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Circulating surfactant protein D as a potential lung-specific biomarker of health outcomes in COPD: a… Sin, Don D; Leung, Rochelle; Gan, Wen Q; Man, SF P Oct 8, 2007

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ralssBioMed CentBMC Pulmonary MedicineOpen AcceResearch articleCirculating surfactant protein D as a potential lung-specific biomarker of health outcomes in COPD: a pilot studyDon D Sin*, Rochelle Leung, Wen Q Gan and SF Paul ManAddress: The University of British Columbia (Respiratory Division), Vancouver, BC and The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research (St. Paul's Hospital), 1081 Burrard Street, Vancouver, BC, Canada, V6Z 1Y6Email: Don D Sin* -; Rochelle Leung -; Wen Q Gan -; SF Paul Man -* Corresponding author    AbstractBackground: There is a paucity of surrogate lung-specific biological markers that can be used totrack disease progression and predict clinical outcomes in chronic obstructive pulmonary disease(COPD). The principal aim of this pilot study was to determine whether circulating surfactantprotein D (SPD) or Clara Cell protein-16 (CC16) levels are associated with lung function or healthstatus in patients with severe COPD.Methods: We studied 23 patients with advanced COPD. Lung function measurements, ChronicRespiratory Disease Questionnaire (CRQ) scores, and serum levels of SPD, CC16, and C-reactiveprotein (CRP) were determined at baseline and at 3 months.Results: At baseline, FEV1 was inversely associated with serum SPD levels (P = 0.045) but not withCC16 (P = 0.675) or CRP levels (P = 0.549). Over a 3 month period, changes in SPD levelscorrelated significantly with changes in CRQ scores (adjusted P = 0.008) such that patients whohad the largest declines in serum SPD levels experienced the largest gains in health status. Theassociation was particularly notable between circulating SPD level and the dyspnea domain of theCRQ score (P = 0.018). Changes in CC16 or CRP levels did not correlate with changes in CRQscores.Conclusion: Changes in serum SPD levels tracked well with changes in health status over a 3month period in patients with severe COPD. These data suggest that circulating SPD levels may beuseful biomarkers to track health outcomes of COPD patients.BackgroundOver 600 million people worldwide have chronic obstruc-tive pulmonary disease (COPD) [1]. Dissimilar to mostother major causes of mortality in the world, COPD mor-bidity and mortality continue to escalate at an alarmingrate [1]. The World Health Organization predicts by 2020,rently 12th) throughout the world [1]. Despite majoradvances in the understanding of COPD pathophysiol-ogy, there is a dearth of effective medications that canmodify its course [2]. One major limitation of drug devel-opment has been the paucity of surrogate biologicalmarkers that can be used to track disease progression (i.e.Published: 8 October 2007BMC Pulmonary Medicine 2007, 7:13 doi:10.1186/1471-2466-7-13Received: 12 June 2007Accepted: 8 October 2007This article is available from:© 2007 Sin et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 7(page number not for citation purposes)COPD will to be the 3rd leading cause of mortality (cur-rently 4th) and the 5th leading cause of morbidity (cur-progressive decline in lung function and increase in symp-toms such as dyspnea) and predict clinical outcomes [3].BMC Pulmonary Medicine 2007, 7:13 is a heterogeneous disorder with multiple different(but related) phenotypes. The development of lung-basedbiomarkers has been impeded by a variety of technicaland logistical factors including lack of standardization ofsample collection, invasiveness of the procedure and poorpatient tolerability [3]. Blood biomarkers are conceptu-ally more appealing owing to the relative ease of procure-ment and standardization of measurements.Encouragingly, recent data suggest that certain inflamma-tory biomarkers (e.g. C-reactive protein, CRP) correlatewith disease severity and with adverse health outcomes ofpatients with mild to moderate disease [4]. However,although CRP is a good predictor of cardiovascular events,it is not a particularly good marker of respiratory healthoutcomes or rate of decline in lung function [4]. This maynot be surprising given that the predominant source of cir-culating CRP is the liver and not the lungs [5]. To capturerespiratory health events, lung-specific biomarkers aredesirable. Surfactant protein D (SPD) and Clara cell pro-tein-16 (CC16) are two proteins that are produced pre-dominantly in the lungs and as such may be useful intracking disease progression and health status of COPDpatients [6]. The principal aim of this pilot study was todetermine whether circulating SPD and CC16 are associ-ated with lung function and health status of patients withadvanced COPD.MethodsIn this pilot study, we used serum samples obtained in arecently completed trial of non-invasive mechanical ven-tilation (NIMV) in advanced COPD patients. The detailsof the trial are published elsewhere [7]. In brief, werecruited study participants with a clinical diagnosis ofCOPD and who were 40 years of age or older and had atleast a 10 pack-year history of cigarette smoking; forcedexpiratory volume in one second (FEV1) to forced vitalcapacity (FVC) ratio of less than 70% and a post-bron-chodilator FEV1 that was less than 70% of predicted. Ateach visit, patients performed spirometry using a rollingseal spirometer and according to published AmericanThoracic Society standards, as previously described [7]. Atthese visits, the patients also completed the Chronic Res-piratory Disease Questionnaire (CRQ) to assess theirhealth status. CRQ is an interviewer administered ques-tionnaire, which asks patients to rate their health status infour domains: dyspnea, fatigue, emotional function, andmastery [8].Venipuncture was also performed at each visit during day-time. The samples were collected in plain tubes and wereallowed to clot for at least 30 minutes. They were thencentrifuged at 1500 × g for 15 minutes at room tempera-ture, divided into aliquots using a sterile plastic transferCzech Republic), and CC16 levels (Biovendor, Modrice,Czech Republic) were determined using commerciallyavailable ELISA kits. They were measured in duplicatewith a coefficient of variation of 3.9% and 1.9%, respec-tively. All samples from the same patient were included inthe same assay and were performed in duplicate with acoefficient of variation of 3.9% and 1.9%, respectively.The analytical limit of detection for SPD was 0.2 ng/mL,with a sensitivity of 1.2 ng/mL and that for CC-16 was 20pg/ml with an assay sensitivity of 500 pg/ml. Sampleswere diluted 1:6 and all fell within the assay's detectionrange. For benchmarking, in these samples, we also meas-ured CRP levels using a highly sensitive commercially-available solid-phase sandwich enzyme-linked immuno-sorbent assay kits (Alpha Diagnostics, San Antonio, Tx).Statistical analysisThere were 13 participants in NIMV group and 10 partici-pants in control group. Two groups were similar in lungfunction, SPD, CC16, and CRP levels at baseline and after3 months of therapy [7]. Therefore, we combined the twogroups together for analytical purposes. As SPD, CC16,and CRP were non-normally distributed, we log-trans-formed these values to achieve normality. We thenemployed linear regression techniques to determinewhether FEV1 or CRQ scores were associated with levels ofthese biomarkers in the systemic circulation and whetherthese biomarker levels were related to each other. We per-formed these analyses for the cross-sectional data at base-line as well as for the longitudinal data over 3 months offollow-up. For the longitudinal component of the study,we regressed the changes in the biomarker levels againstchanges in FEV1 or CRQ scores. To control for potentialconfounders, we conducted a stepwise regression analysisin which covariates (age, sex, body mass index, PO2, PCO2and FEV1) were added to the model one by one andretained if the p-value was 0.15 or less in the multivariateanalysis. All tests were two-tailed in nature and were per-formed using SAS software (version 9.1; SAS Institute;Cary, NC). Continuous variables are expressed as mean ±SD unless otherwise specified.ResultsThere were 23 participants in the study: 11 men and 12women. The average age was 65 years. All of the partici-pants had advanced COPD with an average FEV1 of 31%of predicted. At baseline, the median level of circulatingSPD, CC16, and CRP was 74.7 ng/mL, 4.6 µg/L, and 3.5mg/L, respectively. The baseline demographic and clinicalcharacteristics are summarized in Table 1. The relation-ship between SPD and these clinical characteristics atbaseline are summarized in Table 2.Page 2 of 7(page number not for citation purposes)pipette and frozen in -80°C conditions until use. Thesamples were thawed once and SPD (Biovendor, Modrice,At baseline, FEV1 was inversely associated with SPD levels(P = 0.045) (Table 3, Figure 1) but not with CC16 (P =BMC Pulmonary Medicine 2007, 7:13 or CRP levels (P = 0.549) (Table 3). There was nosignificant correlation between the three biomarkers atbaseline (Table 3). After 3 months of follow-up, thechanges in circulating SPD levels were significantly andinversely associated with the changes in CRQ score (P =0.010, adjusted P = 0.008) (Table 4). The association wasthe strongest between circulating SPD levels and the dys-pnea domain score of CRQ. As circulating SPD levelsincreased, patients experienced increase in dyspnea (P =0.018) and worse health status (Table 3, Figure 2). CRQscores were not associated with changes in CC16 or CRPlevels (Table 4). Moreover, there was no significant over-lap in the changes of these biomarkers over time (Table4). The results from the stepwise multivariate analysiswere similar to those obtained in the univariate analysis.DiscussionCOPD poses a major health burden worldwide, account-ing for nearly 3 million deaths annually [1]. The develop-ment of novel therapeutics for COPD has been impededby lack of good surrogate markers that can track diseaseprogression and predict clinical outcomes [3]. Biomarkersderived from exhaled condensates, induced sputums andbronchial fluids, while specific, have major shortcomingsincluding lack of standardization and difficulty in pro-curement of samples that limit their application in largeclinical trials or studies. Blood biomarkers are more attrac-tive because there are well established procedures for pro-curement and processing of samples and standardizationof measurements. In COPD, the most widely studiedblood biomarker has been CRP. Although it performs wellin large cohorts, clinical application is limited owing tothe poor specificity of the measurement. Any inflamma-tory or infectious insults whether or not they are linkedwith COPD can modify CRP levels over time [9]. In thepresent study, we evaluated two lung-specific bloodbiomarkers as potential surrogates of health outcomes inpatients with severe COPD. We found that circulatingSPD was significantly associated with baseline lung func-tion and changed with changing health status of COPDpatients over a 3 month period.SPD is a large multimeric collagenous glycoprotein weigh-ing ~43 kDa (half of the size of albumin) and is part of thecollectin family of proteins [10]. It is produced mainly bytype II pneumocytes in the lungs though other cells suchas pulmonary Clara cells, endothelial cells and glandularcells in the gastrointestinal tract can produce smallamounts of SPD [11]. SPD plays an important role ininnate immunity and in host defense responses againstinhaled micro-organisms and allergens [11]. Addition-ally, SPD has a major function in regulating surfactanthomeostasis in the lungs by modulating surfactant ultra-structure and promoting reuptake of surfactant by type IIpneumocytes [12]. In general, under-expression of SPD inthe lung is associated with an increased risk of infections[13], while local over-expression has been associated withchronic inflammatory conditions such as asthma [14] andinterstitial pulmonary fibrosis [15]. The impact of circu-lating SPD on lung function is not entirely clear. In thepresent study, we found that at baseline FEV1 wasinversely correlated with log-SPD concentrations in theserum such that the highest FEV1 values were observed inpatients with SPD levels less than 90 ng/ml. Similar find-ings have been noted by Al-Salmi and colleagues [16] in agroup of pediatric patients with interstitial lung disease,Table 2: The Relationship Between Circulating Surfactant Protein (SPD) Levelsand Clinical Characteristicsβ-coefficient* R-value P valueAge (year) -0.014 ± 0.013 0.23 0.296Male vs. female 0.138 ± 0.284 0.11 0.633Body mass index (kg/m2) -0.005 ± 0.022 0.05 0.822PaO2 (mmHg) -0.007 ± 0.015 0.11 0.629PaCO2 (mmHg) 0.015 ± 0.0146 0.22 0.304CRQ Score -0.089 ± 0.136 0.14 0.519Dyspnea -0.225 ± 0.142 0.33 0.128Fatigue -0.022 ± 0.109 0.04 0.844Emotion 0.007 ± 0.114 0.01 0.950Mastery -0.110 ± 0.101 0.23 0.288Six-minute walk test (m) -0.001 ± 0.001 0.11 0.629* Regression coefficient ± SE.Table 1: Baseline characteristics of the study participantsMean ± SDNumber 23Age (year) 64.8 ± 10.6Men (%) 11 (47.8%)Body mass index (kg/m2) 27.7 ± 6.6FEV1 (L) 0.84 ± 0.32FEV1 (% predicted) 30.8 ± 14.8PaO2 (mmHg) 58.6 ± 10.0PaCO2 (mmHg) 44.5 ± 9.8CRQ score 4.1 ± 1.1Dyspnea 3.0 ± 1.0Fatigue 3.5 ± 1.3Emotion 4.9 ± 1.3Mastery 4.5 ± 1.4Six-minute walk test (m) 286.0 ± 123.6SPD (ng/mL)* 74.7 (49.2–128.7)CC16 (µg/L)* 4.6 (3.8–8.7)CRP (mg/L)* 3.5 (1.1–9.8)* Median and interquartile range.Abbreviations: CC16 – Clara cell protein, CRP – C-reactive protein, SPD – Lung surfactant protein D, FEV1 – forced expiratory volume in one second.Page 3 of 7(page number not for citation purposes)and by Krane and Griese [17] in a group of patients withcystic fibrosis. Bronchial hyperresponsiveness may alsoAbbreviations : CRQ – Chronic Respiratory Disease Questionnaire, SPD – surfactant protein D.BMC Pulmonary Medicine 2007, 7:13 to increased SPD levels in serum or plasma. In agroup of asthmatics, Koopman and colleagues found thatserum SPD was associated with acute declines in FEV1 fol-lowing allergen exposure [18]. Additionally, elevated cir-culating SPD levels may predict poor clinical outcomes.Among patients with acute respiratory distress syndromerequiring mechanical ventilation, higher plasma SPD lev-els are associated with a greater risk of multi-organ failure,ventilator-dependence and mortality [19]. In the presentstudy, we found that increases in SPD were associatedwith reduced health status and in particular with anincrease in dyspnea in patients with advanced COPD.Collectively, these data suggest that elevated serum SPD isa good marker of reduced lung function, worsening healthstatus (especially dyspnea) and other poor outcomes inpatients with lung disease. Thus, serum SPD is a promis-ing biomarker for tracking disease progression and pre-dicting clinical outcomes in COPD.There were limitations to this study. Firstly, although thestudy subjects were well characterized, the sample size wassmall, increasing the risk for type I errors (i.e. false nega-tive associations). Additionally, we performed multiplestatistical comparisons, which increased the probabilityfor type 2 errors (i.e. false positives). Larger studies will beneeded in the future to validate these initial findings. Sec-ondly, nearly all of the patients in the study had severe orvery severe COPD. Thus, these data cannot be generalizedto patients with mild or moderate disease. Thirdly, we didnot measure biomarkers other than CRP, CC16 and SPD.Thus, the use of other lung-specific molecules as potentialbiomarkers in COPD is not certain. Fourthly, we did nothave any broncho-alveolar samples for measurement andas such it is uncertain why FEV1 was inversely related toThe relationship between baseline serum Log-SPD levels and baseline FEV1Figure 1The relationship between baseline serum Log-SPD levels and baseline FEV1. Black dot, NIMV group; White dot, Control group. Abbreviation: FEV1- forced expiratory,  P=0.045Baseline Log-SPD (ng/mL)BaselineFEV1(L)Table 3: The Relationship Between Lung function and Serum Protein Biomarkers at baselineBaseline SPD* Baseline CC16* Baseline CRP*β R P value β R P value β R P valueBaseline FEV1 -0.204 0.42 0.045 -0.057 0.09 0.675 0.031 0.13 0.549Baseline SPD* -- -- -0.293 0.23 0.295 0.080 0.17 0.446Baseline CC16* -- -- -- -- -0.059 0.16 0.473* Logarithmic scale.A negative β-coefficient indicates an inverse relationship; whereas a positive β-coefficient indicates a positive linear relationship between the two variables.Abbreviations : CC16 – Clara cell protein-16, CRP – C-reactive protein, FEV1 – forced expiratory volume in one second, SPD – surfactant protein D.Relationship between the Changes in serum Log-SPD levels and changes in he dyspnea Scor  over three monthsFigure 2Relationship between the Changes in serum Log-SPD levels and changes in the dyspnea Score over three months. Black dot, NIMV group; White dot, Control in Log-SPD (ng/mL) ChangeinDyspneaScoreR2=0.32,  P=0.018Page 4 of 7(page number not for citation purposes)volume in one second, SPD – surfactant protein D group. Abbreviation: SPD – surfactant protein DBMC Pulmonary Medicine 2007, 7:13 5 of 7(page number not for citation purposes)Table 4: Association between the changes in serum protein biomarkers, lung function, dyspnea score and total CRQ scores over 3 monthsChange in SPD* Change in CC16* Change in CRP* Change in distance†β R P β R P β R P β R PChange in Dyspnea Score -1.95 (-1.95) 0.56 (0.56) 0.018 (0.018) -1.33 (-1.55) 0.24 (0.28) 0.359 (0.185) 0.42 (0.19) 0.23 (0.10) 0.367 (0.626) -14.63 (-16.91) 0.46 (0.52) 0.063 (0.032)Change in CRQ Score -1.50 (-1.13) 0.61 (0.44) 0.010 (0.008) -1.52 (-2.01) 0.38 (0.49) 0.135 (0.011) -0.14 (-0.35) 0.10 (0.26) 0.688 (0.214) -15.67 (-15.67) 0.36 (0.36) 0.163 (0.163)Change in SPD* -- -- 0.64 (0.64) 0.39 (0.39) 0.119 (0.119) 0.15 (0.15) 0.29 (0.08) 0.261 (0.261) 3.05 (3.05) 0.03 (0.03) 0.916 (0.916)Change in CC16* -- -- -- -- 0.10 (0.10) 0.30 (0.30) 0.248 (0.182) 61.38 (88.51) 0.35 (0.46) 0.175 (0.611)Change in CRP* -5.81 (-5.81) 0.10 (0.10) 0.698 (0.698)* Logarithmic scale.† Change in the distance of six-minute walk test (m).Values in brackets were derived from a stepwise regression model in which age, sex, body mass index, PO2, PCO2 and FEV1 were included in the model.Abbreviations: CC16 – Clara cell protein 16, CRP – C-reactive protein, CRQ – Chronic Respiratory Disease Questionnaire, SPD – surfactant protein D.BMC Pulmonary Medicine 2007, 7:13 SPD levels. Reduced lung expression of SPD is asso-ciated with lung injury and poor lung function [20]. Ingeneral, lung-based SPD measurements correlate posi-tively with FEV1, while blood-based SPD measurementscorrelate negatively with FEV1. Since lung is the majorsource of SPD production, this observation suggests thatwith lung injury, SPD and other similar proteins may leakout from the lung compartments into the systemic circu-lation [21], causing a paradoxical rise in serum SPD, evenin the presence of decreased lung production, a notionthat is supported by animal experiments [22]. There wereseveral other notable observations in our study. Firstly,although the baseline FEV1 correlated with SPD, FEV1failed to change as a function of SPD over 3 months. Onepossibility is that these two variables may not be causallyrelated. Alternatively and more likely is that the 3 monthfollow-up may have been too short to observe any signif-icant changes in FEV1. A larger and longer duration studyis needed to confirm these preliminary observations. Sec-ondly, although the changes in SPD related to changes inthe CRQ scores, especially with the dyspnea scores over 3months, the baseline CRQ scores were not significantlyassociated with baseline SPD scores. One potential expla-nation for this apparent paradox was the relative smallspread of CRQ scores of study participants at baseline. Vir-tually all patients complained of poor health status (meanCRQ score of 4.1 with a SD of 1.1), which made it statis-tically difficult to detect any significant relationships withCRQ. A larger study with a wider variation of CRQ scoresamong study participants is needed to confirm these rela-tionships.ConclusionIn summary, the present study suggests that in advancedCOPD, serum SPD level is negatively associated withFEV1, and its increase over a 3-month period is associatedwith worsening of health status of patients. Serum SPD isa promising lung-specific biomarker to track clinicalhealth outcomes of patients with COPD, pending valida-tion of these early findings with larger clinical studies.CC16: Clara Cell protein-16COPD: Chronic Obstructive Pulmonary DiseaseCRP: C-reactive proteinFEV1: forced expiratory volume in one secondFVC: forced vital capacityNIMV: non-invasive mechanical ventilationCompeting interestsThe work is supported in part by the Canadian Institutesof Health Research. Don Sin is a Senior Scholar with theMichael Smith Foundation for Health Research and aCanadian Research Chair in COPD.Authors' contributionsAll authors have made substantial intellectual contribu-tion to the interpretation of the results and drafting of themanuscript.References1. Murray CJ, Lopez AD: Global mortality, disability, and the con-tribution of risk factors: Global Burden of Disease Study.  Lan-cet 1997, 349(9063):1436-1442.2. 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Koopmans JG, van der Zee JS, Krop EJ, Lopuhaa CE, Jansen HM,Page 6 of 7(page number not for citation purposes)SPD: surfactant protein D Batenburg JJ: Serum surfactant protein D is elevated in allergicpatients.  Clin Exp Allergy 2004, 34(12):1827-1833.Publish with BioMed Central   and  every scientist can read your work free of charge"BioMed Central will be the most significant development for disseminating the results of biomedical research in our lifetime."Sir Paul Nurse, Cancer Research UKYour research papers will be:available free of charge to the entire biomedical communitypeer reviewed and published immediately upon acceptancecited in PubMed and archived on PubMed Central BMC Pulmonary Medicine 2007, 7:13 Eisner MD, Parsons P, Matthay MA, Ware L, Greene K: Plasma sur-factant protein levels and clinical outcomes in patients withacute lung injury.  Thorax 2003, 58(11):983-988.20. 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