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

Abstract

Levels of iron and iron-related proteins including ferritin are higher in the lung tissue and lavage fluid of individuals with chronic obstructive pulmonary disease (COPD), when compared to healthy controls. Whether more iron in the extracellular milieu of the lung associates with distinct clinical phenotypes of COPD, including increased exacerbation susceptibility, is unknown. We measured iron and ferritin levels in the bronchoalveolar lavage fluid (BALF) of participants enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD (SPIROMICS) bronchoscopy sub-study (n = 195). BALF Iron parameters were compared to systemic markers of iron availability and tested for association with FEV1 % predicted and exacerbation frequency. Exacerbations were modelled using a zero-inflated negative binomial model using age, sex, smoking, and FEV1 % predicted as clinical covariates. BALF iron and ferritin were higher in participants with COPD and in smokers without COPD when compared to non-smoker control participants but did not correlate with systemic iron markers. BALF ferritin and iron were elevated in participants who had COPD exacerbations, with a 2-fold increase in BALF ferritin and iron conveying a 24% and 2-fold increase in exacerbation risk, respectively. Similar associations were not observed with plasma ferritin. Increased airway iron levels may be representative of a distinct pathobiological phenomenon that results in more frequent COPD exacerbation events, contributing to disease progression in these individuals.

Conflict of interest statement

Dr. Bowler served on the advisory boards (GlaxoSmithKline, Boehringer Ingelheim, and Mylan Pharmaceuticals) and received research grants from GlaxoSmithKline and Boehringer Ingelheim not related to this manuscript and these activities have not influenced my work on this manuscript. Dr. Christenson reports personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Amgen, personal fees from Glenmark, personal fees from Sunovion, non-financial support from Genentech, non-financial support from Medimmune, outside the submitted work. Dr. Comellas reports grants from NIH, non-financial support from VIDA, personal fees from GSK, outside the submitted work. Dr. Cooper reports grants from Equinox Health Clubs, personal fees from Equinox Health Clubs, grants from Amgen, personal fees from PulmonX, other from GlaxoSmithKline, outside the submitted work; and work part-time on scientific engagement for the GlaxoSmithKline Global Respiratory Franchise. Dr. Criner reports grants from Boehringer- Ingelheim, grants from Novartis, grants from Astra Zeneca, grants from Respironics, grants from MedImmune, grants from Actelion, grants from Forest, grants from Pearl, grants from Ikaria, grants from Aeris, grants from PneumRx, grants from Pulmonx, other from HGE Health Care Solutions, Inc, other from Amirall, other from Boehringer- Ingelheim, other from Holaira, outside the submitted work. Dr. Han reports personal fees from GSK, personal fees from BI, personal fees from AZ, other from Novartis, other from Sunovion, outside the submitted work. Dr. Hansel reports grants and personal fees from AstraZeneca, grants from Boehringer Ingelheim, grants from NIH, grants from COPD Foundation, personal fees from Mylan, outside the submitted work. Dr. Barjaktarevic reports personal fees from Astra Zeneca, personal fees from Boehringer Ingelheim, grants from AMGEN, grants and personal fees from GE Healthcare, personal fees from Grifols, personal fees from Verona Pharma, personal fees from GSK, personal fees from CSL Behring, personal fees from Mylan/Theravance, during the conduct of the study. Dr. Kaner reports personal fees from Boehringer Ingelheim, grants and personal fees from Genentech, outside the submitted work. Dr. Martinez reports personal fees and non-financial support from American College of Chest Physicians, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Boehringer Ingelheim, non-financial support from ProterrixBio, personal fees from Columbia University, personal fees and non-financial support from ConCert, personal fees and non-financial support from Genentech, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax Health System, personal fees from Integritas, personal fees from MD Magazine, personal fees from Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communicatinos, personal fees and non-financial support from National Association for Continuing Education, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Pearl Pharmaceuticals, personal fees and non-financial support from PeerView Communications, personal fees and non-financial support from Prime Communications, personal fees and non-financial support from Puerto Rican Respiratory Society, personal fees and non-financial support from Chiesi, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Theravance, personal fees from UpToDate, personal fees from WebMD/MedScape, personal fees from Western Connecticut Health Network, other from Afferent/Merck, non-financial support from Gilead, non-financial support from Nitto, personal fees from Patara/Respivant, personal fees from PlatformIQ, personal fees and non-financial support from Potomac, other from Biogen, personal fees and non-financial support from University of Alabama Birmingham, other from Veracyte, non-financial support from Zambon, personal fees from American Thoracic Society, grants from NIH, personal fees and non-financial support from Physicians Education Resource, personal fees from Rockpointe, other from Prometic, personal fees from Rare Disease Healthcare Communications, other from Bayer, other from Bridge Biotherapeutics, personal fees and non-financial support from Canadian Respiratory Network, other from ProMedior, personal fees and non-financial support from Teva, personal fees from France Foundation, personal fees and non-financial support from Dartmouth, outside the submitted work. Dr. Woodruff reports personal fees from Glaxosmithkline, personal fees from NGM biopharmaceuticals, personal fees from Amgen, personal fees from Glenmark Pharmaceuticals, personal fees from Theravance, personal fees from Clarus Ventures, personal fees from Astra Zeneca, personal fees from 23andMe, personal fees from Sanofi, personal fees from Regeneron, personal fees from Genentech, outside the submitted work. Dr. Wells reports grants from NIH/NHLBI, during the conduct of the study; grants from NIH/NCATS, grants from Bayer, grants and other from GSK, other from Boehringer Ingelheim, grants and other from Mereo BioPharma, other from Quintiles, other from PRA, outside the submitted work. All other authors have no conflicts to disclose.

Figures

Figure 1

Bronchoalveolar lavage fluid (BALF) ferritin and iron levels are increased in smokers and participants with COPD. (A–E) Ferritin (ng/mL) and iron (mg/L) levels were measured in the BALF of SPIROMICS participants [never-smokers (n = 25), ever-smokers (including current and former smokers) without COPD (n = 86) and ever-smokers with COPD (n = 84, and n = 83 for ferritin and iron respectively)]. (A,D) Grey dots indicate current smokers at the time of baseline visit. (B,E) BALF ferritin and iron levels in current smokers without COPD (n = 39) and with COPD (n = 31) in SPIROMICS. (C) BALF ferritin association with BALF iron in never-smokers (n = 25, red), ever-smokers without COPD (n = 86, green) and ever-smokers with COPD (n = 84, and n = 83 for ferritin and iron respectively, blue) in SPIROMICS. Data (A,B,D,E) are presented as median with box indicating upper and lower quartiles, whiskers indicating extrema, and with P values calculated by non-parametric Kruskal-Wallis test. Linear associations (C) were tested with Pearson’s correlation coefficient.

Figure 2

Plasma ferritin increases in smokers and in COPD but is not associated with BALF ferritin. (A) Plasma ferritin (ng/mL) in never-smokers (n = 20), ever-smokers without COPD (n = 44) and ever-smokers with COPD (n = 55) in the SPIROMICS bronchoscopy sub-study were measured using a Luminex-based multiplex assay system as described. Grey dots indicate current smokers at the time of baseline visit. (B) Plasma ferritin in current smokers without (n = 17) and with COPD (n = 17) in the SPIROMICS bronchoscopy sub-study. (C) Association between plasma ferritin and BALF ferritin. (A,B) median, 25th and 75th percentiles, and extrema; P values by non-parametric Kruskal-Wallis test. Linear associations (C) were tested with Pearson’s correlation coefficient.

Figure 3

Local lung ferritin and iron levels do not correlate with systemic markers of iron storage or inflammation. (A) Haemoglobin (g/dL) and (B) CRP (μg/mL) levels in never-smokers (n = 25,20, red), ever-smokers without COPD (n = 85,44, blue) and ever-smokers with COPD (n = 83,55, green), as previously measured using a Luminex-based multiplex assay system and association with BALF ferritin (ng/mL), BALF iron (μg/L), and plasma ferritin (ng/mL) were tested with a linear model on the log-transformed markers and accounting for batch and site effects. βˆ denotes adjusted increase in log-10 ferritin associated with unit increase in log-10 marker.

Figure 4

Higher BALF ferritin levels are associated with lower lung function. (A–C) Correlation between BALF ferritin (ng/mL), BALF iron (mg/L), and plasma ferritin (ng/mL) in never-smokers (n = 25 for BALF ferritin and iron, 20 for plasma ferritin, red), ever-smokers without COPD (n = 86 for BALF ferritin and iron, 44 for plasma ferritin green) and ever-smokers with COPD (n = 84 for BALF ferritin, 83 for BALF iron, 55 for plasma ferritin, blue) and post-bronchodilator FEV1% predicted. Linear associations (A–C) were tested, adjusting for age, sex, smoking status and study site. βˆ denotes adjusted increase in log-10 ferritin associated with unit increase in log-10 marker.

Figure 5

Higher BALF ferritin and iron levels are associated with increased exacerbation risk. (A,B) BALF ferritin (ng/mL) and BALF iron (µg/mL) in participants who had had one or more acute COPD exacerbation (n = 49 for ferritin, n = 48 for iron) when compared to participants who did not (n = 146). (C) Plasma ferritin levels in participants with (n = 30) versus without (n = 89) exacerbations. (A–C) median, 25th and 75th percentiles, extrema; Adjusted P values (age, sex, smoking status and site) (D–F) Predicted exacerbation rate per SPIROMICS bronchoscopy sub-study participant over 3–5 years of follow up by BALF ferritin (ng/mL) (D), BALF iron (µg/mL) (E) or plasma ferritin (ng/mL) (F) were estimated with a zero-inflated negative binomial model for a participant with a median FEV1 % predicted for (D) BALF ferritin (n = 195), (E) BALF iron (n = 194), and (F) plasma ferritin (n = 119).