Chronic 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. Anaemia is one of the more recently identified co-morbidities, with a prevalence that varies between 4.9% and 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 anaemia. The present review evaluates the published literature on the prevalence and significance of anaemia in COPD. Moreover, it attempts to elucidate the reasons for the high variability reported and investigates the complex pathophysiology underlying the development of anaemia in these patients.

THE PREVALENCE OF ANAEMIA IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

There is a huge variation of anaemia 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 anaemia, haematocrit (Ht), haemoglobin (Hb), 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 anaemia 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, anaemia frequency varied widely from 4.9% to 38% [1,2]. In contrast with expectations, polycythaemia was less common than anaemia; its prevalence ranged from 6% to 18.1% [35], perhaps reflecting more widespread use of domiciliary oxygen and other forms of respiratory support.

Table 1
Studies which were included in the review process and their characteristics

ICD, international code of diseases; GOLD, global initiative for obstructive lung disease; CRF, chronic respiratory failure; PR, pulmonary rehabilitation.

First authorYear of publicationCountryStudy designCOPD population characteristicsSize of COPD populationCOPD diagnosisAnaemia diagnosisAnaemia Prevalence
Almagro [142012 Spain Longitudinal, multicentre Hospitalized for AECOPD 606 Postbronchodilator FEV1<80% predicted and FEV1/FVC<0.70 Based on a questionnaire 19.3% 
Barba [132012 Spain Retrospective, multicentre (Basic Minimum Data Set records) Hospitalized for AECOPD 289077 ICD-9-CM codes ICD-9-CM codes 9.8% 
Boutou [82011 Greece Prospective case–control Stable hospital outpatients 283 Postbronchodilator FEV1/FVC<0.70 Males: Hb < 13 g/dl Females: Hb < 12 g/dl Plus clinical and laboratory criteria for ACD 10.2% 
Boutou [72013 U.K. Retrospective (institution's clinical COPD database) Stable hospital outpatients 294 Postbronchodilator FEV1/FVC<0.70 Hb < 13 g/dl for both male and female 15.6% 
Chambellan [32005 France Retrospective, multicenter (ANDATIR database) Hypoxemic patients under LTOT 2524 FEV1<80% and FEV1/FVC<70% Male: Ht < 39% Female: Ht < 36% Male:12.6% Female:8.2% 
Comeche Casanova [262013 Spain Prospective Stable hospital outpatients 130 GOLD criteria Male: Hb < 13 g/dl Female: Hb < 12 g/dl 6.2% 
Copur [22013 U.S.A. Retrospective Patients referred for LTOT evaluation 317 Postbronchodilator FEV1/FVC < 0.70 plus ≥20 pack/year smoking history Hb < 13 g/dl for both male and female 38% 
Cote [42007 U.S.A. Hb was retrospectively and all other variables were prospectively collected Stable hospital outpatients 683 Post bronchodilator FEV1/FVC < 0.70 plus >20 pack/years Hb < 13 g/dl for both male and female 17% 
Dal Negro [192012 Italy Longitudinal, observational Outpatients under LTOT 132 Criteria according to dedicated institutional database (ISO 9001–2000 certified) Hb < 13 g/dl for both male and female 11.3% 
Freemault [152011 Belgium 1st cohort retrospectively (1980–1984) 2nd cohort prospectively (2001–2005) studied Hospitalized for AECOPD 1st: 51 2nd: 101 1st: ICD-9 2nd: FEV1/FVC < 0.70 plus ≥10 pack/year smoking history Male: Hb < 13g/dl Female: Hb < 12 g/dl 1st: 9.8% 2nd: 27.7% 
Halpern [222006 U.S.A. Retrospective (1999–2001 US Medicare Claims database) Both inpatients and outpatients >65 years old 132424 ICD-9 codes ICD-9 codes 21% 
John [92006 Germany Retrospective Discharged from hospital 312 ICD-9/10 codes Severity according to GOLD Male: Hb < 13.5 g/dl Female: Hb < 12 g/dl 23.1% 
John [232005 Germany Prospective Stable outpatients 101 According to ATS guidelines Male: Hb < 13.5 g/dl Female: Hb < 12 g/dl 13% 
Joo [102012 Korea Retrospective-data derived from a population survey (Korean Health and Nutrition Examination Survey) Patients with COPD in the general population 238 FEV1/FVC < 0.7 among subjects >40 years old Male: Hb < 13 g/dl Female: Hb < 12 g/dl (non-pregnant) or Hb < 11 g/dl (pregnant) 7.3% 
Kollert [52013 Germany Retrospective (database of the Donaustauf Hospital Center for Pneumology) Patients with CRF prior initiating NIV 309 Clinical history and FEV1/FVC < 70% Plus GOLD criteria for stages III/IV Male: Hb < 13 g/dl Female: Hb < 12 g/dl 14.9% 
Krishnan [112006 U.S.A. Retrospective (post-hoc analysis form data derived from a population study) Patients with COPD in the general population 495 According to ATS guidelines in subjects 35–79 years old. Severity according to GOLD Male: Hb < 13 g/dl Female: Hb < 12 g/dl 7.5% 
Martinez-Rivera [282012 Spain Prospective Hospitalized for AECOPD 117 Airflow obstruction according to GOLD plus clinical evaluation and ≥10 pack/year smoking history Hb < 13 g/dl for both male and female 33% 
Nowiński [12011 Poland Longitudinal prospective Hospitalized for AECOPD 464 Diagnostic criteria not described. Severity categorized by GOLD Male: Hb < 13.5 g/dl Female: Hb < 12 g/dl 4.9% 
Nowiński [162013 Poland Retrospective Hospitalized for AECOPD 402 According to Polish Society for Lung Diseases criteria Male: Hb < 13 g/dl Female: Hb < 12 g/dl 26% 
Rasmunssen [182011 Denmark Retrospective Intubated for AECOPD 222 According to GOLD for those with spirometry. Based on physical examination and history for the rest Hb < 12 g/dl for both male and female 18% 
Rutten [212013 The Netherlands Retrospective Patients with moderate to severe COPD, screened for PR 321 According to ERS/ATS guidelines Male: Hb < 13 g/dl Female: Hb < 12 g/dl 20% 
Shorr [242008 U.S.A. Retrospective (healthcare maintenance organization database) Both inpatients and outpatients 2404 ICD-9 Male: Hb < 13 g/dl Female: Hb < 12 g/dl 33% 
Watz [62008 Germany Cross-sectional Stable outpatients (recruited from institution's database) 170 Established by spirometry (no further details given). Severity by GOLD and BODE index Hb < 13 g/dl 5.3% 
Zavarreh [122013 Iran Cross-sectional Stable outpatients 74 Established by spirometry (no further details given). Severity by GOLD Male: Hb < 13 g/dl Female: Hb < 12 g/dl 27% 
First authorYear of publicationCountryStudy designCOPD population characteristicsSize of COPD populationCOPD diagnosisAnaemia diagnosisAnaemia Prevalence
Almagro [142012 Spain Longitudinal, multicentre Hospitalized for AECOPD 606 Postbronchodilator FEV1<80% predicted and FEV1/FVC<0.70 Based on a questionnaire 19.3% 
Barba [132012 Spain Retrospective, multicentre (Basic Minimum Data Set records) Hospitalized for AECOPD 289077 ICD-9-CM codes ICD-9-CM codes 9.8% 
Boutou [82011 Greece Prospective case–control Stable hospital outpatients 283 Postbronchodilator FEV1/FVC<0.70 Males: Hb < 13 g/dl Females: Hb < 12 g/dl Plus clinical and laboratory criteria for ACD 10.2% 
Boutou [72013 U.K. Retrospective (institution's clinical COPD database) Stable hospital outpatients 294 Postbronchodilator FEV1/FVC<0.70 Hb < 13 g/dl for both male and female 15.6% 
Chambellan [32005 France Retrospective, multicenter (ANDATIR database) Hypoxemic patients under LTOT 2524 FEV1<80% and FEV1/FVC<70% Male: Ht < 39% Female: Ht < 36% Male:12.6% Female:8.2% 
Comeche Casanova [262013 Spain Prospective Stable hospital outpatients 130 GOLD criteria Male: Hb < 13 g/dl Female: Hb < 12 g/dl 6.2% 
Copur [22013 U.S.A. Retrospective Patients referred for LTOT evaluation 317 Postbronchodilator FEV1/FVC < 0.70 plus ≥20 pack/year smoking history Hb < 13 g/dl for both male and female 38% 
Cote [42007 U.S.A. Hb was retrospectively and all other variables were prospectively collected Stable hospital outpatients 683 Post bronchodilator FEV1/FVC < 0.70 plus >20 pack/years Hb < 13 g/dl for both male and female 17% 
Dal Negro [192012 Italy Longitudinal, observational Outpatients under LTOT 132 Criteria according to dedicated institutional database (ISO 9001–2000 certified) Hb < 13 g/dl for both male and female 11.3% 
Freemault [152011 Belgium 1st cohort retrospectively (1980–1984) 2nd cohort prospectively (2001–2005) studied Hospitalized for AECOPD 1st: 51 2nd: 101 1st: ICD-9 2nd: FEV1/FVC < 0.70 plus ≥10 pack/year smoking history Male: Hb < 13g/dl Female: Hb < 12 g/dl 1st: 9.8% 2nd: 27.7% 
Halpern [222006 U.S.A. Retrospective (1999–2001 US Medicare Claims database) Both inpatients and outpatients >65 years old 132424 ICD-9 codes ICD-9 codes 21% 
John [92006 Germany Retrospective Discharged from hospital 312 ICD-9/10 codes Severity according to GOLD Male: Hb < 13.5 g/dl Female: Hb < 12 g/dl 23.1% 
John [232005 Germany Prospective Stable outpatients 101 According to ATS guidelines Male: Hb < 13.5 g/dl Female: Hb < 12 g/dl 13% 
Joo [102012 Korea Retrospective-data derived from a population survey (Korean Health and Nutrition Examination Survey) Patients with COPD in the general population 238 FEV1/FVC < 0.7 among subjects >40 years old Male: Hb < 13 g/dl Female: Hb < 12 g/dl (non-pregnant) or Hb < 11 g/dl (pregnant) 7.3% 
Kollert [52013 Germany Retrospective (database of the Donaustauf Hospital Center for Pneumology) Patients with CRF prior initiating NIV 309 Clinical history and FEV1/FVC < 70% Plus GOLD criteria for stages III/IV Male: Hb < 13 g/dl Female: Hb < 12 g/dl 14.9% 
Krishnan [112006 U.S.A. Retrospective (post-hoc analysis form data derived from a population study) Patients with COPD in the general population 495 According to ATS guidelines in subjects 35–79 years old. Severity according to GOLD Male: Hb < 13 g/dl Female: Hb < 12 g/dl 7.5% 
Martinez-Rivera [282012 Spain Prospective Hospitalized for AECOPD 117 Airflow obstruction according to GOLD plus clinical evaluation and ≥10 pack/year smoking history Hb < 13 g/dl for both male and female 33% 
Nowiński [12011 Poland Longitudinal prospective Hospitalized for AECOPD 464 Diagnostic criteria not described. Severity categorized by GOLD Male: Hb < 13.5 g/dl Female: Hb < 12 g/dl 4.9% 
Nowiński [162013 Poland Retrospective Hospitalized for AECOPD 402 According to Polish Society for Lung Diseases criteria Male: Hb < 13 g/dl Female: Hb < 12 g/dl 26% 
Rasmunssen [182011 Denmark Retrospective Intubated for AECOPD 222 According to GOLD for those with spirometry. Based on physical examination and history for the rest Hb < 12 g/dl for both male and female 18% 
Rutten [212013 The Netherlands Retrospective Patients with moderate to severe COPD, screened for PR 321 According to ERS/ATS guidelines Male: Hb < 13 g/dl Female: Hb < 12 g/dl 20% 
Shorr [242008 U.S.A. Retrospective (healthcare maintenance organization database) Both inpatients and outpatients 2404 ICD-9 Male: Hb < 13 g/dl Female: Hb < 12 g/dl 33% 
Watz [62008 Germany Cross-sectional Stable outpatients (recruited from institution's database) 170 Established by spirometry (no further details given). Severity by GOLD and BODE index Hb < 13 g/dl 5.3% 
Zavarreh [122013 Iran Cross-sectional Stable outpatients 74 Established by spirometry (no further details given). Severity by GOLD Male: Hb < 13 g/dl Female: Hb < 12 g/dl 27% 

Several reasons can be proposed for this discrepancy in anaemia prevalence, and the varying characteristics of the populations studied is one of them, as anaemia prevalence has been investigated in stable COPD outpatients [4,612], hospitalized patients for an acute exacerbation of COPD (AECOPD) [1317], intubated patients in the intensive care unit [18], COPD patients from the general population [1011] and COPD patients using long-term oxygen treatment (LTOT) or non-invasive ventilation (NIV) [3,5,19]. 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 anaemia, so results are not easily comparable.

COPD diagnosis, according to European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines, should be based on specific spirometric criteria [20]. Nevertheless, this is not the case for every published study which has investigated anaemia prevalence in COPD patients. Although most authors have used the post-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC)<0.7 [2,4,79,14,21], several have applied the ICD 9/10 codes [13,2224] or identified COPD patients from existing databases without describing the diagnostic criteria in detail [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 anaemia prevalence.

Furthermore, anaemia definition has been variable in published studies. According to current World Health Organization (WHO), anaemia in the general population is defined by Hb levels <13 g/dl in male and <12 g/dl in female [25] and these thresholds have been used by several authors in order to identify anaemic COPD patients [5,8,11,15,26]. However, the use of a Hb <12 g/dl threshold to define anaemia in postmenopausal women is currently under debate [27], so the 13 g/dl threshold for both male and female has also been applied [2,4,7,19]. Controversy is even more evident regarding COPD patients admitted in the ICU, since there is as yet no accepted definition of abnormal Hb values in the critically ill [18]. A final problem with many of the studies is that the prevalence of anaemia was often not measured in an age and sex matched population with similar co-morbidity burden (control population) [3,9,14,26]; thus, it is difficult to establish whether the prevalence of anaemia is increased in COPD.

In one of the first studies in the field, John et al. [9] studied 101 stable severe COPD outpatients; the prevalence of anaemia was 13%. 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 anaemia prevalence ranging between 15% and 17.1% [4,7]. The only study which used both clinical and laboratory criteria to exclude all potential causes of anaemia, apart from anaemia of chronic disease (ACD), estimated the prevalence of the latter to be 10.2% among stable hospital outpatients [8]. Interestingly, the prevalence of anaemia in selected populations with respiratory failure was not very different from that seen in hospital outpatients. Chambellan et al. [3] reported that 12.6% male and 8.2% female of the total 2542 outpatients receiving LTOT were anaemic; these results were similar to the ones of Dal Negro et al. [19] and of Kollert et al. [5], who reported an anaemia prevalence of 11.3% and 14.9% among outpatients receiving LTOT or domiciliary non-invasive ventilation, respectively. Conversely, two large population-based studies estimated a lower prevalence of anaemia among COPD patients, ranging between 7.3% and 7.5% [10,11]; the inclusion of COPD patients with less severe disease burden compared with the ones with respiratory failure or ongoing hospital follow-up is probably the main reason for this discrepancy.

As expected, anaemia 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, anaemia prevalence among COPD patients was 23.1%, comparable with the one among individuals with heart failure [23]. In a longitudinal study by Almagro et al. [14], anaemia prevalence among hospitalized patients for AECOPD was 19.3%, whereas other authors have reported even higher frequencies, ranging from 26% to 33% [15,28]. Hospital-acquired anaemia [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 with previous data, Nowiński et al. [1] and Barba et al. [13] reported a much lower frequency for anaemia 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 anaemia came from two large retrospective studies using healthcare databases. Shorr et al. [24] studied a population of 2404 COPD patients and identified that 788 (33%) of them were anaemic. The study used the WHO definition of anaemia and was conducted in a large patient population; however, patients with chronic kidney disease were not excluded, while there is no information whether Hb was measured during stable state or hospitalization. Halpern et al. [22] indicated that out of the 132424 COPD patients who were included in the US Medicare Claims Database, 27932 COPD (21%) were anaemic. Although it is not known whether anaemia was identified on an inpatient or outpatient basis, the lower percentages of anaemia are probably due to the exclusion of patients with renal insufficiency, along with other causes of anaemia. Although these two studies do not offer further information regarding the specific anaemia prevalence in different COPD populations, they indicate that in a general COPD population of various severity and several co-morbidities, anaemia is a common complication.

In summary, although anaemia occurs frequently in COPD patients, its prevalence varies widely in the published literature. The baseline characteristics of the study population, the various co-morbidities 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 ANAEMIA IN COPD

Although the presence of anaemia has been repeatedly reported, studies that have investigated the specific causes of anaemia in COPD are scarce and many potential aetiological mechanisms, which are not mutually exclusive, exist (Figure 1). Nevertheless, COPD has been increasingly recognized as a disorder with important systemic manifestations [29,30], so the development of ‘ACD’ among COPD patients could be expected.

Complex pathophysiology of anaemia in COPD

Figure 1
Complex pathophysiology of anaemia in COPD

RBC, red blood cells; PaO2, arterial oxygen partial pressure; PaCO2, arterial carbon dioxide partial pressure; B12, vitamin B12.

Figure 1
Complex pathophysiology of anaemia in COPD

RBC, red blood cells; PaO2, arterial oxygen partial pressure; PaCO2, arterial carbon dioxide partial pressure; B12, vitamin B12.

Pathogenesis of ACD

ACD is an immune-driven disorder [31]; it accompanies several diseases which are characterized by sub-acute or chronic immune activation, such as malignancies, systemic autoimmune disorders and inflammatory diseases [3235]. For this reason, ACD has also been characterized as ‘anaemia of inflammation’ [31]. ACD can be classified as anaemia due to reduced erythropoiesis and is usually a mild to moderate normochromic, normocytic anaemia, though less frequently, it can have a hypochromic microcytic pattern [36]. The pathophysiological background of ACD is immunological; cytokines and cells of the reticuloendothelial system induce changes in iron homoeostasis, the proliferation and differentiation of progenitor erythroid cells and the production of erythropoietin (EPO), which all contribute to its establishment [31].

Disorders of iron homoeostasis

One of the most characteristic features of ACD is the development of disorders in iron homoeostasis, 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 [31].

Iron homoeostasis 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 [37,38]. 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 [39], the most significant of which is ferroportin [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 [39]. Different cells use iron in different ways; however, erythrocytes, hepatocytes and reticuloendothelial macrophages are the most important [41]. This complex iron homoeostasis is regulated by several molecules, with hepcidin–a 25 amino acid protein secreted by liver–being the most important [42,43]. Studies in both mice and humans have indicated that hepcidin is involved in the mechanisms of response to hypoxia and anaemia; 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 [44].

Chronic inflammation, as seen in ACD, disrupts iron homoeostasis in multiple ways. Tumour necrosis factor-1α (TNF-α) and interleukin (IL)-1, increase the synthesis of ferritin by liver cells and macrophages by inducing its transcription and translation [45]. IL-6 distorts iron metabolism [46], since it modulates ferritin translation, expression of transferrin mRNA and, possibly, expression of DMT1 [32]. TNF-α and interferon-γ (IFN-γ) induce the production of DMT1 and block the release of iron from macrophages by down-regulating ferroportin expression [31]. IL-10 can also impair iron homoeostasis by inducing ferritin expression and increasing the acquisition of iron by macrophages [47]. Finally, lipopolysaccharide and IL-6 are major stimulants of hepcidin synthesis, leading to hypoferremia within hours of inflammatory stimulant in animal models [44].

Disorders of proliferation and differentiation of erythroid progenitor cells [35]

Cytokine-mediated stem cell proliferation arrest or induction of apoptosis, as well as an interaction with EPO or other major factors that promote erythropoiesis are the potential underlying mechanisms for these disorders [32]. Several cytokines, exert inhibitory effects on erythroid progenitor cells; IL-1a inhibits erythropoiesis in vivo in mice and in vitro in humans [48], TNF-α and IFN-γ inhibit erythroid colony formation in uremic sera [49], while there is an inverse relationship between IFN-γ concentration, reticulocytes count and Hb concentration [50]. 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 [31,51]. Moreover, erythropoiesis is further inhibited by the limited availability of iron to erythroid progenitor cells [32].

Resistance to the action of EPO

EPO is a protein hormone which promotes erythroid cell proliferation; the most potent known stimulus for EPO production is tissue hypoxia [52]. Most patients with ACD have disproportionately low EPO levels for the severity of anaemia present [53,54]. In vitro studies indicate that IL-1 and TNF-α inhibit hypoxia-induced EPO production in a dose-dependent manner [55], whereas in anaemic individuals, high levels of IL-1, IL-6 and TNF-α are associated with low levels of EPO [54]. Cytokine overproduction is the most probable cause for hyporesponsiveness to EPO treatment in anaemic individuals without iron deficiency [56]. Abnormal iron metabolism also contributes to EPO resistance; iron not only becomes unavailable for erythroid progenitor cells [31], but its depletion may also impair EPO transgene expression [57].

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 [5862] are only a few of the inflammatory markers that have been found to be significantly increased among patients with stable disease compared with 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 [58,59,63,64], and with several systemic COPD manifestations and co-morbidities, such as muscle cachexia, pulmonary hypertension, heart disease and depression [6569].

Currently, two studies have evaluated the potential association between inflammatory mediators and anaemia in stable COPD patients; in neither case was an intervention given making causality impossible to assess. John et al. [9] studied a population of 101 COPD patients, 13 of whom were anaemic, and found that CRP and IL-6 levels were significantly elevated in anaemic COPD patients compared with controls, while CRP was also significantly higher in anaemic compared with non-anaemic COPD patients. EPO concentration was also higher in anaemic individuals compared with both non-anaemic patients and healthy controls. 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 IFN-γ) was higher in the group of anaemic compared with non-anaemic COPD patients; However, the between group differences were statistically significant only for IFN-γ and IL-10. Likewise, EPO levels were also higher in anaemic individuals, indicating the presence of EPO resistance due to systemic inflammation [70].

Systemic inflammation and ACD: the role of exacerbations

One of the most important complications in the course of COPD is acute exacerbations (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 with stable patients or controls [60,7173], and this increase often persists after the improvement of lung function [71].

Two studies have studied the potential association between systemic inflammation and EPO levels during an AECOPD, but results are conflicting. Markoulaki et al. [74] used measurements at three time points in a selected cohort of 93 COPD patients who presented with AECOPD. Hb levels were significantly decreased and EPO levels were significantly increased during the acute phase compared with 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, suggesting the presence of EPO resistance during the acute phase of AECOPD.

In a previous report Sala et al. [75] identified lower levels of EPO among exacerbated COPD patients, compared with stable COPD patients, non-COPD smokers and healthy controls. In COPD patients, EPO levels correlated with CRP and circulating neutrophils, whereas in a small (n = 8) subgroup of COPD patients who were studied both at AECOPD and stable phase, EPO levels significantly increased, when the acute phase resolved. These conflicting results indicate that more studies are needed to reveal the complex pathophysiology underlying EPO regulation during an AECOPD, especially now that a distinct COPD phenotype, ‘the frequent exacerbator’ with increased airway and systemic inflammation and a high prevalence of extrapulmonary co-morbidities has been proposed [76].

Oxygen supplementation

As described above, tissue hypoxia is the most potent trigger for EPO production which results in increased erythropoiesis [52]. Thus, one could hypothesize that the treatment of hypoxia in COPD patients would result to the reduction in EPO production and inhibition of erythroid progenitor cells proliferation, leading to anaemia. 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. [77] 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 [77]. In a case-control study of 32 patients and 34 matched non-smokers healthy subjects, Tsantes et al. [78] 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. Moreover, the severity of hypoxaemia could also be of some importance; Fitzpatrick et al. [79] concluded, after studying eight COPD and nine 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. [80] reported that the normal circadian 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.

Against this background, Pavlisa et al. [81] 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 [81]. 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 anaemic patients were smaller [82]. These results indicate that the association between hypoxia, EPO levels and Hb concentration is complex, meaning that the impact of LTOT on Ht level cannot be reliably predicted.

Renal impairment

Renal failure is an important co-morbidity, the high prevalence of which, among COPD patients, has recently been recognized. The study of Incalzi et al. [83] among 356 consecutive elderly (>65 years old) COPD outpatients was the first to indicate that 20.8% of COPD patients presented with reduced estimated glomerular filtration rate (e-GFR) (<60 ml/min per 1.73 m2) and abnormal serum creatinine levels and 22.2% with reduced e-GFR without abnormal serum creatinine levels. More recent studies have confirmed the high prevalence of microalbuminuria [84] and renal dysfunction among COPD patients compared with controls [85], although rates were lower in younger COPD cohorts [86].

The cause of anaemia due to renal impairment is multifactorial. The most well-known cause is reduced EPO production from the peritubular capillary endothelial cells [87,88]. 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 [88,89]. Limited availability of iron to erythroid progenitor cells also results in defective erythropoiesis; iron deficiency could be either true or functional, due to increased systemic inflammation which is often present in patients with renal failure [90,91]. The role of hepcidin in this defective iron utilization is crucial, since decreased e-GFR can result to higher serum hepcidin levels, amplifying iron metabolism abnormalities [92,93].

The renin–angiotensin–aldosterone system

Angiotensin-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 [9496]. 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 [97,98]. 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 [99].

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 3-fold increased among patients with erythrocytosis compared with controls, whereas EPO levels were similar between the groups. Plasma renin and oxygen arterial partial pressure, but not EPO, were independently associated with Ht [100]. 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. [101] 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 in Ht in the active treatment group, but not in the placebo group. 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 [102], the potential impact on erythropoiesis should be taken into consideration in the designing of clinical trials and in the evaluation of their outcome.

Theophylline treatment

Theophylline is a non-selective adenosine receptor antagonist, which can inhibit renal vasoconstriction in response to exogenous and endogenous adenosine [103,104]. In vitro studies have shown that adenosine mediates hypoxia-induced renal EPO production [105], so adenosine receptor antagonists could have an impact on Ht level and possibly induce anaemia. Previous reports have indicated that theophylline attenuates EPO production in both normal subjects and patients with erythrocytosis after renal transplantation [106], whereas the retrospective study of 204 COPD patients by Oren et al. [107] indicated that those treated with theophylline had significantly lower Hb levels, compared with the untreated ones. However, confounding by disease severity may have been an issue in this population.

Androgen deficiency

Sex hormone disturbances are common in COPD; a recent review estimated the prevalence of testosterone deficiency in male COPD patients between 22% and 69% [108]. The cause of this deficiency is multifactorial and it includes chronic hypoxia, disease severity, smoking, corticosteroid therapy, chronic inflammation and aging itself [109]. 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 in hepcidin levels and increase in iron utilization [110,111]. Currently, no study has evaluated the association between testosterone deficiency and anaemia establishment in COPD patients. However, in a population study of 1273 men, low free testosterone levels were associated with lower Ht levels [112], a result likely to be applicable in COPD patients, too.

Growth hormone and insulin-like growth factor-1 abnormalities

There is evidence that the growth hormone (GH) release axis is disturbed in COPD patients, resulting in the establishment of acquired GH resistance [113,114]. 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 [113,115]. In a case–control study, Ye et al. [116] indicated that levels of IGF-1 are reduced in COPD patients compared with controls and they are even lower among COPD patients during an acute exacerbation compared with patients in stable disease state. Similar were the results of Kythreotis et al. [115], who reported a significant decrease in circulating IGF-1 during AECOPD and of Coşkun et al. [117], who indicated that the greater the disease severity, the lower were serum levels of IGF-1. On the other hand, there is some evidence that GH levels are significantly elevated in COPD patients compared with healthy controls [118], whereas a study in mechanically ventilated patients without pulmonary disease indicated that hypercarbia is associated with an increase in GH levels. These two abnormalities (decrease in IGF-1 and increase in 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 GH 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 [119]. In patients with diabetic chronic kidney disease, IGF-1 levels were independently associated with Hb concentration [120], whereas in patients with erythrocytosis, IGF-1 levels were positively associated with Ht level, even in the absence of increased EPO production [121,122]. 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 anaemia establishment in this population. A few trials of GH or ghrelin therapy in COPD exist but changes in Hb were not reported [123,124].

Nutrition

Involuntary 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 [125,126]. Obase et al. [127] reported that daily iron intake among 13 COPD patients was about half of that of 27 age-matched controls; however, literature data on mineral intake among COPD patients are limited, so the frequency and severity of true iron deficiency as a cause of anaemia 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 [128,129], and this could contribute to the establishment of anaemia.

Aging

The prevalence of COPD increases with age, so the course of the disease can be further complicated by the clinical manifestations of aging itself. Anaemia 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 [130,131]. The cause of anaemia is multifactorial. Increased systemic inflammatory markers, such as TNF-α and IL-6 [132,133], decreased sensitivity of erythroid progenitor cells to EPO [134], lower ability of the aging kidney to produce adequate EPO quantities [131], malnutrition [126] and high burden of co-morbidities [130,131] all contribute to the establishment of anaemia in the elderly.

TREATMENT PERSPECTIVES

It 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 anaemic COPD patients with concomitant chronic renal insufficiency led to an improvement of Hb concentration and a reduction in dyspnea [135]. The more intriguing question is whether patients with COPD, normal renal function and low levels of ferritin, with or without anaemia 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 [136,137]. Both COPD and heart failure are characterized in part by impaired oxygen transport (because of ventilator limitation or pump failure respectively). One large [136] and several smaller studies [138140] 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

Anaemia 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 co-morbidities), since these characteristics produce, among other factors, a huge variation in anaemia prevalence, making the results of published studies difficult to compare.

The cause of anaemia 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 anaemia induction in COPD patients are currently lacking and much of the current knowledge has had to be extrapolated from studies on other patient groups or from disease models. Although the role of renal impairment and nutritional deficit seems to be rather straightforward, the impact of hypoxia and hypercarbia (which may be exaggerated during sleep, 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 anaemia; 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 [141], RAS pathway [142] and IGF-1 [143], are associated with the establishment and progression of various disorders. Moreover, in patients with end-stage renal disease and anaemia, several genetic polymorphisms have been associated with the interindividual variability in the severity of established anaemia and the need of exogenous EPO [144]. Thus, it is likely that the balance between factors which inhibit and stimulate erythropoiesis in COPD patients may also be influenced by genetic factors. Future research might give an answer to the question why some patients develop anaemia and others do not by identifying distinct genetic phenotypes, potentially opening the way to personalized medicine in this area.

Abbreviations

     
  • ACD

    anaemia of chronic disease

  •  
  • ACE

    angiotensin-converting enzyme

  •  
  • AECOPD

    acute exacerbation of chronic obstructive pulmonary disease

  •  
  • ARB

    angiotensin II receptor blocker

  •  
  • ATS

    American Thoracic Society

  •  
  • COPD

    chronic obstructive pulmonary disease

  •  
  • CRP

    C-reactive protein

  •  
  • DMT1

    divalent metal transporter 1

  •  
  • e-GFR

    estimated glomerular filtration rate

  •  
  • EPO

    erythropoietin

  •  
  • ERS

    European Respiratory Society

  •  
  • FEV1

    forced expiratory volume in 1 s

  •  
  • FVC

    forced vital capacity

  •  
  • IGF-1

    insulin-like growth factor-1

  •  
  • GH

    growth hormone

  •  
  • IL

    interleukin

  •  
  • Hb

    haemoglobin

  •  
  • Ht

    haematocrit

  •  
  • IFN-γ

    interferon-γ

  •  
  • LTOT

    long-term oxygen treatment

  •  
  • NIV

    non-invasive ventilation

  •  
  • RAAS

    renin–angiotensin–aldosterone system

  •  
  • TNF-α

    tumour necrosis factor-α

  •  
  • WHO

    World Health Organization

FUNDING

This work was supported by the National Institute for Health Research (NIHR) Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College, who part fund M.I.P.'s salary. The views expressed are those of the authors, not the Trust, the NIHR or the Department of Health.

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