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Anaemia secondary to erythropoietin resistance: important predictor of adverse outcomes in chronic obstructive pulmonary disease
  1. Rahul Kumar Sharma,
  2. Shibdas Chakrabarti
  1. Department of Pulmonary, Critical Care and Sleep Medicine, Safdarjung Hospital, New Delhi, India
  1. Correspondence to Dr Rahul Kumar Sharma, Department of Pulmonary, Critical Care and Sleep Medicine, Safdarjung Hospital, New Delhi 110029, India; dr.rahulksharma{at}gmail.com

Abstract

Purpose Anaemia is increasingly being linked to chronic obstructive pulmonary disease (COPD) as comorbidity with erythropoietin resistance secondary to chronic inflammation is hypothesised to have some role. This study purported to evaluate the occurrence of anaemia in COPD and its association with inflammatory markers, erythropoietin levels, severity and exacerbations of COPD.

Methods Two hundred patients with COPD (90% men, mean age 62.4±8.33 years) were enrolled and subjected to detailed clinical and laboratory evaluation, including complete blood count, erythropoietin levels, C-reactive protein (CRP), pulmonary function test, blood gas analysis and chest X-ray. Severity of COPD was defined on the basis of forced expiratory volume in 1 s according to GOLD guidelines.

Results Anaemia was diagnosed in 14% of patients (n=28, predominantly normocytic normochromic type (92.8%)) and polycythmia in 5% of patients (n=10). The prevalence of anaemia increased with increasing severity of COPD (stage 2: 8%, stage 3: 14.4% and stage 4: 17.2%; p=0.46). Serum erythropoietin was significantly higher in more advanced COPD, with mean levels being 30.2±6.5, 31.78±8.09 and 39.33±7.68 mIU/mL in stage 2, 3 and 4 respectively. Moreover erythropoietin levels inversely correlated with mean haemoglobin levels(r=−0.25), indicating erythropoietin resistance. CRP reactivity increased with increasing stage of disease in patients with anaemia (p=0.026). On follow-up, significant inverse correlation was observed between haemoglobin and COPD exacerbations (p<0.001).

Conclusions Anaemia is a significant comorbidity of COPD with a negative prognostic impact on lung health. It can be ascribed to a state of systemic inflammation resulting in blunting of erythropoietin response with increasing severity of disease, leading to greater morbidity and hospitalisation.

  • Anemia
  • Chronic obstructive pulmonary disease
  • Erythropoietin resistance
  • C reactive protein
  • Anemia of Chronic disease

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Introduction

Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality throughout the world, resulting in substantial economic and social burden. It is estimated to become the third leading cause of death worldwide by 2020 as per WHO.1 COPD, primarily characterised by irreversible pulmonary airflow limitation, is accompanied by a myriad of systemic manifestations and comorbidities which increase the risk of mortality.

Anaemia is a common comorbidity in many chronic diseases and its importance in COPD is gaining interest. WHO defines anaemia as a haemoglobin level less than 13 gm/dL in men and 12 gm/dL in women.2 Although COPD is traditionally thought to be associated with polycythmia, the recent recognition of systemic inflammation as a feature of COPD makes it a possible cause of anaemia of chronic disease.3

Preliminary evidence suggests a prevalence of anaemia in 10–15% of patients with COPD.3 A systematic review of the literature (1966–2010) estimates this prevalence to range from 7.5% to 34%, depending on the population selected and the diagnostic tools used.4 Further, lower haemoglobin levels were found to be independently associated with increased functional dyspnoea, reduced exercise capacity, impaired quality of life, premature mortality and greater likelihood of hospitalisations and healthcare resource utilisations.4 Raising haemoglobin through transfusion decreases minute ventilation and work of breathing in patients with COPD, with unloading of respiratory muscles, thereby improving the functional limitation.5

COPD is a known chronic inflammatory disease that affects an aging population. The causes of anaemia in COPD are probably multifactorial, such as nutritional disorders, occult blood loss, drug induced (theophylline, ACE inhibitors), carboxyhaemoglobin effect of cigarette smoking, and even oxygen therapy.4 A particular important cause in these patients may relate to anaemia of chronic disease. Studies have shown the relationship of anaemia in COPD with certain proinflammatory markers such as interleukin and C-reactive protein (CRP).6 Moreover, findings by Tassiopoulos et al7 indicate an inverse correlation between haemoglobin and erythropoietin (EPO) levels in these patients, demonstrating the possible role of inflammation and hormone resistance in the pathogenesis.

Despite these findings from recent studies, there is a lack of consensus regarding the true prevalence of anaemia in COPD, its pathogenesis, correlation with severity and the possible benefits of treatment. There are very few Indian studies which have studied the prevalence and clinical impact of anaemia in COPD. Hence the present study was undertaken to evaluate the prevalence of anaemia in COPD and its association with inflammatory markers, EPO levels, severity and exacerbations of COPD.

Materials and methods

This study was a prospective observational study conducted in the Outpatient Department of Pulmonary, Critical Care and Sleep Medicine of a tertiary care teaching institute. A total of 200 consecutive patients with COPD, satisfying inclusion and exclusion criteria, were recruited for the study between 2009 and 2012 after giving informed consent. The study was approved by the institutional ethical committee.

Inclusion criteria

All patients of both sexes, smokers and non-smokers, aged 40 years or more, presenting to the outpatient department with history and physical findings suggestive of COPD and a spirometric diagnosis of COPD as per GOLD guidelines (ie, forced expiratory volume in 1 s (FEV1) <80% of predicted, and ratio of FEV1 to forced vital capacity (FVC) <0.7 in the post-bronchodilator test)8 were included in the study. All included patients were clinically stable without exacerbations in the last 6 months.

Exclusion criteria

  1. Patients with

  2. acute exacerbation of COPD

  3. renal or liver disease

  4. bleeding diathesis

  5. recent gastrointestinal haemorrhage or any other blood loss

  6. major cardiovascular and cerebrovascular events in the past 6 months, such as coronary artery disease, congestive heart failure, valvular heart disease, atrial fibrillation, myocardial infarction or stroke

  7. refusal of consent.

Methods

All included patients were subjected to detailed history and physical examination as per predefined proforma. They underwent the following investigations:

  1. Pulmonary function test (PFT): (spirometry) measured with standard spirometric techniques with a computerised PFT system (P K Morgan Body Plethysmograph). This included pre and post bronchodilator study and patients were categorised to have mild, moderate, severe and very severe COPD according to spirometeric GOLD guidelines.8

  2. Haemoglobin: 2 mL venous blood was collected and analysed for haemoglobin levels using a Sysmex KX 21 analyser. As per WHO, anaemia was diagnosed by haemoglobin levels less than 13 gm/dL in men and less than 12 gm/dL in women, while polycythmia was defined as levels >17 gm/dL.

  3. CRP: qualitative CRP was determined by a Biolatex CRP-EKO kit using a latex agglutination slide test.

  4. Arterial blood gas: measured using a heparinised syringe and performed in a Radiometer Copenhagen ABL 800 basic analyser.

  5. Random blood sugar, blood urea, serum creatinine and complete liver function test: performed as the baseline investigations using an automated system.

  6. Chest X-ray, electrocardiography and echocardiography: performed when necessary.

All patients with anaemia were further subjected to detailed investigations including the following:

  1. Complete hemogram: including haematocrit and red blood cell (RBC) indices with RBC morphology on peripheral blood film.

  2. Iron profile: including serum iron (using dipyridyl method), total iron binding capacity (using Ramsay’'s method) and serum ferritin (using random access immunoassay method).

  3. Serum EPO: using enzyme-linked immunosorbent assay (Immuno-Biological Laboratories, Hamburg, Germany) on venous blood sample.

  4. Thyroid function test.

All enrolled patients were treated with standard therapy as per GOLD guidelines. They were followed up monthly for a period of 1 year and all adverse events were noted, including exacerbations, any hospital admissions or episodes requiring changes of drugs and all-cause mortality. The collected data were tabulated and analysed using SPSS V.15 with mean and SD used for descriptive analysis and p<0.05 taken as significant for categorical data.

Results

A total of 200 patients were included in the study between 2009 and 2012. The mean age of the studied population was 62.4±8.33 years. The sex-wise distribution included 90% men (n=180) and 10% women (n=20). All patients were categorised into stages of COPD on the basis of FEV1% as per the GOLD guidelines. The majority of patients were classified has having stage III disease (n=104, 52%), with stage II (n=38, 19%) and IV (n=58, 29%) accounting for the rest. No patients had stage I disease.

Prevalence of anaemia

Anaemia was observed in 28 patients (14%), with mean haemoglobin 11.39±0.75 gm/dL. Out of these, 26 were men and two were women (p=0.620), possibly due to the skewed sex distribution of the population. The stage-wise distribution of anaemia showed an increasing frequency with increasing severity of COPD, though the p value was statistically insignificant (table 1).

Table 1

Stage wise prevalence of anaemia in COPD (n=200)

Of the patients with anaemia, the majority had normocytic normochromic anaemia (n=26, 92.8%) and only two patients had microcytic hypochromic anaemia (7.2%). The iron profile of patients with normochromic normocytic anaemia revealed the mean serum iron to be 62.51±22.66 µg/dL, serum ferritin 202.1±47.58 ng/mL and total iron binding capacity 298.5±47.73 µg/dL. The corresponding values in the microcytic hypochromic group were markedly lower, with mean values being 24±2 µg/dL, 19.2±3.2 ng/mL and 397±15 µg/dL respectively, indicating severe iron deficiency. Due to the higher proportion of patients having normocytic normochromic type anaemia, this shows that chronic inflammation rather than nutritional iron deficiency was the cause of anaemia in this study population of COPD.

Polycythmia was present in 5% of the total population (n=10), with the maximum number of patients having stage III disease (n=6) compared with stage II (n=2) and stage IV disease (n=2). A possible explanation may be blunting of hypoxia-driven erythropoiesis in stage IV COPD by oxygen supply, as reported previously in other studies.

Relation of COPD severity with levels of inflammatory markers

CRP reactivity levels were assessed in all patients and they were found to be significantly higher with increasing severity of disease (p=0.026)) (table 2). However, no correlation was found between CRP positivity and haemoglobin levels in patients with anaemia (p=0.75).

Table 2

Severity of COPD with CRP reactivity

Relation of EPO with anaemia in COPD

Serum EPO levels were found to have an inverse correlation with mean haemoglobin levels with increasing severity of COPD (r=−0.25). The mean EPO levels increased with increasing stages of COPD along with a simultaneous decline in mean haemoglobin values, indicating inflammatory mediators induced decreased bone marrow responsiveness and erythropoiesis despite high EPO levels (table 3).

Table 3

Correlation of EPO with haemoglobin in patients with normocytic normochromic type of anaemia (n=26)

Relation between haemoglobin levels and COPD exacerbations

All patients were followed up for 1 year for exacerbations and all-cause mortality. During follow-up, there were 33 dropout cases with no mortality. A large number of dropouts were due to patients being spread over a vast geographical region, who were referred to our tertiary care centre for acute management, with local hospitals catering to their medical needs during the stable phase. A strongly significant inverse correlation was observed between mean haemoglobin levels and number of COPD exacerbations (p=0.001), indicating increased morbidity among patients with anaemia compared with patients without anaemia. In contrast, fewer exacerbations were seen in patients with polycythmia.

A stepwise linear regression analysis was done using the parameters age, sex, EPO levels and history of acute exacerbation to evaluate their independent roles in predicting serum haemoglobin levels in patients with COPD. The salient observation was that patients with a history of acute exacerbation of COPD were significantly more likely to have lower serum haemoglobin levels compared with those without any history of acute exacerbation of COPD (p=0.012) (table 4). The analysis also revealed that men with COPD were more likely to have anaemia compared with women and increased EPO levels were linked to lower haemoglobin levels, though the p value for both was not statistically significant.

Table 4

Stepwise linear regression analysis showing variables that independently predict serum haemoglobin levels in patients with COPD

Discussion

The present study shows the prevalence of anaemia of 14% in patients with stable COPD with mainly normocytic normochromic type of anaemia which worsens with increasing stages of COPD and is associated with increased exacerbations and morbidity. Further, the mean haemoglobin levels inversely correlate with mean EPO levels and CRP reactivity, suggesting possible EPO resistance and chronic inflammation as a mechanism of anaemia in patients with COPD.

Anaemia in COPD is an underestimated issue but with a great clinical importance in this chronic multisystem inflammatory disease. The prevalence of anaemia in previous studies is comparable to the finding of 14% in our study (Boutou et al:9 14%; John et al:10 13%; Cote et al:11 17%). An isolated Indian study by Parveen et al3 also gives the prevalence at around 18%. The prevalence of anaemia was found to be higher in advanced stages of COPD in most of these studies.9 ,11 Cote et al11 recorded polycythmia in 5.9% of patients with COPD, which also corresponds to our study findings.

All these studies have shown a predominance of normocytic normochromic type of anaemia in the study population. This suggests that a major mechanism for the development of anaemia in COPD might be related to its chronic inflammatory nature and the presence of various inflammatory markers such as CRP, IL6, interferon and tumour necrosis factor, leading to shortened RBC survival and relative EPO resistance.10 John et al10 reported an inverse correlation between haemoglobin levels and inflammatory markers (CRP and IL6) with higher CRP levels among patients with anaemia compared with those without anaemia and controls. Pancirov et al12 also demonstrated a similar negative correlation between anaemia and serum CRP levels in patients with stable COPD (r=−0.60, p=0.001). In our study also, the incidence of CRP reactivity was found to be significantly higher in advanced stages of disease, though a significant correlation with haemoglobin levels could not be demonstrated.

Tassiopoulos et al,7 in 2001, were among the first to study anaemia and its compensatory erythropoietic action in patients with COPD. Their findings indicated an inverse correlation between the haemoglobin and EPO concentrations, which suggests that in patients with COPD low haemoglobin correlates with a compensatory EPO response. Attaran et al13 assessed the frequency of anaemia and its relation to serum EPO level and severity of disease in a group of patients with COPD and found a significant correlation between haemoglobin and serum EPO in all patients with COPD who were not anaemic. However, no correlation was found between haemoglobin and serum EPO levels in the anaemic group (r=0.07, p=0.82). In our study, a small but definite inverse correlation was shown between mean EPO levels and mean haemoglobin levels with increasing severity of disease. Further, findings of lower plasma EPO levels and higher CRP concentration and neutrophil cell count during exacerbation of COPD, in a study by Sala et al, is in keeping with the interpretation that EPO is downregulated during acute exacerbation, likely in relation to systemic inflammation.14

A significant observation of the present study was a statistically significant higher incidence of exacerbations among the patients with COPD and anaemia, even if they were in the same stage of severity. Most of these were infective episodes including viral and bacterial infections. The relationship between anaemia and adverse clinical outcomes has been widely recognised in previous studies. The ANTADIR database study emphasised haematocrit as an independent and major predictor of survival, with 3-year survival ranging from 24% for patients with haematocrit <35% to 70% in patients with haematocrit >55%.15 Further, lower haematocrit values were associated with frequent hospitalisations and longer hospital stay. Anaemia compromises oxygen delivery to tissues contributing to functional limitation and decreased exercise tolerance, especially in patients with diminished lung functions. Yet it remains unclear whether correction of anaemia favourably influences the clinical course of patients with COPD. There are limited data regarding RBC transfusion in patients with COPD and anaemia. In a small prospective study, minute ventilation and work of breathing were significantly reduced following blood cell transfusion.16 However, the advantages of increasing the haemoglobin level may be countered by the potentially severe consequences of negatively altering blood gases. Further research is warranted into the effects of blood transfusion as a remedial intervention in patients with COPD and anaemia.

In the past decade, a lot of emphasis has been given on recognising the prevalence and effects of anaemia in patients with COPD in developed countries. However, the literature from developing countries regarding the same is sparse. To the best of our knowledge, there are only two such prevalence studies from India.3 ,17 Parveen et al3 demonstrated a prevalence of 18% of patients with anaemia among their study population, with significant association of anaemia with number of COPD exacerbations and hospital admissions. The study by Khandelwal et al17 had fewer subjects with no follow-up. However, none of these studies examined the pathophysiology of anaemia in COPD. Our study shows a small but definite relation of anaemia to inflammatory mediators and EPO, establishing the role of chronic inflammation in its pathogenesis. Moreover, a significant correlation of number of exacerbations with mean haemoglobin levels on follow-up demonstrates a need for routine assessment and monitoring of haemoglobin levels in all patients with COPD.

Conclusion

Anaemia is a significant comorbidity of COPD, with a negative prognostic impact on lung health. It can be ascribed to a state of systemic inflammation, resulting in blunting of EPO response with increasing severity of disease, leading to greater morbidity and hospitalisation. There is a need for further research using well designed studies and long-term follow-up to fully demonstrate the casual role of anaemia in the morbidity of patients with COPD and the promising role of EPO, blood transfusions or anti-inflammatory agents as novel therapy for COPD.

Main messages

  • Anaemia is a significant comorbidity in patients with chronic obstructive pulmonary disease (COPD) and is associated with increased disease severity, morbidity and exacerbations.

  • Erythropoietin resistance secondary to inflammatory mediator induced bone marrow suppression is a plausible mechanism for anaemia in COPD.

  • All patients with COPD should be routinely assessed for anaemia and monitored for haemoglobin levels during follow-up.

Current research questions

  • Larger studies to evaluate the clinical impact of anaemia on morbidity and mortality in chronic obstructive pulmonary disease (COPD).

  • Possibility of decrease in frequency of COPD exacerbations with correction of anaemia.

  • Therapeutic role of erythropoietin administration in anaemia in patients with COPD.

  • Therapeutic role of anti-inflammatory agents in patients with COPD.

References

Footnotes

  • Contributors Conceptualisation of the study and design of the analysis were done by SC. Data collection, analyses, interpretation and initial drafting of the paper were undertaken by RKS with contributions from SC. Both authors participated in manuscript editing and critically reviewed all sections of the text for important intellectual content.

  • Competing interests None declared.

  • Ethics approval Institutional Ethical Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.