70. 50. Maciejewski JP, Selleri C, Sato T, Cho HJ, Keefer LK, Nathan CF and Young NS. (1995) Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha. J Clin Invest, 96(2):1085–92. 51. Van der Putten K, Braam B, Jie KE and Gaillard CAJM. (2008) Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure. Nat Clin Pract Nephrol, 4(1):47–57. 52. Miller CB, Jones RJ, Piantadosi S, Abeloff MD and Spivak JL. (1990) Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med, 322(24):1689–92. 53. Ferrucci L, Guralnik JM, Woodman RC, Bandinelli S, Lauretani F, Corsi AM, Chaves PH, Ershler WB and Longo DL. (2005). Proinflammatory state and circulating erythropoietin in persons with and without anemia. Am J Med, 118(11):1288. 54. Faquin WC, Schneider TJ and Goldberg MA. (1992) Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood, 79(8):1987–94. 55. Cooper AC, Mikhail A, Lethbridge MW, Kemeny DM and Macdougall IC. (2003) Increased expression of erythropoiesis inhibiting cytokines (IFN-γ, TNF-α, IL-10, and IL-13) by T Cells in patients exhibiting a poor response to erythropoietin therapy. J Am Soc Nephrol, 14(7):1776–84. 56. Dalle B, Payen E and Beuzard Y. (2000) Modulation of transduced erythropoietin expression by iron. Exp Hematol, 28(7):760–4. 57. Karadag F, Kirdar S, Karul AB and Ceylan E. (2008) The value of C-reactive protein as a marker of systemic inflammation in stable chronic obstructive pulmonary disease. Eur J Intern Med, 19(2):104–8. 58. Garcia-Rio F, Miravitlles M, Soriano JB, Munoz L, Duran-Tauleria E, Sanchez G, Sobradillo V, Ancochea J; EPI-SCAN Steering Committee.. (2010) Systemic inflammation in chronic obstructive pulmonary disease: a population-based study. Respir Res, 11(1):63. 59. Valipour A, Schreder M, Wolzt M, Saliba S, Kapiotis S, Eickhoff P and Burghuber OC.(2008) Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obstructive pulmonary disease. Clin Sci (Lond), 115(7):225–32. 60. Karadag F, Karul AB, Cildag O, Yilmaz M and Ozcan H. (2008) Biomarkers of systemic inflammation in stable and exacerbation phases of COPD. Lung, 186(6):403–9. 61. Von Haehling S1, Hopkinson NS, Polkey MI, Niethammer M, Anker SD and Genth-Zotz S. (2009) Elevated TNFalpha production in whole blood in patients with severe COPD: the potential link to disease severity. Wien Klin Wochenschr, 121(9-10):303-8.62. Gaki E, Kontogianni K, Papaioannou AI, Bakakos P, Gourgoulianis KI, Kostikas K, Alchanatis M, Papiris S and Loukides S. (2011) Associations between BODE index and systemic inflammatory biomarkers in COPD. COPD, 8(6):408–13. 63. Hacievliyagil SS, Gunen H, Mutlu LC, Karabulut AB and Temel I. (2006) Association between cytokines in induced sputum and severity of chronic obstructive pulmonary disease. Respir Med, 100(5):846–54. 64. Ubhi BK, Riley JH, Shaw PA, Lomas DA, Tal-Singer R, MacNee W, Griffin JL and Connor SC. (2012) Metabolic profiling detects biomarkers of protein degradation in COPD patients. Eur Respir J, 40(2):345–55. 65. Joppa P, Petrasova D, Stancak B, Tkacova R. (2006) Systemic inflammation in patients with COPD and pulmonary hypertension. Chest, 130(2):326–33. 66. Eid AA, Ionescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB, Griffiths TL and Shale DJ. (2001) Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 164(8 Pt 1):1414–8. 67. Al-shair Khaled, Kolsum U, Dockry R, Morris J, Singh D and Vestbo J. (2011) Biomarkers of systemic inflammation and depression and fatigue in moderate clinically stable COPD. Respir Res, 12(1):3. 68. Miller J, Edwards LD, Agustí A, Bakke P, Calverley PMA, Celli B, Coxson HO, Crim C, Lomas DA, Miller BE, Rennard S, Silverman EK, Tal-Singer R, Vestbo J, Wouters E, Yates JC, Macnee W; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. (2013) Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort. Respir Med, 107(9):1376–84. 69. Boutou AK, Pitsiou GG, Stanopoulos I, Kontakiotis T, Kyriazis G and Argyropoulou P. (2012) Levels of inflammatory mediators in chronic obstructive pulmonary disease patients with anemia of chronic disease: a case-control study. QJM, 105(7):657–63. 70. Kersul AL, Iglesias A, Ríos ?, Noguera A, Forteza A, Serra E, Agustí A and Cosío BG. (2011) Molecular mechanisms of inflammation during exacerbations of chronic obstructive pulmonary disease. Arch Bronconeumol, 47(4):176–83. 71. Bathoorn E, Liesker JJW, Postma DS, Ko?ter GH, van der Toorn M, van der Heide S, Ross HA, van Oosterhout AJ and Kerstjens HA. (2009) Change in inflammation in out-patient COPD patients from stable phase to a subsequent exacerbation. Int J Chron Obstruct Pulmon Dis, 4:101–9. 72. Groenewegen KH, Dentener MA and Wouters EFM. (2007) Longitudinal follow-up of systemic inflammation after acute exacerbations of COPD. Respir Med, 101(11):2409–15. 73. Markoulaki D, Kostikas K, Papatheodorou G, Koutsokera A, Alchanatis M, Bakakos P, Gourgoulianis KI, Roussos C, Koulouris NG and Loukides S. (201) Hemoglobin, erythropoietin and systemic inflammation in exacerbations of chronic obstructive pulmonary disease. Eur J Intern Med, 22(1):103–7. 74. Sala E, Balaguer C, Villena C, Ríos A, Noguera A, Nú?ez B and Agustí A. (2010) Low erythropoietin plasma levels during exacerbations of COPD. Respiration, 80(3):190–7. 75. Wedzicha JA, Brill SE, Allinson JP and Donaldson GC. (2013) Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med, 11:181. 76. Guidet B, Offenstadt G, Boffa G, Najman A, Baillou C, Hatzfeld C and Amstutz P. (1987) Polycythemia in chronic obstructive pulmonary disease. A study of serum and urine erythropoietin and medullary erythroid progenitors. Chest, 92(5):867–70. 77. Tsantes AE, Papadhimitriou SI, Tassiopoulos ST, Bonovas S, Paterakis G, Meletis I and Loukopoulos D. (2004) Red cell macrocytosis in hypoxemic patients with chronic obstructive pulmonary disease. Respir Med, 98(11):1117–23. 78. Fitzpatrick MF, Mackay T, Whyte KF, Allen M, Tam RC, Dore CJ, Cotes PM and Douglas NJ. (1993) Nocturnal desaturation and serum erythropoietin: a study in patients with chronic obstructive pulmonary disease and in normal subjects. Clin Sci (Lond), 84(3):319–24. 79. Casale R and Pasqualetti P. (1997) Diurnal rhythm of serum erythropoietin circulating levels in chronic obstructive pulmonary disease. Panminerva Med, 39(3):183–5. 80. Pavlisa G, Vrbanic V, Kusec V and Jaksic B. (2004) Erythropoietin response after correction of severe hypoxaemia due to acute respiratory failure in chronic obstructive pulmonary disease patients. Clin Sci (Lond), 106(1):43. 81. Dal Negro RW, Tognella S, Bonadiman L and Turco P. (2012) Changes in blood hemoglobin and blood gases PaO2 and PaCO2 in severe COPD overa three-year telemonitored program of long-term oxygen treatment. Multidiscip Respir Med, 7(1):15. 82. Incalzi RA, Corsonello A, Pedone C, Battaglia S, Paglino G and Bellia V. (2010) Chronic renal failure: A neglected comorbidity of copd. Chest, 137(4):831–7. 83. Casanova C, de Torres JP, Navarro J, Aguirre-Jaíme A, Toledo P, Cordoba E, Baz R and Celli BR. (2010) Microalbuminuria and hypoxemia in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 182(8):1004–10. 84. Mapel DW and Marton JP. (2013) Prevalence of renal and hepatobiliary disease, laboratory abnormalities, and potentially toxic medication exposures among persons with COPD. Int J Chron Obstruct Pulmon Dis, 8:127–34. 85. Gjerde B, Bakke PS, Ueland T, Hardie JA and Eagan TML. (2012) The prevalence of undiagnosed renal failure in a cohort of COPD patients in western Norway. Respir Med, 106(3):361–6. 86. Babitt JL and Lin HY. (2012) Mechanisms of Anemia in CKD. J Am Soc Nephrol, 23(10):1631–4. 87. Lankhorst CE and Wish JB. (2010) Anemia in renal disease: diagnosis and management. Blood Rev, 24(1):39–47. 88. Eschbach JW Jr, Funk D, Adamson J, Kuhn I, Scribner BH and Finch CA. (1967) Erythropoiesis in patients with renal failure undergoing chronic dialysis. N Engl J Med, 276(12):653–8. 89. Pecoits-Filho R, Lindholm B and Stenvinkel P. (2003) End-stage renal disease: a state of chronic inflammation and hyperleptinemia. Eur J Clin Invest, 33(6):527–8. 90. Valocikova I, Kristofova B and Valocik G. (2008) Cardiac biomarkers and chronic renal diseases. Bratisl Lekárske Listy, 109(8):341–4. 91. Portillo K, Martinez-Rivera C and Ruiz-Manzano J. (2013) Anaemia in chronic obstructive pulmonary disease. Does it really matter? Int J Clin Pract, 67(6):558–65. 92. Zaritsky J, Young B, Wang H-J, Westerman M, Olbina G, Nemeth E, Ganz T, Rivera S, Nissenson AR and Salusky IB. (2009) Hepcidin--a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol, 4(6):1051–6. 93. King SJ, Booyse FM, Lin PH, Traylor M, Narkates AJ and Oparil S. (1989) Hypoxia stimulates endothelial cell angiotensin-converting enzyme antigen synthesis. Am J Physiol, 256(6 Pt 1):C1231–1238. 94. Mascitelli L, Pezzetta F and Goldstein MR. (2008) Inhibition of the renin–angiotensin system in severe COPD. Eur Respir J, 32(4):1130–1130. 95. Raff H and Roarty TP. (1988) Renin, ACTH, and aldosterone during acute hypercapnia and hypoxia in conscious rats. Am J Physiol, 254(3 Pt 2):R431–435. 96. Vlahakos DV, Marathias KP and Madias NE. (2010) The Role of the Renin-Angiotensin System in the Regulation of Erythropoiesis. Am J Kidney Dis, 56(3):558–65. 97. Mrug M, Stopka T, Julian BA, Prchal JF and Prchal JT. (1997) Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin Invest, 100(9):2310–4. 98. Marathias KP, Agroyannis B, Mavromoustakos T, Matsoukas J and Vlahakos DV. (2004) Hematocrit-lowering effect following inactivation of renin-angiotensin system with angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Curr Top Med Chem, 4(4):483–6. 99. Vlahakos DV, Kosmas EN, Dimopoulou I, Ikonomou E, Jullien G, Vassilakos P and Marathias KP. (1999) Association between activation of the renin-angiotensin system and secondary erythrocytosis in patients with chronic obstructive pulmonary disease. Am J Med., 106(2):158–64. 100. Andreas S, Herrmann-Lingen C, Raupach T, Lüthje L, Fabricius JA, Hruska N, K?rber W, Büchner B, Criée CP, Hasenfuss G and Calverley P. (2006) Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial. Eur Respir J., 27(5):972–9. 101. Shrikrishna D, Astin R, Kemp PR and Hopkinson NS. (2012) Renin-angiotensin system blockade: a novel therapeutic approach in chronic obstructive pulmonary disease. Clin Sci (Lond)., 123(8):487–98. 102. Daly JW, Jacobson KA and Ukena D. (1987) Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res., 230:41–63. 103. Osswald H, Gleiter C and Mühlbauer B. (1995) Therapeutic use of theophylline to antagonize renal effects of adenosine. Clin Nephrol., 43 Suppl 1:S33–37. 104. Nagashima K and Karasawa A.(1996) Modulation of erythropoietin production by selective adenosine agonists and antagonists in normal and anemic rats. Life Sci., 59(9):761–71. 105. Bakris GL, Sauter ER, Hussey JL, Fisher JW, Gaber AO and Winsett R. (1990) Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation. N Engl J Med., 323(2):86–90. 106. Oren R, Beeri M, Hubert A, Kramer MR and Matzner Y. (1997) Effect of theophylline on erythrocytosis in chronic obstructive pulmonary disease. Arch Intern Med., 157(13):1474–8. 107. Balasubramanian V and Naing S. (2012) Hypogonadism in chronic obstructive pulmonary disease: incidence and effects. Curr Opin Pulm Med., 18(2):112–7. 108. Creutzberg EC and Casaburi R. (2003) Endocrinological disturbances in chronic obstructive pulmonary disease. Eur Respir J., 22(46 suppl):76s–80s. 109. Bachman E, Feng R, Travison T, Li M, Olbina G, Ostland V, Ulloor J, Zhang A, Basaria S, Ganz T, Westerman M and Bhasin S. (2010) Testosterone Suppresses Hepcidin in Men: A Potential Mechanism for Testosterone-Induced Erythrocytosis. J Clin Endocrinol Metab., 95(10):4743–7. 110. Guo W, Bachman E, Li M, Roy CN, Blusztajn J, Wong S, Chan SY, Serra C, Jasuja R, Travison TG, Muckenthaler MU, Nemeth E and Bhasin S. (2013) Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells. Aging Cell., 12(2):280–91. 111. Paller CJ, Shiels MS, Rohrmann S, Menke A, Rifai N, Nelson WG, Platz EA and Dobs AS. (2012) Association between sex steroid hormones and hematocrit in a nationally representative sample of men. J Androl., 33(6):1332–41. 112. Koehler F, Doehner W, Hoernig S, Witt C, Anker SD and John M. (2007) Anorexia in chronic obstructive pulmonary disease--association to cachexia and hormonal derangement. Int J Cardiol., 119(1):83–9. 113. Raguso CA and Luthy C. (2011) Nutritional status in chronic obstructive pulmonary disease: role of hypoxia. Nutrition., 27(2):138–43. 114. Kythreotis P, Kokkini A, Avgeropoulou S, Hadjioannou A, Anastasakou E, Rasidakis A and Bakakos P. (2009) Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease. BMC Pulm Med., 9:11. 115. Ye M, Yu H, Yu W, Zhang G, Xiao L, Zheng X and Wu J. (2012) Evaluation of the significance of circulating insulin-like growth factor-1 and C-reactive protein in patients with chronic obstructive pulmonary disease. J Int Med Res., 40(3):1025–35. 116. Co?kun F, Ege E, Uzaslan E, Ediger D, Karada? M and G?zü O. (2009) Evaluation of thyroid hormone levels and somatomedin-C (IGF-1) in patients with chronic obstructive pulmonary disease (COPD) and relation with the severity of the disease. Tüberküloz Ve Toraks., 57(4):369–75. 117. Scalvini S, Volterrani M, Vitacca M, Clark AL, Solfrini R, Panzali AM, Ferrari R and Levi GF. (1996) Plasma hormone levels and haemodynamics in patients with chronic obstructive lung disease. Monaldi Arch Chest Dis., 51(5):380–6. 118. Sivan B, Lilos P and Laron Z. (2003) Effects of insulin-like growth factor-I deficiency and replacement therapy on the hematopoietic system in patients with Laron syndrome (primary growth hormone insensitivity). J Pediatr Endocrinol Metab., 16(4):509–20. 119. Kim D-H, Kim T-Y, Kim S-M, Yoo S-J, Oh D-J and Yu S-H. (2007) IGF-1 is an independent risk factor for anemia in diabetic pre-dialysis patients. Korean J Intern Med., 22(3):186–91. 120. Jimeno L, Rodado R, Barrios Y, Campos M, Llorente S, Nicolas F and Minguela A. (2005) Influence of angiotensin-converting enzyme polymorphism gene, IGF-1, and other factors in the response rate of hematocrit to enalapril treatment in patients with posttransplant erythrocytosis. Transplant Proc., 37(2):1012–3. 121. Shih LY, Huang JY and Lee CT. (1999) Insulin-like growth factor I plays a role in regulating erythropoiesis in patients with end-stage renal disease and erythrocytosis. J Am Soc Nephrol., 10(2):315–22. 122. Burdet L, de Muralt B, Schutz Y, Pichard C and Fitting JW. (1997) Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease. A prospective, randomized, controlled study. Am J Respir Crit Care Med., 156(6):1800–6. 123. Miki K, Maekura R, Nagaya N, Nakazato M, Kimura H, Murakami S, Ohnishi S, Hiraga T, Miki M, Kitada S, Yoshimura K, Tateishi Y, Arimura Y, Matsumoto N, Yoshikawa M, Yamahara K, Kangawa K. (2012) Ghrelin treatment of cachectic patients with chronic obstructive pulmonary disease: a multicenter, randomized, double-blind, placebo-controlled trial. PloS One, 7(5):e35708. 124. King DA, Cordova F and Scharf SM. Nutritional aspects of chronic obstructive pulmonary disease. (2008) Proc Am Thorac Soc., 5(4):519–23. 125. Battaglia S, Spatafora M, Paglino G, Pedone C, Corsonello A, Scichilone N, Antonelli-Incalzi R, Bellia V. (2011) Ageing and COPD affect different domains of nutritional status: the ECCE study. Eur Respir J., 37(6):1340–5. 126. Obase Y, Mouri K, Shimizu H, Ohue Y, Kobashi Y, Kawahara K and Oka M. (2011) Nutritional deficits in elderly smokers with respiratory symptoms that do not fulfill the criteria for COPD. Int J Chron Obstruct Pulmon Dis., 6:679–83. 127. Fimognari FL, Loffredo L, Di Simone S, Sampietro F, Pastorelli R, Monaldo M, Violi F and D'Angelo A. (2009) Hyperhomocysteinaemia and poor vitamin B status in chronic obstructive pulmonary disease. Nutr Metab Cardiovasc Dis., 19(9):654–9. 128. Andersson I, Gr?nberg A, Slinde F, Bosaeus I and Larsson S. (2007) Vitamin and mineral status in elderly patients with chronic obstructive pulmonary disease. Clin Respir J., 1(1):23–9. 129. Berliner N. (2013) Anemia in the Elderly. Trans Am Clin Climatol Assoc, 124:230–7. 130. Vanasse GJ and Berliner N. (2010) Anemia in Elderly Patients: An Emerging Problem for the 21st Century. ASH Educ Program Book, 2010(1):271–5. 131. Brüünsgaard and Pedersen BK.(2003) Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am., 23(1):15–39. 132. Ferrucci L, Corsi A, Lauretani F, Bandinelli S, Bartali B, Taub DD Guralnik JM, and Longo DL. (2005) The origins of age-related proinflammatory state. Blood, 105(6):2294–9. 133. Kario K, Matsuo T and Nakao K. (1991) Serum erythropoietin levels in the elderly. Gerontology, 37(6):345–8. 134. Silverberg DS, Mor R, Weu MT, Schwartz D, Schwartz IF and Chernin G.(2014) 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., Feb 24;14:24. 135. 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. (2009) Ferric Carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. , 361(25):2436–48. 136. Dunn LL, Suryo Rahmanto Y and Richardson DR. (2007) Iron uptake and metabolism in the new millennium. Trends Cell Biol., 17(2):93–100. 137. Bolger AP, Bartlett FR, Penston HS, O’Leary J, Pollock N, Kaprielian R and Chapman CM. (2006) Intravenous iron alone for the treatment of anemia in patients with chronic heart failure. J Am Coll Cardiol., 48(6):1225–7. 138. Okonko DO, Grzeslo A, Witkowski T, Mandal AKJ, Slater RM, Roughton M, Foldes G, Thum T, Majda J, Banasiak W, Missouris CG, Poole-Wilson PA, Anker SD and Ponikowski P. (2008) Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol., 51(2):103–12. 139. Toblli JE, Lombra?a A, Duarte P and Di Gennaro F. (2007) Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol., 50(17):1657–65. 140. Qidwai T and Khan F. (2011) Tumour necrosis factor gene polymorphism and disease prevalence. Scand J Immunol., 74(6):522–47. 141. Wong C, Kanetsky P and Raj D. (2008) Genetic polymorphisms of the RAS-cytokine pathway and chronic kidney disease. Pediatr Nephrol . 23(7):1037–51. 142. Dhaunsi GS, Uppal SS and Haider MZ. (2012) Insulin-like growth factor-1 gene polymorphism in rheumatoid arthritis patients. Scand J Rheumatol., 41(6):421–5. 143. Girndt M, Heine GH, K?hler H; DialGene Consortium. (2006) Gene polymorphism association studies in dialysis: anemia and host immunity. Semin Dial., 19(3):227–31. ................
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