Background
Chronic obstructive pulmonary disease (COPD) has become the third leading cause of death worldwide and is projected to be the disease with the seventh greatest burden worldwide in 2030. It is a major chronic cause of morbidity and mortality all over the world. Many patients suffer from this disease for many years, and die prematurely due to itself or its complications [
1‐
3].
Pulmonary hypertension (PH) is a pathophysiological disorder involving multiple clinical disciplines, which majorly include multiple cardiovascular and respiratory diseases [
4]. It may develop in the advanced stage of COPD and is basically due to hypoxic vasoconstriction of pulmonary capillaries, eventually leading to structural changes which include intimal hyperplasia and the consequent smooth muscle hypertrophy [
5‐
7]. Once PH develops in patients with COPD, what may follow are the deteriorated exercise capacity, worsened hypoxemia and shortened survival [
8‐
10].
In patients with COPD, systemic inflammatory mediators may contribute to skeletal muscular atrophy or cachexia, and initiate or aggravate anemia [
11], meanwhile, anemia is common in patients with PH and may be associated with reduced exercise capacity, and with a higher mortality [
12‐
16]. Therefore, since anemia had been evident to be prevalent in both COPD and PH, we wondered how the prognostic role anemia was in PH due to COPD. For patients with COPD related PH, there are many shared prognostic factors between COPD and PH, such as DLcO, 6MWD, PaO
2, mMRC score and peak VO
2 which all decline worse than in either of COPD or PH alone providing the inter-related basis for the assessment of COPD-PH. To date, no existing studies have concerned this subject. Therefore, this study was designed to explore the potential prognostic value of anemia in PH due to COPD.
Discussion
In consideration of anemia may have certain prognostic value in patients with pulmonary hypertension due to COPD, whereas little of them was known quoad hoc, thus we performed this study. In this study, we found that, among COPD-PH-anemia group, COPD-PH group, COPD-anemia group, and COPD group, the patients in COPD-PH-anemia group had the most deterioration in exercise capacity, hypoxemia, life quality, and highest risk of acute exacerbations, except for the similar overall survival rates among all groups, in a 12-month interval.
To our best knowledge, no existing comparable study is eligible to be the contrast with this study, therefore, what we can discuss hereby is this investigation exclusively. Since PH is also a concomitant co-morbidity just like anemia, we primarily regarded the subjects as COPD patients, then as PH or not. In order to present the the impact of anemia on COPD-PH to the maximum extent, we set up not only COPD-PH, but also COPD-anemia and COPD as control. Besides the information of impact of anemia on COPD-PH, we could also obtain the information regarding the different impact of anemia on COPD-PH and COPD, respectively, by contrast with sole COPD. It cannot be denied that secondary polycythemia is a common phenomenon in patients with COPD just like anemia, in other words, the two pathophysiologic processes may potentially happen in patients with COPD simultaneously, especially in early stage of COPD. Therefore, since the basic hemoglobin level of COPD may be higher than that of normal person, we adopted the diagnostic criteria of WHO for anemia which are < 13 g/dL for males and < 12 g/dL for females, respectively, instead of the criteria of anemia in China which are <12 g/l for male and <11 g/l for female, respectively, to eliminate the potential confounding of secondary polycythemia.
To start with, except for hemoglobin which was predetermined to be different among four groups, the demographics showed that no statistical difference was found in regard to age, sex ratio, smoking history, AE history, FEV
1, GOLD stages, and COPD groups, suggesting the homogeneity was considerable at least from the perspective of COPD, among all eligible patients at the baseline. Nevertheless, some variables such as mPAP, 6MWD, NT-pro BNP, PaO
2, and peak VO
2 were heterogenous among all eligible patients at the baseline partially attributable to the role of PH. Interestingly, the BMI in COPD-PH-anemia group was lowest among four groups suggesting anemia may interrelate with nutritional status. It is noteworthy that the cause of anemia was majorly due to normocytic type which conformed to the characteristics of COPD [
11]. As for microcytic type being the second major cause, we believe it is related to PH [
12‐
16].
After the follow-up, the results showed no dramatic variation regarding the FEV1 which is a COPD-related variable concerning airflow limitation, whereas the variations of NT-pro BNP, CAT score, PaO2 and Peak VO2 were significant among four groups in which the COPD-PH-anemia group had the worst deterioration. This indicated that, anemia impacted more seriously on patients with COPD-PH than on mere COPD, encompassing the perspectives of life quality, ventricular dysfunction, and hypoxemia especially whilst exercise, except for airflow limitation. On account of the impairment of oxygen-transporting function in anemia, patients with COPD-PH-anemia are naturally more liable to develop ingravescent fatigue, heart failure and hypoxemia rather than airflow limitation, by contrast with either COPD-PH or COPD.
The next comparison of cumulative overall survival showed no difference of cumulative one-year survival rates among four groups. This could be interpreted as that anemia makes no difference on the survival of patients with COPD-PH or COPD for at least 1 year. By contrast, in the study of Pernille et al., anemia could be used to predict mortality. In view of Pernille’s study was a five-year retrospective review, while ours was a one-year prospective investigation, the investigating period in this study may be too limited to uncover the difference of mortality among different groups [
20].
In the study of Pernille, et al., low level of hemoglobin are frequent in COPD patients with acute exacerbations [
20]. In our study, the comparison of exacerbations demonstrated that COPD-PH-anemia group had the most mean annual exacerbations or hospitalizations counting, the highest prevalent rate of exacerbations or hospitalizations, and lowest cumulative exacerbation-free rate among patients among four groups. It means that, by contrast with simple COPD, anemic COPD, or simple COPD-PH, COPD-PH-anemia has the highest risk for developing an exacerbation. It is believed that, by deteriorating life quality, ventricular dysfunction, and hypoxemia, anemia contributes to the aggravation of exacerbations.
The last correlation analysis between risk factors and hospitalizations showed that, being similar with some exacerbation-related classical predictors in COPD such as AE history and COPD groups [
11], hemoglobin was an independently contributing factor for the probability of hospitalizations ≧ 1/year in COPD patients especially patients with COPD-PH-anemia. Decremental hemoglobin is a promoting factor for the incremental exacerbations or hospitalizations. By the way, we also performed a correlation analysis between some dyshemoglobins which were carboxyhemoglobin as well as methemoglobin and hospitalizations. The results demonstrated that carboxyhemoglobin was positively correlated with the development of hospitalizations ≧ 1/year in all four groups especially in COPD-PH-anemia group rather than methemoglobin. Likewise, in the study of Yasuda et al., the carboxyhemoglobin level at exacerbations were significantly higher than those at stable stage, the increased arterial carboxyhemoglobin was correlated to the severity of COPD resulting from systemic inflammation and reactive oxygen species [
21].
Some systematic inflammatory diseases such as connective tissue disease are frequently concomitant with anemia of chronic disease through the mechanism of the production of inflammatory mediators damaging the generation of erythrocytes. Likewise, COPD which is one of systematic inflammatory diseases is generally concomitant with the elevation of IL-1, IL-6 and TNF-a level in circulation inducing the development of anemia [
22]. Some studies demonstrated that anemia was closely related to C reactive protein which is an inflammatory biomarker [
23,
24]. Besides, inflammatory mediators may also result in skeletal muscular atrophy and cachexia further deteriorating anemia [
11]. On the other hand, patients with pulmonary hypertension commonly develop right ventricular dysfunction in which 15% are concomitant with anemia [
25‐
28]. Its mechanism is due to the release of inflammatory mediators whilst heart failure, the activation of renin-angiotensin system [
28]. All these may explain the impressive prevalence of anemia in COPD-PH.
The clinical implications of this study are considered to be the following: first, the results of our study may urge clinicians to be aware of the serious prevalence of anemia in COPD patients concomitant with PH; second, clinician could be vigilant about the severely adverse impact of anemia on the prognosis of COPD-PH in order to inform patients’ family members timely and take action in advance; third, under some circumstances in which a dilemma exists in the assessment of prognosis, anemia could be an eligible weight which can be taken into account.
The strength of this study consisted in: first, the eligible patients being studied all underwent RHC which is the only gold standard for the diagnosis of PH to date, to ascertain wether they had PH or not, ensuring the eligibility of PH-negative COPD controls; second, we compared the longitudinal variation and variation rate between the baseline and the endpoint instead of comparing the variables at the endpoint, to reflect the time-dependent impact that anemia would result in. Nevertheless, several limitations existed in this study. First, the sample size was not very large due to the nature of prospective investigation. A large-scale study is warranted in the future. Second, obviously we have no comments to make on the potential difference of overall survival amongst different groups beyond one-year follow-up which might be too short to show the discrepancy. The last but not least, in view of the patients being reviewed in this study were all Chinese patients, the results of this study may not be applicable for other races.
Acknowledgements
We sincerely thank Dr. Lan Wang, Dr. Jian Guo, Dr. Sugang Gong, Dr. Jing 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. Chuanyu Wang of Department of Cardiopulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China, for their assistance in this study.