Anemia in Chronic Obstructive Pulmonary Disease: an insight into its prevalence and pathophysiology

Afroditi K. Boutou, Nicholas S. Hopkinson, Michael I. Polkey

NIHR Respiratory Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UK

Short title: Anemia in Chronic Obstructive Pulmonary Disease

Corresponding author

Afroditi K Boutou

Stratigou Sarafi 9-13, 55132, Thessaloniki, Greece

Email: afboutou@yahoo.com

Telephone number: 00306946611433

Keywords:

Anemia;

Chronic Obstructive Pulmonary Disease;

Epidemiology;

Systemic Inflammation;

Aetiology

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Abstract

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. 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.

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The prevalence of anemia in COPD

There 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%.(1)(2) In contrast to expectations, polycythemia was less common than anemia, its prevalence ranging from 6-18.1%.(3)(4)(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,(6)(4)(7)(8)(9)(10)(11)(12) hospitalized patients for an acute exacerbation of COPD (AECOPD),(13)(14)(15)(15)(17) intubated patients in the intensive care unit(18), COPD patients from the general population(10)(11) 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 anemia, so results are not easily comparable.

COPD diagnosis, according to ERS/ATS guidelines, should be based on specific spirometric criteria.(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,(4)(7)(8)(9)(14)(2)(21) several have applied the ICD 9/10 codes (13)(22)(23)(24) 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 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 (25) and these thresholds have been used by several authors in order to identify anemic COPD patients.(5)(8)(11)(15)(26) However, the use of a Hb <12 g/dL threshold to define anemia in postmenopausal women is currently under debate,(27) so the 13g/dL threshold for both male and female has also been applied.(4)(7)(2)(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.(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);(3)(9)(14)(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%.(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

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prevalence ranging between 15%-17.1%.(7)(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.(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(3); these results were similar to the ones of Dal Negro et al(19) and of Kollert et al,(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%(10)(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.(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%.(15)(28) Hospital-acquired anemia (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(1) and Barbra et al(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.(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.(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 COPD

Although 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

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increasingly recognized as a disorder with important systemic manifestations,(30) so the development of “anemia of chronic disease” (ACD) among COPD patients could be expected.

Pathogenesis of anemia of chronic disease

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.(32)(33)(34)(35) For this reason ACD has also been characterized as “anemia of inflammation”.(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.(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.(31)

a) disorders of iron homeostasis

One 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.(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.(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 ferroprotein.(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 homeostasis is regulated by several molecules, with hepcidin - a 25 amino acid protein secreted by liver - being the most important.(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.(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.(44) IL-6 distorts iron metabolism,(45) since it modulates ferritin translation, expression of transferrin mRNA and, possibly, expression of DMT1.(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. (31) IL-10 can also impair iron homeostasis by inducing ferritin expression and increasing the acquisition of iron by macrophages.(46) Finally, lipopolysaccharide and IL-6 are major stimulants of hepcidin synthesis, leading to hypoferremia within hours of inflammatory stimulant in animal models.(43)

b) disorders of proliferation and differentiation of erythroid progenitor cells(35)

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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.(32) Several cytokines, exert inhibitory effects on erythroid progenitor cells; IL-1a inhibits erythropoiesis in vivo in mice and in vitro in humans,(47) TNF-a and INF-γ inhibit erythroid colony formation in uremic sera,(48) while there is an inverse relationship between INF-γ concentration, reticulocytes count and hemoglobin (Hb) concentration.(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.(31)(50) Moreover, erythropoiesis is further inhibited by the limited availability of iron to erythroid progenitor cells.(32)

c) resistance to the action of erythropoietin

Erythropoietin (EPO) is a protein hormone which promotes erythroid cell proliferation; the most potent known stimulus for EPO production is tissue hypoxia.(51) Most patients with ACD have disproportionately low erythropoietin levels for the severity of anemia present.(52)(53) In vitro studies indicate that IL-1 and TNF-α inhibit hypoxia-induced EPO production in a dose-dependent manner,(54) while in anemic individuals high levels of IL-1, IL-6 and TNF-α are associated with low levels of EPO.(53) Cytokine overproduction is the most probable cause for hyporesponsiveness to EPO treatment in anemic individuals without iron deficiency.(55) Abnormal iron metabolism also contributes to EPO resistance; iron not only becomes unavailable for erythroid progenitor cells,(31) but its depletion may also impair erythropoietin transgene expression.(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 (57)(58)(59)(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,(57)(58)(62)(63) and with several systemic COPD manifestations and comorbidities, such as muscle cachexia, pulmonary hypertension, heart disease and depression.(64)(65)(66)(67)(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. (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.(69)

Systemic inflammation and ACD: The role of exacerbations

One 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

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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,(59)(70)(71)(72) and this increase often persists after the improvement of lung function.(70)

Two studies have studied the potential association between systemic inflammation and EPO levels during an AECOPD, but results are conflicting. Markoulaki et al(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(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.(75)

Oxygen supplementation

As described above, tissue hypoxia is the most potent trigger for EPO production which results in increased erythropoiesis.(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.(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.(77) Moreover, the severity of hypoxemia could be of some importance, apart from its presence; Fitzpatrick et al (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.(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

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lower initial EPO levels and erythrocyte count, EPO levels significantly increased.(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.(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 impairment

Renal 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.(82) More recent studies have confirmed the high prevalence of microalbuminuria (83) and renal dysfunction among COPD patients compared to controls,(84) although rates were lower in younger COPD cohorts.(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.(86)(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)(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.(89)(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.(91)(92)

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.(93)(94)(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.(96)(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.(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.(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.(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,(101) the potential impact on erythropoiesis should be taken into consideration in the designing of clinical trials and in the evaluation of their outcome.

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Theophylline treatment

Theophylline is a non-selective adenosine receptor antagonist, which can inhibit renal vasoconstriction in response to exogenous and endogenous adenosine.(102)(103) In vitro studies have shown that adenosine mediates hypoxia-induced renal EPO production,(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,(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.(106) 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 22-69%.(107) The cause of this deficiency is multifactorial and it includes chronic hypoxia, disease severity, smoking, corticosteroid therapy, chronic inflammation and aging itself.(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.(109)(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,(111) 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.(112)(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. (112)(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.(115) Similar were the results of Kythreotis et al, who reported a significant decrease of circulating IGF-1 during AECOPD (114) and of Coskun et al, who indicated that the greater the disease severity, the lower were serum levels of IGF-1.(116) On the other hand, there is some evidence that GH levels are significantly elevated in COPD patients compared to healthy controls, (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.(118) In patients with diabetic chronic kidney disease, IGF-1 levels were independently associated with hemoglobin concentration,(119) while in patients with erythrocytosis, IGF-1 levels were positively associated with hematocrit level, even in the absence of increased EPO production.(120)(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

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establishment in this population. A few trials of GH or ghrelin therapy in COPD exist but changes in hemoglobin were not reported.(122)(123)

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.(124)(125) Obase et al reported that daily iron intake among 13 COPD patients was about half of that of 27 age matched controls;(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,(127)(128) and this could contribute to the establishment of anemia.

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. 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.(129)(130) The cause of anemia is multifactorial. Increased systemic inflammatory markers, such as TNF-α and IL-6,(131)(132) decreased sensitivity of erythroid progenitor cells to EPO,(133) lower ability of the aging kidney to produce adequate EPO quantities,(130) malnutrition(125) and high burden of comorbidities(129)(130) all contribute to the establishment of anemia 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 anemic COPD patients with concomitant chronic renal insufficiency led to an improvement of hemoglobin concentration and a reduction in dyspnea.(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.(135)(136) Both COPD and heart failure are characterized in part by impaired oxygen transport (because of ventilator limitation or pump failure respectively). One large(135) and several smaller studies(137)(138)(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.

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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,(140) RAS pathway,(141) and IGF-1,(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.(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.

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

First author Year of publica

tion

Country Study design COPD population characteristics

Size of COPD

population

COPD diagnosis Anemia diagnosis Anemia prevalence

Almagro (14) 2012 Spain Longitudinal, multicenter Hospitalized for AECOPD

606 Postbronchodilator FEV1<80% predicted and FEV1/FVC<0.70

Based on a questionnaire

19.3%

Barbra (13) 2012 Spain Retrospective, multicenter(Basic Minimum Data Set records)

Hospitalized for AECOPD

289,077 ICD-9-CM codes ICD-9-CM codes 9.8%

Boutou (8) 2011 Greece Prospective case-control Stable hospital outpatients

283 Postbronchodilator FEV1/FVC<0.70

Males: Hb<13 g/dlFemales: Hb<12 g/dlPlus clinical and laboratory criteria for ACD

10.2%

Boutou (7) 2013 UK 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 (3) 2005 France Retrospective, multicenter(ANDATIR database)

Hypoxemic patients under LTOT

2,524 FEV1<80% and FEV1/FVC<70%

Male: Ht<39%;Female: Ht<36%

Male:12.6%Female:8.2%

Comeche Casanova (26)

2013 Spain Prospective Stable hospital outpatients

130 GOLD criteria Male: Hb<13g/dlFemale Hb<12 g/dl

6.2%

Copur (2) 2013 USA 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 (4) 2007 USA 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 (19) 2012 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 (15) 2011 Belgium 1st cohort retrospectively (1980-1984)2nd cohort prospectively (2001-2005) studied

Hospitalized for AECOPD

1st: 512nd: 101

1st: ICD-92nd: FEV1/FVC<0.70 plus ≥10 pack/year smoking history

Male: Hb<13g/dlFemale Hb<12 g/dl

1st: 9.8%2nd: 27.7%

Halpern (22) 2006 USA Retrospective (1999-2001 US Medicare Claims database)

Both inpatients and outpatients >65 years old

132,424 ICD-9 codes ICD-9 codes 21%

John (9) 2006 Germany Retrospective Discharged from hospital

312 ICD-9/10 codesSeverity according to GOLD

Male: Hb<13.5 g/dlFemale: Hb<12 g/dl

23.1%

John (23) 2005 Germany Prospective Stable outpatients 101 According to ATS guidelines

Male: Hb<13.5 g/dlFemale: Hb<12 g/dl

13%

Joo (10) 2012 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/dlFemale Hb<12 g/dl (non-pregnant)Female: Hb<11 g/dl (pregnant)

7.3%

Kollert (5) 2013 Germany Retrospective (database ofthe Donaustauf Hospital Center for Pneumology)

Patients with CRF prior initiating NIV

309 Clinical history and EV1/FVC<70%Plus GOLD criteria for stages III/IV

Male: Hb<13 g/dlFemale: Hb<12 g/dl

14.9%

Krishnan (11) 2006 USA 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/dlFemale: Hb<12 g/dl

7.5%

Martinez-Rivera (28)

2012 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%

Nowinski (1) 2011 Poland Longitudinal prospective Hospitalized for 464 Diagnostic criteria Male: Hb<13.5 g/dl 4.9%

12

AECOPD not described. Severity categorized by GOLD

Female: Hb:<12 g/dl

Nowinski (16) 2013 Poland Retrospective Hospitalized for AECOPD

402 According to Polish Society for Lung Diseases criteria

Male: Hb<13 g/dlFemale: Hb<12 g/dl

26%

Rasmunssen (18)

2011 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 (21) 2013 Netherlands Retrospective Patients with moderate to severe COPD, screened for PR

321 According to ERS/ATS guidelines

Male: Hb<13 g/dlFemale: Hb<12 g/dl

20%

Shorr (24) 2008 USA Retrospective ( healthcare maintenance organization database)

Both inpatients and outpatients

2,404 ICD-9 Male: Hb<13 g/dlFemale: Hb<12 g/dl

33%

Watz (6) 2008 Germany Cross-sectional Stable outpatients (recruited form institution’s database)

170 Established by spirometry (no further details given).Severity by GOLD and BODE index

Hb<13 g/dl 5.3%

Zavarreh (12) 2013 Iran Cross-sectional Stable outpatients 74 Established by spirometry (no further details given).Severity by GOLD

Male: Hb<13 g/dlFemale: Hb<12 g/dl

27%

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 Rehabilitation

Figure 1. The complex pathophysiology of anemia in COPD.

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