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Serum bilirubin and the risk of chronic obstructive pulmonary disease exacerbations Brown, Kirstin E; Sin, Don D; Voelker, Helen; Connett, John E; Niewoehner, Dennis E; Kunisaki, Ken M Oct 24, 2017

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RESEARCH Open AccessSerum bilirubin and the risk of chronicobstructive pulmonary diseaseexacerbationsKirstin E. Brown1,2, Don D. Sin3, Helen Voelker2, John E. Connett2, Dennis E. Niewoehner1,2, Ken M. Kunisaki1,2*and for the COPD Clinical Research NetworkAbstractBackground: Bilirubin is a potent anti-oxidant and higher serum concentrations of bilirubin have been associatedwith better lung function, slower lung function decline, and lower incidence of chronic obstructive pulmonary disease(COPD). We sought to determine whether elevated bilirubin blood concentrations are associated with lower risk foracute exacerbations of COPD (AECOPD).Methods: We performed a secondary analyses of data in the Simvastatin for Prevention of Exacerbations inModerate-to-Severe COPD (STATCOPE) and the Azithromycin for Prevention of Exacerbations of COPD (MACRO) studies.We used time-dependent multivariable Cox proportional hazards analyses, using bilirubin concentrations prior to firstAECOPD as the exposure variable and time to first AECOPD as the outcome variable. STATCOPE was used for modeldevelopment, with validation in MACRO.Results: In STATCOPE (n = 853), higher bilirubin was associated with a lower but statistically insignificant hazard forAECOPD, (adjusted hazard ratio [aHR] 0.89 per log10 increase [95%CI: 0.74 to 1.09; p = 0.26]). In the validation MACROstudy (n = 1018), higher bilirubin was associated with a significantly lower hazard for AECOPD (aHR 0.80 per log10increase [95%CI: 0.67 to 0.94; p = 0.008]).Conclusions: Bilirubin may be a biomarker of AECOPD risk and may be a novel therapeutic target to reduce AECOPD risk.Trial registrations: ClinicalTrials.gov NCT01061671 (registered 02 February 2010) and ClinicalTrials.gov NCT00325897(registered 12 May 2006).Keywords: Bilirubin, Biomarker, Pulmonary disease, Chronic obstructiveBackgroundAcute exacerbations of chronic obstructive pulmonarydisease (AECOPD) are associated with accelerated lungfunction decline, lower quality of life, increased mortality,and higher healthcare costs [1–3]. AECOPD patho-genesis is complex, but oxidative stress is commonlyobserved in AECOPD.Anti-oxidant interventions such as carbocysteine andN-acetylcysteine have been shown to reduce risk forAECOPD in some [4, 5] but not all [6] trials. Theseinterventions are targeted at increasing intracellular andextracellular concentrations of glutathione, a major en-dogenous antioxidant. Bilirubin is another potent antioxi-dant that protects lipids against oxidant stress and inhibitsmembrane-bound nicotinamide adenine dinucleotidephosphate oxidase, which is a large intracellular source ofreactive oxygen species [7–9].These antioxidant mechanisms may help explain whyseveral large observational studies have shown thathigher serum bilirubin concentrations are associatedwith better lung function [10], slower rate of FEV1 de-cline over 3 to 9 years [11] and a lower incidence ofCOPD, lung cancer, and all-cause mortality [12].Together, these data suggest that higher serum bilirubinconcentrations are associated with a lower risk of* Correspondence: kunis001@umn.edu1Minneapolis VA Health Care System, Pulmonary, Critical Care, and SleepApnea (111N), One Veterans Drive, Minneapolis, MN 55417, USA2University of Minnesota, Minneapolis, MN, USAFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe 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.Brown et al. Respiratory Research  (2017) 18:179 DOI 10.1186/s12931-017-0664-0incident COPD and lower rates of COPD diseaseprogression. No studies have investigated the associationbetween serum bilirubin concentrations and AECOPD.Given the important role of oxidant stress in AECOPDpathogenesis, we hypothesized that higher serumconcentrations of bilirubin would be associated with alower risk of AECOPD. We tested this hypothesis usingdata from two large multi-center cohorts of patientswith COPD at high risk of AECOPD.MethodsWe performed secondary analyses of data in theSimvastatin for the Prevention of Exacerbations inModerate-to-Severe COPD (STATCOPE; Clinical-Trials.gov NCT01061671) and the Macrolide Azithro-mycin to Prevent Rapid Worsening of SymptomsAssociated With Chronic Obstructive Pulmonary Disease(MACRO; ClinicalTrials.gov NCT00325897) studies.Study participantsSTATCOPE and MACRO were designed as multi-centerrandomized controlled trials to test the efficacy of dailysimvastatin (STATCOPE) and daily azithromycin(MACRO) to reduce the risk of acute exacerbations ofCOPD (AECOPD). The COPD Clinical ResearchNetwork conducted both studies with funding from theUS National Heart, Lung and Blood Institute andCanadian Institutes of Health Research (for STATCOPE).The studies were approved by each participating center’sinstitutional review board and all study participantsprovided informed consent for study participation.Study participantsThe design and results of both studies have beenpublished [13, 14]. Inclusion criteria in both studiesincluded age ≥ 40 years, post-bronchodilator forcedexpiratory volume in one second (FEV1)/forced vitalcapacity (FVC) <70%, FEV1 < 80% of predicted, ≥10pack-year smoking history, and an increased risk ofAECOPD (defined as home oxygen use, systemic cor-ticosteroid or antibiotic usage for AECOPD, or havingan emergency department visit or hospitalization forAECOPD in the year prior to study entry). Exclusion cri-teria included alcoholism and active liver disease(defined as transaminase elevations >1.5 times the upperlimit of normal in STATCOPE, and >3 times the upperlimit of normal in MACRO). STATCOPE additionallyexcluded those already treated with statins, those withindications to be on a statin according to the AdultTreatment Panel III risk stratification, and those withcontraindications to statins. MACRO additionallyexcluded those with asthma, a resting heart rate greaterthan 100 beats per minute, a prolonged corrected QT(QTc) interval (>450 msec), the use of QT-prolongingmedications, or hearing impairment.STATCOPE was performed at 45 sites, and studyfollow-up time ranged from 21 to 1263 days, with amedian (interquartile range) of 635 (329 to 990) days.The wide range of follow-up time in STATCOPE waslargely due to the recommendation by the Data Safetyand Monitoring Board for early termination of the trial,at a time when participants were still being activelyrecruited into the study. In contrast, MACRO continuedto its planned closure date and had a follow-up time thatranged from 0 to 380 days, with a median of 200 (IQR60 to 357) days. MACRO was performed at 17 sites.Data collectionAECOPD was defined identically in both studies as acomplex of respiratory symptoms (increased or newonset) of more than one of the following: cough, sputum,wheezing, dyspnea, or chest tightness with a duration of atleast three days requiring treatment with antibiotics orsystemic steroids. Study personnel assessed AECOPDstatus monthly via clinic visits or telephone contacts.Bilirubin concentrations were measured at baseline inboth studies. In STATCOPE follow-up bilirubin wasmeasured at months 6, 12, 18, and 24. In MACRO,follow-up bilirubin was measured more frequently, atmonths 1, 3, 6, 9, and 12.Statistical methodsWe first utilized STATCOPE to develop and calibrate ouranalytic model and then validated the model using datafrom MACRO. The rationale for this ordering was due toseveral limitations of the STATCOPE cohort, compared tothe MACRO cohort for this analysis, including STAT-COPE’s smaller sample size, variable follow-up times, andless frequent bilirubin measurements (every 6 months inSTATCOPE vs. every 1–3 months in MACRO).We included all study participants who had at least onebilirubin measurement and at least one follow-up contact.One hundred five participants were in both STATCOPEand MACRO; these participants were included in theSTATCOPE development/calibration dataset and werethen excluded from the MACRO validation analysis.We used time-dependent multivariable Cox propor-tional hazards analyses, using log10-transformed bilirubinconcentrations prior to first AECOPD as the exposurevariable of interest and time to first AECOPD as theoutcome variable of interest. In contrast to traditional (i.e.non-time dependent) Cox models using only a staticmeasure of exposure, time-dependent models account forintrinsically variable exposures that might influenceoutcomes (in our case serum bilirubin that has beenshown to vary between several visits over a year [15]).Time-dependent models also can be more robust thanBrown et al. Respiratory Research  (2017) 18:179 Page 2 of 7static models, as they utilize all available data. Due to theavailability of repeated bilirubin measurements inboth of our cohorts, we elected to use this time-dependent approach.Our development and calibration model includedanalyses of several clinical variables treated as continuousor categorical data, along with interaction terms. Covari-ates were those previously shown to affect AECOPD riskincluding age, sex, race, body mass index (BMI), chronicbronchitis, respiratory health status (as assessed by the St.George’s Respiratory Questionnaire [SGRQ] score), ethanolconsumption, smoking status, post-bronchodilator FEV1%-predicted, inhaled medications, use of supplementaloxygen, hospitalization or emergency department visitwithin the previous year, and steroid or antibiotic usewithin the previous year. Although simvastatin was shownto not affect AECOPD risk, we felt it important to alsoinclude treatment assignment (i.e. simvastatin vs. placebo)into the initial full development model. Covariates from thisfull STATCOPE development model were included in afinal reduced STATCOPE model if they were significant atp < 0.10 by backwards stepwise regression; we forced treat-ment assignment into the reduced model also. We did notaccess the MACRO dataset until after the final reducedSTATCOPE model was agreed upon.In the better-powered MACRO validation analysis, weapplied the final STATCOPE model, and we forcedtreatment assignment (i.e. azithromycin vs. placebo) intothe model, due to azithromycin’s proven effect inreducing AECOPD risk and unclear effects on bilirubinconcentrations [14].Statistical analyses were conducted using SAS 9.3(SAS Institute, Cary, NC, USA).ResultsAmong the 885 participants enrolled in STATCOPE,853 had bilirubin concentrations measured and had atleast one follow-up contact for determination ofAECOPD status. These 853 participants formed thedevelopment/calibration sample for this study. Mean ageof these STATCOPE participants was 62 years, 56% weremale, 30% were current smokers, mean FEV1 was 1.19 L(42% of predicted), and 51% had been to an emergencydepartment or hospitalized for AECOPD within the yearprior to enrollment. Mean bilirubin concentrations werebetween 0.62–0.65 mg/dL, which is well within thegeneral population normal range of 0.20–1.20 mg/dL.Additional baseline characteristics of these STATCOPEparticipants are presented in Table 1.Of these STATCOPE participants, 475 (56%) experi-enced an AECOPD during the study. Covariates thatwere independently associated (at p < 0.10) with time tofirst AECOPD included male sex, black race, BMI,chronic bronchitis, supplemental oxygen use, St.George’s Respiratory Questionnaire (SGRQ) score,inhaler use, and steroid or antibiotic use within the pastone year (Table 2). Covariates that were not independ-ently associated with time to AECOPD included age,hospitalization for AECOPD within the previous year,ethanol use, FEV1% predicted, and current smoking.Follow-up bilirubin concentrations were not differentbetween those assigned to simvastatin vs. placebo.Table 1 Participant characteristics in development/calibrationdataset (STATCOPE = Simvastatin for the Prevention ofExacerbations in Moderate-to-Severe COPD) and validationdataset (MACRO = Macrolide Azithromycin to Prevent RapidWorsening of Symptoms Associated With Chronic ObstructivePulmonary Disease)STATCOPE(n = 853)MACRO(n = 1018)Age, years 62 ± 8 66 ± 9Male sex - no. (%) 479 (56%) 606 (60%)Race - no. (%)Black 177 (21%) 138 (14%)White 651 (77%) 830 (82%)Other 20 (2%) 50 (5%)BMI, kg/m2 27.2 ± 6.9 27.8 ± 6.2Alcohol consumption, drinks per day 0.48 ± 0.85 0.40 ± 1.03Currently smoking - no. (%) 257 (30%) 222 (22%)Oxygen use - no. (%) 408 (48%) 604 (59%)ED visit or hospitalized for AECOPD in yearprior to enrollment - no. (%)434 (51%) 517 (51%)Steroids or antibiotics in previous year - no. (%) 715 (84%) 865 (85%)FEV1/FVC ratio, % 44 ± 13 43 ± 13Post-bronchodilator FEV1, L 1.19 ± 0.57 1.12 ± 0.51Post-bronchodilator FEV1, % predicted 42 ± 18 40 ± 16GOLD category - no. (%)1 – 1 (0.1%)2 278 (33%) 277 (27%)3 293 (35%) 410 (40%)4 277 (33%) 327 (32%)Mean Serum Bilirubin (mg/dL)Enrollment/baseline 0.65 ± 0.30 0.64 ± 0.29Month 1 – 0.63 ± 0.28Month 3 – 0.63 ± 0.28Month 6 0.62 ± 0.28 0.63 ± 0.27Month 9 – 0.63 ± 0.28Month 12 0.65 ± 0.28 0.64 ± 0.28Month 18 0.63 ± 0.27 –Month 24 0.65 ± 0.28 –Abbreviations: AECOPD acute exacerbation of chronic obstructivepulmonary disease, BMI body mass index, ED emergency department,FEV1 forced expiratory volume in one second, FVC forced vitalcapacity, GOLD Global Initiative for Chronic Obstructive Lung DiseaseBrown et al. Respiratory Research  (2017) 18:179 Page 3 of 7In the STATCOPE development dataset, higher bilirubinconcentrations were independently associated with a lowerbut statistically insignificant hazard ratio for AECOPD(adjusted hazard ratio [aHR] in the final reduced model of0.89 per log10 increase in bilirubin [95%CI: 0.74 to 1.09;p = 0.26) (Table 3).This final model was then applied to the larger, better-powered MACRO validation cohort. Of the 1142MACRO participants, 1024 did not participate in STAT-COPE. 1018 of the 1024 participants had a measuredbilirubin concentration with at least one follow-up con-tact for AECOPD status determination and this com-prised the validation cohort. MACRO participants weresimilar to STATCOPE participants, with a mean age of66 years, 60% were male, 22% were current smokers,and mean FEV1 was 1.12 L (40% of predicted) (Table 1).640 (63%) of MACRO participants experienced anAECOPD during the study. Follow-up bilirubin concen-trations were not different between those assigned toazithromycin vs. placebo. In this validation dataset,higher bilirubin concentrations were independently asso-ciated with a statistically significantly lower hazard ratiofor AECOPD. The point estimate was similar to thatobserved in STATCOPE, but with a narrower confidenceinterval (aHR 0.80 per log10 increase in bilirubin [95%CI:0.67 to 0.94; p = 0.008]) (Table 4).DiscussionOur data lend support to the hypothesis that highercirculating bilirubin concentrations are associated with alower risk of AECOPD. Our findings are consistent withother observational data suggesting clinically importantcardiopulmonary health benefits associated with higherbilirubin concentrations.Several studies in the cardiac literature have demon-strated that higher blood bilirubin concentrations areassociated with a lower risk of cardiovascular diseaseincluding peripheral vascular disease, carotid intimal-medial thickness, and stroke [16]. A study in theFramingham Heart Study Offspring cohort showed thatamong 1780 individuals with 24 years of follow-up, thosewith higher bilirubin due to a genetic polymorphismaffecting the UGT1A1 enzyme of bilirubin metabolism(the enzyme defect that leads to Gilbert’s syndrome) hadapproximately one-third the risk of cardiovascular eventscompared to wild-type carriers with normal bilirubinconcentrations [17]. The significant relationship betweengenetically determined bilirubin and cardiovascularTable 2 Full STATCOPE development model. Time-dependentmultivariable Cox proportional hazards analyses for risk of acuteexacerbation of chronic obstructive pulmonary disease(AECOPD) and bilirubin prior to first AECOPDParameter aHR 95% CI p-valueSTATCOPE Full Development Cohort ModelTreatment assignment 0.93 0.77–1.11 0.41Age 1.00 0.99 to 1.01 0.69Male sex 0.84 0.69–1.01 0.07Black race 0.66 0.51–0.86 0.002BMI, kg/m2 0.99 0.97–1.00 0.07Chronic bronchitis 1.22 1.00–1.49 0.05Supplemental oxygen use 1.26 1.02–1.58 0.04SGRQ score 1.02 1.01–1.02 <0.001Inhaler usea - none (0 of 3 classes: LABA,LAMA, ICS)0.57 0.39–0.84 0.02Inhaler usea - 1 of 3 classes 0.96 0.72–1.29 0.10Inhaler usea - 2 of 3 classes 0.74 0.59–0.93 0.40Steroid or antibiotic use for AECOPD inyear prior to enrollment1.52 1.13–2.05 0.006Hospitalized for AECOPD in year prior toenrollment1.13 0.92–1.39 0.25Ethanol use, drinks/day 0.99 0.88–1.10 0.79FEV1, % predicted 1.00 0.99–1.00 0.19Current smoker 0.84 0.66–1.05 0.13BILIRUBIN (per log10 increase) 0.90 0.74–1.09 0.28Abbreviations: AECOPD acute exacerbation of chronic obstructivepulmonary disease, BMI body mass index, ED emergency department,FEV1 forced expiratory volume in one second, ICS inhaled corticosteroid,LABA long-acting beta agonist, LAMA long-acting antimuscarinic, SGRQ St.George’s Respiratory QuestionnaireaReferent group is 3-class inhaler therapy (long-acting beta agonist,long-acting antimuscarinic, and inhaled corticosteroid)Bilirubin is presented in bold, as this was the primary predictor variableTable 3 Reduced STATCOPE development cohort model.Time-dependent multivariable Cox proportional hazards analysesfor risk of acute exacerbation of chronic obstructive pulmonarydisease (AECOPD) and bilirubin prior to first AECOPDParameter aHR 95% CI p-valueSTATCOPE Reduced Development Cohort ModelTreatment assignment 0.92 0.77–1.11 0.38Male sex 0.86 0.72–1.04 0.12Black race 0.66 0.51–0.84 <0.001BMI (kg/m2) 0.98 0.97–1.00 0.02Chronic bronchitis 1.17 0.97–1.42 0.11Supplemental oxygen use 1.37 1.12–1.67 0.002SGRQ score 1.02 1.01–1.02 <0.001Inhaler usea - none (0 of 3 classes: LABA,LAMA, ICS)0.52 0.36–0.76 0.007Inhaler usea - 1 of 3 classes 0.91 0.68–1.22 0.12Inhaler usea - 2 of 3 classes 0.72 0.58–0.90 0.51Steroid or antibiotic use in year prior toenrollment1.62 1.22–2.16 0.001BILIRUBIN (per log10 increase) 0.89 0.74–1.09 0.26Abbreviations: BMI body mass index, ICS inhaled corticosteroid, LABAlong-acting beta agonist, LAMA long-acting antimuscarinic, SGRQ St.George’s Respiratory QuestionnaireaReferent group is 3-class inhaler therapy (long-acting beta agonist,long-acting antimuscarinic, and inhaled corticosteroid)Bilirubin is presented in bold, as this was the primary predictor variableBrown et al. Respiratory Research  (2017) 18:179 Page 4 of 7events (an example of a so-called ‘Mendellianrandomization’ study design) provides some additionalsupport to a causal relationship. However, a more recentmeta-analysis did not support an association betweengenetically elevated bilirubin and reduced risk of ische-mic heart disease [18], thus, the potential protective roleof bilirubin in cardiovascular disease pathogenesis is notfully known.In addition to the data suggesting a potential cardiacbenefit to higher blood bilirubin concentrations,emerging data suggest pulmonary benefits as well. Across-sectional, population-based spirometry study of4195 smokers and non-smokers in Switzerland showedthat elevated serum concentrations of bilirubin and agenetic polymorphism associated with higher bilirubinconcentrations were both independently associated withbetter lung function [10].These cross-sectional findings were supported by asubsequent longitudinal study of 4680 North Americansmokers aged 35 to 60 years old with mild to moderateCOPD at study entry, where higher serum bilirubin atbaseline was associated with higher baseline FEV1 and asignificantly slower rate of FEV1 decline over 3 to 9 yearsof prospective follow-up [11]. In this cohort of personswith COPD, there was also an association betweenhigher serum bilirubin and a lower risk of coronaryheart disease mortality over 15 years.The largest study to investigate the associationbetween serum bilirubin and pulmonary outcomes wasconducted using a UK primary care research database[12]. In this longitudinal sample of 504,206 adults with amedian follow-up time of 8 years, higher serum bilirubinconcentrations were associated with a significantly lowerincidence of COPD (adjusted incidence rate ratio of 0.92[0.89 to 0.95] per 0.1 mg/dL increase in bilirubin in menand 0.89 [0.86 to 0.93] in women]. Higher bilirubin wasalso associated with a lower incidence of lung cancerand all-cause mortality.Together, these data suggest that higher bilirubinconcentrations are associated with a lower risk ofincident COPD and lower rates of disease progression.We extend these data by demonstrating that elevatedserum bilirubin concentrations are associated with alower risk of AECOPD, one of the most importantclinical outcomes for patients with COPD.Our study has several strengths, including the abilityto perform analyses in two large, multi-center trials thatused very similar entry criteria and carefully collectedAECOPD data, the primary outcome of both originalstudies. Unlike many epidemiologic studies that conductanalyses within only a single cohort, we were uniquelyable to develop our analytic model in an exploratoryfashion in the STATCOPE dataset, knowing from theoutset that this would be a somewhat underpoweredcohort due to infrequent bilirubin measurements,smaller sample size, fewer exacerbations, and variablefollow-up time. We were thus able to reserve the better-powered MACRO dataset for validation purposes only.Moreover, the serial measurements of serum bilirubinduring the observational period, especially the frequentmeasures in the MACRO validation dataset, enabled usto use a dynamic and flexible time-dependent Coxmodel to determine the relationship between bilirubinand incident exacerbations.Our study has some limitations, including its relianceon bilirubin assays performed in clinical laboratories atstudy sites, rather than in a central laboratory. However,bilirubin is a well-established assay with well-establishedstandard operating procedures in clinical laboratories,and an inter-laboratory coefficient of variation of only1% to 3% [19]. The study population was also limited tothose from North America at high risk of AECOPD, soour data do not apply to those at lower risk of COPDand may not apply to patients with COPD in other re-gions of the world. Perhaps most importantly, our studyis observational and therefore unable to prove causality.High bilirubin concentrations could potentially be con-founded by other healthy behaviors associated with thesepulmonary outcomes.Our study was not designed to answer mechanisticquestions regarding how bilirubin might conferTable 4 MACRO validation cohort model. Time-dependentmultivariable Cox proportional hazards analyses for risk of acuteexacerbation of chronic obstructive pulmonary disease (AECOPD)and bilirubin prior to first AECOPDParameter aHR 95% CI p-valueMACRO Validation Cohort ModelTreatment assignment 0.73 0.63–0.86 <0.001Male sex 0.78 0.66–0.91 0.002Black race 1.01 0.80–1.27 0.95BMI (kg/m2) 0.99 0.98–1.00 0.07Chronic bronchitis 1.22 1.03–1.44 0.02Supplemental oxygen use 1.29 1.09–1.53 0.003SGRQ score 1.01 1.00–1.01 0.003Inhaler usea - none (0 of 3 classes: LABA,LAMA, ICS)0.74 0.54–1.03 0.20Inhaler usea - 1 of 3 classes 0.84 0.66–1.07 0.71Inhaler usea - 2 of 3 classes 0.91 0.76–1.09 0.52Steroid or antibiotic use in year prior toenrollment1.64 1.28–2.10 <0.001BILIRUBIN (per log10 increase) 0.80 0.67–0.94 0.008Abbreviations: BMI body mass index, ICS inhaled corticosteroid, LABAlong-acting beta agonist, LAMA long-acting antimuscarinic, SGRQ St.George’s Respiratory QuestionnaireaReferent group is 3-class inhaler therapy (long-acting beta agonist, long-acting antimuscarinic, and inhaled corticosteroid)Bilirubin is presented in bold, as this was the primary predictor variableBrown et al. Respiratory Research  (2017) 18:179 Page 5 of 7pulmonary benefits, but biologic plausibility comes frompublications demonstrating that bilirubin is a potentantioxidant [7]. Indeed, bilirubin may be the most potentin vivo antioxidant to protect lipids against oxidantstress, tissue degeneration and death [8]. Smoking andother environmental oxidant insults significantly reduceserum bilirubin concentrations, but shortly after smok-ing cessation, serum bilirubin rapidly increases [20]. Arecent study using a rat model of COPD showed that ex-ogenous administration of bilirubin (as a therapeuticagent) reduced lung and systemic inflammation, sup-pressed regional oxidative lipid damage and preventedprogression of histological changes of emphysema [21].Bilirubin also inhibits membrane-bound nicotinamideadenine dinucleotide phosphate oxidase, which is a largeintracellular reactive oxygen species source [9].In summary, cellular and animal model data suggestthat higher concentrations of bilirubin provide antioxi-dant benefits to the lung, while observational humandata support the notion that higher bilirubin concentra-tions are associated with better COPD-related outcomes.Our data are consistent with these observations and sug-gest that higher bilirubin concentrations are associatedwith a lower risk for AECOPD.ConclusionsAmong individuals with moderate-to-severe COPDwithout active liver disease, higher serum bilirubin con-centrations are independently associated with a lowerrisk for AECOPD. Bilirubin may be a novel biomarker ofAECOPD risk and may represent a novel therapeutictarget for future investigations.AcknowledgementsWe thank the participants who participated in the STATCOPE and MACROstudies.The views expressed in this article are those of the authors and do notnecessarily represent the views of the Minneapolis VA Health Care System,the U.S. Department of Veterans Affairs, the National Institutes of Health, theU.S. Government, or the authors’ affiliated academic institutions.The funders had no role in the conduct, analysis, writing, or decision tosubmit for publication, for either the original studies or this current analysis.FundingStudy supported by National Heart, Lung, and Blood Institute awards toCOPD Clinical Research Network sites: U10 HL074407, U10 HL074408, U10HL074409, U10 HL074416, U10 HL074418, U10 HL074422, U10 HL074424,U10 HL074428, U10 HL074431, U10 HL074439, U10 HL074441. Study alsosupported by Canadian Institutes for Health Research.Availability of data and materialsThe datasets analyzed during the current study are available from thecorresponding author on reasonable request.Authors’ contributionsKEB made substantial contributions to the conception of the work andinterpretation of data, drafted the manuscript, revised it critically for importantintellectual content, and approved the final version to be published. DDS madesubstantial contributions to the conception of the work and interpretation ofdata, revised the manuscript critically for important intellectual content, andapproved the final version to be published. HV made substantial contributions tothe acquisition, analysis, and interpretation of data, and approved the finalversion to be published. JEC made substantial contributions to the conceptionof the work, the acquisition, analysis, and interpretation of data, revised themanuscript critically for important intellectual content, and approved the finalversion to be published. DEN made substantial contributions to the analysis andinterpretation of data, revised the manuscript critically for important intellectualcontent, and approved the final version to be published. KMK made substantialcontributions to the conception and design of the work, the acquisition, analysis,and interpretation of data, drafted the manuscript and revised it critically forimportant intellectual content, and approved the final version to be published.Ethics approval and consent to participateEthics approval was obtained at each study site in the original trials fromwhich this secondary analysis was conducted. All participants providedinformed consent.Consent for publicationN/ACompeting interestsDDS has received advisory board honoraria, research funding and speakingfees from AstraZeneca, meeting honoraria and research funding fromBoehringer Ingelheim, research funding from Merck Frosst, and advisoryboard honoraria from Novartis.DEN has received consulting fees from GlaxoSmithKline, BoehringerIngelheim, and AstraZeneca.KEB, HV, JEC, and KMK declare no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Minneapolis VA Health Care System, Pulmonary, Critical Care, and SleepApnea (111N), One Veterans Drive, Minneapolis, MN 55417, USA. 2Universityof Minnesota, Minneapolis, MN, USA. 3University of British Columbia,Vancouver, BC, Canada.Received: 2 June 2017 Accepted: 17 October 2017References1. Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA. 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