Malay Sarkar, Puja Negi Rajta, Jasmin Khatana, Departments of Pulmonary Medicine,

Departments of Physiology, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
(2015) http://www.lungindia.com/temp/LungIndia322142-2007091_053430.pdf

ANEMIA IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Abstrak

Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable

lifestyle-related disease with high global prevalence. COPD is associated with significant
morbidity and mortality worldwide. Comorbidities are important events in the natural history of
the disease and have a negative effect on the morbidity and mortality of COPD patients. Cardiac
diseases, lung cancer, osteoporosis, and depression are common comorbidities reported for
COPD. Recently, anemia has been recognized as a frequent comorbidity in COPD patients. The
prevalence of anemia in patients with COPD varies from 7.5% to 33%. Anemia of chronic disease
(ACD) is probably the most common type of anemia associated with COPD. ACD is driven by
COPD-mediated systemic inflammation. Anemia in COPD is associated with greater healthcare
resource utilization, impaired quality of life, decreased survival, and a greater likelihood of
hospitalization.

Matthias John, MD, PhD; Soeren Hoernig, MD; Wolfram Doehner, MD; Darlington D. Okonko,
MD; Christian Witt, MD, PhD; Stefan D. Anker, MD, PhD

CHEST. 2005;127(3):825-829. https://www.medscape.com/viewarticle/501430_4

ANEMIA AND INFLAMATION IN COPD

Discussion

This study documents that anemia occurs relatively frequently in COPD patients and is related to
the presence of inflammation. Anemia is an understudied issue in COPD but may be of great
importance in this disease. In our cohort, anemia (with hemoglobin concentrations < 12.0 g/dL
in women and < 13.5 g/dL in men) was present in as many as 13% of all COPD patients. This may
be an underestimation of the anemia prevalence, as we have excluded patients with anemia
related to bleeding and known folate or vitamin B12 deficiency. Furthermore, anemic COPD
patients showed increased levels of erythropoietin compared to nonanemic patients and normal
control subjects.
Anemia of chronic illness is typically a normocytic anemia and is most commonly observed in
patients with concurrent infectious, and inflammatory or neoplastic diseases. COPD fulfills the
criteria of a chronic, inflammatory, multisystemic disease leading to the expectation of anemia.
While anemia in chronic heart failure or renal insufficiency has been frequently investigated, it is
understudied in COPD.

The mechanism of anemia development in COPD might be similar to that in other chronic
diseases. It has been shown that mediators of the immune and inflammatory response, such as
tumor necrosis factor-α, IL-6, and interferon-γ are potentially involved in the development of
anemia in chronic illness.[7] The increased levels of inflammatory cytokines lead to a shortened
RBC survival, with a demand for a slight increase in RBC production. The bone marrow cannot
adequately respond to the increased demand for RBCs. This is caused by a relative erythropoietin
resistance due to an impaired ability of RBC progenitors to respond to erythropoietin. An
impaired mobilization of reticuloendothelial iron stores is an additional pathophysiologic
factor.[3,8]

The observed increased inflammatory response in anemic patients confirms the pathophysiologic
understanding of anemia in chronic disease, in that anemia is at least partially due to excessive
production of inflammatory cytokines such as IL-6, which inhibit the production and the effect of
erythropoietin and iron at the level of the bone marrow.[9–11] Once anemia has developed, an
autoregulatory up-regulation of erythropoietin occurs to maintain the homeostasis. However
anemic COPD patients do not respond to increased levels of erythropoietin. The increased levels
indicate a relative peripheral erythropoietin resistance in COPD. This is similar to other diseases
and fits into the pathophysiology of anemia in chronic disease. The hypothesized relationship of
anemia to weight loss and cachexia was not observed in our cohort, indicating that the
development of anemia is independent from nutritional factors.

In chronic heart failure, it was demonstrated that the mortality rate correlated with the severity
of anemia and that anemia is an independent risk factor for increased mortality. [12,13]
Furthermore, it has been shown that a hemoglobin concentration below the physiologic range is
a predictor of exercise limitation and mortality in chronic heart failure. [2] Whether anemia
contributes to symptoms or exercise limitations in COPD is presently unknown. However, in our
study overall COPD severity according to standard criteria of lung function was not related to
frequency of anemia and hemoglobin levels ( Table 1 and Table 3 ). More studies are needed to
study these issues.

The present study is limited by a relative small number of patients. For future investigations,
larger study populations are needed. This would allow investigating whether anemia is related to
the primary disease process per se or to secondary systemic manifestations such as weight loss,
loss of lean tissue mass, hypoxia, or systemic inflammation.

Anemia in COPD is understudied. There are no previous reports on anemia frequency and
pathophysiology in COPD. More detailed investigations on hematologic and clinical parameters (
ie , prevalence of anemia in COPD and its gender relatedness, exercise capacity, 6-min walk test)
and prognosis are required to provide indications whether anemia is merely a marker or a
mediator of pathophysiologic processes that may impair physical functioning in COPD.
Interventions with erythropoietin and iron supplementation would then seem very promising in
order to improve the poor health status and prognosis of patients with COPD.

ANAEMIA OF CHRONIC DISEASE: AN IN-DEPTH REVIEW

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588399/ (2016)

Anaemia is the most common haematological disorder affecting humanity and is usually
observed in chronic disease states such as non-specific anaemia, which may cause diagnostic
difficulties. In chronically ill patients with anaemia, this has a negative impact on quality of life as
well as survival. This paper aims at reviewing the pathogenesis of this form of anaemia with a
view to suggesting future targets for therapeutic intervention. The ability to diagnose this
disorder depends on the ability of the physician to correlate the possible clinical pathways of the
underlying disease with the patients' ferrokinetic state. It is important to rule out iron deficiency
and other causes of anaemia as misdiagnosis will in most cases lead to refractoriness to standard
therapy. The cytokines and acute-phase proteins play important roles in the pathogenesis of
anaemia of chronic disease. Alterations in the metabolism of iron via the molecule hepcidin and
ferritin are largely responsible for the consequent anaemia. Concomitant iron deficiency might
be present and could affect the diagnosis and therapeutic protocol. Treatment options involve
the use of erythropoiesis-stimulating agents, blood transfusion, and iron supplementation, in
addition to treating the underlying disease.

Key Words: Anaemia, Chronic disease/inflammation, Hepcidin, Ferritin, Pathogenesis, Cytokines

ANEMIA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE - ASSOCIATION

WITH COMORBIDITIES
https://erj.ersjournals.com/content/48/suppl_60/PA3778 (2015)
Methods: Data was collected retrospectively from 96 patients diagnosed with COPD based on
the GOLD criteria2. Oxygen saturation, Medical Research Council (MRC) dyspnoea score, COPD
Assessment Test (CAT), Body Mass Index (BMI) and comorbidities were registered. Blood samples
were analyzed for hemoglobin and C-reactive protein (CRP).

Results: Patients were classified in A(n=35), B(n=20), C(n=14) and D(n=29) with reference to the
GOLD criteria. Anemia was found in 14% of the patients (13/96). There was an equal distribution
of patients with/without anemia in group A vs. group B+C+D but no significant association
between COPD severity and the frequency of anemia (p=0.2). Patients with/without anemia were
comparable on gender, age, CRP, CAT, BMI and lung function; but significantly different with
respect to MRC score (p=0.0009) and comorbidities when comparing patients with 1 comorbidity
with those with ≥2 (p=0.03). A significantly higher proportion of patients with concomitant kidney
and/or heart disease had anemia compared to those without (p=0.03vs.0.009).

Conclusion: COPD patients with anemia have more comorbidities, especially kidney and heart
disease and have more respiratory symptoms than patients without anemia.