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The relationship of systemic inflammation to prior hospitalization in adult patients with cystic fibrosis Ngan, David A; Wilcox, Pearce G; Aldaabil, May; Li, Yuexin; Leipsic, Jonathon A; Sin, Don D; Man, SF P Feb 14, 2012

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RESEARCH ARTICLE Open AccessThe relationship of systemic inflammation toprior hospitalization in adult patients withcystic fibrosisDavid A Ngan, Pearce G Wilcox, May Aldaabil, Yuexin Li, Jonathon A Leipsic, Don D Sin and SF Paul Man*AbstractBackground: In cystic fibrosis (CF) patients, it has been suggested that systemic inflammation may be animportant risk factor for poor health outcomes. The relationship of plasma inflammatory biomarkers to lungfunction and hospitalization history remains largely unexplored.Methods: This cross-sectional study included 58 consecutive, clinically stable adults from the CF Clinic at St. Paul’sHospital (Vancouver, Canada). Blood levels of interleukin (IL)-6, IL-1b, C-reactive protein (CRP), interleukin (IL)-6, IL-1b, granzyme B (GzmB), chemokine C-C motif ligand 18 (CCL18/PARC), surfactant protein D (SP-D),lipopolysaccharide (LPS)-binding protein, and soluble cluster of differentiation 14 (sCD14) were measured usingenzyme-linked immunosorbent assays, and LPS levels were measured using a Limulus amebocyte lysate assay.Spirometry was also performed. Multivariable linear regression analysis was used to assess relationships of theblood biomarkers to lung function.Results: Lung function impairment was independently associated with elevated plasma levels of CRP (P < 0.01), IL-6 (P = 0.04), IL-1b (P < 0.01), and LBP (P < 0.01). Increasing age (P < 0.01), reduced body mass index (P = 0.02),prior hospitalizations (P = 0.03), and presence of Pseudomonas aeruginosa in sputum cultures (P < 0.01) were alsoassociated with reduced lung function. Elevated concentrations of LPS in plasma were associated with a previoushistory of hospitalization (P < 0.05). There was a trend towards an increase in plasma IL-6 (P = 0.07) and IL-1b (P =0.06) levels in patients who were previously hospitalized.Conclusions: IL-6 and IL-1b are promising systemic biomarkers for lung function impairment and history ofhospitalization in adult patients with CF.BackgroundCystic fibrosis (CF) is a progressive, debilitating diseasethat affects nearly 30,000 Americans and occurs with afrequency of about 1 in 3500 births [1]. It is character-ized by persistent lung infection and lung functionimpairment. It also affects other organs including thesinuses, gastrointestinal tract, endocrine glands, and thebone [2-5]. Although all CF cases are caused by a muta-tion in the gene for the CF transmembrane conductanceregulator, there is considerable heterogeneity in the rateat which the disease progresses [6]. The traditional riskfactors for rapid progression include reduced body massindex, colonization of the airways with pathogenic bac-teria such as Pseudomonas aeruginosa, and female sex[7-9]. More recently, some have suggested that systemicinflammation may be another important risk factor forpoor health outcomes in CF independent of these tradi-tional risk factors [3,8,10,11]. However, the studies thathave evaluated this issue have produced inconsistentresults and have measured different components of theimmune system, making cross comparisons difficult.Moreover, none of these studies have evaluated thesebiomarkers on hard clinical outcomes such as exacerba-tions or hospitalizations, which are important endpointsin CF. In this study, we determined the relationship ofplasma inflammatory biomarkers to lung function andhospitalization history in adult patients with CF. Theplasma biomarkers were carefully chosen to represent* Correspondence: pman@providencehealth.bc.caUBC James Hogg Research Centre, Institute for Heart + Lung Health at St.Paul’s Hospital and Department of Medicine, University of British Columbia,Vancouver, BC, CanadaNgan et al. BMC Pulmonary Medicine 2012, 12:3http://www.biomedcentral.com/1471-2466/12/3© 2012 Ngan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.innate or adaptive immunity, a by-product of Gram-negative pathogens, or lung-based proteins.MethodsStudy Population and Blood CollectionWe enrolled 58 consecutive adult patients from the Cys-tic Fibrosis (CF) Clinic at St. Paul’s Hospital (Vancouver,British Columbia, Canada) between April and December2009, who were clinically stable at the time of assess-ment. For inclusion, patients had to have one or moreclinical features consistent with the CF phenotype [12]as well as a genotype with two identifiable disease-caus-ing CF transmembrane conductance regulator (CFTR)mutations and sweat chloride measurements greaterthan 60 mmol/L on two occasions. Patients who had anexacerbation within the previous 4 weeks were excludedfrom the study. This study was conducted with theapproval of the University of British Columbia - Provi-dence Health Care Research Ethics Board (UBC-PHCREB). Following informed consent, we collected venousblood samples and performed spirometry using standardtechniques, in accordance with guidelines from theAmerican Thoracic Society [13]. Demographic and clini-cal data were obtained by chart review.Clinical InformationThe subjects’ infection status was determined by micro-bial review within the preceding 3 years of study entry.Those who had at least one sputum culture positive ofPseudomonas aeruginosa were considered to be infectedby this organism. We also performed chart review andretrieved data from the hospital database to determinewhether the patients had a hospitalization for CFexacerbation in the previous 5 years.Biomarker AssaysPlasma was prepared from the collected blood samplesand a select number of circulating inflammatory pro-teins were measured using high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits that werecommercially available. These included interleukin (IL)-6 and IL-1b (R&D Systems, Minneapolis, MN), cyto-kines involved in the early phase inflammatory response;C-reactive protein (CRP; R&D Systems), an acute phaseresponse protein; granzyme B (GzmB; eBioscience, SanDiego, CA), a protein involved in adaptive immunity;chemokine C-C motif ligand 18/pulmonary and activa-tion-regulated chemokine (CCL18/PARC; R&D Systems)and surfactant protein D (SP-D; Biovendor, Brno, CzechRepublic), pneumo-proteins (i.e. proteins synthesizedpredominantly in the lungs) [14,15]; and LPS-bindingprotein (LBP; Hycult Biotech, Uden, The Netherlands)and soluble cluster of differentiation 14 (sCD14; R&DSystems), proteins involved in lipopolysaccharide (LPS)signalling. The coefficients of variation for these kitswere 7.4%, 12.3%, 3.1%, 5.8%, 1.2%, 2.2%, 1.7%, and 5.9%respectively, and the lower detection limits were 0.039pg/mL, 0.057 pg/mL, 0.010 ng/mL, 0.2 pg/mL, 0.01 ng/mL, and 0.2 ng/mL, 4.4 ng/mL, and 0.125 ng/mLrespectively. LPS levels were measured using a commer-cially-available kinetic chromogenic Limulus amebocytelysate (LAL) assay kit (Lonza Walkersville, Walkersville,MD) following plasma dilution and heat inactivationpre-treatment steps to diminish interference fromplasma proteins. The coefficient of variation for theassay was 2.2%, and the lower detection limit was 0.5pg/mL. Of these biomarker assays, only the IL-1b ELISAhad samples with values below the limit of detection (18undetectable out of 58 samples, or 31%). In plasma sam-ples, the manufacturers’ reported ranges for IL-6, IL-1b,CRP, GzmB, and sCD14 measurements in healthyvolunteers were 0.428 to 8.8 pg/mL, non-detectable to0.452 pg/mL, 104 to 4185 ng/mL, 0.8 to 24.1 pg/mL,and 1200 to 3100 ng/mL, respectively. Reference rangeswere not available for CCL18/PARC, SP-D, LBP, andLPS, and the dynamic ranges of these assays were 7.8 to500 pg/mL, 1.56 to 100 ng/mL, 4.4 to 50 ng/mL, and0.5 to 500 pg/mL, respectively.Statistical AnalysisData for the biomarker measurements were analyzedafter natural log transformation due to their skeweddistribution, and values below the limit of detectionwere assigned the value of the lower detection limit forthe particular kit. The relationships of the biomarkersto lung function (FEV1 as a percentage of predicted)and to each other were assessed using linear regres-sion. Multivariable linear regression analysis was per-formed to assess the role of possible confoundingfactors such as age, sex, and pseudomonal status.Plasma biomarker levels were compared between thosewho did and did not experience a hospitalization inthe past using a Student’s t-test for independent sam-ples. Fisher’s exact test was used to analyze categoricaldata. The independent relationship of plasma biomar-kers to FEV1% predicted was ascertained using multipleregression analysis. To ensure parsimony and enhancethe robustness of the model, we used a stepwiseapproach to select only those covariates that signifi-cantly impacted on the relationship (the significancelevel for entering, P ≤ 0.05 and the significance levelfor stay, P ≤ 0.05). To facilitate interpretation andcross-comparisons of beta-coefficients of plasma bio-markers from the regression model, we standardizedthe beta-coefficients to their standard deviation. Thus,the beta-coefficients are presented per 1 SD increase inthe plasma biomarker expression. P-values less than0.05 were considered significant (two-tailed test). AllNgan et al. BMC Pulmonary Medicine 2012, 12:3http://www.biomedcentral.com/1471-2466/12/3Page 2 of 7analyses were conducted using SAS (Carey, N.C.) ver-sion 9.1.ResultsPatient DemographicsThe age of the study subjects ranged from 18 to 61years (Table 1). The baseline clinical characteristics ofthe study subjects are summarized in Table 1 in twogroups based on the median value of FEV1% predicted.Greater mean age, reduced BMI, hospitalizations in theprevious 5 years, and presence of Pseudomonas aerugi-nosa in sputum cultures were all significantly asso-ciated with below-median FEV1% predicted values. Ofthe 58 subjects, 21 had been hospitalized (36% of total)and 37 had not. 42 of the subjects were classified asPseudomonas+ based on sputum microbiology (72.41%of total) and 16 were Pseudomonas-. A greater portionof patients with below-median FEV1% predicted valueshad been administered Azithromycin and Tobramycinversus patients with above-median FEV1% predictedvalues.Systemic Inflammation and Lung FunctionCRP, IL-6, IL-1b, and LBP were significantly correlatedwith lung function impairment in both univariable andmultivariable analysis (Table 2). LPS was significantlyrelated to FEV1 only in the multivariable analysis. Theuse of standardized beta-coefficient (i.e. the change inFEV1% predicted per 1 standard deviation increase inthe plasma concentrations of the biomarker) allows forcomparison of the beta-coefficients across biomarkers.CRP had the highest standardized beta-coefficient,followed by LBP, IL-6 and IL-1b, suggesting that CRP ismost strongly associated with FEV1. Geometric meanplasma levels of IL-6, IL-1b, CRP, and LBP of patientswith below-median FEV1% predicted values were 3.0 pg/mL, 0.21 pg/mL, 4.6 μg/mL, and 33.2 μg/mL, respec-tively. These were all significantly higher than inpatients with above-median FEV1% predicted values (1.6pg/mL, 0.12 pg/mL, 2.0 μg/mL, and 22.9 μg/mL, respec-tively) (Figure 1). The geometric mean plasma level ofGzmB was significantly lower in patients with below-median FEV1% predicted values (71.6 pg/mL) comparedto those with above-median FEV1% predicted values(166.3 pg/mL).Circulating Systemic Inflammatory Biomarkers andHospitalization HistoryThe geometric mean plasma levels of IL-6, IL-1b, andLPS of hospitalized CF subjects were 3.6 pg/mL, 0.19pg/mL, and 1.3 ng/mL, respectively. These were all sig-nificantly higher than in non-hospitalized subjects (1.7pg/mL, 0.10 pg/mL, and 0.97 ng/mL, respectively)(Table 3). After adjustment for FEV1% predicted, BMIand pseudomonal status in sputum, the relationshipsweakened (Table 3). There was a significant associationbetween plasma IL-6 levels and IL-1b levels (Figure 2).Geometric mean plasma concentrations of CRP, GzmB,CCL18, SP-D, LBP, and sCD14 did not significantly dif-fer between the previously hospitalized and non-hospita-lized groups (Table 3). The c-statistic of FEV1, BMI andpseudomonal status together was 0.797. There was amodest improvement in the c-statistic by adding IL-6,IL-1b, or LPS (0.837, 0.828, and 0.841, respectively).Table 1 Patient demographics and clinical characteristicsTotal(n = 58)FEV1% predicted≥ median(n = 29)FEV1% predicted< median(n = 29)P-valueAge, years range 18 - 61 18 - 49 19 - 61 < 0.01Sex, male n (%) 34 (58.62) 18 (62.1) 16 (55.2) 0.79BMI, kg/m2 ± SD 23.24 ± 3.25 24.2 ± 3.4 22.3 ± 2.9 0.02FEV1, % predicted ± SD 71.93 ± 24.80 92.9 ± 12.9 51.0 ± 13.2 -Current medicationsAzithromycin, n (%) 18 (31.03) 3 (10.3) 15 (51.7) < 0.01Ciprofloxacin, n (%) 2 (3.45) 1 (3.4) 1 (3.4) 1.00Dornase alfa, n (%) 24 (41.38) 11 (37.9) 13 (44.8) 0.79Ibuprofen, n (%) 2 (3.45) 2 (6.9) 0 (0) 0.49Prednisone, n (%) 0 (0) 0 (0) 0 (0) -Tobramycin, n (%) 13 (22.41) 2 (6.9) 11 (37.9) 0.01Inhaled steroids, n (%) 37 (63.79) 15 (51.7) 22 (75.9) 0.10Diabetes, n (%) 22 (37.93) 10 (34.5) 12 (41.4) 0.79Hospitalization, n (%) 21 (36.2) 6 (20.7) 15 (51.7) 0.03Pseudomonas, n (%) 42 (72.41) 15 (51.7) 27 (93.1) < 0.01Ngan et al. BMC Pulmonary Medicine 2012, 12:3http://www.biomedcentral.com/1471-2466/12/3Page 3 of 7DiscussionThis was a unique study investigating the relationship ofsystemic inflammation to lung function impairment andhospitalization history among clinically stable CFpatients. This study produced several important find-ings. First, biomarkers that are related to innate immu-nity or early acute phase reactants such as IL-6, IL-1b,CRP, and LBP were significantly associated with reducedlung function in CF patients independent of age, pseu-domonal status, or history of hospitalization, suggestingthat systemic inflammation is an independent risk factorfor disease progression in CF. The directionality of therelationship is uncertain. Thus, it remains unknownwhether the rise in these biomarkers is the result or thecause of impaired lung function. Our data extend thefindings of a previous study that examined a cohort ofadult CF patients aged 30 years or greater. Levy et al.found an association between lower FEV1 percent pre-dicted and higher serum CRP levels, but they did notadjust for sex or pseudomonal status of the patients,and the study cohort was limited to an older population[11]. Furthermore, their retrospective study design pre-vented them from obtaining serum samples and per-forming pulmonary function tests within a closeproximity of time. While our current study did notmake comparisons to healthy controls, previous studieshave found that median plasma or serum concentrationsof IL-6, IL-1b, IL-1 receptor antagonist (IRAP) [16],neutrophil granule proteins, and CRP [17] were higherin CF patients versus healthy subjects. Collectively, theuse of plasma markers of systemic inflammation, espe-cially IL-6 and CRP, provides additional indicators ofclinical status and may add to our understanding of therelationship between inflammation and the severity oflung disease in CF patients.Second, in addition to the traditional factors such asreduced BMI, poor lung function as measured by FEV1percent predicted, and presence of Pseudomonas aerugi-nosa in sputum cultures, we found that plasma levels oftwo early phase inflammatory cytokines, IL-6 and IL-1b,were significantly associated with prior hospitalization inpatients with CF, independent of the traditional factors.However, there was no significant relationship of GzmB,a marker of adaptive immunity, lung-based proteinssuch as CCL18/PARC and SP-D, or acute-phase reac-tants such as CRP, LBP, and sCD14 [18] with hospitali-zation history. Together, these data suggest that earlyphase inflammatory cytokines may be good candidateplasma biomarkers of health outcomes in CF.Our third important finding was that plasma LPSderived from Gram-negative bacteria is significantlyhigher in those who were previously hospitalized for aCF exacerbation than those who were not. LPS is animmunologically active antigen, which can cause anintense inflammatory process in the lung and elsewhere.Its presence in the systemic circulation may enhance thesystemic inflammatory response in CF, as previouslyseen in a murine model [19]. We postulate that some ofthe LPS expression in the systemic circulation may bederived from the lungs through a process called translo-cation. It is conceivable that the diseased respiratorytract in CF may facilitate translocation of bacterial com-ponents or pro-inflammatory cytokines from the lungsto the systemic circulation where it incites an inflamma-tory response. This biological plausibility is supportedby a study in rabbits where it was shown that it is physi-cally possible for LPS to undergo pulmonary-to-systemictranslocation under certain conditions, specifically inmechanical ventilation strategies [20]. While our meth-ods did not allow us to determine the originating sourceof plasma LPS, we speculate that the LPS we measuredis likely derived from P. aeruginosa in the lungs or otherGram-negative, CF-related bacteria. Future studies willbe needed to test this hypothesis.Table 2 Relationship between FEV1 percent predicted and biomarkers in CF subjects per 1 log increase in thebiomarkers (n = 58)Unadjusted Adjusted* Standardized Beta-Coefficient(per 1 SD increase in the levels of biomarker)Biomarker b ± SE P-value b ± SE P-valueCRP, mg/L -10.61 ± 2.65 < 0.01 -7.04 ± 1.98 < 0.01 -0.3134IL-6, pg/mL -10.72 ± 3.11 < 0.01 -5.53 ± 2.66 0.04 -0.2159IL-1b, pg/mL -6.97 ± 3.36 0.04 -4.65 ± 2.67 < 0.01 -0.1784SP-D, μg/mL -17.70 ± 7.95 0.03 -9.83 ± 5.93 0.10 -0.1584CCL18, pg/mL -6.33 ± 5.93 0.29 -3.01 ± 4.23 0.48 -0.0672GzmB, pg/mL 4.09 ± 2.27 0.08 -0.33 ± 1.89 0.86 -0.0187LPS, pg/mL 1.07 ± 7.44 0.89 13.30 ± 5.41 0.02 0.0239sCD14, μg/mL 1.88 ± 9.67 0.85 -10.26 ± 6.96 0.15 -0.1414LBP, μg/mL -22.28 ± 6.63 < 0.01 -16.02 ± 4.74 < 0.01 -0.2946* Adjusted for age, pseudomonal status, and history of hospitalization, which were significantly related to reduced lung functionNgan et al. BMC Pulmonary Medicine 2012, 12:3http://www.biomedcentral.com/1471-2466/12/3Page 4 of 7Figure 1 Plasma biomarker concentrations in cystic fibrosis subjects with above-median (n = 29) and below-median (n = 29) FEV1%predicted values. (A-D) Geometric mean plasma levels of IL-6, IL-1b, CRP, and LBP were higher in subjects with below-median FEV1% predictedvalues than in those with above-median FEV1% predicted values. (E) The geometric mean plasma level of GzmB was lower in subjects withbelow-median FEV1% predicted values than in those with above-median FEV1% predicted values.Ngan et al. BMC Pulmonary Medicine 2012, 12:3http://www.biomedcentral.com/1471-2466/12/3Page 5 of 7There were important limitations to our study. This isa cross-sectional study, which precludes firm conclu-sions on causality or directionality of the relationship.While we postulate that systemic inflammation drivesdisease progression, it is entirely possible that diseaseprogression is responsible for systemic inflammation,and a comprehensive prospective longitudinal studywould be needed to address this issue. Longitudinal datamay also provide insight into plasma biomarker profilesduring acute exacerbations and following antibiotictreatment. Additionally, we did not measure other pro-inflammatory biomarkers such as TNF-a and IL-8 orthose with known anti-inflammatory effects such as IL-10, which has been shown in a mouse model to reducethe inflammatory response to Pseudomonas aeruginosa[21]. Future investigation into these regulators of theinflammatory response could provide a clearer pictureof the complex interactions involved that lead fromexcessive inflammation to disease progression.ConclusionsNotwithstanding the limitations, we found that moreintense systemic inflammation, mediated by the innateimmune system, is associated with prior CF hospitaliza-tions and with lung function impairment in CF. IL-6and IL-1b, in particular, are promising systemic biomar-kers for disease progression and hospitalization in CF. Alarge prospective study testing these promising biomar-kers would be of great value in determining their useful-ness as a clinical tool in managing patients with CF.AcknowledgementsThe authors acknowledge the assistance of Cystic Fibrosis Clinic studycoordinators Vincent Zenarosa and Wen Wang for recruitment of subjects inthis study as well as for blood collection. This work is supported by theCanadian Institutes of Health Research.Authors’ contributionsDAN carried out the immunoassays, contributed to the acquisition andinterpretation of the data, performed statistical analysis, and drafted themanuscript for important intellectual content; PGW participated in thedesign of the study and contributed to the acquisition and interpretation ofthe data; MA contributed to the acquisition and interpretation of the data;YL contributed to the acquisition of the data; JAL participated in the designof the study and contributed to the acquisition and interpretation of thedata; DDS participated in the design of the study, performed statisticalTable 3 Geometric means (and interquartile ranges) of biomarkers in CF patients who were and were not previouslyhospitalizedBiomarker Total(n = 58)*Previously hospitalized(n = 21)*Not previously hospitalized(n = 37)*P-value Adjusted P-value† c-statisticsCRP, μg/mL 3.0(1.5, 6.1)3.5(2.0, 8.0)2.8(1.3, 5.6)0.50 0.51 0.795IL-6, pg/mL 2.2(1.1, 4.2)3.6(2.8, 5.8)1.7(1.0, 3.1)< 0.01 0.07 0.837IL-1b, pg/mL 0.16(0.06, 0.29)0.19(0.06, 0.50)0.10(0.06, 0.20)< 0.01 0.06 0.828SP-D, ng/mL 84.3(64.0, 112.3)87.5(75.3, 106.1)82.6(63.7, 113.2)0.60 0.26 0.804CCL18, ng/mL 59.5(41.4, 75.3)60.1(38.7, 73.5)59.2(44.5, 75.9)0.92 0.92 0.797GzmB, pg/ml 109.2(25.5, 389.8)90.7(25.4, 384.9)121.2(26.2, 389.8)0.46 0.83 0.792LPS, ng/mL 1.1(0.9, 1.3)1.3(1.0, 1.4)1.0(0.8, 1.3)0.01 0.04 0.841sCD14, μg/mL 1.1(0.9, 1.3)1.1(1.0, 1.3)1.1(0.8, 1.3)0.89 0.49 0.789LBP, μg/mL 27.6(22.0, 39.9)30.8(23.7, 41.2)25.9(18.8, 35.7)0.17 0.79 0.781* Data are presented as geometric mean (25th, 75th percentile)† Adjusted for FEV1% predicted, BMI, and pseudomonal status, which collectively had a c-statistic (or area under the curve) value of 0.797Figure 2 Plasma IL-6 was significantly correlated with plasmaIL-1b in cystic fibrosis subjects (n = 58). b ± SE = 0.595 ± 0.105;IL-6 and IL-1b ln-transformed. R2 = 0.37; P < 0.01.Ngan et al. BMC Pulmonary Medicine 2012, 12:3http://www.biomedcentral.com/1471-2466/12/3Page 6 of 7analysis, contributed to interpretation of the data, and drafted themanuscript for important intellectual content; SFPM conceived the study,participated in the design of the study, contributed to interpretation of thedata, and drafted the manuscript for important intellectual content. Allauthors read and approved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Received: 30 May 2011 Accepted: 14 February 2012Published: 14 February 2012References1. Cystic Fibrosis Foundation: Cystic Fibrosis Foundation Patient Registry:2009 Annual Data Report. Bethesda, MD; 2011.2. Shead EF, Haworth CS, Barker H, Bilton D, Compston JE: Osteoclastfunction, bone turnover and inflammatory cytokines during infectiveexacerbations of cystic fibrosis. J Cyst Fibros 2010, 9(2):93-98.3. 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Pediatr Pulmonol 1993, 15(5):292-297.17. Rayner RJ, Wiseman MS, Cordon SM, Norman D, Hiller EJ, Shale DJ:Inflammatory markers in cystic fibrosis. Respir Med 1991, 85(2):139-145.18. Bas S, Gauthier BR, Spenato U, Stingelin S, Gabay C: CD14 is an acute-phase protein. J Immunol 2004, 172(7):4470-4479.19. Tamagawa E, Suda K, Wei Y, Xing L, Mui T, Li Y, van Eeden SF, Man SF,Sin DD: Endotoxin-induced translocation of interleukin-6 from lungs tothe systemic circulation. Innate Immun 2009, 15(4):251-258.20. Murphy DB, Cregg N, Tremblay L, Engelberts D, Laffey JG, Slutsky AS,Romaschin A, Kavanagh BP: Adverse ventilatory strategy causespulmonary-to-systemic translocation of endotoxin. Am J Respir Crit CareMed 2000, 162(1):27-33.21. Chmiel JF, Konstan MW, Knesebeck JE, Hilliard JB, Bonfield TL, Dawson DV,Berger M: IL-10 attenuates excessive inflammation in chronicPseudomonas infection in mice. Am J Respir Crit Care Med 1999,160(6):2040-2047.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/12/3/prepubdoi:10.1186/1471-2466-12-3Cite this article as: Ngan et al.: The relationship of systemicinflammation to prior hospitalization in adult patients with cysticfibrosis. BMC Pulmonary Medicine 2012 12:3.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitNgan et al. BMC Pulmonary Medicine 2012, 12:3http://www.biomedcentral.com/1471-2466/12/3Page 7 of 7

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