title: Clinical diagnostic utility of IP-10 and LAM antigen levels for the diagnosis of tuberculous pleural effusions in a high burden setting.
abstract: BACKGROUND
  Current tools for the diagnosis of tuberculosis pleural effusions are sub-optimal. Data about the value of new diagnostic technologies are limited, particularly, in high burden settings. Preliminary case control studies have identified IFN-gamma-inducible-10 kDa protein (IP-10) as a promising diagnostic marker; however, its diagnostic utility in a day-to-day clinical setting is unclear. Detection of LAM antigen has not previously been evaluated in pleural fluid.
  
  
  METHODS
  We investigated the comparative diagnostic utility of established (adenosine deaminase [ADA]), more recent (standardized nucleic-acid-amplification-test [NAAT]) and newer technologies (a standardized LAM mycobacterial antigen-detection assay and IP-10 levels) for the evaluation of pleural effusions in 78 consecutively recruited South African tuberculosis suspects. All consenting participants underwent pleural biopsy unless contra-indicated or refused. The reference standard comprised culture positivity for M. tuberculosis or histology suggestive of tuberculosis.
  
  
  RESULTS
  Of 74 evaluable subjects 48, 7 and 19 had definite, probable and non-TB, respectively. IP-10 levels were significantly higher in TB vs non-TB participants (p<0.0001). The respective outcomes [sensitivity, specificity, PPV, NPV %] for the different diagnostic modalities were: ADA at the 30 IU/L cut-point [96; 69; 90; 85], NAAT [6; 93; 67; 28], IP-10 at the 28,170 pg/ml ROC-derived cut-point [80; 82; 91; 64], and IP-10 at the 4035 pg/ml cut-point [100; 53; 83; 100]. Thus IP-10, using the ROC-derived cut-point, missed approximately 20% of TB cases and mis-diagnosed approximately 20% of non-TB cases. By contrast, when a lower cut-point was used a negative test excluded TB. The NAAT had a poor sensitivity but high specificity. LAM antigen-detection was not diagnostically useful.
  
  
  CONCLUSIONS
  Although IP-10, like ADA, has sub-optimal specificity, it may be a clinically useful rule-out test for tuberculous pleural effusions. Larger multi-centric studies are now required to confirm our findings.
authors.affiliation: Lung Infection and Immunity Unit & CTBRI, UCT Lung Institute & Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa. keertan.dheda@uct.ac.za
authors.forename: Keertan
authors.initials: K
authors.lastname: Dheda
authors.forename: Richard N
authors.initials: RN
authors.lastname: Van-Zyl Smit
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Sechi
authors.forename: Motasim
authors.initials: M
authors.lastname: Badri
authors.forename: Richard
authors.initials: R
authors.lastname: Meldau
authors.forename: Gregory
authors.initials: G
authors.lastname: Symons
authors.forename: Hoosein
authors.initials: H
authors.lastname: Khalfey
authors.forename: Igshaan
authors.initials: I
authors.lastname: Carr
authors.forename: Alice
authors.initials: A
authors.lastname: Maredza
authors.forename: Rodney
authors.initials: R
authors.lastname: Dawson
authors.forename: Helen
authors.initials: H
authors.lastname: Wainright
authors.forename: Andrew
authors.initials: A
authors.lastname: Whitelaw
authors.forename: Eric D
authors.initials: ED
authors.lastname: Bateman
authors.forename: Alimuddin
authors.initials: A
authors.lastname: Zumla
mesh_terms: D000243:Adenosine Deaminase / Q000032:analysis; D000942:Antigens, Bacterial / Q000032:analysis*; D015415:Biomarkers; D001706:Biopsy; D054357:Chemokine CXCL10 / Q000032:analysis*; D003937:Diagnosis, Differential; D019353:Endemic Diseases; D008070:Lipopolysaccharides / Q000032:analysis*; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000302:isolation & purification; D021141:Nucleic Acid Amplification Techniques; D010996:Pleural Effusion / Q000175:diagnosis* / Q000276:immunology / Q000382:microbiology; D016066:Pleural Effusion, Malignant / Q000175:diagnosis; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D013019:South Africa / Q000453:epidemiology; D014396:Tuberculosis, Pleural / Q000175:diagnosis* / Q000453:epidemiology / Q000276:immunology / Q000382:microbiology / Q000473:pathology
chemical_list: D000942:Antigens, Bacterial; D015415:Biomarkers; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D008070:Lipopolysaccharides; C050016:lipoarabinomannan; D000243:Adenosine Deaminase