Post on 12-Feb-2016
description
2012-TTD-Antalya 1
Bio-markers in pleural effusions
Dr. Öner DikensoyDepartment of Pulmonary Diseases
Gaziantep UniversityGaziantep-Turkey
dikensoy@yahoo.com
I have no conflict of interest related to content of this
presentation
Plan
• Definition of biomarker • Epidemiology of pleural effusions• Widely used pleural biomarkers• New biomarkers• Future bio-markers• Final summary
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
Definition of ideal biomarker
• Easy and standardized method• Cheap• Widely available• Reproducible cut-off values• High sensitivity and specifity
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
EpidemiologyCHF 500,000 (%36)PNEUMONIA 300,000 (%22)MALIGNANT EFFUSION200,000 (%14)PULMONARY EMBOLI 150,000 (%11)UNDIAGNOSED (?VIRAL) 100,000 POST-CABG 50,000CHIROSSIS-ASCITES 50,000GASTROINTESTINAL 25,000CONNECTIVE TD 6,000TUBERCULOSIS 3,000
Light RW.Pleural Diseases 4th ed.2001
%83
%17
1.384.000 cases/yr
Common causes of pleural effusions
• CHF (>90% OF ALL TRANS)• MALIGNANT EFFUSION • PNEUMONIA• TUBERCULOSIS• PULMONARY EMBOLI
85%
Biomarkers for most common pleural effusions?
• CHF
• PNEUMONIA
• MALIGNANT EFF
• PULMONARY EMBOLI
• TUBERCULOSIS
Natriuretic peptides
Ph, LDH, Glucose
Tm markers, mesothelinosteopontin
??
ADA, Gama-IF
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
Not recomended to use in clinical practice
• Classical tumor markers (CEA, CA 125, CA 15–3 and CYFRA 21–1, etc.)
Porcel JM, et al. Chest 2004;126:1757
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 1. Porcel JM. Lung 2009; 187: 263–702. Liang QL, Shi HZ,Wang K et al. Respir.Med.2008; 102: 744–54.3. Baba K, Hoosen AA, Langeland N et al. PLoS One 2008; 3:e2788.4. Perez-Rodriguez E, Castro DJ. Curr.Opin.Pulm.Dis. 2000; 6: 259–66.
Where can we measure ADA?
• All kind of effusions (peritonitis, pericarditis, menengitis, pus)1
• New studies suggest: sputum2, blood3
1. Koc I, Arslan E, Isik F, Dikensoy Ö. IJCRI 2011;2(3):5-8. 2. Dimakou K, etal. Int J Tuberc Lung Dis 2009; 13:744–748. 3. Erer B, et al. Rheumatol Int 2009; 29:651–654.
ADA1 or ADA2 ?
• 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)
Current Opinion in Pulmonary Medicine. 16(4):367-375, 2010.
•Separation of ADA is not necessary
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.
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.
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%
Does high and low ADA mean the same in every country?
Greco S, Girardi E, Masciangelo R, et al. Int J Tuberc Lung Dis 2003; 7:777–786
These means that: •High TB prevalence setting: •high ADA means TB very likely•Low TB prevalence setting: •Low ADA means TB very unlikely
Biomarkers for Tuberculosis:Gama-interferon (IF)
• It is a cytokine released by activated CD4 (+) T lymphocytes
• It increases the mycobactericidal activity of macrophages.
ADA vs. Gama-IF
Greco S, et al. IJTLD 2003:7:777
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
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
Natriuretic Peptide Family
1. A-type natriuretic peptides (ANP, proANP, NT-proANP, and mid-regional-proANP),
2. B-type natriuretic peptides (BNP, NT-proBNP, and pro-BNP),
3. C-type natriureticpeptides (CNP and NT-proCNP),
4. Urodilatin (an isoform of ANP), 5. Dendroaspis natriuretic peptide (DNP)
Taub PR, et al. Congest Heart Fail 2010; 16 (Suppl 1):S19–S24.
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
• 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
What are the Cut-off levels?
Mohammed AA, Januzzi JL Jr. Heart Fail Clin 2009; 5:489–500.
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.
Porcel JM, Chorda J, Cao G, et al. Respirology 2007; 12:654–659.
It looks like there is no need to measure pleural NPs
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
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
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
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.
• 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
Is SMRP an ideal biomarker?
Scherpereel A, et al. Am J Respir Crit Care Med 2006; 173:1155Creaney J, et al.Thorax. 2007 ;62:569-76.
• False positive: high in ovarian, pancreatic lung CAs and non-Hodgkin’s lymphoma
• False negative: in sarcomatoid MM
Is SMRP an ideal biomarker?
Scherpereel A, et al. Am J Respir Crit Care Med 2006; 173:1155Creaney J, et al.Thorax. 2007 ;62:569-76.
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
Robinson BWS, et al. Lancet 2003; 362:1612–1616
At present: 1-There is no effective cure2- No data to support that early detection alter outcome
• Serum osteopontin, have little value in distinguishing mesothelioma from metastatic pleural carcinomas or benign asbestos pleural diseases.
Biomarkers for Mesothelioma:Osteopontin
Scherpereel A, Lee YCG. Curr Opin Pulm Med 2007;13:339–343
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; 362:1612–1616Hassan R, etal. Clin Can Res 2006;12:447
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
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.
New biomarkers:Ischemia Modified Albumin (IMA):
Dikensoy O, et al. Respir Med. 2011;105:1712-7.
New biomarkers:Ischemia Modified Albumin (IMA):
• Higher in transudates especially due to CHF
Dikensoy O, et al. Respir Med. 2011;105:1712-7.
•It looks promising•There is need to conduct new studies
Future Biyo-markers
• Proteomics• FISH • PCR• Elektronic Nose• Nano-mekanic cell analysis
Final Summary
• There is no perfect biomarker yet• There are many ongoing studies• At present biomarkers look useful when
they are used in conjunction with clinical and laboratory data