Anemia and Adverse Outcomes in a Chronic Obstructive Pulmonary Disease Population with a High Burden of Comorbidities. An Analysis from SPIROMICS

Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and associated with a significant burden of comorbidities. Although anemia is associated with adverse outcomes in COPD, its contribution to outcomes in individuals with other comorbid chronic diseases is not well understood. Objectives: This study examines the association of anemia with outcomes in a large, well-characterized COPD cohort, and attempts to understand the contribution of anemia to outcomes and phenotypes in individuals with other comorbidities. Methods: Participants with COPD from SPIROMICS (the Subpopulations and Intermediate Outcome Measures in COPD Study) were analyzed in adjusted models to determine the associations of normocytic anemia with clinical outcomes, computed tomographic measures, and biomarkers. Analysis was additionally performed to understand the independence and possible interactions related to cardiac and metabolic comorbidities. Results: A total of 1,789 individuals with COPD from SPIROMICS had data on hemoglobin, and of these 7.5% (n = 135) were found to have normocytic anemia. Anemic participants were older with worse airflow obstruction, a higher proportion of them were African Americans, and they had a higher burden of cardiac and metabolic comorbidities. Anemia was strongly associated with 6-minute walk distance (b, 261.43; 95% confidence interval [CI], 285.11 to 237.75), modified Medical Research Council dyspnea questionnaire (b, 0.27; 95% CI, 0.11-0.44), and St. George's Respiratory Questionnaire (b, 3.90; 95% CI, 1.09-6.71), and these adjusted associations were stronger among those with two or more cardiac and metabolic comorbidities. Anemia was associated with higher levels of serum C-reactive protein, soluble receptor for advanced glycosylation endproducts, and epithelial cadherin-1, findings that persisted when in those with a high burden of comorbidities. Conclusions: Anemia is associated with worse exercise capacity, greater dyspnea, and greater disease severity among adults with COPD, particularly among those with comorbid chronic cardiac and metabolic diseases. The biomarkers found in anemic individuals suggest inflammation, lung tissue injury, and oxidative stress as possible pathways for the adverse correlations of anemia with outcomes in COPD; however, substantial further study is required to better understand these potential mechanisms. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Anaemia and iron dysregulation: untapped therapeutic targets in chronic lung disease?

“…Consistent with the physiological relevance of anaemia, several clinical studies in COPD have reported a significant deleterious effect of anaemia on exercise capacity, with anaemic patients being more dyspnoeic and exhibiting functional exercise limitation12 14 36 and reduced maximal O 2 consumption 12. In a regression analysis, higher Hb levels were independently associated with improved exercise capacity and HRQoL 37.…”

“…Inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-10, IL-22, interferon-γ and tumour necrosis factor 1-α interfere with the normal function of several molecules involved in iron metabolism 41 42. These inflammatory markers are generally increased in anaemic patients with chronic lung disease and are associated with reduced serum iron levels and decreased iron availability for erythropoiesis;36 43 they are believed to do this through the destruction of red blood cell precursors and decreasing the number of EPO receptors on progenitor cells 44. Interestingly, this increase in inflammatory cytokines, particularly IL-6, is also considered to be an innate immune response to infection as it reduces iron availability for the growth of extracellular pathogens and is relevant to respiratory populations predisposed to bacterial and viral infections 42.…”

Insights into Chronic Obstructive Pulmonary Disease Epidemiology, Phenotypes and Outcomes from SPIROMICS

“…bIOMArKErs Complete blood counts are frequently obtained in clinical practice and are readily available for many patients. Both normocytic anaemia and thrombocytosis were found to be independently associated with worse dyspnoea and respiratory-related quality of life in individuals with COPD 32,33 . In addition, thrombocytosis was linked to a higher likelihood of all COPD exacerbations (adjusted OR 1.5; 95% CI 1.1-2.0) and severe COPD exacerbations (adjusted OR 1.5; 95% CI 1.1-2.2) during the preceding year in a combined analysis of the SPIROMICS and COPDGene cohorts 33 .…”

Increased airway iron parameters and risk for exacerbation in COPD: an analysis from SPIROMICS

“…Furthermore, total levels of non-heme iron and of other iron-binding molecules including lipocalin-2 and lactoferrin, are increased in lung tissue, sputum, BALF, and AMs of COPD patients, relative to non-smokers 9,[11][12][13][14][15][16][17][18][19][20][21] . Conversely, there is also ample evidence for iron deficiency in COPD, and anaemia in COPD is associated with worse patient outcomes, including mortality 22,23 . The biological relevance of such observations remains to be elucidated; however, these data strongly support a local iron overload signature in the extracellular milieu of the lung in COPD that is distinctive to systemic iron handling, which is intriguing as mainstream cigarette smoke contains little iron 24,25 .…”