Hemoglobin Levels Above Anemia Thresholds Are Maximally Predictive for Long-Term Survival in COPD With Chronic Respiratory Failure
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* Florian Kollert
* Andrea Tippelt
* Carolin Müller
* Rudolf A Jörres
* Christine Porzelius
* Michael Pfeifer
* Stephan Budweiser

## Abstract

**BACKGROUND:** In patients with COPD, chronic anemia is known as an unfavorable prognostic factor. Whether the association between hemoglobin (Hb) levels and long-term survival is restricted to anemia or extends to higher Hb levels has not yet been systematically assessed.

**METHODS:** We determined Hb levels in 309 subjects with COPD and chronic respiratory failure prior to initiation of noninvasive ventilation, accounting for confounders that might affect Hb. Subjects were categorized as anemic (Hb < 12 g/dL in females, Hb < 13 g/dL in males), polycythemic (Hb ≥ 15 g/dL in females, Hb ≥ 17 g/dL in males), or normocythemic. In addition, percentiles of Hb values were analyzed with regard to mortality from any cause.

**RESULTS:** Two-hundred seven subjects (67.0%) showed normal Hb levels, 46 (14.9%) had anemia, and 56 (18.1%) had polycythemia. Polycythemic subjects showed a higher survival rate than anemic (*P* = .01) and normocythemic subjects (*P* = .043). In a univariate Cox hazards model, Hb was associated with long-term survival (hazard ratio 0.855; 95% CI 0.783–0.934, *P* < .001). The 58th percentiles of Hb (14.3 g/dL in females, 15.1 g/dL in males) yielded the highest discriminative value for predicting survival (hazard ratio 0.463, 95% CI 0.324–0.660, *P* < .001). In the multivariate analysis this cutoff was an independent predictor for survival (hazard ratio 0.627, 95% CI 0.414–0.949, *P* = .03), in addition to age and body mass index.

**CONCLUSIONS:** In subjects with COPD and chronic respiratory failure undergoing treatment with noninvasive ventilation and LTOT, high Hb levels are associated with better long-term survival. The optimal cutoff level for prediction was above the established threshold defining anemia. Thus, predicting survival only on the basis of anemia does not fully utilize the prognostic potential of Hb values in COPD.

*   COPD
*   chronic respiratory failure
*   long-term survival
*   hemoglobin
*   anemia
*   noninvasive ventilation
*   polycythemia

## Introduction

COPD is characterized by chronic air-flow limitation, inflammation, and lung remodeling,1 and associated with extra-pulmonary systemic manifestations (eg, cardiovascular diseases, malnutrition, osteoporosis, renal failure, depression, and anxiety).2–4 Anemia, most likely of multifactorial origin, is also a common comorbidity.5–8 In a large cohort of subjects with severe COPD receiving long-term oxygen therapy (LTOT), Chambellan and co-workers found that a low hematocrit (Hc) was not uncommon, and was associated with higher mortality and morbidity.7 Also, in stable COPD of widely ranging disease severity the prevalence of anemia was high (17%) and related to a reduction of functional capacity and survival time.8 Recent data showed anemia in 18% of COPD patients treated for acute respiratory failure, and a link between anemia and 90-day mortality.9

However, hypoxia-induced “secondary” polycythemia is also common in severe COPD. In contrast to anemia, polycythemia may reflect that an adequate compensatory physiologic response to hypoxemia is still present, despite the systemic inflammation. Historically, phlebotomy has been used in patients with high hemoglobin (Hb)/Hc levels. Moreover, in numerous studies, functional benefits of phlebotomy in hypoxic pulmonary disease have been described.10–16 Conversely, polycythemia contributes to the development of cor pulmonale and pulmonary hypertension, which are linked to poor prognosis.17 However, most of these studies were performed prior to the widespread use of LTOT and domiciliary noninvasive ventilation (NIV), and large systematic trials on phlebotomy in polycythemic patients are lacking. For patients with polycythemia due to hypoxic lung diseases, guidelines primarily recommend the evaluation for LTOT or mechanical ventilation by a respiratory physician.18 Phlebotomy is suggested only in patients with symptoms of hyperviscosity or Hc above 56%.18

In the study by Cote et al, the prevalence of polycythemia (Hb ≥ 17 g/dL) was low (5.9%), and not associated with worsened outcomes in COPD patients.8 Chambellan et al found the longest survival in polycythemic patients receiving LTOT. However, their analysis was based on Hc levels and did not exclude patients with comorbidities or conditions that might interfere with red blood cell count. Accordingly, it was claimed that more studies would be desirable to explore the impact of red cell mass on clinical outcomes, in particular, survival.7,8

Based on these considerations, we investigated the prognostic impact of Hb levels in a large cohort of COPD subjects with chronic respiratory failure, who were under optimized therapy, including LTOT and domiciliary NIV, while accounting for major confounders of Hb levels. The aim was to assess whether the association of Hb and mortality is linear or not, and whether the optimal Hb cutoff levels for the prediction of long-term survival are similar to or different from the common clinically used cutoff values of anemia or polycythemia.

### QUICK LOOK

#### Current knowledge

In patients with COPD, anemia is a common comorbidity and is associated with reduced functional capacity, poor outcome, and early mortality. Anemia may represent inability to compensate for hypoxemia in COPD patients with chronic respiratory failure.

#### What this paper contributes to our knowledge

In patients with COPD and chronic respiratory failure, higher hemoglobin level was associated with longer survival. Hemoglobin of ≥ 14.3 g/dL in females, and ≥ 15.1 g/dL in males was independently associated with better outcome.

## Methods

### Study Subjects

Patients were identified from an electronic database of the Donaustauf Hospital Center for Pneumology, in which all patients treated with domiciliary NIV are registered. The decision for NIV was made on the basis of international recommendations,19 pronounced nocturnal hypercapnia, or clinical criteria. Demographic and anthropometric data, as well as diagnoses; concomitant diseases (coronary heart disease, left heart failure, arterial hypertension, diabetes mellitus, cardiac arrhythmia); medication (angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, β blockers, β2 agonists, parasympatholytics, theophylline, systemic steroids); blood gas values; parameters of lung function and exercise testing; and laboratory parameters were documented. Starting in January 2002, data were entered prospectively. In the present analysis, only patients with COPD stage III/IV (GOLD, Global Initiative for Chronic Obstructive Lung Disease) who received NIV between April 1992 and March 2007 were included. The diagnosis was based on clinical history and a ratio of FEV1 to inspiratory vital capacity of < 70%, and FEV1 being < 30% of predicted or < 50% of predicted plus chronic respiratory failure.1

We included only patients in whom blood count data were obtained at admission prior to the initiation of NIV. Moreover, based on the medical records, patients with the following confounders of Hb levels not causatively related to COPD were excluded: previous invasive ventilation; renal failure with estimated glomerular filtration rate < 30 mL/min/1.73 m2; malignancies/hematological disorders within the last 5 years; surgeries, interventions, accidents or hemorrhage within the last 3 months; additional chronic inflammatory, autoimmune or infectious disease; previous gastrointestinal resection; substitution of iron, folate, or vitamin B12; and phlebotomy due to polycythemia or blood transfusion.

### Measurements

Demographic, anthropometric, and laboratory data (Hb, leukocytes, C-reactive protein, creatinine) were assessed upon admission. Subjects were categorized as anemic (Hb < 12 g/dL in females, Hb < 13 g/dL in males),20 polycythemic (Hb 15 ≥ g/dL in females, Hb ≥ 17 g/dL in males),8 or normocythemic. The estimated glomerular filtration rate was calculated by the Modification of Diet in Renal Diseases (MDRD) equation, which is known to be particularly accurate in elderly patients.21

Spirometry and body plethysmography (MasterScreen, Cardinal Health, Höchberg, Germany) were performed according to the guidelines of the American Thoracic Society/European Respiratory Society,22 using European Respiratory Society reference values.23 Six-min walk distance was determined according to the American Thoracic Society statement,24 using reference values by Enright and Sherrill.25 Blood gases were assessed from the hyperemic earlobe after incision, using a capillary tube and blood gas analyzer (RapidLab, Bayer, Leverkusen, Germany). Only values obtained without oxygen supply were included.

### Follow-up

Vital status was determined through telephone contact to the subjects' relatives or family physicians, and by review of medical records. Informed written consent of the subjects or their relatives was obtained. All subjects underwent a follow-up period of at least 5 months, until July 1, 2007, or death. Mortality was documented as overall mortality, including all causes of death. The study approach was approved by the local ethics committee of the University of Regensburg.

### Statistical Analysis

Normality of data distribution was checked by the Kolmogorov-Smirnov test. Data are shown as medians and IQRs. For the comparison of subgroups the non-parametric Kruskal-Wallis test was used, for categorical variables the chi-square test. Univariate Cox proportional hazards regression models were run to assess the impact of single predictors on survival. Predictors with *P* < .05 were included in a multivariate Cox proportional hazards regression model to adjust for prognostic factors other than Hb.

To identify the optimal cutoff values for Hb and to compare them with the standard cutoff values, the following analyses were conducted. For each individual, the probability of death within 1 year was obtained from the multivariate Cox proportional hazards model, as described above. The relationship between Hb level and these probabilities was visualized in a scatter plot, together with a non-linear LOESS (locally weighted polynomial regression) smoother. Each percentile of Hb, taken separately for females and males, was used to define 2 subgroups with low and high Hb level. Univariate Cox proportional hazards models were fitted for each of these levels, and the one with the smallest *P* value yielded the optimal cutoff for Hb. Survival probabilities of the commonly used Hb categories and the ones identified by us were plotted as Kaplan-Meier curves, which were compared by the log rank test. To compare the prognostic impact of the newly found Hb cutoff values and the standard Hb categories, univariate Cox proportional hazards regression models were employed.

## Results

### Subjects' Characteristics

A total of 534 subjects with COPD GOLD stage III/IV were analyzed. After exclusion of subjects with comorbidities, or conditions potentially contributing to abnormalities in red blood cell count, and subjects with a lack of follow-up, 309 subjects remained. Their median (IQR) Hb was 14.5 g/dL (15.9–13.1 g/dL), and 207 subjects (67.0%) were categorized as normocythemic, 102 (33.0%) as abnormal. Among the latter, 46 subjects (14.9%) were anemic and 56 (18.1%) polycythemic. There were differences in the distributions of sex (*P* = .002), age (*P* < .001), survival time (*P* = .008), and comorbidities between anemic, normocythemic and polycythemic subjects (Table 1). Medical therapy (angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, β blockers, β2 agonists, parasympatholytics, theophylline, systemic steroids) was not linked to the presence of anemia.

View this table:
[Table 1.](http://rc.rcjournal.com/content/58/7/1204/T1)

Table 1. 
Subjects' Demographic and Clinical Characteristics According to Hemoglobin Categories

In males (*n* = 222), Hb abnormalities were predominately due to anemia (*n* = 40, 18.0%) and not polycythemia (*n* = 31, 14.0%). Females (*n* = 87) mostly showed polycythemia (*n* = 56, 28.7%), while anemia occurred less frequently (*n* = 6, 6.9%, *P* = .002). Before inclusion, 170 subjects (55.0%) were treated with LTOT. At discharge, all subjects were treated with NIV (*n* = 309, 100%) and nearly all had LTOT (*n* = 293, 94.8%). Further subject characteristics are given in Table 1.

### Hemoglobin Levels and Long-Term Survival

A total of 139 subjects (45.0%) died during the study period (mean ± SD follow-up 36.1 ± 31.1 months). The causes of death were cardiopulmonary 116 (83.5%), malignancy 7 (5.0%), other 5 (3.6%), and unknown 11 (7.9%).

Twenty-two anemic (15.8%), 95 normocythemic (68.3%), and 22 polycythemic (15.8%) subjects died. The median survival of polycythemic subjects was 112 months, while normocythemic subjects survived 51 and anemic subjects 29 months. The survival probability of polycythemic subjects was higher than that of normocythemic (*P* = .043) and anemic subjects (*P* = .01), and that of normocythemic was higher than that of anemic subjects (*P* = .041, Fig. 1). The 1-year survival probability of all subjects as a function of Hb values is depicted in Figure 2.

![Fig. 1.](http://rc.rcjournal.com/https://rc.rcjournal.com/content/respcare/58/7/1204/F1.medium.gif)

[Fig. 1.](http://rc.rcjournal.com/content/58/7/1204/F1)

Fig. 1. 
Kaplan-Meier survival curves for anemic (dotted line), normocythemic (solid line), and polycythemic (dashed line) subjects. The log rank sum test showed differences between these conditions: *P* = .043 for polycythemic vs normocythemic, *P* = .01 for polycythemic vs anemic, *P* = .041 for normocythemic vs anemic.

![Fig. 2.](http://rc.rcjournal.com/https://rc.rcjournal.com/content/respcare/58/7/1204/F2.medium.gif)

[Fig. 2.](http://rc.rcjournal.com/content/58/7/1204/F2)

Fig. 2. 
LOESS (locally weighted polynomial regression) smoother curve for hemoglobin level versus predicted probability of death (1 year).

When analyzing every percentile of Hb values with regard to long-term survival, the optimal cutoff value of Hb was identified as 14.3 g/dL for females and 15.1 g/dL for males (58th percentiles each, Table 2). Regarding the association with the probability of death, these values were superior to the cutoffs used for the definition of anemia according to the World Health Organization (Hb < 12 g/dL in females, Hb < 13 g/dL in males, Fig. 3).

View this table:
[Table 2.](http://rc.rcjournal.com/content/58/7/1204/T2)

Table 2. 
Univariate Cox Proportional Hazards Models for the Prediction of Death Regarding Percentiles of Hemoglobin

![Fig. 3.](http://rc.rcjournal.com/https://rc.rcjournal.com/content/respcare/58/7/1204/F3.medium.gif)

[Fig. 3.](http://rc.rcjournal.com/content/58/7/1204/F3)

Fig. 3. 
Kaplan-Meier survival curves of subjects either above or below the optimal cutoff value. The upper black line illustrates either female subjects with hemoglobin ≥ 14.3 g/dL or male subjects with hemoglobin ≥ 15.1 g/dL. The lower black line illustrates either female subjects with hemoglobin < 14.3 g/dL or male subjects with hemoglobin < 15.1 g/dL. The grey lines show survival of subjects with or without anemia using the threshold of the World Health Organization (12 g/dL for female or 13 g/dL for male). The black lines represent the 58th percentile: females 14.3 g/dL, males 15.1 g/dL, hazard ratio 0.463, IQR 0.324–0.660, *P* < .001. The gray lines represents anemic versus non-anemic subjects: hazard ratio 0.572, IQR 0.361–0.907, *P* = .02.

### Multivariate Analysis

In the univariate Cox proportional hazards models, age, sex, body mass index (BMI), FEV1, 6-min walk distance, Hb, leukocyte levels, and arterial hypertension were associated with survival (*P* < .05 for each, Table 3). A multivariate Cox proportional hazards model containing age, sex, BMI, FEV1, Hb, leukocyte level, and arterial hypertension revealed only age and BMI to be predictive, while Hb as a continuous linear variable failed statistical significance (*P* = .09). However, when the categorical Hb cutoff values (female 14.3 g/dL, male 15.1 g/dL) were included in the multivariate panel, these cutoffs were also revealed as independent predictors of survival (Table 4), which indicates a nonlinear relationship.

View this table:
[Table 3.](http://rc.rcjournal.com/content/58/7/1204/T3)

Table 3. 
Univariate Cox Proportional Hazards Models for Predicted Probability of Death

View this table:
[Table 4.](http://rc.rcjournal.com/content/58/7/1204/T4)

Table 4. 
Multivariate Cox Proportional Hazards Model for Predicted Probability of Death*

## Discussion

The present study demonstrates that in subjects with severe COPD and chronic respiratory failure, Hb levels prior to the initiation of NIV were linked to long-term survival. We identified Hb values of 14.3 g/dL for females and 15.1 g/dL for males as conferring the highest predictive value. These Hb values were, in addition to age and BMI, independent predictors for survival, and markedly higher than the World Health Organization's definitions of anemia. Our findings demonstrate that in subjects with COPD and chronic respiratory failure the prognostic value of Hb is not fully exploited when only using the common cutoff values for anemia that have been introduced to define pathological conditions, but not as clinical predictors.

As part of the view that COPD is a disease with multiple alterations beyond the lung,2 chronic anemia has been revealed as a common systemic manifestation.6–9 Low red cell mass impairs pulmonary hemodynamics, oxygen delivery, and gas exchange,6 which seems particularly relevant for COPD patients presenting with chronic respiratory failure. Conversely, polycythemia can contribute to pulmonary hypertension, reduced cerebral blood flow, and increased risk of venous thromboembolic disease,26,27 and thus may also negatively influence the prognosis. On the other hand, a higher red cell mass may indicate that an adequate physiologic response to hypoxemia is still present, which may be particularly relevant in a systemic inflammatory disease such as COPD. Irrespective of these considerations, it is an open question whether the World Health Organization's definition of anemia or other definitions adequately utilize the information conferred by Hb in COPD. Therefore, we analyzed the impact of a wide range of Hb levels on long-term survival in COPD patients undergoing NIV and LTOT in detail.

According to established definitions, 14.9% of the subjects of our sample presented with anemia, while 18.1% were polycythemic. In comparison to earlier studies7–9 the present cohort comprised a considerably higher proportion of subjects with polycythemia. These subjects also showed a higher survival than those with anemia and even normocythemia. Using similar definitions, a study on stable, only moderately ill, predominately male (96%) COPD subjects also found anemia to be common (17.1%) and associated with higher mortality, while polycythemia was less frequent (5.9%). The prognostic value of polycythemia versus normoglobulia and anemia was not explicitly reported, but survival was at least not different between polycythemic and non-polycythemic subjects.8 In a large investigation of subjects with COPD and hypoxemic respiratory failure requiring LTOT,7 anemia occurred in 8.2% of females and 12.6% of males, while polycythemia again was present in only 5.9% of females and 8.9% of males, and associated with better survival. However, these findings were based on the assessment of Hc and not Hb.7 In contrast to Hc, Hb is a direct measure for oxygen carrying capacity, more stable against changes in plasma volume, and thus more reliable for the assessment of anemia, while Hc may underestimate anemia.28 Moreover, in comparison to our investigation, the authors provided no data on comorbidities (eg, cancer, renal failure, or other chronic inflammatory diseases) or conditions (eg, gastrointestinal hemorrhage or blood loss) that might lead to changes in the red blood cell count. In our experience, this is a substantial proportion of patients, and a potential source of bias, as most of these comorbidities per se influence survival. We had to exclude 42% of primarily considered patients to circumvent this.

Nonetheless, the previously studied population7 appeared to be comparable to our cohort, insofar as all subjects received LTOT. The fact that the prevalence of polycythemia was lower than in our cohort was possibly due to a more severely impaired gas exchange in our study cohort, as indicated by chronic hypercapnia and the need for NIV. The beneficial effect of polycythemia on survival stands in contrast to the traditional view on COPD.14 As all the subjects in the present study received NIV and LTOT, which counteract polycythemia and hyperviscosity,29–31,18 the “protective” effect of polycythemia might, however, be true only for patients with optimized treatment.

Our results confirm the high prevalence of anemia (14.9%) and its association with reduced survival in COPD,7–9 specifically in patients with chronic respiratory failure. Univariate Cox regression analyses showed Hb to be a predictor of long-term survival, similarly to age, sex, BMI, FEV1, 6-min walk distance, and leukocyte number. In a multivariate model, however, Hb as a continuous variable failed statistical significance (*P* = .09). In view of the inevitable correlations between predictors, this does not appear as an unexpected finding. In the study by Chambellan et al,7 red blood cell mass in terms of Hc was found as an independent prognostic factor. However, the authors did not exclude patients with severe comorbidities that are often associated with both low Hb and worse long-term survival.7 This may have led to an overestimation of the prognostic impact of red cell mass in their cohort.

In a clinical setting, deviations of red blood cell count are often only recognized when values are not within the normal range. Most studies addressing the importance of Hb and/or Hc in COPD have focused on the common definitions of anemia and polycythemia,32–34 despite the fact that the respective cutoff values have never been validated with regard to their prognostic value in COPD. To evaluate the clinical impact of Hb levels in detail and to answer the question whether there is an optimal threshold and where it is, we checked all percentiles of Hb and found optimal cutoff values of 14.3 g/dL for females and 15.1 g/dL for males for predicting long-term survival. These cutoff values ultimately chosen optimized the prediction, although the nature of the statistical analysis, in combination with the still finite number of subjects, resulted in broad and overlapping formal confidence intervals. The fact that these values are markedly higher than the common definitions of non-anemia (females ≥ 12 g/dL, males ≥ 13 g/dL) suggests that, in COPD, Hb levels are related to prognosis at levels far away from common “anemia.” Noteworthy enough, when the optimal cutoff values were introduced as categorical variables in the multivariate model, Hb remained a significant independent predictor, despite the fact that categories might be associated with a loss of statistical power, compared to continuous variables. The discrepancy points toward a nonlinear relationship of Hb to survival. In view of this, it is even more remarkable that this nonlinear transition occurred far above the established World Health Organization cutoff values. Of course, this does not invalidate the usefulness of those values, which are for clinical purposes, and not for prediction of survival. Our data point out that cutoff values must be adapted to their purpose and that patients with Hb values above anemia levels can also be at risk. Possibly, a higher Hb level in the presence of chronic hypoxemia prior to treatment reflects adequate bone marrow function35 and response to inflammation and/or hypoxia26,31 and therefore indicates patients with a better prognosis.

Of course, our findings are purely observational. Thus, the thresholds proposed should be validated prospectively in separate cohorts. In particular, the study design does not allow establishing a novel threshold for red blood cell transfusion. The association between higher threshold values and better prognosis most likely reflects an adequate physiological response to chronic respiratory failure in these patients. Which mechanisms are underlying these associations, possibly defining a specific phenotype of COPD, has to be addressed in future studies.

One of the limitations of the present study is that it was not designed to identify the patterns of pathophysiological factors underlying the abnormalities of Hb. We tried to deal with this as far as possible by the exclusion of known, trivial causes of anemia, in order to keep the analysis as unbiased as possible. With regard to the prognostic impact of Hb, we also accounted for additional comorbidities and typical concomitant medication, which, however, cannot be fully distracted from COPD. In addition, data were collected over a long period of time, and a change in therapeutic attitude, including prescribed medication, cannot be ruled out. Although the subjects were seen regularly at follow-up visits in the hospital, adherence to LTOT and NIV could not be assessed over the total study period. Finally, blood gas values were obtained from the earlobe and were not available without oxygen supply in all subjects, which could affect their value as potential predictors.

## Conclusions

In conclusion, in subjects with severe COPD and chronic respiratory failure requiring NIV and LTOT, Hb levels were gradually linked to long-term survival, and a higher Hb was associated with better survival. This is in line with known data. However, as optimal independent predictors of survival, we identified 14.3 g/dL for females and 15.1 g/dL for males, which corresponded to the 58th percentiles of the distributions. These values are markedly higher than the World Health Organization's definition of anemia or similar clinical criteria that are suited to define a definite pathological condition but do not fully exploit the prognostic potential of Hb values in severe COPD.

## Footnotes

*   Correspondence: Stephan Budweiser MD, Division of Pulmonary and Respiratory Medicine, Department of Internal Medicine III, RoMed Clinical Center Rosenheim, Pettenkoferstraße 10, 83022 Rosenheim, Germany. E-mail: stephan.budweiser{at}ro-med.de.
*   The authors have disclosed no conflicts of interest.

*   Copyright © 2013 by Daedalus Enterprises

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