Clinical diagnostic utility of IP-10 and LAM antigen levels for the diagnosis of tuberculous pleural effusions in a high burden setting

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-γ-inducible-10kDa 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 antigendetection 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. Principal Findings: 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 ~20% of TB cases and mis-diagnosed ~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 antigendetection was not diagnostically useful. Conclusion: 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

Letter from Helen Wainright to John Muir, 1904 Jul 10.

Browns FlatSonora July 10th1904Mr MuirDear SirI was much surprised last night at receiving your butifule present, it brought to my mind some recolections of erly days, that we spend in the old town of Dunbar, in Scotland the Home of the enlightment and the brave little did we think we would at this time be denesens of this faraway land of our childhood days I have now lived in California thirty five years Married to an English man that time03402https://scholarlycommons.pacific.edu/jmcl/28853/thumbnail.jp

Letter from Helen Wainright to John Muir, 1904 Jul 10.

I have read in the Examiner much about you with entrest and pleasure, and am over joyed to renew old aquantance altough it is by corspondence, I am glad you have arived safley Home after your long, and I hope enjoible journey much wiser and better enformed of the Love of creation and pleas accept a thousand thanks for your nice book, hoping this is not the last corespondence we will have and if ever you or any of the Muir Family come to Sonora or near by try and come to see me I take the H Courer which keeps me posted about Dunbar and the auld village of Belhaven Hoping to Here from you some other timeI remain your TrulyHelen WainwrightAdressMrs John WainwrightBrowns FlatSonoraTuolumne CountyCalifhttps://scholarlycommons.pacific.edu/jmcl/28854/thumbnail.jp

Letter from Helen Wainright to John Muir, 1904 Jul 10.

I have read in the Examiner much about you with entrest and pleasure, and am over joyed to renew old aquantance altough it is by corspondence, I am glad you have arived safley Home after your long, and I hope enjoible journey much wiser and better enformed of the Love of creation and pleas accept a thousand thanks for your nice book, hoping this is not the last corespondence we will have and if ever you or any of the Muir Family come to Sonora or near by try and come to see me I take the H Courer which keeps me posted about Dunbar and the auld village of Belhaven Hoping to Here from you some other timeI remain your TrulyHelen WainwrightAdressMrs John WainwrightBrowns FlatSonoraTuolumne CountyCalifhttps://scholarlycommons.pacific.edu/jmcl/28854/thumbnail.jp

Utility of quantitative T-cell responses <i>versus</i> unstimulated interferon-γ for the diagnosis of pleural tuberculosis

The clinical utility of antigen-specific interferon (IFN)-γ release assays (IGRAs) using pleural mononuclear cells, for the diagnosis of tuberculosis (TB), requires clarification. We compared the diagnostic utility of unstimulated pleural IFN-γ levels with several pleural antigen-specific T-cell IGRAs (early secretory antigenic target-6 and culture filtrate protein-10 (T-SPOT.®TB, QuantiFERON®-TB Gold In-tube), purified protein derivative (PPD) and heparin-binding haemagglutinin (HBHA)) in 78 South African TB suspects. Test results were compared against a clinical score and a reference standard. Out of 74 evaluable subjects 48, seven and 19 had definite, probable and no TB, respectively. 11 (15%) out of 74 pleural samples (nine (19%) out of 48 of the definite TB cases) had total cell counts that were inadequate for T-cell processing. In the remaining 63 samples, the sensitivity, specificity, positive predictive value and negative predictive value of different diagnostic methods were as follows. Maximal bioclinical score: 54, 89, 92 and 43%, respectively; T-SPOT.®TB: 86, 60, 84 and 64%, respectively; QuantiFERON®-TB Gold In-tube: 57, 80, 87 and 44%, respectively; HBHA-specific IGRA: 59, 31, 64 and 27%, respectively; PPD-specific IGRA: 81, 40, 76 and 46%, respectively; and pleural fluid unstimulated IFN-γ: 97, 100, 100 and 94%, respectively. Unstimulated IFN-γ was the most accurate test for distinguishing TB from non-TB effusions in a high-burden setting. The antigen-specific T-cell IGRAs were limited by suboptimal accuracy and the inability to isolate sufficient mononuclear cells to perform the assay

Scatter-plots (left panel) and area under the ROC (right panel) of a standardized nucleic-acid amplification test using pleural fluid from patients with tuberculous (TB) and non-tuberculous (non-TB) effusions.

<p>Area under the ROC values are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004689#pone-0004689-t001" target="_blank">table 1</a>. Positive (culture and amplification) and negative controls (culture and amplification) from 6 independent runs are shown.</p

Summary and flow chart of the established and newer technologies evaluated.

<p>Summary and flow chart of the established and newer technologies evaluated.</p

Individual and incremental value of different test combinations.

*<p> = 47 iu/l cut-point and non-asterisked values refer to the 30 iu/l cut-point.</p>$<p> = maximal clinical score. Unless, otherwise stated all IP-10 outcomes refer to the 28170 pg/ml cut-point.</p

Performance outcomes of ADA, microbiological investigations, a nucleic-acid-amplification-test [NAAT] and unstimulated IFN-γ levels for the diagnosis of TB pleural effusion in 74 TB suspects when the <i>definite and probable TB groups are combined</i>.

<p>( ; ) = 95% CI.</p>**<p>Cut-point used in day-to-day clinical practice in Cape Town, South Africa, where the test guides the institution of anti-TB treatment.</p><p>AUC = area under the ROC curve.</p>***<p>AUC-derived cut-point.</p>#<p>cut-point with a high NPV.</p><p>RLU = relative light units detectable using a luminometer.</p