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Bio- markers in pleural effusions

Bio- markers in pleural effusions. Dr. Öner Dikensoy Department of Pulmonary Diseases Gaziantep University Gaziantep-Turkey dikensoy@yahoo.com . I have no conflict of interest related to content of this presentation. Plan. Definition of biomarker Epidemiology of p leural e ffusions

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Bio- markers in pleural effusions

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  1. Bio-markers in pleural effusions Dr. Öner Dikensoy Department of Pulmonary Diseases Gaziantep University Gaziantep-Turkey dikensoy@yahoo.com 2012-TTD-Antalya

  2. I have no conflict of interest related to content of this presentation

  3. Plan • Definition of biomarker • Epidemiology of pleural effusions • Widely used pleural biomarkers • New biomarkers • Future bio-markers • Final summary

  4. What is a biomarker? • Biomarker is a term often used to refer to a protein measured in body fluids that reflects the severity or presence of some disease state. Wikipedia-Medicine-2011

  5. Definition of ideal biomarker • Easy and standardized method • Cheap • Widely available • Reproducible cut-off values • High sensitivity and specifity

  6. Potential benefits of bio-markers • Separation of transudate and exudate • Separation of malignant and bening • Disease specific diagnosis • Prediction of drainage need in PPE • Monitorization of treatment • Identification of High risk subjects

  7. Epidemiology 1.384.000 cases/yr CHF 500,000 (%36) PNEUMONIA 300,000 (%22) MALIGNANT EFFUSION 200,000 (%14) PULMONARY EMBOLI 150,000 (%11) UNDIAGNOSED (?VIRAL) 100,000 POST-CABG 50,000 CHIROSSIS-ASCITES 50,000 GASTROINTESTINAL 25,000 CONNECTIVE TD 6,000 TUBERCULOSIS3,000 %83 %17 Light RW.Pleural Diseases 4th ed.2001

  8. Common causes of pleural effusions • CHF (>90% OF ALL TRANS) • MALIGNANT EFFUSION • PNEUMONIA • TUBERCULOSIS • PULMONARY EMBOLI 85%

  9. Biomarkers for most common pleural effusions? • CHF • PNEUMONIA • MALIGNANT EFF • PULMONARY EMBOLI • TUBERCULOSIS Natriuretic peptides Ph, LDH, Glucose Tm markers, mesothelin osteopontin ?? ADA, Gama-IF

  10. Recomended to use in clinical practice for diagnostic purpose • Adenosine deaminase • BNP, NT-proBNP • Mesothelin ***All needs to be used in conjunction with clinical and other lab data

  11. Classical tumor markers (CEA, CA 125, CA 15–3 and CYFRA 21–1, etc.) Not recomended to use in clinical practice Porcel JM, et al. Chest 2004;126:1757

  12. Biomarkers for Tuberculosis:Adenosine deaminase (ADA) • Predominantly T-lymphocyte enzyme • adenosine/deoxyadenosine inosine/deoxyinosine • The method is easy/inexpensive • High in HIV patients with very low CD4 • Widely accepted cut-off : 35 U/L(35-47) • Molecular forms: ADA1 and ADA2 • Porcel JM. Lung 2009; 187: 263–70 • Liang QL, Shi HZ,Wang K et al. Respir.Med.2008; 102: 744–54. • Baba K, Hoosen AA, Langeland N et al. PLoS One 2008; 3:e2788. • Perez-Rodriguez E, Castro DJ. Curr.Opin.Pulm.Dis. 2000; 6: 259–66.

  13. Where can we measure ADA? • All kind of effusions (peritonitis, pericarditis, menengitis, pus)1 • New studies suggest: sputum2, blood3 • Koc I, Arslan E, Isik F, Dikensoy Ö. IJCRI 2011;2(3):5-8. • Dimakou K, etal. Int J Tuberc Lung Dis 2009; 13:744–748.  • Erer B, et al. Rheumatol Int 2009; 29:651–654. 

  14. ADA1 is found in all cells (mostly lympho and monocytes) ADA2 is found only in monocytes,macrophages ADA2 is more prevalent in TB pleural fluid ADA1 / total ADA < 0.42 (slightly increases sensitivity/ specificity) ADA1 or ADA2 ? • Separation of ADA is not necessary Current Opinion in Pulmonary Medicine. 16(4):367-375, 2010.

  15. Is ADA an ideal biomarker? • A recent meta-analysis of 63 studies • 2796 patients with TB pleuritis • 5297 with non-TB effusion • the sensitivity/specificity: 92% / 90% • The positive likelihood ratio: 9.03, • The negative likelihood: 0.10, Liang QL, Shi HZ,Wang K et al. Respir.Med.2008; 102: 744–54.

  16. Is ADA an ideal biomarker? There are two major concerns: • False negative: • ADA levels might be low in the early stage of TB pleurisy • False positive: • Parapneumonic, empyema, malignant, rheumatoid effusions might have ADA levels>40 IU   • Elevated ADA level might be expected: • 1/2 - 2/3 of empyemas • 1/10 - 1/3 of PPEs.  Valdés L, etal. Eur J Intern Med 2003; 14:77–88 Dikensoy O, et al. Respirology 2008; 13:473–474. Porcel JM. Lung 2009; 187:263–270.  

  17. Does high and low ADA mean the same in every country? The predictive value of ADA depends local prevalence of the TB: • Low prevalence (5%) :PPV of high ADA 41%. • High prevalence (85%) PPV of high ADA 99% The opposite relation refers to negative predictive value (NPV): • Low prevalence (5%): NPV of low ADA 99.6%, • High prevalence (85%) NPV of low ADA 86%  • These means that: • High TB prevalence setting: • high ADA means TB very likely • Low TB prevalence setting: • Low ADA means TB very unlikely  Greco S, Girardi E, Masciangelo R, et al. Int J Tuberc Lung Dis 2003; 7:777–786

  18. Biomarkers for Tuberculosis:Gama-interferon (IF) • It is a cytokine released by activated CD4 (+) T lymphocytes • It increases the mycobactericidal activity of macrophages.

  19. ADA vs. Gama-IF • Summary: • It is impossible to establish a cut-off value • Higher the level higher the possibility • ADA is simpler and less expensive than • Gama-IF • Always add clinic+laboratory together Greco S, et al. IJTLD 2003:7:777

  20. Biomarkers for CHF:Cardiac Natriuretic Peptides • They are secreted by the cardiomyocytes in response to stretch and elevated pressure • They are diuretic, natriuretic, hypotensive • Both serum and pleural levels are increased in CHF Porcel JM. COPM 2011,17:215–219

  21. Natriuretic Peptide Family • A-type natriuretic peptides (ANP, proANP, NT-proANP, and mid-regional-proANP), • B-type natriuretic peptides (BNP, NT-proBNP, and pro-BNP), • C-type natriureticpeptides (CNP and NT-proCNP), • Urodilatin (an isoform of ANP), • Dendroaspis natriuretic peptide (DNP) Taub PR, et al. Congest Heart Fail 2010; 16 (Suppl 1):S19–S24.

  22. BNP and NT-proBNP • They are the most widely studied NPs • Automated assays are readily available • Both appear equally accurate and clinically useful when measured in the blood • NT-proBNP has theoretical advantages due to its stability and longer half-life. Porcel JM. COPM 2011,17:215–219

  23. What are the Cut-off levels? • serum BNP < 100 pg/ml • NT-proBNP < 300 pg/ml • serum BNP > 500 pg/ml • NT-proBNP >450-1800 pg/ml* • (*cut off points depends on and increasing with the patient’s age) HF unlikely HF likely Mohammed AA, Januzzi JL Jr. Heart Fail Clin 2009; 5:489–500.

  24. Do we need pleural NPs ? • NT-proBNP > 1500 pg/mL the accuracy of identifying PEs due to HF was 89% for serum and 90% for pleura • The AUC for the diagnosis of PEs due to HF • 0.931, (95% CI: 0.871-0.991) for pleura and • 0.919, (95% CI: 0.855-0.984) for serum NT-proBNP.  It looks like there is no need to measure pleural NPs Porcel JM, Chorda J, Cao G, et al. Respirology 2007; 12:654–659.

  25. Are they useful in misclassified effusions? • Light’s criteria misclassify the 25% of transudates as exudate • Pleural NT-proBNP>1300 pg/ml labeled 27 of 31 (87%) • Protein gradient labeled 16 of 30 (53%), • Albumin gradient labeled 11 of 14 (79%) Porcel JM, Vives M, Cao G, et al. Am J Med 2004; 116:417–420.. Porcel JM, Chorda J, Cao G, et al. Respirology 2007; 12:654–659. Porcel JM, Martı´nez-Alonso M, Cao G, et al. Chest 2009; 136:671–677

  26. Summary • Natriuretic peptides are most useful in intermediate probability of heart failure • Higher the value higher the probability • Values < cut-off exclude CHF • Best in misclassified effusions • Serum levels seems enough to establish a diagnosis of pleural effusion due to CHF

  27. Biomarkers for Mesothelioma • A universally fatal malignancy and its incidence is rising exponentially in Western Europe • Asbestos is still widely used in developing countries, • Cytologic differentiation of MM from normal or reactive mesothelial cells is very difficult. • A reliable biomarker would be very helpful

  28. Soluble mesothelin related peptides (SMRPs) • Mesothelin: • a differentiation antigen present in mesothelial cells • Soluble Mesothelin: • a soluble protein in serum captured using antibodies targeting mesothelin • SMRPs released into the circulation from malignant cells that overexpress mesothelin Hassan R, Bera T, Pastan I.Clin Cancer Res 2004; 10:3937–3942. Maeda M, Hino O. Pathol Int 2006; 56:649–654.

  29. Is SMRP an ideal biomarker? • The sensitivity and specificity of SMRPs: • 77%-76% in a multicenter study from France • 67%-98% in a Western Australian cohort of 234 patients • The diagnostic accuracy of pleural fluid SMRP was as good as serum SMRP Scherpereel A, et al. Am J Respir Crit Care Med 2006; 173:1155 Creaney J, et al.Thorax. 2007 ;62:569-76.

  30. Is SMRP an ideal biomarker? • False positive: high in ovarian, pancreatic lung CAs and non-Hodgkin’s lymphoma • False negative: in sarcomatoid MM Scherpereel A, et al. Am J Respir Crit Care Med 2006; 173:1155 Creaney J, et al.Thorax. 2007 ;62:569-76.

  31. Can we use SMRPs in populations exposed to asbestosis? • 40 subjects exposed to asbestosis • 7 had elevated serum SMRPs levels • 3 of 7 developed MPM in 5 years • 1 of 7 developed lung CA • 33 of 40 followed for 8 yrs without any problem At present: 1-There is no effective cure 2- No data to support that early detection alter outcome Robinson BWS, et al. Lancet 2003; 362:1612–1616

  32. Biomarkers for Mesothelioma:Osteopontin • Serum osteopontin, have little value in distinguishing mesothelioma from metastatic pleural carcinomas or benign asbestos pleural diseases. Scherpereel A, Lee YCG. Curr Opin Pulm Med 2007;13:339–343

  33. Can we use mesothelioma markers for disease monitoring? • Serum SMRP levels are higher in subjects with larger tumor load • Serum SMRP levels decreased ovarian CA patients underwent tumor debulking surgery Robinson BWS, et al. Lancet 2003; 362:1612–1616 Hassan R, etal. Clin Can Res 2006;12:447

  34. Summary • SMRP seems to have the best sensitivity and specifity to diagnose mesothelioma • High in ovarian, pancreatic and lung CA • Low in sarcomatoid type • Not recomended for screening • There is a hope for disease monitoring • SMRP can be used to support diagnosis

  35. New biomarkers:Ischemia Modified Albumin (IMA): • IMA is a relatively new biomarker advocated in the early diagnosis of cardiac ischemia • We hypothesized that IMA should be higher in the pleural effusion of subjects with CHF Dikensoy O, et al. Respir Med. 2011;105:1712-7.

  36. New biomarkers:Ischemia Modified Albumin (IMA): Dikensoy O, et al. Respir Med. 2011;105:1712-7.

  37. Higher in transudates especially due to CHF New biomarkers:Ischemia Modified Albumin (IMA): • It looks promising • There is need to conduct new • studies Dikensoy O, et al. Respir Med. 2011;105:1712-7.

  38. Future Biyo-markers • Proteomics • FISH • PCR • Elektronic Nose • Nano-mekanic cell analysis

  39. Final Summary • There is no perfect biomarker yet • There are many ongoing studies • At present biomarkers look usefulwhen they are used in conjunction with clinical and laboratory data

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