Xiong et al.

BMC Pulmonary Medicine (2018) 18:143

https://doi.org/10.1186/s12890-018-0693-6

RESEARCH ARTICLE Open Access

The influence of anemia on one-year

exacerbation rate of patients with COPD-PH
Wei Xiong1,2, Mei Xu3, Bigyan Pudasaini2, Xuejun Guo1 and Jinming Liu2*

Abstract
Background: Anemia is prevalent not only in COPD but also in pulmonary hypertension. We postulated that
anemia may have certain prognostic value in COPD concomitant with PH due to COPD (COPD-PH).
Methods: We performed a 12-month prospective investigation to follow up COPD patients with or without PH
assessed by right heart catheterization. Eligible patients were enrolled, stratified into COPD-PH-anemia group (n = 40),
COPD-PH group (n = 42), COPD-anemia group (n = 48), and COPD group(n = 50), and then followed up for 12 months.
Results: After the follow-up, for both of the actual variation value and variation rate, the increase of NT-pro BNP (P<0.001;
P = 0.03) and CAT score (P = 0.001; 0.002), as well as the decrease of PaO2 (P = 0.03; 0.086) and Peak VO2 (P = 0.021; 0.009)
in COPD-PH-anemia group were highest among four groups. The cumulative one-year survival rates were similar among
four groups (P = 0.434). The cumulative exacerbation-free rate was lowest in COPD-PH-anemia group among four groups
(P<0.001). Hemoglobin was an independent promoting factor for the probability of hospitalization due to exacerbation
≧ 1/year in patients with COPD-PH-anemia [HR 3.121(2.325–5.981); P<0.001].
Conclusions: Anemia is a promoting factor for the worsening of exercise capacity, deterioration of hypoxemia, declining
of life quality, and aggravation of exacerbations in patients with COPD-PH-anemia, by contrast with COPD-PH, COPD-
anemia, and COPD.
Keywords: COPD, Pulmonary hypertension, Anemia, Prognosis, Hemoglobin

Background consequent smooth muscle hypertrophy [5–7]. Once PH

Chronic obstructive pulmonary disease (COPD) has be- develops in patients with COPD, what may follow are
come the third leading cause of death worldwide and is the deteriorated exercise capacity, worsened hypoxemia
projected to be the disease with the seventh greatest and shortened survival [8–10].
burden worldwide in 2030. It is a major chronic cause of In patients with COPD, systemic inflammatory media-
morbidity and mortality all over the world. Many pa- tors may contribute to skeletal muscular atrophy or
tients suffer from this disease for many years, and die cachexia, and initiate or aggravate anemia [11], mean-
prematurely due to itself or its complications [1–3]. while, anemia is common in patients with PH and may
Pulmonary hypertension (PH) is a pathophysiological be associated with reduced exercise capacity, and with a
disorder involving multiple clinical disciplines, which higher mortality [12–16]. Therefore, since anemia had
majorly include multiple cardiovascular and respiratory been evident to be prevalent in both COPD and PH, we
diseases [4]. It may develop in the advanced stage of wondered how the prognostic role anemia was in PH
COPD and is basically due to hypoxic vasoconstriction due to COPD. For patients with COPD related PH, there
of pulmonary capillaries, eventually leading to structural are many shared prognostic factors between COPD and
changes which include intimal hyperplasia and the PH, such as DLcO, 6MWD, PaO2, mMRC score and
peak VO2 which all decline worse than in either of
COPD or PH alone providing the inter-related basis for
* Correspondence: [email protected] the assessment of COPD-PH. To date, no existing studies
Xuejun Guo and Jinming Liu are joint corresponding authors have concerned this subject. Therefore, this study was
2
Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital,
Tongji University School of Medicine, Shanghai, China
Full list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Xiong et al. BMC Pulmonary Medicine (2018) 18:143 Page 2 of 8

designed to explore the potential prognostic value of diagnosis of anemia defined as a hemoglobin concentra-
anemia in PH due to COPD. tion of < 13 g/dL for males and 12 g/dL−for females [17].
Exclusion criteria: 1) a diagnosis of other chronic pulmon-
Methods ary diseases including, asthma or asthma-COPD overlap
Study design (ACO), bronchiectasis, tuberculosis, obliterative bronchio-
We performed a 12-month prospective study to investi- litis, diffuse panbronchiolitis, interstitial lung disease, or
gate the role of anemia in COPD concomitant with PH. combined pulmonary fibrosis and emphysema; 2) a diag-
All eligible patients were screened out according to inclu- nosis of PH in Group 1, Group 2, Group 4, or Group 5 ac-
sion and exclusion criteria and then stratified into cording to the classifications in 2015 ESC/ERS guidelines
COPD-PH-anemia group, COPD-PH group, COPD- [4]; 3) patients with hematological diseases including sec-
anemia group, and COPD group, to be followed up for ondary anemia such as anemia due to cancer or immuno-
12 months. Variables encompassing routine blood test logical diseases or hemorrhage, or receive regimens which
(RBT), COPD assessment test (CAT), pulmonary function affect hemoglobin except for anti-anemia therapy; 4) pa-
test (PFT), cardiopulmonary exercise test (CPET), 6 min tients who lived on plateau all the time; 5) patients who
walk distance (6MWD), and arterial blood gas analysis were lost to follow-up or who did not comply with
(ABGA) were assessed at the baseline and the endpoint. COPD-related or PH-related treatments.
Cumulative exacerbation counting and all-cause mortality
were documented during the follow-up. All relevant vari- Assessments
ables were compared amongst the four groups after the fin- We performed the assessments encompassing several as-
ish of follow-up. During the enrollment of the patients, we pects which were exercise capacity, hypoxemia, life qual-
equalized the variables of factors which might impact the ity, acute exacerbation and all-cause mortality. The
prognosis to the maximum extent except for hemoglobin. detailed variables we focused were hemoglobin, carboxy-
Since our subjects were primarily patients with COPD, so hemoglobin, methemoglobin in RBT, PaO2 in ABGA,
we focused mainly on the equalization of GOLD stage, AE FEV1 of the predicted value in PFT, peak VO2 in CPET,
history, and co-morbidities. Meanwhile, we eliminated the CAT score, NT-pro BNP and 6MWD. All assessments
difference of therapies by standardizing the treatment were performed when patients were at their stable status.
according to the guidelines. This protocol was approved by In case of patients happened to be in an exacerbated state
the institutional review board of Shanghai Pulmonary at the moment of assessment, the evaluation would be
Hospital. Written informed consent was obtained from all postponed till patients recovered from exacerbations. Ex-
patients. acerbation was defined as an acute worsening of respira-
tory symptoms that result in additional therapy [18, 19].
Study population At the end of each month during the follow-up, study
All eligible patients were enrolled from a cohort of pa- personnel determined the patients’ status including exac-
tients with COPD with or without PH assessed by right erbations, hospitalizations due to exacerbations, and sur-
heart catheterization (RHC) between 2013 and 2016 of vival status in the previous month by telephone contact.
the department of cardiopulmonary circulation of Shang-
hai Pulmonary Hospital Tongji University, due to at least Statistical analysis
one of the following reasons: 1) episodes of RV failure or According to the prevalence of COPD (11.7%), the
suspected PH by echocardiographic findings; 2) suspected anemia prevalence in COPD (12.3–23%), and the preva-
PAH or CTEPH; 3) candidates for lung transplantation or lence of PH in COPD (50–90%), to ensure the 95% con-
lung volume reduction. fidential interval, we estimated we at least needed to
Eligible patients were enrolled according to the inclu- measure in total of 159 cases of COPD patients, in
sion criteria and the exclusion criteria. Inclusion criteria: which at least 82 cases of COPD-anemia in total, 75
1) age ≥ 40 yrs.; 2) a diagnosis of COPD at all stages/ cases of COPD-PH in total, and at least 36 cases of
groups, defined as an FEV1: FVC ratio of less than 0.70 COPD-PH-anemia.
after bronchodilator use plus respiratory symptoms, a Measurement data was presented as mean ± standard
history of exposure to risk factors (e.g., smoking, air pol- deviation or median with interquartile range according
lution, biomass combustion), or both, measured 20 min to their distribution. Categorical data was presented as
after the inhalation of 400 μg of albuterol (Ventolin, frequencies and percentages. Exacerbation-free rates and
Glaxo Wellcome) [11]; 3) a diagnosis with PH on the survival rates at different time-points were estimated by
presence of mean pulmonary arterial pressure (mPAP) means of Kaplan–Meier method, and any differences be-
≧25 mmHg and pulmonary artery wedge pressure tween groups were evaluated with a stratified log-rank
(PAWP) ≤18 mmHg in RHC or an exclusion of PH by test. The multiple testing among all groups was con-
mPAP< 25 mmHg in RHC [4]; 4) with or without a ducted by using ANOVA with Bonferroni correction.
Xiong et al. BMC Pulmonary Medicine (2018) 18:143 Page 3 of 8

The change of patients’ variables between the baseline and 131/49, respectively. No statistical difference was found
the study completion was calculated: change = (variable at among four groups in regard to age, sex ratio, smoking
completion- variable at baseline); the change rate was cal- history, AE history, FEV1, GOLD stages, and COPD
culated: change rate = (variable at completion-variable at groups (P > 0.05 for all comparisons), except for BMI (P
baseline)/variable at baseline. Cox regression analysis was = 0.025), mPAP (P = 0.016), 6MWD (P = 0.003), NT-pro
performed to assess the correlation between variables and BNP (P<0.001), PaO2 (P = 0.006), peak VO2(P = 0.018)
the probability of hospitalizations due to exacerbations ≧ and hemoglobin (P = 0.036) at the baseline. By means of
1 time per year. A p-value < 0.05 was defined as being of a routine blood test, among 88 cases with anemia, 45
statistical significance. cases were identified to be normocytic anemia, 33 cases
were microcytic anemia, and 10 cases were macrocytic
Results anemia. Demographics and characteristics of the patients
Demographics and characteristics of the patients at the baseline were summarized in Table 1. LTOT was
This investigation was launched in January, 2016, and prescribed according to patients’ indication before and
finished in December, 2017, following the finish of during the study period. No statistical difference regard-
follow-up of the last enrolled patient. After the exclusion ing LTOT was found among four groups (P = 0.085).
of 10 cases with at least one of the following diagnoses
of asthma, bronchiectasis, tuberculosis, obliterative
bronchiolitis, diffuse panbronchiolitis, interstitial lung Comparison of variation of variables between the
disease, or combined pulmonary fibrosis and emphy- baseline and the endpoint among four groups
sema, 6 cases with a diagnosis of PH in Group 1, Group The results demonstrated that no statistical difference
2, Group 4, or Group 5, and 3 cases with hematological were found regarding the FEV1 among four groups in
diseases, or receive regimens which affect hemoglobin both aspects of actual variation value and variation rate
except for anti-anemia therapy, amongst 207 cases, fi- (P = 0.057;0.062). Except the variation rates of PaO2 were
nally, a total of 188 eligible patients were screened out similar among four groups(P = 0.086), no matter regard-
to access to the follow-up program. Then after the loss ing actual variation value or variation rate, the increase
of 8 cases to the follow-up, in the end, 180 cases entered of NT-pro BNP (P<0.001;P = 0.03) and CAT score (P =
into the final full analysis set. Throughout all of them, 0.001;0.002) in COPD-PH-anemia group were signifi-
the cases in COPD-PH-anemia group, COPD-PH group, cantly highest among four groups, whereas the decrease
COPD-anemia group, and COPD group were 40, 42, 48, of PaO2 (P = 0.03;0.086) and Peak VO2 (P = 0.021;0.009)
and 50, respectively. The overall mean age and male/fe- in COPD-PH-anemia group were significantly highest
male sex ratio of all eligible patients were 66.1 years and among four groups (Table 2).

Table 1 Demographics and characteristics of all the patients at the baseline

Variables COPD-PH-anemia (n = 40) COPD-PH (n = 42) COPD-anemia (n = 48) COPD (n = 50) P value
Age-yrs 65.9 ± 5.3 68.7 ± 8.1 62.6 ± 6.7 67.2 ± 7.5 0.587
Sex (M/F)-% 75.0/25.0 71.4/28.6 68.8/31.2 76.0/24.0 0.661
2
BMI-kg/m 18.5 ± 5.8 21.6 ± 6.2 22.4 ± 4.7 25.1 ± 7.1 0.025
Smoking history (Y/N)-% 90.0/10.0 88.1/11.9 85.4/14.6 86.0/14.0 0.549
FEV1 of predicted value-% 40.7 ± 25.9 43.8 ± 19.6 47.7 ± 22.6 42.3 ± 17.8 0.383
AE history- no. 2.8 ± 1.5 2.5 ± 2.3 2.6 ± 1.7 2.2 ± 1.8 0.446
GOLD (I/II/III/IV)-% 0/7.5/47.5/45.0 0/11.9/45.2/42.9 0/8.3/41.7/50.0 0/10.0/43.1/46.9 0.125
Group (A/B/C/D)-% 0/12.5/40.0/47.5 0/14.3/47.6/38.1 0/14.6/43.8/41.6 0/16.0/40.0/44.0 0.374
mPAP-mmHg 33.8 ± 18.5 30.2 ± 22.6 20.6 ± 15.3 18.9 ± 25.4 0.016
CAT score-points 23.5 ± 10.2 16.9 ± 13.8 22.2 ± 8.6 18.7 ± 15.1 0.186
6MWD-m 298.9 ± 183.4 353.6 ± 164.7 382.1 ± 173.7 452.3 ± 152.2 0.003
NT-pro BNP-ng/L 1608.2 ± 679.8 1344.9 ± 852.4 556.7 ± 391.1 374.6 ± 421.0 <0.001
PaO2-mmHg 45.3 ± 13.8 50.7 ± 18.1 55.6 ± 16.4 65.7 ± 17.2 0.006
Peak VO2-ml/min/kg 13.9 ± 5.7 15.2 ± 7.3 18.5 ± 6.2 22.2 ± 8.1 0.018
Hemoglobin-g/dL−1 9.4 ± 5.5 14.2 ± 6.7 10.7 ± 8.3 13.8 ± 4.9 0.036
Note: COPD chronic obstructive pulmonary disease, PH pulmonary hypertension, BMI body mass index, FEV1 forced expiatory volume in 1 s, AE acute exacerbation,
GOLD global Initiative for Chronic Obstructive lung Disease, mPAP mean pulmonary arterial pressure, CAT COPD assessment test, 6MWD 6-min walking distance,
NT-proBNP N-terminal pro-brain natriuretic peptide, PaO2 arterial blood oxygen tension, Peak VO2 peak oxygen consumption
Xiong et al. BMC Pulmonary Medicine (2018) 18:143 Page 4 of 8

Table 2 Comparison of the change and changing rate of patients’ variables between the baseline and the endpoint among four
groups
Variables COPD-PH-anemia (n = 40) COPD-PH (n = 42) COPD-anemia (n = 48) COPD (n = 50) P value
FEV1-% (%) −8.8 ± 3.6(− 10.1 ± 5.3) −8.5 ± 6.4(− 10.6 ± 4.6) − 7.2 ± 5.1(− 8.3 ± 7.2) −7.6 ± 4.2(−9.1 ± 4.8) 0.057(0.062)
CAT score-points (%) 12.6 ± 5.8(23.7 ± 15.1) 6.5 ± 3.7(19.2 ± 12.4) 6.6 ± 4.0(22.3 ± 10.6) 4.7 ± 3.2(20.1 ± 8.8) 0.001(0.002)
6MWD-m (%) −59.5 ± 45.6(− 32.2 ± 18.8) −34.3 ± 41.2(− 26.5 ± 14.3) −28.4 ± 40.1(− 20.5 ± 16.2) − 19.7 ± 38.3(− 16.5 ± 12.3) 0.007(0.01)
NT-pro BNP- ng/L (%) 597.1 ± 154.4(31.3 ± 20.4) 466.8 ± 191.0(25.5 ± 22.3) 125.7 ± 112.1(19.5 ± 17.2) 133.6 ± 108.5(15.2 ± 13.3) <0.001(0.03)
PaO2-mmHg (%) −10.7 ± 5.8(− 10.9 ± 8.6) −7.6 ± 5.3(− 11.7 ± 7.0) −6.6 ± 5.4(−8.8 ± 7.5) − 4.9 ± 4.5(− 7.9 ± 7.2) 0.03(0.086)
Peak VO2-ml/min/kg (%) −3.5 ± 1.6(− 32.4 ± 10.3) −2.8 ± 1.9(− 25.5 ± 13.6) −2.4 ± 2.1(− 17.7 ± 8.8) −1.8 ± 1.4(− 10.3 ± 11.7) 0.021(0.009)
Note: FEV1 forced expiatory volume in 1 s, CAT COPD assessment test, 6MWD 6-min walking distance, NT-proBNP N-terminal pro-brain natriuretic peptide, PaO2
arterial blood oxygen tension, Peak VO2 peak oxygen consumption

Comparison of cumulative overall survival, exacerbation- hemoglobin, the hazard ratio of hospitalizations ≧ 1/year
free rate amongst four groups was 3.121, being similar with some variables such as AE
At the end of the follow-up, the cumulative overall mor- history and COPD groups. Also in a multivariate regres-
tality were 19 cases, in which 7cases were in COPD- sion analysis between dyshemoglobins which were carb-
PH-anemia group, 5 cases were in COPD-PH group, 4 oxyhemoglobin as well as methemoglobin and the risk for
cases were in COPD-anemia group, and 3cases were in hospitalizations ≧ 1/year, the results showed that only
COPD group(P = 0.096). Among all the deceased, 10 pa- carboxyhemoglobin was positively correlated with the de-
tients died of respiratory failure, 7 patients died of heart velopment of hospitalizations ≧ 1/year especially in
failure, 2 cases died of sudden death. In a Kaplan–Meier COPD-PH-anemia group (Table 3.)
analysis, the results demonstrated that the cumulative
one-year survival rates were similar amongst COPD- Discussion
PH-anemia group, COPD-PH group, COPD-anemia In consideration of anemia may have certain prognostic
group, and COPD group (P = 0.434) (Fig. 1.) Throughout value in patients with pulmonary hypertension due to
the whole process of follow-up, the mean annual exacer- COPD, whereas little of them was known quoad hoc, thus
bations or hospitalizations counting per patient were 3.5 we performed this study. In this study, we found that,
and 1.8 times in COPD-PH-anemia group, 2.6 and 1.7 among COPD-PH-anemia group, COPD-PH group,
times in COPD-PH group, 2.4 and 1.3 times in COPD-anemia group, and COPD group, the patients in
COPD-anemia group, as well as 1.8 and 0.8 times in COPD-PH-anemia group had the most deterioration in
COPD group, respectively (P = 0.005;P = 0.018). At the exercise capacity, hypoxemia, life quality, and highest risk
end of the follow-up, the cases with at least one exacer- of acute exacerbations, except for the similar overall sur-
bation or one hospitalization were 118(65.6%) and 66 vival rates among all groups, in a 12-month interval.
(36.7%) cases, respectively. The prevalence of exacerba- To our best knowledge, no existing comparable study
tions or hospitalizations were 35(87.5%) and 16(40.0%) in is eligible to be the contrast with this study, therefore,
COPD-PH-anemia group, 28(66.7%) and 15(35.7%) in what we can discuss hereby is this investigation exclu-
COPD-PH group, 30(62.5%) and 12(25.0%) in COPD- sively. Since PH is also a concomitant co-morbidity just
anemia group, as well as 25 (50%) and 10(20.0%) in COPD like anemia, we primarily regarded the subjects as COPD
group [P = 0.033(P<0.001);P = 0.065(P = 0.005)]. In a patients, then as PH or not. In order to present the the
Kaplan–Meier analysis, the results demonstrated that the impact of anemia on COPD-PH to the maximum extent,
cumulative exacerbation-free proportion was lowest in we set up not only COPD-PH, but also COPD-anemia
COPD-PH-anemia group, and highest in COPD group, and COPD as control. Besides the information of impact
whereas no statistical difference was found between of anemia on COPD-PH, we could also obtain the infor-
COPD-PH group and COPD-anemia group(P<0.001) mation regarding the different impact of anemia on
(Fig. 2.). COPD-PH and COPD, respectively, by contrast with sole
COPD. It cannot be denied that secondary polycythemia
Correlation between risk factors and exacerbations in is a common phenomenon in patients with COPD just
each group by multivariate regression analysis like anemia, in other words, the two pathophysiologic
After an univariate analysis between risk factors and the processes may potentially happen in patients with COPD
development of hospitalizations due to exacerbations ≧ 1/ simultaneously, especially in early stage of COPD.
year, then adjusting for age, sex, smoking history and BMI, Therefore, since the basic hemoglobin level of COPD
a multivariate analysis demonstrated that, for patients with may be higher than that of normal person, we adopted
COPD-PH-anemia, along with per decrease of 1 g/dL− 1 of the diagnostic criteria of WHO for anemia which are
Xiong et al. BMC Pulmonary Medicine (2018) 18:143 Page 5 of 8

Fig. 1 Comparison of cumulative one-year overall survival rate among COPD-PH-anemia group, COPD-PH group, COPD-anemia group, and COPD
group (P = 0.434)

Fig. 2 Comparison of cumulative one-year exacerbation-free rate among COPD-PH-anemia group, COPD-PH group, COPD-anemia group, and
COPD group (P<0.001)
Xiong et al. BMC Pulmonary Medicine (2018) 18:143 Page 6 of 8

Table 3 Correlation between risk factors and the probability of hospitalizations ≧ 1/year in each group by multivariate regression
analysis
Variables COPD-PH-anemia (n = 40) COPD-PH (n = 42) COPD-anemia (n = 48) COPD (n = 50)
HR (95%CI), P value HR (95%CI), P value HR (95%CI), P value HR (95%CI), P value
FEV1-per decrease of 10% 2.565(1.225–3.764) 0.003 2.439(1.219–3.664) 0.002 2.108(1.321–4.214) 0.005 1.884(0.871–3.265) 0.003
AE history-per increase of 1 time 3.338(1.532–4.698) <0.001 3.157(1.339–5.310)< 0.001 2.541(1.210–4.311)0.001 2.226(1.722–3.827)0.001
GOLD-per progression of 1 stage 2.765(1.555–3.827)0.008 2.672(1.246–3.981)0.005 2.519(1.433–3.646)0.001 1.987(0.592–3.218)0.037
Group-per progression of 1 level 3.102(1.426–3.223) <0.001 2.453(1.002–3.528)0.002 2.313(1.038–3.297)0.004 2.124(0.762–3.281)0.014
PaO2-per decrease of 10 mmHg 2.384(1.542–3.456)0.02 2.176(1.256–3.642)0.006 2.987(1.777–3.562)0.007 1.733(0.888–3.213)0.028
Peak VO2-per decrease of 2.182(1.214–3.628)0.003 2.815(1.118–3.823)0.033 2.143(1.143–3.427)0.004 2.054(1.076–3.665)0.029
10 ml/min/kg
6MWD-per decrease of 100 m 1.676(0.662–3.186)0.036 1.501(0.855–3.222)0.044 1.453(0.337–3.212)0.038 1.222(0.443–3.251)0.057
Hemoglobin -per decrease 3.121(2.325–5.981) <0.001 1(reference) 2.756(1.985–3.784) <0.001 1(reference)
of 1 g/dL− 1
Carboxyhemoglobin-per 2.838(1.698–5.210)0.001 2.663(1.520–3.228)0.001 2.437(1.265–3.884)0.001 1.688(1.104–3.651)0.002
increase of 0.1 g/dL−1
Note: COPD chronic obstructive pulmonary disease, PH pulmonary hypertension, FEV1 forced expiatory volume in 1 s, AE acute exacerbation, GOLD global Initiative
for Chronic Obstructive lung Disease, PaO2 arterial blood oxygen tension, Peak VO2 peak oxygen consumption, 6MWD 6-min walking distance

< 13 g/dL for males and < 12 g/dL for females, respect- impairment of oxygen-transporting function in anemia,
ively, instead of the criteria of anemia in China which patients with COPD-PH-anemia are naturally more li-
are <12 g/l for male and <11 g/l for female, respectively, able to develop ingravescent fatigue, heart failure and
to eliminate the potential confounding of secondary hypoxemia rather than airflow limitation, by contrast
polycythemia. with either COPD-PH or COPD.
To start with, except for hemoglobin which was prede- The next comparison of cumulative overall survival
termined to be different among four groups, the demo- showed no difference of cumulative one-year survival rates
graphics showed that no statistical difference was found among four groups. This could be interpreted as that
in regard to age, sex ratio, smoking history, AE history, anemia makes no difference on the survival of patients
FEV1, GOLD stages, and COPD groups, suggesting the with COPD-PH or COPD for at least 1 year. By contrast,
homogeneity was considerable at least from the perspec- in the study of Pernille et al., anemia could be used to pre-
tive of COPD, among all eligible patients at the baseline. dict mortality. In view of Pernille’s study was a five-year
Nevertheless, some variables such as mPAP, 6MWD, retrospective review, while ours was a one-year prospect-
NT-pro BNP, PaO2, and peak VO2 were heterogenous ive investigation, the investigating period in this study
among all eligible patients at the baseline partially attrib- may be too limited to uncover the difference of mortality
utable to the role of PH. Interestingly, the BMI in among different groups [20].
COPD-PH-anemia group was lowest among four groups In the study of Pernille, et al., low level of hemoglobin
suggesting anemia may interrelate with nutritional sta- are frequent in COPD patients with acute exacerbations
tus. It is noteworthy that the cause of anemia was ma- [20]. In our study, the comparison of exacerbations dem-
jorly due to normocytic type which conformed to the onstrated that COPD-PH-anemia group had the most
characteristics of COPD [11]. As for microcytic type be- mean annual exacerbations or hospitalizations counting,
ing the second major cause, we believe it is related to the highest prevalent rate of exacerbations or hospitaliza-
PH [12–16]. tions, and lowest cumulative exacerbation-free rate among
After the follow-up, the results showed no dramatic patients among four groups. It means that, by contrast
variation regarding the FEV1 which is a COPD-related with simple COPD, anemic COPD, or simple COPD-PH,
variable concerning airflow limitation, whereas the va- COPD-PH-anemia has the highest risk for developing an
riations of NT-pro BNP, CAT score, PaO2 and Peak VO2 exacerbation. It is believed that, by deteriorating life qual-
were significant among four groups in which the ity, ventricular dysfunction, and hypoxemia, anemia con-
COPD-PH-anemia group had the worst deterioration. tributes to the aggravation of exacerbations.
This indicated that, anemia impacted more seriously on The last correlation analysis between risk factors and
patients with COPD-PH than on mere COPD, en- hospitalizations showed that, being similar with some
compassing the perspectives of life quality, ventricular exacerbation-related classical predictors in COPD such
dysfunction, and hypoxemia especially whilst exercise, as AE history and COPD groups [11], hemoglobin was
except for airflow limitation. On account of the an independently contributing factor for the probability
Xiong et al. BMC Pulmonary Medicine (2018) 18:143 Page 7 of 8

of hospitalizations ≧ 1/year in COPD patients especially pa- time-dependent impact that anemia would result in.
tients with COPD-PH-anemia. Decremental hemoglobin is Nevertheless, several limitations existed in this study.
a promoting factor for the incremental exacerbations or First, the sample size was not very large due to the na-
hospitalizations. By the way, we also performed a correl- ture of prospective investigation. A large-scale study is
ation analysis between some dyshemoglobins which were warranted in the future. Second, obviously we have no
carboxyhemoglobin as well as methemoglobin and hospital- comments to make on the potential difference of overall
izations. The results demonstrated that carboxyhemoglobin survival amongst different groups beyond one-year
was positively correlated with the development of hosp- follow-up which might be too short to show the discrep-
italizations ≧ 1/year in all four groups especially in ancy. The last but not least, in view of the patients being
COPD-PH-anemia group rather than methemoglobin. Like- reviewed in this study were all Chinese patients, the re-
wise, in the study of Yasuda et al., the carboxyhemoglobin sults of this study may not be applicable for other races.
level at exacerbations were significantly higher than those at
stable stage, the increased arterial carboxyhemoglobin was Conclusions
correlated to the severity of COPD resulting from systemic In summary, in this study, we may draw a conclusion
inflammation and reactive oxygen species [21]. that anemia is a promoting factor for worse deterior-
Some systematic inflammatory diseases such as con- ation of exercise capacity, deterioration of hypoxemia,
nective tissue disease are frequently concomitant with declining of life quality, as well as aggravation of exacer-
anemia of chronic disease through the mechanism of the bations or hospitalizations in patients with COPD-PH-
production of inflammatory mediators damaging the anemia, by contrast with patients with COPD-PH,
generation of erythrocytes. Likewise, COPD which is one COPD-anemia, or COPD.
of systematic inflammatory diseases is generally con-
Abbreviations
comitant with the elevation of IL-1, IL-6 and TNF-a 6MWD: 6 min walk distance; ABGA: Arterial blood gas analysis; AE: Acute
level in circulation inducing the development of anemia exacerbation; BMI: Body mass index; CAT: COPD assessment test;
[22]. Some studies demonstrated that anemia was closely COPD: Chronic obstructive pulmonary disease; CPET: Cardiopulmonary
exercise test; CTEPH: Chronic thromboembolic pulmonary hypertension;
related to C reactive protein which is an inflammatory FEV1: Forced expiatory volume in 1 s; GOLD: Global Initiative for Chronic
biomarker [23, 24]. Besides, inflammatory mediators Obstructive lung Disease; mPAP: Mean pulmonary arterial pressure; NT-
may also result in skeletal muscular atrophy and cach- proBNP: N-terminal pro-brain natriuretic peptide; PAH: Pulmonary arterial
hypertension; PaO2: Arterial blood oxygen tension; PAWP: Pulmonary artery
exia further deteriorating anemia [11]. On the other wedge pressure; Peak VO2: Peak oxygen consumption; PFT: Pulmonary
hand, patients with pulmonary hypertension commonly function test,; PH: Pulmonary hypertension; RBT: Routine blood test;
develop right ventricular dysfunction in which 15% are RHC: Right heart catheterization; RV: Right ventricular
concomitant with anemia [25–28]. Its mechanism is due Acknowledgements
to the release of inflammatory mediators whilst heart We sincerely thank Dr. Lan Wang, Dr. Jian Guo, Dr. Sugang Gong, Dr. Jing
failure, the activation of renin-angiotensin system [28]. He, Dr. Qinhua Zhao, Dr. Rong Jiang, Dr. Cijun Luo, Dr. Hongling Qiu, Dr.
Wenhui Wu, Dr. Minqi Liu, Dr. Tianxiang Chen, Dr. Xingxing Sun, and Dr.
All these may explain the impressive prevalence of Chuanyu Wang of Department of Cardiopulmonary Circulation, Shanghai
anemia in COPD-PH. Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China,
The clinical implications of this study are considered for their assistance in this study.
to be the following: first, the results of our study may Funding
urge clinicians to be aware of the serious prevalence of This work was supported by the following funds: The Program of Shanghai
anemia in COPD patients concomitant with PH; second, Natural Science Foundation (16ZR1429000); the Program of Development
Center for Medical Science and Technology, National Health and Family
clinician could be vigilant about the severely adverse im- Planning Commission of the People’s Republic of China (ZX-01-C2016144)
pact of anemia on the prognosis of COPD-PH in order
to inform patients’ family members timely and take ac- Availability of data and materials
tion in advance; third, under some circumstances in Please contact Wei Xiong for data requests.

which a dilemma exists in the assessment of prognosis, Authors’ contributions

anemia could be an eligible weight which can be taken WX conceived of the study, and participated in its design, performance,
into account. statistics, coordination, drafting and revising of the manuscript. MX
conceived of the study, and participated in its design, statistics, coordination,
The strength of this study consisted in: first, the eli- drafting and revising of the manuscript. XJG conceived of the study, and
gible patients being studied all underwent RHC which is participated in its design, statistics, coordination, and revising of the
the only gold standard for the diagnosis of PH to date, manuscript. BP participated in its design, statistics, performance,
coordination, drafting and revising of the manuscript. JML conceived of the
to ascertain wether they had PH or not, ensuring the eli- study, and participated in its design, coordination and revising of the
gibility of PH-negative COPD controls; second, we com- manuscript. All authors read and approved the final manuscript.
pared the longitudinal variation and variation rate
Ethics approval and consent to participate
between the baseline and the endpoint instead of com- This protocol was approved by the institutional review board of Shanghai
paring the variables at the endpoint, to reflect the Pulmonary Hospital. Written informed consent was obtained from all patients.
Xiong et al. BMC Pulmonary Medicine (2018) 18:143 Page 8 of 8

Consent for publication 18. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and
Not applicable prevention. Lancet. 2007;370(9589):786–96.
19. Seemungal TA, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality
Competing interests of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit
The authors declare that they have no competing interests. Care Med. 1998;157(5Pt1):1418–22.
20. Pernille A, Petersen T, Pedersen CT, et al. Association between hemoglobin
and prognosis in patients admitted to hospital for COPD. Int J COPD.
Publisher’s Note 2016;11:2813–20.
Springer Nature remains neutral with regard to jurisdictional claims in 21. Yasuda H, Yamaya M, Nakayama K, et al. Increased arterial
published maps and institutional affiliations. carboxyhemoglobin concentrations in chronic obstructive pulmonary
disease. Am J Respir Crit Care. 2005;171:1246–51.
Author details 22. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;
1
Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiaotong 352:1011–23.
University School of Medicine, No. 1665, Kongjiang Road, Yangpu District, 23. John M, Hoernig S, Doehner W, et al. Anemia and inflammation in COPD.
Shanghai 200092, People’s Republic of China. 2Department of Chest. 2005;127:825–9.
Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, Tongji 24. Markoulaki D, Kostikas K, Papatheodorou G, et al. Hemoglobin,
University School of Medicine, Shanghai, China. 3Department of Pediatrics, erythropoietin and systemic inflammation in exacerbations of chronic
Dinghai Community Health Service Center, Tongji University School of obstructive pulmonary disease. Eur J Intern Med. 2011;22:103–7.
Medicine, Shanghai, China;Department of Pediatrics, Kongjiang Hospital, 25. Tanner H, Moschovitis G, Kuster GM, et al. The prevalence of anemia in
Yangpu District, Shanghai, China. chronic heart failure. Int J Cardiol. 2002;86:115–21.
26. Cromie N, Lee C, Struthers AD. Anaemia in chronic heart failure: what is its
Received: 9 April 2018 Accepted: 19 July 2018 frequency in the UK and its underlying causes? Heart. 2002;87:377–8.
27. Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart
failure and is associated with poor outcomes: insights from a cohort of
12065 patients with new-onset heart failure. Circulation. 2003;107:223–5.
References 28. Okonko DO, Anker SD. Anemia in chronic heart failure: pathogenetic
1. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 mechanisms. J Card Fail. 2004;10(Suppl. 1):S5–9.
causes of death for 20 age groups in 1990 and 2010: a systematic analysis for
the global burden of disease study 2010. Lancet. 2012;380:2095–128.
2. Yang G, Wang Y, Zeng Y, et al. Rapid health transition in China, 1990-2010:
findings from the global burden of disease study 2010. Lancet. 2013;381:
1987–2015.
3. Mathers CD, Loncar D. Projections of global mortality and burden of disease
from 2002 to 2030. PLoS Med. 2006;3(11):e442.
4. Galiè N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS guidelines for the
diagnosis and treatment of pulmonary hypertension. Eur Respir J.
2015;46:879–82.
5. Sakao S, Voelkel NF, Tatsumi K. The vascular bed in COPD: pulmonary
hypertension and pulmonary vascular alterations. Eur Respir Rev. 2014;
23(133):350–5.
6. Peinado VI, Pizarro S, Barbera JA. Pulmonary vascular involvement in COPD.
Chest. 2008;134(4):808–14.
7. Wells JM, Washko GR, Han MK, et al. Pulmonary arterial enlargement and
acute exacerbations of COPD. N Engl J Med. 2012;367(10):913–21.
8. Oswald-Mammosser M, Weitzenblum E, Quoix E, et al. Prognostic factors in
COPD patients receiving long-term oxygen therapy. Importance of
pulmonary artery pressure. Chest. 1995;107:1193–8.
9. Kessler R, Faller M, Weitzenblum E, et al. “Natural history” of pulmonary
hypertension in a series of 131 patients with chronic obstructive lung
disease. Am J Respir Crit Care Med. 2001;164:219–24.
10. Lettieri CJ, Nathan SD, Barnett SD, et al. Prevalence and outcomes of
pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis.
Chest. 2006;129:746–52.
11. Global Strategy for the Diagnosis, Management and Prevention of COPD,
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Publication
list; 2017. http://goldcopd.org/gold-2017-global-strategy-diagnosis-
management-prevention-copd/.
12. Ruiter G, Lankhorst S, Boonstra A, et al. Iron deficiency is common in
idiopathic pulmonary arterial hypertension. Eur Respir J. 2011;37:1386–91.
13. Ruiter G, Lanser IJ, de Man FS, et al. Iron deficiency in systemic sclerosis
patients with and without pulmonary hypertension. Rheumatology (Oxford).
2014;53:285–92.
14. Broberg CS, Bax BE, Okonko DO, et al. Blood viscosity and its relationship to
iron deficiency, symptoms, and exercise capacity in adults with cyanotic
congenital heart disease. J Am Coll Cardiol. 2006;48:356–65.
15. Rhodes CJ, Howard LS, Busbridge M, et al. Iron deficiency and raised
hepcidin in idiopathic pulmonary arterial hypertension clinical prevalence,
outcomes, and mechanistic insights. J Am Coll Cardiol. 2011;58:300–9.
16. Van De Bruaene A, Delcroix M, Pasquet A, et al. Iron deficiency is associated
with adverse outcome in Eisenmenger patients. Eur Heart J. 2011;32:2790–9.
17. World Health Organization. Iron deficiency anemia. assessment, prevention,
and control. A guide for programme managers. Geneva: WHO; 2001.