Anemia and iron deficiency in COPD patients: prevalence and the effects of correction of the anemia with erythropoiesis stimulating agents and intravenous iron
BMC Pulmonary Medicine
Anemia and iron deficiency in COPD patients: prevalence and the effects of correction of the anemia with erythropoiesis stimulating agents and intravenous iron
Donald S Silverberg 0
Ram Mor 2
Melanie Tia Weu 1
Doron Schwartz 0
Idit F Schwartz 0
Gil Chernin 0
0 Nephrology Department, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University , Tel-Aviv , Israel
1 Department of Nephrology, CHU de Yopougon Hospital , Abidjan, Ivory Coast
2 Pulmonology Institute, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University , Tel-Aviv , Israel
Background: Little is known about iron deficiency (ID) and anemia in Chronic Obstructive Pulmonary Disease (COPD). The purposes of this study were: (i) To study the prevalence and treatment of anemia and ID in patients hospitalized with an exacerbation of COPD. (ii) to study the hematological responses and degree of dyspnea before and after correction of anemia with subcutaneous Erythropoiesis Stimulating Agents (ESAs) and intravenous (IV) iron therapy, in ambulatory anemic patients with both COPD and chronic kidney disease. Methods: (i) We examined the hospital records of all patients with an acute exacerbation of COPD (AECOPD) to assess the investigation, prevalence, and treatment of anemia and ID. (ii) We treated 12 anemic COPD outpatients with the combination of ESAs and IV-iron, given once weekly for 5 weeks. One week later we measured the hematological response and the severity of dyspnea by Visual Analogue Scale (VAS). Results: (i) Anemia and iron deficiency in hospitalized COPD patients: Of 107 consecutive patients hospitalized with an AECOPD, 47 (43.9%) were found to be anemic on admission. Two (3.3%) of the 60 non-anemic patients and 18 (38.3%) of the 47 anemic patients had serum iron, percent transferrin saturation (%Tsat) and serum ferritin measured. All 18 (100%) anemic patients had ID, yet none had oral or IV iron subscribed before or during hospitalization, or at discharge. (ii) Intervention outpatient study: ID was found in 11 (91.7%) of the 12 anemic ambulatory patients. Hemoglobin (Hb), Hematocrit (Hct) and the VAS scale scores increased significantly with the ESAs and IV-iron treatment. There was a highly significant correlation between the ΔHb and ΔVAS; rs = 0.71 p = 0.009 and between the ΔHct and ΔVAS; rs = 0.8 p = 0.0014. Conclusions: ID is common in COPD patients but is rarely looked for or treated. Yet correction of the ID in COPD patients with ESAs and IV iron can improve the anemia, the ID, and may improve the dyspnea.
Iron deficiency; Anemia; COPD; Renal failure; Erythropoietin
Anemia is seen in 10-30% of Chronic Obstructive
Pulmonary Disease (COPD) patients [
]. The anemia is
associated with increased mortality and morbidity
including increased hospitalization and increased health
care costs [
]. The anemia in COPD has been
associated with a negative effect on dyspnea and walking
], on circulatory efficiency (as compared to
non-anemic COPD patients) as judged by lower peak
oxygen uptake and lower peak work rate [
] and with
the need for home oxygen therapy and lower mean
peripheral oxygen values both at rest and during exercise [
Although there are many contributors to the anemia it is
probably caused mainly by the inflammatory nature of
], with the increased cytokine production
causing anemia and iron deficiency (ID) [
Little information exists on the role of iron deficiency
(ID) in COPD although serum iron and %TSat levels
were found in a US population-based cross sectional
study to be directly related to one second Forced
Expiratory Volume (FEV 1) levels [
]. In addition iron intake
in COPD patients has been found to be about half that
of normal controls [
Surprisingly, not a single study has, to our knowledge,
been reported using either of these two agents,
Erythropoiesis Stimulating Agents (ESAs) or intravenous (IV)
iron, in the treatment of the anemia and/or iron
deficiency of COPD.
Our hypothesis was that functional ID may be a
prevalent condition in patients with COPD. To test this
hypothesis, we reviewed retrospectively a series of 107
patients admitted for AECOPD.
In our medical clinic devoted to the treatment of
anemia due to chronic kidney disease (CKD) and
congestive heart failure (CHF) [
], we found 12 patients
that were also suffering from COPD. We evaluated the
clinical effect of treating anemia and ID with ESAs and
Approval of the study was granted by the Ethical
Committee of the Tel-Aviv Medical Center.
We examined the hospital records of all patients
admitted with an AECOPD between January 1, 2012 to
December 31 2012 to assess the prevalence, the
investigation and treatment of anemia and ID in these
patients. COPD diagnosis was based on information
encoded in the administrative database.
We identified 12 anemic (defined as Hb < 12 g/dl)
patients with an established diagnosis of COPD who had
been treated in our clinic. We analyzed the effects of the
combination of subcutaneous ESAs and IV-iron on
dyspnea in these patients. Patient characteristics that were
examined at baseline included presence of CKD, CHF,
hypertension, diabetes, dyslipidemia and the medications
The anemia was corrected with the combination of
ESAs and IV-iron given once weekly for 5 weeks and the
final assessment was done one week after the last dose.
IV iron (200 mg of elemental iron) was given as two
5 ml ampoules- each containing a total of 100 mg of
elemental iron) of Venofer -Ferric Sucrose (Vifor Int, St.
Galen, Switzerland). The doses were given one week
apart (a total of 1000 mg elemental iron) for 5 weeks.
ESAs were given weekly in the form of 10,000
International Units (IU) of subcutaneous (sc) Recormon
(Roche, Basel, Switzerland) for five weeks at the same
time that the IV iron was given. Weight, height, and
blood pressure were measured on every weekly visit.
Blood work, done initially, at every visit and one week
after the fifth treatment, included: Hemoglobin (Hb),
Hematocrit (Hct), Red Blood Cells (RBCs) and RBC
indices, Red Cell Distribution Width (RDW), platelets, serum
iron, Transferrin, percent transferrin saturation (%Tsat)
defined as serum iron divided by serum transferrin
multiplied by 100%, serum ferritin, albumin, SGOT, SGPT,
serum creatinine. Several definitions for ID were
] and here we defined ID by three different
criteria: (i) serum ferritin of <100 ng/ml, (ii) %TSat <20%,
or (iii) either a serum ferritin of <100 ng/ml or the
combination of serum ferritin of 100-300 ng/ml and %TSat
of <20%. Estimated glomerular filtration rate (eGFR) was
calculated by the MDRD equation [
Pulmonary function was performed by spirometry
which was performed in accordance with the
recommendations of the American Thoracic Society [
one second Forced Expiratory Volume (FEV 1), Forced
Vital Capacity (FVC) and the FEV1/FVC, all assessed as
percent of predicted values, were measured before but
not after the EPO-IV iron therapy.
Health perception was assessed at baseline and one
week after the fifth injection of EPO and IV iron. We
used a Visual Analog Scale (VAS) making a line 10 cm
in length, in which a score of 0 at one end corresponds
to extremely severe dyspnea on walking a short distance
or at rest and a score of 10 at the other end corresponds
to no dyspnea on walking or at rest. The patient placed
an X on what they considered their current status
before and 1 week after the last dose of the combination
All results of Study 2 are reported as median and
interquartile range [IQR]. All variables did not follow a
normal distribution and were therefore analyzed by the
Wilcoxon signed rank sum test to evaluate the changes
in them after treatment. The Spearman correlation
coefficients were calculated between pre- and post values of
all parameters to examine the relationships between the
two measurements. A two-tailed value of p < 0.05 was
considered to be significant.
Statistical analysis was performed by SAS for windows
Study 1- Prevalence of anemia and iron deficiency in
patients hospitalized with AECOPD
Of 107 consecutive hospital records examined of
patients admitted with AECOPD, 47 patients (43.9%) were
found to be anemic on admission (Hb < 12 g/dl) and 60
(56.1%) not anemic (Table 1). Only two (3.3%) of the 60
non-anemic patients were investigated for ID (serum
iron, %TSat and serum ferritin) as compared to18
(38.3%) of the 47 anemic patients. All 18 (100%) of the
anemic patients had ID by our criteria, yet none had oral
or IV iron subscribed either before admission, during
hospitalization, or at the time of discharge. In the 18
anemic patients, if ID was only defined as a serum
ferritin of <100 ng/ml it was found in 11/18 (61.1%). If ID
was defined only as %TSat <20%, in 18/18 (100%). If
defined as either a serum ferritin of <100 ng/ml or the
combination of serum ferritin of 100-300 ng/ml and
%TSat of <20% it was found in 18/18 (100%). By whatever
definition used, ID was very common. In the two non
anemic patients, in which the iron status was measured,
one had a %TSat of 40% and a serum ferritin of 200 ng/ml
and was not iron deficient while the other had a %TSat
of 14% and a serum ferritin of 160 ng/ml and was iron
Study 2- Outpatients intervention study
The anthropological and clinical characteristics of the 12
patients (Table 2) showed a median age of 74.0 years
[66.5-79.5]. A past medical history of hypertension,
Abbreviations: CHF, congestive heart failure; CHD, coronary heart disease;
Hb, hemoglobin; Hct, hematocrrit; SD, standard deviation; *, p > 0.05 (not
CKD, CHF, diabetes and dyslipidemia and a past or
present history of smoking were very common; indeed
all had CKD. Angiotensin Converting Enzyme Inhibitors
(ACEIs) and/or Angiotensin II Receptor Blockers (ARBs),
beta blockers and statins were being used frequently. All
were on bronchodilators.
The baseline FEV1 was 46.5% [
] of predicted
values and the baseline FEV1/FVC was 65.5% [
predicted values. The median basal oxygen saturation
measured by pulse oximetry was 94.5% [92–96].
Red cell indices
The anemia was normocytic and normochromic in all,
with normal mean values for MCH, MCV and MCHC.
The mean RDW was increased.
Prevalence of iron deficiency
If defined as only a serum ferritin of <100 ng/ml it was
found in 6/12 (50%). If defined only as %TSat <20%, in
9/12 (75%). If defined as the combination of serum
ferritin of <300 ng/ml and %TSat of <20% it was found
in 9/12 (75%). If defined (as we defined it) as either a
serum ferritin of < 100 ng/ml or the combination of
serum ferritin of 100-300 ng/ml and %TSat of <20%, it
was found in 11/12 (91.6%) of the cases. By whatever
definition used, iron deficiency was very common in
these ambulatory anemic COPD patients.
Results of treatment
Hemoglobin and red cell indices
The Hb rose from an initial median of 9.9 g/dl [9.2-10.6]
to 12.35 g/dl [11.6-13.0] (p = 0.0005) by one week after
the last injection. The Hct similarly increased from 29.9%
[28.0-31.5] to 38.1% [35.0-39.4] (p = 0.0005). The median
RBC count increased from 3.3 cells/mcL [3.2-3.7] to 3.9
cells/mcL [3.6-4.3] (p = 0.01).
The serum ferritin and %TSat increased significantly by
one week after the last dose versus baseline. Serum
ferritin from 99 ng/ml [48.6-127.4] to 330.6 ng/ml
[243.4615.2] (p = 0.005) and %TSat from 12.8% [11–19.1] to
24.0% [18.5-27.9] (p = 0.005).
Other blood parameters
The changes in the RDW, WBC, lymphocytes and
platelets were not significant (Table 3).
Hemoglobin and Hematocrit correction and improvement
The VAS scale increased from an initial 2.5 [
] to 8.5
] (p = 0.0005).
There was no significant correlation between baseline
Hb and VAS or baseline Hct and VAS. There was a highly
significant correlation between the ΔHb and ΔVAS;
rs = 0.71 p = 0.009 and between the ΔHct and ΔVAS;
rs = 0.8 p = 0.0014 (Figure 1).
As seen in Table 3 the mean SBP and DBP, weight, BMI,
serum albumin, cholesterol, SGOT, and SGPT remained
unchanged. Neither the serum creatinine nor the eGFR
The median follow-up period after termination of ESAs
and IV-iron treatment was 1.9 years (range 0.4-4.5 years).
Four patients died after follow-up of 0.4 to 3.8 years. Of
these four patients, two reached end-stage renal disease
with the need for hemodialysis. Only one of the four
deaths was directly attributed to respiratory disease. Six
patients continued treatment in our clinic with ESAs
and/or IV iron therapy as needed and another two
patients were lost during follow-up.
AECOPD episodes, in the first year after anemia
treatment, were documented in seven of the nine patients that
were followed for more than a year. The median time from
termination of anemia therapy to first exacerbation in these
seven patients was 131 days (range 23–307 days).
We have shown that anemia and ID are very common in
hospitalized AECOPD patients but ID is neither sought
for or, if found, is not treated. Patients hospitalized for
AECOPD have relatively severe COPD. It was suggested
that the prevalence of anemia is likely higher in this group
compared to the general COPD population [
Surprisingly, there are scarce data about ID in COPD.
Recently, Comeche Casanova et al. have shown in a cohort
of 130 patients with stable COPD that serum iron was
significantly lower in anemic patients than in those without
We have also shown in a small retrospective study in
anemic outpatients with moderate to severe COPD that
treatment with ESA and IV-iron significantly improved
the anemia and ID, and that this was associated with a
significant improvement in self-assessed shortness of
breath. The improvement in the VAS dyspnea score was
directly related to the increase in Hb and Hct. The
hematological improvement of the anemia in this group
of patients with COPD was similar to the effect that we
have previously shown when ESAs and IV-iron were
used in renal failure and heart failure, even without
These results are consistent with the findings of others
who treated anemia in COPD with either anabolic
] or blood transfusions [
]. The study
involving the use of anabolic steroids in COPD 
showed that the improvement in the Hb that was found
was associated with an improvement in pulmonary
function as judged by maximal inspiratory mouth pressure
and peak workload. In another study, transfusion of a
mean of 2.2 units of packed cells in 10 anemic COPD
patients in an intensive care unit was shown to lead to a
significant reduction of both minute ventilation and
work of breathing [
]. In a second study by the same
], blood transfusions allowed five anemic
COPD patients, in whom trials of weaning from a
respirator before the transfusions had been unsuccessful, to
be successfully weaned after the transfusions. All these
studies, in addition to the present study, suggest that
correction of the anemia in COPD may improve
pulmonary functions and respiratory symptoms.
Anemia in patients with COPD is likely due to a
combination of several factors [
]: (i) Elevated
cytokines levels, especially Tumor Necrosis Factor alpha
(TNF α) and interleukin-6 (IL-6) [
Moreover, persistent inflammation may be associated
with poor clinical outcome for COPD patients .
The elevation of cytokines can lead to reduced production
of erythropoietin (EPO), reduced erythropoietic response
of the bone marrow to EPO (i.e. resistance to EPO),
hepcidin-induced failure of iron absorption from the gut,
and hepcidin-induced trapping of iron in iron stores in the
macrophages and hepatocytes [
]. (ii) Concomitant CKD
with reduced production EPO [
]. (iii) Use of
Angiotensin Converting Enzyme Inhibitors (ACE-I) and
Angiotensin Receptor Blockers (ARBs) that can cause reduced
activity of EPO in the bone marrow [
]. (iv) Concomitant
Diabetes Mellitus [
] and (v) Gastrointestinal causes,
especially with use of steroids [
There have been several studies suggesting that ID
may contribute to pulmonary dysfunction. In a recent
US Third National Health and Nutrition Examination
survey (NHANES) [
] there was a direct correlation
between pulmonary function as judged by the one second
forced expiratory volume (FEV1) and the iron status as
judged by the %TSat and ferritin, suggesting that reduced
pulmonary function may be commonly associated with
ID. In addition ID is common in cystic fibrosis [
pulmonary tuberculosis [
]. Pulmonary hypertension of
different causes is often associated with iron deficiency
and indeed treatment of iron deficiency can improve
pulmonary hypertension [
In CHF, the correction of the anemia with ESAs and
oral or IV iron or even with IV iron alone has been
shown in many studies to improve cardiac and patient
function and cardiac structure [
], and more than
20% of COPD patients have also CHF [
a recent large long-term double blind study with the
ESA, Darbepoetin alpha, did not meet its primary
endpoint of reducing the composite endpoint of time to
death from any cause or first hospital admission for
worsening heart failure in patients with systolic CHF
]. Thus the role of ESAs alone in CHF is still
uncertain. There are concerns about complications related
to ESAs therapy, since its use in renal failure has been
associated with an increase in cardiovascular and
thromboembolic phenomena, especially when given in
high doses [
]. Correction of ID with or without
anemia in CHF may improve symptoms, functional
capacity, and quality of life . However, some concerns
have also been raised about the safety of IV iron with its
possible worsening of oxidative stress and reduced
immunological function with possible increased tendency to
Our study has limitations as it is a non-randomized,
retrospective observation in a single medical center. In
the intervention study (study 2), the patients had a very
high rate of comorbidities including CKD, CHF, diabetes
and hypertension- a higher rate than is seen with the
usual COPD patients. In fact, all 12 patients had CKD
and it is possible that CKD predominated over their
other comorbidities. However the doses of CKD and
CHF medications were unchanged during the study.
Unfortunately we did not study pulmonary function at the
termination of the treatment period in any of these 12
patients and are therefore unable to assess the effect of
anemia correction on lung function. Another limitation
is that the VAS scale for dyspnea was used since it is the
common practice in our clinic. For patients with COPD
it is preferred to use the Modified Medical Research
Council Dyspnea Scale (mMRC) [
]. Nevertheless, our
results here suggest that correction of anemia with ESAs
or iron may benefit COPD patients, similarly to the
benefits seen in CHF.
Any studies of anemia in COPD using ESAs, IV Iron
or the combination of these agents, should be adequately
powered, double-blind placebo-controlled, and of
sufficient duration to assess the advantages and
disadvantages of the therapy. But such an effort would seem to
us worthwhile in these anemic and frequently iron
deficient COPD patients in view of the possible
improvement in cardiac and pulmonary function, hospitalization
and mortality, exercise capacity and Quality of Life that
might occur with correction of the their anemia and/or
These studies suggest that ID is common in hospitalized
COPD but generally not sought after and, if found,
generally not treated. Our small retrospective
intervention outpatient study also suggested that correction
of anemia and ID in COPD patients may improve
dyspnea. If further studies confirm our preliminary
observations, evaluation and treatment of ID could become
standard practice in COPD as is currently the case for
] and CHF [
Written informed consent was obtained from the patient
for the publication of this report and any accompanying
The authors declare that they have no competing interests.
DSS- participated in the design and draft of manuscript (the major contributor).
RM- participated in the acquisition and analyzing of clinical data and in the draft
of manuscript. MTW,EB,DS,IFS- participated in the acquisition and analyzing of
clinical data. GC- conceived of the study, and participated in its design and
critically revisited the draft. All authors read and approved the final manuscript.
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