Hemoglobin, erythropoietin and systemic inflammation in exacerbations of chronic obstructive pulmonary disease

doi:10.1016/j.ejim.2010.07.010

European Journal of Internal Medicine

Volume 22, Issue 1, February 2011, Pages 103-107

https://doi.org/10.1016/j.ejim.2010.07.010 Get rights and content

Abstract

Background

Systemic inflammation may represent a possible cause of anemia. Previous data support that anemic patients with COPD present high erythropoietin (EPO) levels, suggestive of EPO resistance, possibly mediated through inflammatory mechanisms.

Objectives

We aimed to determine whether systemic inflammation, which is usually up-regulated during exacerbations of COPD (ECOPD) is associated with low hemoglobin levels expressing erythropoietin resistance.

Methods

Hemoglobin (Hb), EPO and serum biomarkers of systemic inflammation [CRP, TNF-α, fibrinogen and IL-6] were assessed at three time points (admission, resolution and stable phases) in a selected cohort of 93 COPD patients.

Results

Hemoglobin levels were significantly lower on admission compared to resolution and stable phases (median 12.1 g/dl [interquartile ranges 11.2–12.7], vs 13.5 [12.4–14.3] vs 13.4 [12.7–14.08], respectively p = 0.002), whereas EPO was significantly higher on admission compared to resolution and stable phases. A negative association between Hb and IL-6 and a positive association between EPO and IL-6 were observed only during the acute phase of exacerbation. EPO and Hb were negatively associated during the acute phase, whereas they were positively associated during discharge and stable phase.

Conclusions

In this observational study we have shown that during admission for ECOPD Hb levels are decreased and EPO levels are increased. We have also identified a negative association between Hb and EPO. The above association is mainly related to increased IL-6 levels, indicating a possible EPO resistance through the mechanism of increased systemic inflammatory process.

Introduction

Anemia of chronic disease (ACD) is immune driven and mainly inflammatory in nature. Three possible mechanisms are thought to lead to ACD: shortened RBC survival, iron homeostasis dysregulation, and impaired bone marrow erythropoietic response [1]. Several cytokines and chemokines are involved in the aforementioned mechanisms and interfere in haematopoiesis, having a key role in ACD. The physiologic regulator of red cell production, erythropoietin (EPO), is produced and released by peritubular capillary lining kidney cells [1]. EPO governs day-to-day production of red cells and ambient levels of hormone are measurable in plasma.

Chronic obstructive pulmonary disease (COPD) profoundly affects mortality and morbidity worldwide [2]. Exacerbations of COPD (ECOPD) are associated with worsening of lung function, decreased quality of life, increased systemic inflammation and have a significant impact on survival [3]. During ECOPD there is an up-regulation of airway and systemic inflammation [4], associated with an increase of various biomarkers compared to stable disease [5]. However, several aspects related to the mechanisms of increased systemic inflammation and its consequences during ECOPD remain speculative.

Polycythemia is present in a fraction of untreated hypoxemic COPD patients, while anemia represents a more common problem and is related to poorer prognosis [6]. Moreover, systemic inflammation may represent a possible cause of anemia [7]. Previous data support that anemic patients with COPD present high EPO levels, suggestive of EPO resistance, possibly mediated through inflammatory mechanisms [8].

The aim of the present study was to evaluate the levels of hemoglobin, EPO and biomarkers of systemic inflammation in patients hospitalized for ECOPD, during the acute phase, on resolution and on stable condition. We hypothesized that the increased inflammatory burden during the acute phase of ECOPD would be associated with a decrease in hemoglobin levels, despite the presence of high EPO levels. Possible associations between hemoglobin, EPO and systemic inflammation in the acute and recovery phases of ECOPD were further evaluated.

Section snippets

Study subjects

COPD patients admitted to two university hospitals for ECOPD were evaluated. All patients were diagnosed for COPD according to the Global initiative for Obstructive Lung Diseases (GOLD) guidelines [2], and ECOPD was graded as levels II to III according to the ERS/ATS consensus criteria [9]. Only patients fulfilling the Anthonisen's criteria for type 1 ECOPD were selected [10]. All patients were managed according to the ERS/ATS guidelines, with bronchodilators, systemic corticosteroids (30–40 mg

Results

Fig. 1 presents the flow chart of patients included in the study. Demographic characteristics of the 93 patients included in the final analysis are presented in Table 1. All patients had normal values of reticulocytes in all study phases.

Discussion

In this observational study we have shown a statistically significant negative association between Hb and EPO on admission for an ECOPD. This negative association was subsequently reversed to a positive one during resolution and on the stable phase. The initial negative association is mainly related to the increased IL-6 levels, indicating a possible EPO resistance through mechanisms related to the increased systemic inflammatory response, which is usually up-regulated during the acute phase of

Learning points

•
Polycythemia is present in a fraction of untreated hypoxemic COPD patients, while anemia represents a more common problem and is related to poorer prognosis.
•
In the present observational study we have shown a statistically significant negative association between Hb and erythropoietin on admission for a COPD exacerbation. This negative association was subsequently reversed to a positive one during resolution and on the stable phase. The initial negative association is mainly related to the

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Importantly, secondary polycythemia resulting from persisting hypoxia and/or inhalative noxes may further affect pulmonary circulation and oxygenation.130,131 Systemic inflammation can be causative of COPD, with the pulmonary manifestation being part of multiple organ involvement, or a consequence of the disease due to systemic “spill-over” of pulmonary inflammation and infections, especially during exacerbations.132,133 Increased IL-6 and hepcidin levels in patients with COPD are likely the most relevant iron-related mechanisms that lead to the establishment of anemia that is often combined with absolute iron deficiency.128,134,135
Anemia of inflammation (AI) is a highly prevalent comorbidity in patients affected by chronic inflammatory disorders, such as chronic kidney disease, inflammatory bowel disease, or cancer, that negatively affect disease outcome and quality of life. The pathophysiology of AI is multifactorial, with inflammatory hypoferremia and iron-restricted erythropoiesis playing a major role in the context of disease-specific factors. Here, we review the recent progress in our understanding of the molecular mechanisms contributing to iron dysregulation in AI, the impact of hypoferremia and anemia on the course of the underlying disease, and (novel) therapeutic strategies applied to treat AI.
Anemia in chronic obstructive pulmonary disease: A systematic review
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However, owing to the inhibitory effect of inflammatory cytokines on erythroid progenitors, there is resistance to EPO. Findings from the studies conducted by Sharma et al. agree with this [5,6,42]. Pirotte et al., in their report, revealed that anemia is associated with systematic inflammation and increased hospitalization in COPD patients [26].
Chronic obstructive pulmonary disease (COPD) is a type of obstructive lung disease that is characterized by poor airflow and airway inflammation. It is estimated that the global prevalence of COPD is about 13.1%. Anemia is associated with increased morbidity and hospitalization duration. In this systematic review, we investigate the association between all types of anemia and COPD progression.
We systematically searched electronic databases, including Scopus, Medline/PubMed, EMBASE, Web of Sciences (WOS), and Cochrane Library, using the following mesh-standardized keywords: (((anemia∗ OR anaemia∗) OR “chronic anemia disease” [Mesh] OR “CAD” OR “iron deficiency anemia” OR” IDA” OR) AND (“COPD” [Mesh] OR “chronic obstructive pulmonary disease”)) until February 2022.
Overall of 11,158 studies were included. Ultimately, 59 studies were included in the analysis. The most apparent findings from the analysis were that exacerbation of COPD, increased hospitalization, and increased long-term mortality were associated with anemia. Further analysis showed that iron deficiency (ID) is a common finding in COPD and is accompanied by an increase in the systolic pulmonary artery pressure.
Despite the comfortable control of anemia, the absence of treatment can be life-threatening in patients with COPD. Our systematic results showed significant homogeneity between studies on the increased mortality rate in anemic COPD, increased hospitalization, and decreased quality of life.
The impact of anaemia and iron deficiency in chronic obstructive pulmonary disease: A clinical overview
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Non-clinical and clinical evidence suggests that EPO production could be inhibited by the effects of inflammatory cytokines.44–46 However, some clinical studies have also identified increased levels of EPO in COPD patients18,47–49 (consistent with normal response to tissue hypoxia). In any case, even increased EPO levels in COPD are not necessarily translated to enhanced erythropoiesis, which has been explained by EPO resistance in this population due to systemic inflammation.48,50
Anaemia is increasingly recognised as an important comorbidity in the context of chronic obstructive pulmonary disease (COPD), but remains undervalued in clinical practice. This review aims to characterise the impact of anaemia and iron deficiency in COPD.
Literature review of studies exploring the relationship between anaemia/iron deficiency and COPD, based on targeted MEDLINE and Google Scholar queries.
The reported prevalence of anaemia in COPD patients, ranging from 4.9% to 38.0%, has been highly variable, due to different characteristics of study populations and lack of a consensus on the definition of anaemia. Inflammatory processes seem to play an important role in the development of anaemia, but other causes (including nutritional deficiencies) should not be excluded from consideration. Anaemia in COPD has been associated with increased morbidity, mortality, and overall reduced quality of life. The impact of iron deficiency, irrespective of anaemia, is not as well studied, but it might have important implications, since it impacts production of red blood cells and respiratory enzymes. Treatment of anaemia/iron deficiency in COPD remains poorly studied, but it appears reasonable to assume that COPD patients should at least receive the same type of treatment as other patients.
Anaemia and iron deficiency continue to be undervalued in most COPD clinical settings, despite affecting up to one-third of patients and having negative impact on prognosis. Special efforts should be made to improve clinical management of anaemia and iron deficiency in COPD patients as a means of achieving better patient care.
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^☆: The study was supported by research grants from the Greek Thorax Foundation and National Kapodistrian Research Program from Athens University.

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Original articleHemoglobin, erythropoietin and systemic inflammation in exacerbations of chronic obstructive pulmonary disease☆

Abstract

Background

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Study subjects

Results

Discussion

Learning points

Respir Med

Chest

J Chronic Dis

J Clin Epidemiol

Semin Nephrol

Blood

Lancet

Semin Arthritis Rheum

Anemia of chronic disease

N Engl J Med

Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary

Am J Respir Crit Care Med

Exacerbations of chronic obstructive pulmonary disease

Eur Respir J

Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Haemoglobin level and its clinical impact in a cohort of patients with COPD

Eur Respir J

The potential impact of anaemia of chronic disease in COPD

Eur Respir J

Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper

Eur Respir J

Original article
Hemoglobin, erythropoietin and systemic inflammation in exacerbations of chronic obstructive pulmonary disease☆