Anemia in Chronic Obstructive Pulmonary Disease and the Potential Role of Iron Deficiency

Figures & data

Table 1. Possible indicators of iron deficiency anemia, anemia of chronic disease, and combined anemia of chronic disease with iron deficiency (14,19–21,34)

Indicator	IDA	ACD	ACD with Functional Iron Deficiency
Hemoglobin	< 13 males	< 13 males	< 13 males
	< 12 females	< 12 females	< 12 females
%Transferrin Saturation	< 20%	> 20%	< 20%
Ferritin	< 100 ng/mL	>300 ng/mL	100–300 ng/mL
%HRC	≥ 6%	< 6%	≥ 6%
CHr	< 29 pg	>29 pg	< 29 pg

Abbreviations: IDA (iron deficiency anemia), ACD (anemia of chronic disease), %HRC (percent hypochromic red cells), CHr (reticulocyte hemoglobin content).

Table 2. The effects of anemia on COPD outcomes (2–12)

Author	Sample Characteristics	Anemia Prevalence	Outcomes Associated with Anemia	Other
Krishnan et al. (4)	General population, 35–79 years (n = 2,704; 495 had moderate/severe COPD)	7.5% of COPD participants (Hb <12 g/dL F, < 13 g/dL M)	Reduction in quality-of-life score for physical component summary (p=0.003).	Sampling from general population and low proportion with anemia may have indicated a healthier study population.
Schnecke-npointner et al. (2)	Patients with chronic respiratory failure being followed for intermittent home mechanical ventilation (n = 185, 85 with COPD)	17.6% COPD participants (n = 15; Hb <12 g/dL F, <13 g/dL M)	Hb and TSAT ≥20% independently associated with improved health-related quality-of-life scores (Hb p=.036, TSAT p=.005) and dyspnea (Hb p=.005, TSAT p=.006). Multivariate analysis: serum iron and TSAT were independent prognostic indicators (p < .05 each)	Researchers evaluated IDA (n = 9), ACD (n = 13) and mixed ACD+IDA (n = 1) within study population. IDA defined as TSAT<20% and ferritin< 35 ng/mL; ACD+IDA as TSAT < 20%, ferritin 35–199 mg/mL with sTFR/log ferritin ≥ 1.5; ACD as TSAT < 20%, ferritin ≥ 200 ng/mL or TSAT < 20%, Ferritin 35—199 ng/mL and sTFR/log ferritin < 1.5.
Cote et al. (6)	Clinically stable COPD outpatients (n = 683, of which 677 included in analysis)	17% Hb < 13 g/dL	Multivariate regression analysis: anemia independent predictor of dyspnea (p < 0.05) and lower 6-minute walk distance (p=0.001)	Anemia defined similar in M/F due to debate on appropriate postmenopausal F Hb levels and low proportion of F (4%). Hb differed among survivors (p < 0.01) but with multiple regression anemia was not an independent mortality predictor.
Chambellan et al. (7)	Entered into the French homecare database for chronic respiratory insufficiency and being followed for home oxygen support, mechanical ventilation or continuous positive airway pressure (n = 2,524)	12.6% M (Hct < 39%) and 8.2% F (Hct <36%)	Hct associated with FEV1 percentage of predicted (r = -0.054, p=0.006) and FEV1/VC (r = -0.084, p < 0.001) Multivariate regression: Hct independent predictor of survival (p < 0.001) hospital admission rates (p < 0.002) and cumulative duration of hospitalization (p < 0.001). Average 3-year survival 24% when hct < 35% (95% CI 16–33%) and 70% when hct ≥ 55% (95% CI 63–76%).	Researchers had limited access to co-morbidity data. Only a small percentage with Hct > 55% (8.4%).
Boutou et al. (8)	Stable COPD outpatients (n = 283 for the prevalence study, 27 cases with ACD matched to 27 controls for exercise testing)	10% ACD (Hb < 12 g/dL F, <13 g/dL M, ferritin >30 mg/mL, TIBC< 250 ug/dL, TSAT 15-50%)	ACD was associated with a higher dyspnea score (p < 0.001), lower VO2% predicted (p=0.005), peak work rate (p=0.014, percent predicted p=0.023) and peak VO2/heart rate (percent predicted p=0.01, ml/beat p=0.023)	Patient stability defined as: no exacerbation, hospital admission, respiratory infection, or change in medication for 3 months prior to entering study
Boutou et al. (9)	Stable COPD outpatients (n = 294)	15.6% (Hb <13 g/dL)	Anemia independent predictor of mortality (HR 1.87, 95% CI 1.06–3.29) Anemia associated with shorter median survival (p=0.035)	Anemia defined similar in M/F due to debate on appropriate postmenopausal F Hb levels Mortality associated to anemia, not Hb level
Halpern et al. (3)	U.S. Medicare database claims from 1997–2001 (n = 132,424)	21% (ICD-9 code or receipt of transfusion)	Medicare payments greater for anemic patients (∃1,466 vs. ∃649, p < 0.001) Multivariate analysis: Anemia associated with ∃3,582 increase in per patient annual reimbursements. Anemia associated with higher mortality rate (p < 0.001), ICU admission (p < 0.001), ventilation episodes (p < 0.001), and nursing home admission (p < 0.001).	Patients with other possible causes of anemia were excluded by ICD-9 coding (end stage renal disease, cancer, gastrointestinal bleeding, known nutritional or hereditary anemias) Possibility of coding bias
Shorr et al. (11)	Retrospective cohort of claims made by an integrated healthcare system in the Mid-Western US from 1997-2005 (n=2,404)	33% (Hb < 12 g/dL F, < 13 g/dL M twice in 14–356 days)	Higher annual costs for anemic COPD patients (∃17,240 vs. ∃6,492, p < 0.001), greater healthcare encounters (p=0.0001), hospitalization rates (p=0.0001) and days of duration (p=0.0001). Multiple regression analysis: anemia increased annual cost by ∃7,929 per patient (p < 0.0001)	Anemia was verified in the records; however, identification of COPD was dependent on ICD-9 coding
Ozyilmaz et al. (12)	Patients admitted for COPD exacerbation to out- or inpatient clinics (n = 107)	n/a	Multivariate logistic regression analysis: Hct < 41% independent predictor of frequent exacerbations (p=0.009), Hct negatively correlated with frequent severe exacerbations (p=0.014) Multivariate analysis: Hct < 41% independent predictor of hospital readmission within 2 months (p=0.002)	A cutoff of Hct < 41% was used because within the study population it demonstrated the greatest sensitivity/specificity.
Kollert et al. (5)	Patients being treated with home noninvasive ventilation (n = 309)	14.9% (Hb < 12 g/dL F, <13 g/dL M)	Multivariate analysis: Improvement in survival associated with Hb of 14.3 mg/dL in F, 15.1 mg/dL in M (p < 0.001), these levels independently predicted survival (p=0.03) Hb associated with long term survival (p < .001) Higher survival rate in polycythemic patients vs. anemic patients (p=0.01)	18.1% had polycythemia (Hb ≥ 15 g/dL F, ≥17 g/dL M)
Martinez-Rivera et al. (10)	Patients hospitalized with acute COPD exacerbation (n = 117)	33% (Hb < 13 g/dL)	Anemia independently associated with increased mortality (p=0.000, χ^2 test), shorter mean survival (p < 0.000, log rank test) Anemic patients had a RR of death of 5.9 IC 95% 1.9–18.9, p=0.003).	Exclusion criteria included patients requiring immediate ICU monitoring and/or invasive or noninvasive ventilation. Anemia defined similar in M/F due to debate on appropriate postmenopausal F Hb levels and low proportion of F (7%).

Abbreviations: COPD: chronic obstructive pulmonary disease, Hb: hemoglobin, TSAT: transferrin saturation, Hct: hematocrit, sTFR: serum transferrin receptor, TIBC: total iron binding capacity, M: males, F: females, IDA: iron deficiency anemia, ACD: anemia of chronic disease, FEV₁: forced expiratory volume in 1 second, VC: vital capacity, VO₂: oxygen uptake, U.S.: United States, ICU: intensive care unit.

Table 3. Studies of iron in COPD or on lung function (35–38)

Author	Study Design	Findings	Comments
McKeever et al. (35)	Data from the Third NHANES (US population cross-sectional study). Measured serum markers of 21 nutrients and FEV1	Increased serum iron correlated with increased FEV1 (p=0.0054).	Serum iron may also influenced by inflammation.
Obase et al. (36)	13 stable COPD patients, 10 smokers with COPD symptoms, 27 healthy controls, 70 years/older. Respiratory function and diet intake was evaluated.	% predicted FEV1 correlated with iron intake in the COPD group (p=0.03) Symptomatic smokers and those with COPD had lower iron intake (p < 0.0001)	Diet intake evaluated over 24 hours.
Hirayama et al. (37)	278 COPD patients ages 50–75 years, control group 340 community dwelling adults. Respiratory function was evaluated with intake of 6 minerals.	Lower COPD risk with higher energy adjusted intakes of iron (OR 0.68, 95% CI 0.39–0.99, test for linear trend p=0.01) Iron intake associated with % predicted FEV1 (p=0.001)	Food frequency questionnaire used for dietary evaluation.
Smith et al. (38)	16 healthy volunteers with normal iron status were exposed to hypoxia either with or without prior iron supplementation.	Iron supplementation prior to hypoxic insult resulted in a lower rise in baseline PASP with prolonged hypoxia (p < 0.001) and attenuated the increase in PASP response to acute hypoxia (p=0.002)	Increases in PASP resulting from disease related hypoxia can be seen in COPD.

Abbreviations: COPD: chronic obstructive pulmonary disease, NHANES: National Health and Nutrition Examination Survey, U.S.: United States, FEV₁: forced expiratory volume in 1 second, PASP: pulmonary arterial systolic pressure.

Table 4. Studies on correction of anemia in COPD (14,43–45)

Author	Study Design	Treatment	Findings
Silverberg et al. (14)	Prevalence study: 107 patients hospitalized for acute exacerbation of COPD Treatment study: 11 of 12 patients with COPD/chronic renal failure meeting criteria for iron deficiency	None IV Iron and ESA (Recormon)	43.9% were anemic. Of the anemic patients 18 had iron studies completed during admission, all 18 met criteria for iron deficiency. None received treatment during hospitalization or at discharge. Change in Hb correlated to the change in severity of dyspnea (VAS) (r = 0.71, p=0.009). Change in Hct correlated to the change in VAS (r = 0.8, p=0.0014).
Schönhofer et al. (43)	Case studies: 5 anemic patients with COPD and difficulty weaning from ventilator support	PRBC provided to achieve Hb ≥ 12 g.dL^-1	After receiving PRBC to correct the anemia, patients were able to wean from ventilator support.
Schönhofer et al. (44)	20 anemic adults (Hb < 11 g/dL) 10 with severe COPD, 10 without lung disease	1 unit PRBC for each g/dL Hb was below 11–12 g/dL	Reduction in mean minute ventilation (p < 0.0001), decreased work of breathing (p < 0.0001), increased capillary PCO2 (p < 0.05) decreased PO2 (p < 0.05). No change seen in lung function measures for the control group.
Creutzberg et al. (45)	Double blind, randomly assigned 63 COPD patients to either treatment or control group	On days 1, 15, 29, 43 injection of nandrolone decanoate (50 mg) in arachis oil or arachis oil alone	Treatment group had a tendency towards increases in Hct (p=0.1), Hb (p=0.15) and erythropoietin (p=0.15). Change in maximal inspiratory mouth pressure (r = 0.29, p=0.039) and peak workload (r = 0.33, p=0.019) significantly associated with change in Hb independent of change in FFM. Change in work of lower extremities associated with change in erythropoietin independent of change in FFM (r = .37, p=0.015).

Abbreviations: COPD: chronic obstructive pulmonary disease, Hb: hemoglobin, Hct: hematocrit, VAS: visual analogue scale (measures severity of dyspnea), PRBC: packed red blood cells, FFM: fat free mass.

Table 5. Comparison of IV iron preparations and their dosing guidelines (51,58–63)

	LMW Iron Dextran*	Ferric Gluconate	Ferumoxytol	Iron Sucrose	Ferric Carboxymaltose
Benefits	Total dose infusion in a single treatment can be accommodated	Well established	Higher dosing threshold	Has been evaluated in studies of functional iron deficiency in CHF	Slower release of iron may provide a lower oxidative burden. Higher dosing threshold.
Limitations	Higher rates of significant adverse drug events Requires a test dose	Only approved for patients receiving dialysis and epoetin therapy	Only approved for adults with iron deficiency and CKD Can alter MRI studies Newer iron preparation	Only approved for patients with chronic kidney disease While single doses up to 500 mg are approved, recommended not to exceed 300 mg	Newer iron preparation.
Product Dosing Guidelines	Daily doses for adults not to exceed 100 mg	125 mg per dialysis session	510 mg dose with a second 510-mg dose 3–8 days later	1,000 mg provided in multiple 200-mg doses over a 14-day period Larger amounts (300 mg) can be accommodated	For patients over 50 kg 1,500 mg provided in two doses of 750 mg at least 7 days apart.

LMW (low molecular weight), CHF (congestive heart failure), CKD (chronic kidney disease), MRI (magnetic resonance imaging).

*Use of high molecular weight iron dextran preparations is not recommended due to higher incidence of adverse reactions.

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