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  1. I have no conflict of interest

  2. BIOMARKERS in OBSTRUCTIVE DISEASE Assoc. Prof. Dr. Gamze KIRKIL FiratUniversity, Department of ChestDisease

  3. Presentation Plan Bronchialbiopsy BAL Sputum Exhaledbreathcondensate Serum • Definition • Biomarkers in COPD • Biomarkers in Asthma • Biomarkers in CysticFibrosis • Conclusion Bronchialbiopsy BAL Sputum Exhaledbreathcondensate Serum

  4. Definition • Biomarker is a physicalsignorlaboratorymeasurementthat is evaluated as an indicator of normal biologicalprocesses, pathogenicprocesses, orpharmacologicresponsestotherapeuticinterventions It is helpful in evaluatingthe; • Activity of thedisease • Responsetothetherapyand • Prognosis

  5. An ideal biomarkermust be; • Minimallyinvasive, easilymeasurableandreproducible • Used in confirmingthediagnosisordefining a specialclinicfenotype • Itmustshowdose-responserelation, must be a guidefordeterminingthetherapyneeds • Used in predictingtheadverseevents, andclinicaloutcomesthatwillappear in thefuture

  6. Whyarebiomarkersnecessaryforrespiratorydisease? • Tissuebiopsy is rarelyused in definingbenignpathologies • Scanningmethodsandphysiologicalmeasurementshavelimitations • Thestructureandfunctions in diseaselikeasthmaand COPD changeintermittentorprogressively • Becausesymptomsarenonspesificandmultifactorial in patientswithcomorbidities, biomarkersareneeded

  7. Biomarkers in COPD

  8. Biomarkers in determiningthe COPD occurrence risk • Low FEV1 measured at meanage 25-yearsoldwaspredictive of the presence of airflowobstructionmeasured 20 yearslaterindependent of cigarettesmoking Kalhan R, et al. Am J Med 2010; 123: 468-e1-7 • Higher CRP levelswereassociatedwithlowerlungfunction in ages 26-32 unrelatedtosmoking, obesity, andasthma Hancox RJ, et al. Thorax 2007; 62: 1064-8

  9. Subjects 55 years of ageandolder, CRP wasassociatedwithincreased risk of COPD Van Durme YMTA, et al. Am J respirCritCareMed 2009; 179: 375-82 • High CRP andfibrinogen in youngadulthoodwerebothassociatedwithaccelerateddecline in the FVC and FEV1 overthesubsequent 13-15 years Kalhan R, et al. Plos ONE 2010; 5:e11431

  10. Biomarkers in theActivity, Prognosis, andTherapyResponse in COPD PulmonaryBiomarkers NonpulmonaryBiomarkers • Bronchialbiopsy • BAL • Sputum • Exhaledbreathcondensate • Serum • Urine

  11. BronchialBiopsy Is usefulfordeterminingthe; • Structuralchanges • Cellularpatterns • Expression of inflammatoryproteins

  12. Advantage of bronchialbiopsies; • They can provide an assesment of structuralcomponents of theairwaywall • Biomarkers of structuraldamage can be measured • Thedifferentinflammatorycellsubtypes can be identified in theirmicroenvironment, thusallowinginvestigation of interactionbetweeninflammatoryandresidentcells

  13. Limitations of bronchialbiopsies; • Itmay be difficulttoperform in studieswhichrequirerepeatedbiopsies • Itmay be difficulttoperform in patientswithcardiaccomorbidity, significanthypercapnia, anddesaturation • Thebiopsy of proximalairwaysmay not closelyreflectallthepathologicchangespresent in peripheralairwaysandlungparenchyma • There is a relativellyhighvariability in baselinemeasurements of inflammatorycells, whichnecessitatesmultiplebiopsies

  14. Instable COPD; • There is increasedinfiltration of CD8+ T lymphocytesandmacrophages Barnes P, et al. Am J RespirCritCareMed 2006; 174: 6-14 • Chemokinereceptorexpressionrelatedwithtype-1 response is seen Saetta M, et al. Am J RespirCritCareMed 2002; 165: 1404-09 • Prominentneutrophilia is present in theairwaylumen, tissueneutrophilnumberincreaseswithseverity of disease DiStefano A, et al. Am J RespirCritCareMed 1998; 158: 1277-1285

  15. Thenumber of IL-22+, IL-23+ immunoreactivecells is increased in thebronchialepitelium • Inallsmokersand in patientswith COPD, thenumber of IL-22+ cellscorrelatedwiththenumber of CD4+ and CD8+ cells in thebronchialmucosa • Endothelialcellsexpresshighlevels of IL-17A and IL-22 DiStefano A, et al. ClinExpImmunol 2009; 157: 316-24

  16. Smokers with COPD had elevated levels of YKL-40 in serum and BAL, more YKL-40-positive cells in bronchial biopsiesthan smokers without COPD or never-smokers • YKL-40 levels in serum and BAL were associated with airflow obstruction and impaired diffusion lung capacity Letuve S, et al. J Immunol 2008; 181: 5167-73

  17. Increased expression of NF-KB in bronchial biopsies from smokers and patients with COPD DiStefano A, et al. EurRespir J 2002; 20: 556-63

  18. Altered surfactant protein-A expression in type II pneumocytes in COPD Vlachaki EM, et al. Chest 2010; 137: 37-45

  19. Duringexacerbations; • Expression of neutrophilchemoattractantsincrease (CXCL5, CXCR1, CXCR-2) • Accumulation of eosinophilsincrease Saetta M, et al. Am J RespirCritCareMed 1994; 150: 1646-1652 Zhu J, et al. Am J RespirCritCareMed 2001; 164: 109-116 Qiu Y, et al. Am J RespirCritCareMed 2003; 168: 968-75

  20. Inhaledsteroidsdecreasethenumber of attacksbydecreasingthenumber of mastcells, but have a littleeffect on airwayinflammation Hattotuwa KL, et al. Am J RespirCritCareMed 2002; 165: 1592-96 Verhoeven GT, et al. Thorax 2002;57:694–700

  21. Antiinflammatory effects of salmeterol/fluticasone propionate in COPD 140 moderate-severe COPD (currentsmokerorexsmoker) 13 weekplacebo/ SALM/FP(50-500 mikrogr) Bronchial biopsies obtained at baseline and at Week 12 Barnes NC, et al. Am J RespirCritCareMed 2006; 173(7):736-43.

  22. Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast in COPD 59 COPD patients 12 weekcilomilast 15 mg 2x1 orplacebo Bronchial biopsies obtained at baseline and at Week 10 CD8 CD68 Gamble E, et al. Am J RespirCritCareMed 2003; 168: 976-82

  23. BAL Advantage; • Itsamplestheinflammation in thelungperiphery • It is usually a safeprocedure • Whenperformedwithbronchialbiopsy, it can provideadditionalinformation

  24. Limitations; • It is an invasiveprocedure • Itmaycausetransientfever • Thereturn of fluid is oftenreduced in patientswith COPD • Quantification of biomarkers in supernatant is a problem

  25. Cellularcomposition; • Thecellularcomposition in individualswith COPD is predominantlyalveolarmacrophages (>80%) • Smoking is associatedwithincreasednumbers of neutrophils • Lymphocytesaregenerallyhigher in ex-smokersthan in smokers • Somepatientswith COPD havehighereosinophilpercentagesthanhealthysmokers Cazzola M, et al. EurRespir J 2008, 31: 416-69

  26. Thepercentage of CD8+ T lymphocytes is higher in COPD andhealthysmokerscomparedwithhealthynon-smokers • Thepercentage of CD4+ T cells is lower in COPD Hodge G, et al. ClinExpImmunol 2007; 150: 22-9

  27. Tissueculture of macrophagesfrompatientswith COPD showsincreasedexpression of inflammatoryproteins, such as TNF-α, IL-8, matrixmetalloproteinase (MMP)-9 Culpitt SV, et al. Am J RespirCritCareMed 2003;167(1):24-31 Russell RE, et al. Am J RespirCellMolBiol 2002;26(5):602-9

  28. InflammatoryMediators; • Levels of eosinophilcationic protein, myeloperoxidase, and IL-8 areincreased in patientswith COPD comparedwithhealthynonsmokers Barnes P, et al. Am J RespirCritCareMed 2006; 174: 6-14 • Patientswith COPD had higherlevels of tryptaseandhistamine Kalenderian R. Chest 1988;94:119-123 Pesci A. EurRespir J 1998;12:380-386

  29. Total elastaseactivity is increased, andantielastaseactivitydecreased in patientswith COPD whencomparedwithhealthysmokers Fujita J. AmRevRespirDis 1990;142:57-62

  30. BAL andepithelialcell CD8+ T cellnumberswereinverselyassociatedwith FEV1 Hodge G, et al. ClinExpImmunol 2007; 150: 22-9 Soler N, et al. EurRespir J 1999; 14: 1015-22 • ECP andeotaxin-1 levelswerepositivelyassociatedwithbroncodilatorresponseandtheextent of radiographicemphysema Miller M, et al. J AllergyClinImmunol 2007; 120: 1118-25

  31. Inthe BAL fluidcompartment of COPD patients, total lipidmetaboliteamount (particularly PGD2 andeicosapentaenoicacid) show a remarkablelinearcorrelationwithlungfunction Csanky E, et al. Electrophoresis 2009; 30: 1228-34

  32. Sputum • Noninvasivemethod • Spontaneoussputumcontainslargeamount of deadcells • Manypatients can not expectoratespontaneously • Soinducedsputum is prefered

  33. Limitations of inducedsputum • Largeairways is predominantlysampled • Sputuminductioninducestransientneutrophilia, an longtimeeosinophilia • Repeatedinductionmust be madeafter 48 hour • Solubilization of sputumwithdithiothreitolinhibitstherecognition of proteins, somecytokinesandchemokinesbyantibodies • Proteases in sputummaydegradecertain protein mediators

  34. Cellularcomposition; • CD8+ T cellsareincreased in inducedsputum of patientswith COPD Tzanakis N, et al. RespirMed 2004;98:57-65 • Thepercentage of neutrophilesincreasedtypically in inducedsputum of patientswith COPD Dragonieri S, et al. MonaldiArchChestDis 2009; 71: 119-26

  35. Sputumpercentage of neutrophilesincreaseswithsmoking, andprogression of disease Perng DW, et al. Chest 2004; 126: 375-81 • Some COPD patientsshow an increasednumber of eosinophils, thisseemstopredict a betterresponsetobronchodilatorsandinhaledcorticosteroids Papi A, et al. Am J RespirCritCareMed 2000; 162: 1773-7

  36. InflammatoryMediators; • Sputum IL-8 is increased in patientswith COPD comparedwithsmokers • It is relatedtodiseaseseverity Franciosi LG, et al. PulmPharmacolTher 2006; 19: 189-99

  37. TNF-αconcentrationsincreased in sputum of COPD patientswhencomparedwithhealthysmokers Vernooy JH, et al. Am J RespirCritCareMed 2002; 166: 1218-1224

  38. Thelevels of inflammatorymediatorsinvolved in neutrophilrecruitment (GROα, LTB4, neutrophilelastase, monocytechemotactic protein-1, humanneutrophillipocalin, myeloperoxidase) areincreased in sputum of patientswith COPD Barnes P, et al. Am J RespirCritCareMed 2006; 174: 6-14

  39. 8-Isoprostane as a marker of oxidative stress in nonsymptomatic cigarette smokers and COPD Kinnula VL, et al. EurRespir J 2007; 29: 51-5

  40. Interleukin-18 in induced sputum: association with lung function in COPD Rovina N, et al. RespirMed 2009; 103: 1919-25

  41. Apolipoprotein A1 andlipocalin-1 reduced in patients with COPD when compared with healthy smokers • Theyarecorrelatedwiththeseverity of COPD, and it has beensuggestedthattheirreductionindicates a deficientinnatedefencesystem in airwaysdisease Nicholas BL, et al. Am J RespirCritCareMed2010;181(10):1049-60

  42. Thelevels of of neutrophilelastase, MMP-1, 8, 9, and 12 increased in thesputum of COPD patients • MMP-8 concentrationsand MMP-9 activitycorrelatenegativelywith FEV1, andarepositivelycorrelatedwiththenumber of neutrophils Hill AT, et al. Am J RespirCritCareMed 1999; 160: 893-898 Beeh KM, et al. RespirMed 2003; 97:634-639 Vernooy JH, et al. Chest 2004; 126: 1802-1810 Culpitt SV, et al. RespirMed 2005; 99: 703-710 Demets IK, et al. Thorax 2006; 61: 196-201

  43. No differences in theconcentrations of thetachykinins, subtance P, andneurokinin A werefoundbetweenpatientswith COPD, normal smokers, andnonsmokers, althoughtherewas a reduction in tachykininsduringexacerbations of COPD Boschetto P, et al. PulmPharmacolTher 2005; 18: 199-205

  44. The expression of urokinase-typeplasminogenactivatorreceptor (uPAR) on induced sputumneutrophils and macrophages was significantly higherin COPD patients compared with healthy non-smokersand healthy smokers • SputumuPARand humancationicantimicrobial protein 18 (CAP18) levels showed significant inverse correlationswith FEV1% and 6MWD, and significantpositive correlations with St. George’s RespiratoryQuestionnairescores Jiang Y, et al. Respirology 2010; 15: 939–946

  45. A meta-analysisshowedthat at least 6 weeks of inhaledcorticosteroidtherapyresults in a reduction of thesputumneutrophilcount in patientswithstable COPD Gan WQ, et al. Chest 2005; 127: 558-64 • Erythromycinwasassociatedwithsignificantlyreducedsputumneutrophiliaafter 6 monthsandwasaccompaniedby a reduction in COPD exacerbation He ZY, et al. Respiration 2010; 80: 445-52

  46. Induced sputum neutrophilswassignificantly reduced by about 22% by theophylline Culpitt S, et al. Am J RespirCritCareMed 2002; 165: 1371-6

  47. N-alpha-PGP and PGP, potential biomarkers and therapeutic targets for COPD O’Reilly P, et al. RespirRes 2009; 10: 38

  48. ExhaledBiomarkers • Measuringbiomarkers in thebreath a non-invasivemethod • Repeatedsampling can be done • Inflammation in theperipheralairways can be assessed